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12970106 | 12970106 | [
{
"id": "12970106_title",
"type": "title",
"text": [
"Agonist actions of dihydroergotamine at 5-HT2B and 5-HT2C receptors and their possible relevance to antimigraine efficacy."
],
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},
{
"id": "12970106_abstract",
"type": "abstract",
"text": [
"1. The pharmaceutical compound, dihydroergotamine (DHE) is dispensed to prevent and reduce the occurrence of migraine attacks. Although still controversial, the prophylactic effect of this drug is believed to be caused through blockade and/or activation of numerous receptors including serotonin (5-HT) receptors of the 5-HT2 subtype. 2. To elucidate if 5-HT2 receptors (5-HT2Rs) may be involved in DHE prophylactic effect, we performed investigations aimed to determine the respective pharmacological profile of DHE and of its major metabolite 8'-hydroxy-DHE (8'-OH-DHE) at the 5-HT2B and 5-HT2CRs by binding, inositol triphosphate (IP3) or cyclic GMP (cGMP) coupling studies in transfected fibroblasts. 3. DHE and 8'-OH-DHE are competitive compounds at 5-HT2B and 5-HT2CRs. 8'-OH-DHE interaction at (5-HT2BRs) was best fitted by a biphasic competition curve and displayed the highest affinity with a Ki of 5 nm. These two compounds acted as agonists for both receptors in respect to cGMP production with pEC50 of 8.32+/-0.09 for 8'-OH-DHE at 5-HT2B and 7.83+/-0.06 at 5-HT2CRs. 4. Knowing that the antimigraine prophylactic effect of DHE is only observed after long-term treatment, we chronically exposed the recombinant cells to DHE and 8'-OH-DHE. The number of 5-HT2BR-binding sites was always more affected than 5-HT2CRs. At 5-HT2BRs, 8'-OH-DHE was more effective than DHE, with an uncoupling that persisted for more than 40 h for IP3 or cGMP. By contrast, the 5-HT2CR coupling was reversible after either treatment. 5. Chronic exposure to 8'-OH-DHE caused a persistent agonist-mediated desensitisation of 5-HT2B, but not 5-HT2CRs. This may be of relevance to therapeutic actions of the compound."
],
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] | [
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"id": "12970106_T1",
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"8'-OH-DHE"
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{
"id": "12970106_T2",
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"DHE"
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"id": "12970106_T3",
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"DHE"
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"8'-OH-DHE"
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"8'-OH-DHE"
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"id": "12970106_T6",
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"DHE"
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"IP3"
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"id": "12970106_T11",
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"5-HT"
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{
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"5-HT2B"
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"5-HT2CRs"
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"5-HT2BR"
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"5-HT2BRs"
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"5-HT2CR"
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"(5-HT) receptors"
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"5-HT2"
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"5-HT2BRs"
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"5-HT2C"
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}
] | [] | [] | [
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}
] |
19620795 | 19620795 | [
{
"id": "19620795_title",
"type": "title",
"text": [
"[Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma]."
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{
"id": "19620795_abstract",
"type": "abstract",
"text": [
"The mammalian target of rapamycin(mTOR)and its molecular pathways are supposed to be activated frequently in human renal cell carcinoma as well as other cancers. It has a kinase activity for 40S ribosomal protein kinase and eukaryotic translation initiation factor 4E-binding protein 1. These proteins, when phosphorylated, promote protein translation and RNA transcription in the nutrient-rich condition. mTOR inhibitors such as Temsirolimus (CCI779) and Everolimus (RAD001) are effective for suppressing cell growth with inhibiting mTOR kinase activity. Rapamycin and its related analogs such as Temsirolimus and Everolimus are less toxic for humans compared with other anti-VEGFR inhibitors and has been used as an immunosuppressive agent. These agents have an inhibitory activity against the mTORC1 complex. Since they do not have inhibitory activity against mTORC2 complex, the ability of mTOR inhibition by Temsirolimus is supposed to be 40 to 50% of full inhibition in mTOR kinase. Temsirolimus has modest anticancer activity against advanced clinical RCC patients with poor risk. The objective response rate was only 7%, 26% of patients experienced minor responses and another 17% of patients had stable disease that lasted 6 months. The median time to tumor progression and median survival for the study patients were 5.8 and 15.0 months, respectively. The overall survival of patients treated with Temsirolimus alone was statistically longer than in those treated with IFN alone in the 626 cases in phase II study. Combinations of mTOR with other anti- VEGFR agents were not effective. Vertical therapies of mTOR inhibitor in combination with AKT inhibitors, or newly development of stronger mTOR kinase which can suppress both mTORC1 and mTORC2 are planned at present."
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"id": "19620795_5",
"type": "INHIBITOR",
"arg1_id": "19620795_T4",
"arg2_id": "19620795_T28",
"normalized": []
},
{
"id": "19620795_6",
"type": "INHIBITOR",
"arg1_id": "19620795_T5",
"arg2_id": "19620795_T28",
"normalized": []
},
{
"id": "19620795_7",
"type": "INHIBITOR",
"arg1_id": "19620795_T6",
"arg2_id": "19620795_T28",
"normalized": []
},
{
"id": "19620795_8",
"type": "INHIBITOR",
"arg1_id": "19620795_T3",
"arg2_id": "19620795_T29",
"normalized": []
},
{
"id": "19620795_9",
"type": "INHIBITOR",
"arg1_id": "19620795_T4",
"arg2_id": "19620795_T29",
"normalized": []
},
{
"id": "19620795_10",
"type": "INHIBITOR",
"arg1_id": "19620795_T5",
"arg2_id": "19620795_T29",
"normalized": []
},
{
"id": "19620795_11",
"type": "INHIBITOR",
"arg1_id": "19620795_T6",
"arg2_id": "19620795_T29",
"normalized": []
},
{
"id": "19620795_12",
"type": "INHIBITOR",
"arg1_id": "19620795_T10",
"arg2_id": "19620795_T33",
"normalized": []
},
{
"id": "19620795_13",
"type": "INHIBITOR",
"arg1_id": "19620795_T10",
"arg2_id": "19620795_T34",
"normalized": []
},
{
"id": "19620795_14",
"type": "INHIBITOR",
"arg1_id": "19620795_T10",
"arg2_id": "19620795_T35",
"normalized": []
}
] |
23474014 | 23474014 | [
{
"id": "23474014_title",
"type": "title",
"text": [
"Time-dependent effects of corticosterone on reward-based decision-making in a rodent model of the Iowa Gambling Task."
],
"offsets": [
[
0,
117
]
]
},
{
"id": "23474014_abstract",
"type": "abstract",
"text": [
"Corticosteroid hormones, released after stress, are known to change neuronal activity in two time-domains: within minutes via non-genomic pathways and with a delay of >1 h through pathways involving transcriptional regulation. Recent evidence in rodents and humans indicates that these two modes of corticosteroid action differently affect cognitive tasks. Here, we investigated whether reward-based decision-making, in a rat model of the Iowa Gambling Task (rIGT), is also differently altered by rapid versus delayed actions of corticosterone. We targeted the rapid and delayed time domain by injecting corticosterone (CORT, 1 mg/kg, s.c.) at 30 min (rapid) or 180 min (delayed) respectively prior to behavioural testing, during the final 3 days of the behavioural paradigm. In saline treated rats, the number of visits to the disadvantageous arm decreased over trial blocks, whilst this was attenuated when CORT was administered 30 min before testing. This attenuation was associated with a significantly increased c-Fos expression in the lateral orbitofrontal cortex and insular cortex, and a trend for an increase in the infralimbic cortex. The rapid corticosteroid effect contrasted with treatment 180 min before testing, where the number of visits to the disadvantageous arm as well as c-Fos labelling was not affected. These findings indicate that rapid corticosteroid actions impair reward-based decision-making."
],
"offsets": [
[
118,
1538
]
]
}
] | [
{
"id": "23474014_T1",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
"offsets": [
[
647,
661
]
],
"normalized": []
},
{
"id": "23474014_T2",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
"offsets": [
[
722,
736
]
],
"normalized": []
},
{
"id": "23474014_T3",
"type": "CHEMICAL",
"text": [
"CORT"
],
"offsets": [
[
738,
742
]
],
"normalized": []
},
{
"id": "23474014_T4",
"type": "CHEMICAL",
"text": [
"CORT"
],
"offsets": [
[
1027,
1031
]
],
"normalized": []
},
{
"id": "23474014_T5",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
"offsets": [
[
26,
40
]
],
"normalized": []
},
{
"id": "23474014_T6",
"type": "GENE-Y",
"text": [
"c-Fos"
],
"offsets": [
[
1135,
1140
]
],
"normalized": []
},
{
"id": "23474014_T7",
"type": "GENE-Y",
"text": [
"c-Fos"
],
"offsets": [
[
1410,
1415
]
],
"normalized": []
}
] | [] | [] | [] |
2450203 | 2450203 | [
{
"id": "2450203_title",
"type": "title",
"text": [
"Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture."
],
"offsets": [
[
0,
141
]
]
},
{
"id": "2450203_abstract",
"type": "abstract",
"text": [
"Effects of benzodiazepines (BDZs) and beta carbolines (beta CCs) on sustained repetitive firing at high frequency (SRF) of action potentials of mouse spinal cord neurons in cell culture were examined using intracellular recording techniques. In control medium neurons responded to depolarizing current pulses with SRF. Limitation of SRF was produced by the anticonvulsant BDZs (diazepam, clonazepam, nitrazepam and lorazepam) at low to mid nanomolar concentrations, by a convulsant BDZ which does not bind to high affinity BDZ receptors (Ro 5-4864) at high nanomolar concentrations and by a BDZ receptor weak partial agonist (Ro 15-1788) at micromolar concentrations. The limitation of SRF was accompanied by use- and voltage-dependent reduction of maximal rate of rise (Vmax) of sodium-dependent action potentials. Partial agonist and inverse agonist beta CCs did not limit SRF at concentrations up to 200 nM. The limitation of SRF by diazepam was not prevented by inverse or partial agonists at the BDZ receptor, including Ro 15-1788 and the beta CCs. These findings suggest that limitation of SRF was produced by binding of BDZs, but not beta CCs, to voltage-dependent sodium channels and not to high affinity central BDZ receptors, and that BDZs limit SRF by slowing recovery of sodium channels from inactivation. We propose that the limitation of SRF may contribute to the efficacy of BDZs against generalized tonic-clonic seizures and status epilepticus."
],
"offsets": [
[
142,
1602
]
]
}
] | [
{
"id": "2450203_T1",
"type": "CHEMICAL",
"text": [
"BDZ"
],
"offsets": [
[
1143,
1146
]
],
"normalized": []
},
{
"id": "2450203_T2",
"type": "CHEMICAL",
"text": [
"Ro 15-1788"
],
"offsets": [
[
1167,
1177
]
],
"normalized": []
},
{
"id": "2450203_T3",
"type": "CHEMICAL",
"text": [
"beta CCs"
],
"offsets": [
[
1186,
1194
]
],
"normalized": []
},
{
"id": "2450203_T4",
"type": "CHEMICAL",
"text": [
"benzodiazepines"
],
"offsets": [
[
153,
168
]
],
"normalized": []
},
{
"id": "2450203_T5",
"type": "CHEMICAL",
"text": [
"BDZs"
],
"offsets": [
[
1269,
1273
]
],
"normalized": []
},
{
"id": "2450203_T6",
"type": "CHEMICAL",
"text": [
"beta CCs"
],
"offsets": [
[
1283,
1291
]
],
"normalized": []
},
{
"id": "2450203_T7",
"type": "CHEMICAL",
"text": [
"sodium"
],
"offsets": [
[
1314,
1320
]
],
"normalized": []
},
{
"id": "2450203_T8",
"type": "CHEMICAL",
"text": [
"BDZ"
],
"offsets": [
[
1363,
1366
]
],
"normalized": []
},
{
"id": "2450203_T9",
"type": "CHEMICAL",
"text": [
"BDZs"
],
"offsets": [
[
1387,
1391
]
],
"normalized": []
},
{
"id": "2450203_T10",
"type": "CHEMICAL",
"text": [
"sodium"
],
"offsets": [
[
1425,
1431
]
],
"normalized": []
},
{
"id": "2450203_T11",
"type": "CHEMICAL",
"text": [
"BDZs"
],
"offsets": [
[
1532,
1536
]
],
"normalized": []
},
{
"id": "2450203_T12",
"type": "CHEMICAL",
"text": [
"BDZs"
],
"offsets": [
[
170,
174
]
],
"normalized": []
},
{
"id": "2450203_T13",
"type": "CHEMICAL",
"text": [
"BDZs"
],
"offsets": [
[
514,
518
]
],
"normalized": []
},
{
"id": "2450203_T14",
"type": "CHEMICAL",
"text": [
"diazepam"
],
"offsets": [
[
520,
528
]
],
"normalized": []
},
{
"id": "2450203_T15",
"type": "CHEMICAL",
"text": [
"beta carbolines"
],
"offsets": [
[
180,
195
]
],
"normalized": []
},
{
"id": "2450203_T16",
"type": "CHEMICAL",
"text": [
"clonazepam"
],
"offsets": [
[
530,
540
]
],
"normalized": []
},
{
"id": "2450203_T17",
"type": "CHEMICAL",
"text": [
"nitrazepam"
],
"offsets": [
[
542,
552
]
],
"normalized": []
},
{
"id": "2450203_T18",
"type": "CHEMICAL",
"text": [
"lorazepam"
],
"offsets": [
[
557,
566
]
],
"normalized": []
},
{
"id": "2450203_T19",
"type": "CHEMICAL",
"text": [
"BDZ"
],
"offsets": [
[
624,
627
]
],
"normalized": []
},
{
"id": "2450203_T20",
"type": "CHEMICAL",
"text": [
"BDZ"
],
"offsets": [
[
665,
668
]
],
"normalized": []
},
{
"id": "2450203_T21",
"type": "CHEMICAL",
"text": [
"Ro 5-4864"
],
"offsets": [
[
680,
689
]
],
"normalized": []
},
{
"id": "2450203_T22",
"type": "CHEMICAL",
"text": [
"beta CCs"
],
"offsets": [
[
197,
205
]
],
"normalized": []
},
{
"id": "2450203_T23",
"type": "CHEMICAL",
"text": [
"BDZ"
],
"offsets": [
[
733,
736
]
],
"normalized": []
},
{
"id": "2450203_T24",
"type": "CHEMICAL",
"text": [
"Ro 15-1788"
],
"offsets": [
[
768,
778
]
],
"normalized": []
},
{
"id": "2450203_T25",
"type": "CHEMICAL",
"text": [
"sodium"
],
"offsets": [
[
922,
928
]
],
"normalized": []
},
{
"id": "2450203_T26",
"type": "CHEMICAL",
"text": [
"diazepam"
],
"offsets": [
[
1078,
1086
]
],
"normalized": []
},
{
"id": "2450203_T27",
"type": "CHEMICAL",
"text": [
"Benzodiazepines"
],
"offsets": [
[
0,
15
]
],
"normalized": []
},
{
"id": "2450203_T28",
"type": "CHEMICAL",
"text": [
"beta carbolines"
],
"offsets": [
[
25,
40
]
],
"normalized": []
},
{
"id": "2450203_T29",
"type": "GENE-N",
"text": [
"BDZ receptor"
],
"offsets": [
[
1143,
1155
]
],
"normalized": []
},
{
"id": "2450203_T30",
"type": "GENE-N",
"text": [
"voltage-dependent sodium channels"
],
"offsets": [
[
1296,
1329
]
],
"normalized": []
},
{
"id": "2450203_T31",
"type": "GENE-N",
"text": [
"BDZ receptors"
],
"offsets": [
[
1363,
1376
]
],
"normalized": []
},
{
"id": "2450203_T32",
"type": "GENE-N",
"text": [
"sodium channels"
],
"offsets": [
[
1425,
1440
]
],
"normalized": []
},
{
"id": "2450203_T33",
"type": "GENE-N",
"text": [
"BDZ receptors"
],
"offsets": [
[
665,
678
]
],
"normalized": []
},
{
"id": "2450203_T34",
"type": "GENE-N",
"text": [
"BDZ receptor"
],
"offsets": [
[
733,
745
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "2450203_0",
"type": "AGONIST",
"arg1_id": "2450203_T24",
"arg2_id": "2450203_T34",
"normalized": []
},
{
"id": "2450203_1",
"type": "AGONIST-INHIBITOR",
"arg1_id": "2450203_T2",
"arg2_id": "2450203_T29",
"normalized": []
},
{
"id": "2450203_2",
"type": "AGONIST",
"arg1_id": "2450203_T2",
"arg2_id": "2450203_T29",
"normalized": []
},
{
"id": "2450203_3",
"type": "AGONIST-INHIBITOR",
"arg1_id": "2450203_T3",
"arg2_id": "2450203_T29",
"normalized": []
},
{
"id": "2450203_4",
"type": "AGONIST",
"arg1_id": "2450203_T3",
"arg2_id": "2450203_T29",
"normalized": []
},
{
"id": "2450203_5",
"type": "DIRECT-REGULATOR",
"arg1_id": "2450203_T5",
"arg2_id": "2450203_T30",
"normalized": []
},
{
"id": "2450203_6",
"type": "ACTIVATOR",
"arg1_id": "2450203_T9",
"arg2_id": "2450203_T32",
"normalized": []
},
{
"id": "2450203_7",
"type": "DIRECT-REGULATOR",
"arg1_id": "2450203_T5",
"arg2_id": "2450203_T31",
"normalized": []
}
] |
23437843 | 23437843 | [
{
"id": "23437843_title",
"type": "title",
"text": [
"Discovery, biological evaluation, and structure-activity and -selectivity relationships of 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-methylacetamides, a novel class of potent and selective monoamine oxidase inhibitors."
],
"offsets": [
[
0,
226
]
]
},
{
"id": "23437843_abstract",
"type": "abstract",
"text": [
"The use of selective inhibitors of monoamine oxidase A (MAO-A) and B (MAO-B) holds a therapeutic relevance in the treatment of depressive disorders and Parkinson's disease (PD), respectively. Here, the discovery of a new class of compounds acting as monoamine oxidase inhibitors (MAO-Is) and bearing a 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-alkylacetamide skeleton is reported. 6'-Sulfonyloxy derivatives exhibited outstanding affinities to MAO-A (7.0 nM < IC50 < 49 nM, much higher than moclobemide) and a pronounced MAO-A/B selectivity. The corresponding 6'-benzyloxy derivatives showed potent MAO-B inhibition and inverted selectivity profile. The rigid E-geometry of the exocyclic double bond allowed a more efficient binding conformation compared to more flexible and less active 2-(1-benzofuran-3-yl)-N-methylacetamide isomers and 4-N-methylcarboxamidomethylcoumarin analogues. Focused structural modifications and docking simulations enabled the identification of key molecular determinants for high affinity toward both MAO isoforms. These novel MAO-Is may represent promising hits for the development of safer therapeutic agents with a potential against depression, PD, and other age-related neurodegenerative pathologies."
],
"offsets": [
[
227,
1469
]
]
}
] | [
{
"id": "23437843_T1",
"type": "CHEMICAL",
"text": [
"monoamine"
],
"offsets": [
[
477,
486
]
],
"normalized": []
},
{
"id": "23437843_T2",
"type": "CHEMICAL",
"text": [
"6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-alkylacetamide"
],
"offsets": [
[
529,
593
]
],
"normalized": []
},
{
"id": "23437843_T3",
"type": "CHEMICAL",
"text": [
"monoamine"
],
"offsets": [
[
262,
271
]
],
"normalized": []
},
{
"id": "23437843_T4",
"type": "CHEMICAL",
"text": [
"6'-Sulfonyloxy"
],
"offsets": [
[
616,
630
]
],
"normalized": []
},
{
"id": "23437843_T5",
"type": "CHEMICAL",
"text": [
"moclobemide"
],
"offsets": [
[
726,
737
]
],
"normalized": []
},
{
"id": "23437843_T6",
"type": "CHEMICAL",
"text": [
"6'-benzyloxy"
],
"offsets": [
[
795,
807
]
],
"normalized": []
},
{
"id": "23437843_T7",
"type": "CHEMICAL",
"text": [
"2-(1-benzofuran-3-yl)-N-methylacetamide"
],
"offsets": [
[
1023,
1062
]
],
"normalized": []
},
{
"id": "23437843_T8",
"type": "CHEMICAL",
"text": [
"4-N-methylcarboxamidomethylcoumarin"
],
"offsets": [
[
1075,
1110
]
],
"normalized": []
},
{
"id": "23437843_T9",
"type": "CHEMICAL",
"text": [
"monoamine"
],
"offsets": [
[
197,
206
]
],
"normalized": []
},
{
"id": "23437843_T10",
"type": "CHEMICAL",
"text": [
"6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-methylacetamides"
],
"offsets": [
[
91,
157
]
],
"normalized": []
},
{
"id": "23437843_T11",
"type": "GENE-N",
"text": [
"MAO"
],
"offsets": [
[
1266,
1269
]
],
"normalized": []
},
{
"id": "23437843_T12",
"type": "GENE-N",
"text": [
"MAO"
],
"offsets": [
[
1292,
1295
]
],
"normalized": []
},
{
"id": "23437843_T13",
"type": "GENE-N",
"text": [
"monoamine oxidase"
],
"offsets": [
[
477,
494
]
],
"normalized": []
},
{
"id": "23437843_T14",
"type": "GENE-N",
"text": [
"MAO"
],
"offsets": [
[
507,
510
]
],
"normalized": []
},
{
"id": "23437843_T15",
"type": "GENE-Y",
"text": [
"monoamine oxidase A"
],
"offsets": [
[
262,
281
]
],
"normalized": []
},
{
"id": "23437843_T16",
"type": "GENE-Y",
"text": [
"MAO-A"
],
"offsets": [
[
679,
684
]
],
"normalized": []
},
{
"id": "23437843_T17",
"type": "GENE-N",
"text": [
"MAO-A/B"
],
"offsets": [
[
756,
763
]
],
"normalized": []
},
{
"id": "23437843_T18",
"type": "GENE-Y",
"text": [
"MAO-A"
],
"offsets": [
[
283,
288
]
],
"normalized": []
},
{
"id": "23437843_T19",
"type": "GENE-Y",
"text": [
"MAO-B"
],
"offsets": [
[
834,
839
]
],
"normalized": []
},
{
"id": "23437843_T20",
"type": "GENE-Y",
"text": [
"MAO-B"
],
"offsets": [
[
297,
302
]
],
"normalized": []
},
{
"id": "23437843_T21",
"type": "GENE-N",
"text": [
"monoamine oxidase"
],
"offsets": [
[
197,
214
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23437843_0",
"type": "INHIBITOR",
"arg1_id": "23437843_T10",
"arg2_id": "23437843_T21",
"normalized": []
},
{
"id": "23437843_1",
"type": "INHIBITOR",
"arg1_id": "23437843_T2",
"arg2_id": "23437843_T13",
"normalized": []
},
{
"id": "23437843_2",
"type": "INHIBITOR",
"arg1_id": "23437843_T2",
"arg2_id": "23437843_T14",
"normalized": []
},
{
"id": "23437843_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "23437843_T4",
"arg2_id": "23437843_T16",
"normalized": []
},
{
"id": "23437843_4",
"type": "INHIBITOR",
"arg1_id": "23437843_T6",
"arg2_id": "23437843_T19",
"normalized": []
}
] |
23287710 | 23287710 | [
{
"id": "23287710_title",
"type": "title",
"text": [
"Dose dependent molecular effects of acrylamide and glycidamide in human cancer cell lines and human primary hepatocytes."
],
"offsets": [
[
0,
120
]
]
},
{
"id": "23287710_abstract",
"type": "abstract",
"text": [
"Recently published studies suggest a weak positive correlation between increased dietary acrylamide intake and the increased risk of endometrial and ovarian cancer. However, risk assessment of acrylamide remains difficult because the carcinogenic mechanisms are still unknown and in particular the molecular effects of low level acrylamide exposure as seen by dietary intake are not well understood. Therefore, we analyzed in ovarian and endometrial cancer cell lines as well as in primary hepatocytes the expression of genes involved in cancer development and xenobiotic metabolism after high and low dose exposure (1-0.001mM) of acrylamide and its metabolite glycidamide. In conclusion our in vitro results demonstrate that exposure to high doses of glycidamide/acrylamide - exceeding the dietary exposure of the general population by far - can induce genes with growth promoting potential like the oncogene cMYC and genes involved in the MAPK pathway. However, low-dose exposure seems to activate primarily genes involved in the elimination of the toxicant."
],
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17471183 | 17471183 | [
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"id": "17471183_title",
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"text": [
"Tricyclic antidepressant pharmacology and therapeutic drug interactions updated."
],
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0,
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"id": "17471183_abstract",
"type": "abstract",
"text": [
"New data on the pharmacology of tricyclic antidepressants (TCAs), their affinities for human cloned CNS receptors and their cytochrome P450 enzyme inhibition profiles, allow improved deductions concerning their effects and interactions and indicate which of the TCAs are the most useful. The relative toxicity of TCAs continues to be more precisely defined, as do TCA interactions with selective serotonin reuptake inhibitors (SSRIs). TCA interactions with monoamine oxidase inhibitors (MAOIs) have been, historically, an uncertain and difficult question, but are now well understood, although this is not reflected in the literature. The data indicate that nortriptyline and desipramine have the most pharmacologically desirable characteristics as noradrenaline reuptake inhibitors (NRIs), and as drugs with few interactions that are also safe when coadministered with either MAOIs or SSRIs. Clomipramine is the only available antidepressant drug that has good evidence of clinically relevant serotonin and noradrenaline reuptake inhibition (SNRI). These data assist drug selection for monotherapy and combination therapy and predict reliably how and why pharmacodynamic and pharmacokinetic interactions occur. In comparison, two newer drugs proposed to have SNRI properties, duloxetine and venlafaxine, may have insufficient NRI potency to be effective SNRIs. Combinations such as sertraline and nortriptyline may therefore offer advantages over drugs like venlafaxine that have fixed ratios of SRI/NRI effects that are not ideal. However, no TCA/SSRI combination is sufficiently safe to be universally applicable without expert knowledge. Standard texts (e.g. the British National Formulary) and treatment guidelines would benefit by taking account of these new data and understandings."
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] |
22790794 | 22790794 | [
{
"id": "22790794_title",
"type": "title",
"text": [
"Novel electrophysiological properties of dronedarone: inhibition of human cardiac two-pore-domain potassium (K2P) channels."
],
"offsets": [
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0,
123
]
]
},
{
"id": "22790794_abstract",
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"text": [
"Dronedarone is currently used for the treatment of paroxysmal and persistent atrial fibrillation (AF). Pharmacological inhibition of cardiac two-pore-domain potassium (K(2P)) channels results in action potential prolongation and has recently been proposed as novel antiarrhythmic strategy. We hypothesized that blockade of human K(2P) channels contributes to the electrophysiological efficacy of dronedarone in AF. Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record K(2P) currents from Xenopus oocytes and Chinese hamster ovary cells. All functional human K(2P) channels were screened for dronedarone sensitivity, revealing significant and concentration-dependent inhibition of cardiac K(2P)2.1 (TREK1; IC(50) = 26.7 muM) and K(2P)3.1 channels (TASK1; IC(50) = 18.7 muM) with maximum current reduction of 60.3 and 65.5 % in oocytes. IC(50) values obtained from mammalian cells yielded 6.1 muM (K(2P)2.1) and 5.2 muM (K(2P)3.1). The molecular mechanism of action was studied in detail. Dronedarone block affected open and closed channels. K(2P)3.1 currents were reduced in frequency-dependent fashion in contrast to K(2P)2.1. Mutagenesis studies revealed that amino acid residues implicated in K(2P)3.1 drug interactions were not required for dronedarone blockade. The class III antiarrhythmic drug dronedarone targets multiple human cardiac two-pore-domain potassium channels, including atrial-selective K(2P)3.1 currents. K(2P) current inhibition by dronedarone represents a previously unrecognized mechanism of action that extends the multichannel blocking profile of the drug."
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257,
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851,
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"id": "22790794_T24",
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"TREK1"
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861,
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"id": "22790794_T26",
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"TASK1"
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910,
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"id": "22790794_T29",
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"human cardiac two-pore-domain potassium (K2P) channels"
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68,
122
]
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}
] | [] | [] | [
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}
] |
23471540 | 23471540 | [
{
"id": "23471540_title",
"type": "title",
"text": [
"Global analysis of Drosophila Cys2-His2 zinc finger proteins reveals a multitude of novel recognition motifs and binding determinants."
],
"offsets": [
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0,
134
]
]
},
{
"id": "23471540_abstract",
"type": "abstract",
"text": [
"Cys2-His2 zinc finger proteins (ZFPs) are the largest group of transcription factors in higher metazoans. A complete characterization of these ZFPs and their associated target sequences is pivotal to fully annotate transcriptional regulatory networks in metazoan genomes. As a first step in this process, we have characterized the DNA-binding specificities of 129 zinc finger sets from Drosophila using a bacterial one-hybrid system. This data set contains the DNA-binding specificities for at least one encoded ZFP from 70 unique genes and 23 alternate splice isoforms representing the largest set of characterized ZFPs from any organism described to date. These recognition motifs can be used to predict genomic binding sites for these factors within the fruit fly genome. Subsets of fingers from these ZFPs were characterized to define their orientation and register on their recognition sequences, thereby allowing us to define the recognition diversity within this finger set. We find that the characterized fingers can specify 47 of the 64 possible DNA triplets. To confirm the utility of our finger recognition models, we employed subsets of Drosophila fingers in combination with an existing archive of artificial zinc finger modules to create ZFPs with novel DNA-binding specificity. These hybrids of natural and artificial fingers can be used to create functional zinc finger nucleases for editing vertebrate genomes."
],
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135,
1562
]
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}
] | [
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"id": "23471540_T1",
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145,
149
]
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},
{
"id": "23471540_T2",
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"zinc"
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1357,
1361
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},
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"id": "23471540_T3",
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"zinc"
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1509,
1513
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"id": "23471540_T4",
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"zinc"
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499,
503
]
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},
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"id": "23471540_T5",
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"Cys"
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30,
33
]
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},
{
"id": "23471540_T6",
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"His"
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35,
38
]
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},
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"id": "23471540_T7",
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"zinc"
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40,
44
]
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},
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"id": "23471540_T8",
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"Cys2-His2 zinc finger proteins"
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135,
165
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],
"normalized": []
},
{
"id": "23471540_T9",
"type": "GENE-N",
"text": [
"zinc finger"
],
"offsets": [
[
1357,
1368
]
],
"normalized": []
},
{
"id": "23471540_T10",
"type": "GENE-N",
"text": [
"ZFPs"
],
"offsets": [
[
1387,
1391
]
],
"normalized": []
},
{
"id": "23471540_T11",
"type": "GENE-N",
"text": [
"zinc finger nucleases"
],
"offsets": [
[
1509,
1530
]
],
"normalized": []
},
{
"id": "23471540_T12",
"type": "GENE-N",
"text": [
"ZFPs"
],
"offsets": [
[
278,
282
]
],
"normalized": []
},
{
"id": "23471540_T13",
"type": "GENE-N",
"text": [
"ZFPs"
],
"offsets": [
[
167,
171
]
],
"normalized": []
},
{
"id": "23471540_T14",
"type": "GENE-N",
"text": [
"zinc finger"
],
"offsets": [
[
499,
510
]
],
"normalized": []
},
{
"id": "23471540_T15",
"type": "GENE-N",
"text": [
"ZFP"
],
"offsets": [
[
647,
650
]
],
"normalized": []
},
{
"id": "23471540_T16",
"type": "GENE-N",
"text": [
"ZFPs"
],
"offsets": [
[
751,
755
]
],
"normalized": []
},
{
"id": "23471540_T17",
"type": "GENE-N",
"text": [
"ZFPs"
],
"offsets": [
[
940,
944
]
],
"normalized": []
},
{
"id": "23471540_T18",
"type": "GENE-N",
"text": [
"Drosophila Cys2-His2 zinc finger proteins"
],
"offsets": [
[
19,
60
]
],
"normalized": []
}
] | [] | [] | [] |
9572299 | 9572299 | [
{
"id": "9572299_title",
"type": "title",
"text": [
"Modulation of the N-methyl-D-aspartate receptor by haloperidol: NR2B-specific interactions."
],
"offsets": [
[
0,
91
]
]
},
{
"id": "9572299_abstract",
"type": "abstract",
"text": [
"The dopaminergic antagonist haloperidol has an eight- to 10-fold higher affinity for NMDA receptors containing the NR2B (epsilon2) subunit, showing the same subunit specificity as ifenprodil, polyamines, and magnesium. In the present study, we have compared the effects of mutations altering polyamine and ifenprodil sensitivity on haloperidol sensitivity of NMDA receptors. As seen for spermidine stimulation, high-affinity haloperidol inhibition is governed by the region around amino acid 198, based on results from chimeric murine NR2A/NR2B (epislon1/epsilon2) receptors. Mutation of epsilon2E201 in this region to asparagine or arginine causes a 10-fold decrease in the ability of haloperidol to inhibit 125I-MK-801 binding. Epsilon2E201 does not govern the interactions of ifenprodil, because all of the mutants at epsilon2E201 exhibited wild-type affinity for ifenprodil. Mutation of epsilon2R337 causes a 400-fold loss in apparent affinity for ifenprodil but does not change the effects of haloperidol. The structural determinants of spermidine stimulation do not perfectly match those for haloperidol inhibition, as mutations of E200 remove haloperidol inhibition but do not alter polyamine stimulation. The present results thus demonstrate that although spermidine, haloperidol, and ifenprodil share subunit selectivity and overlapping pharmacology, they also have specific structural determinants."
],
"offsets": [
[
92,
1500
]
]
}
] | [
{
"id": "9572299_T1",
"type": "CHEMICAL",
"text": [
"spermidine"
],
"offsets": [
[
1134,
1144
]
],
"normalized": []
},
{
"id": "9572299_T2",
"type": "CHEMICAL",
"text": [
"haloperidol"
],
"offsets": [
[
1190,
1201
]
],
"normalized": []
},
{
"id": "9572299_T3",
"type": "CHEMICAL",
"text": [
"haloperidol"
],
"offsets": [
[
1242,
1253
]
],
"normalized": []
},
{
"id": "9572299_T4",
"type": "CHEMICAL",
"text": [
"polyamine"
],
"offsets": [
[
1282,
1291
]
],
"normalized": []
},
{
"id": "9572299_T5",
"type": "CHEMICAL",
"text": [
"spermidine"
],
"offsets": [
[
1356,
1366
]
],
"normalized": []
},
{
"id": "9572299_T6",
"type": "CHEMICAL",
"text": [
"haloperidol"
],
"offsets": [
[
1368,
1379
]
],
"normalized": []
},
{
"id": "9572299_T7",
"type": "CHEMICAL",
"text": [
"ifenprodil"
],
"offsets": [
[
1385,
1395
]
],
"normalized": []
},
{
"id": "9572299_T8",
"type": "CHEMICAL",
"text": [
"ifenprodil"
],
"offsets": [
[
272,
282
]
],
"normalized": []
},
{
"id": "9572299_T9",
"type": "CHEMICAL",
"text": [
"polyamines"
],
"offsets": [
[
284,
294
]
],
"normalized": []
},
{
"id": "9572299_T10",
"type": "CHEMICAL",
"text": [
"haloperidol"
],
"offsets": [
[
120,
131
]
],
"normalized": []
},
{
"id": "9572299_T11",
"type": "CHEMICAL",
"text": [
"polyamine"
],
"offsets": [
[
384,
393
]
],
"normalized": []
},
{
"id": "9572299_T12",
"type": "CHEMICAL",
"text": [
"ifenprodil"
],
"offsets": [
[
398,
408
]
],
"normalized": []
},
{
"id": "9572299_T13",
"type": "CHEMICAL",
"text": [
"haloperidol"
],
"offsets": [
[
424,
435
]
],
"normalized": []
},
{
"id": "9572299_T14",
"type": "CHEMICAL",
"text": [
"NMDA"
],
"offsets": [
[
451,
455
]
],
"normalized": []
},
{
"id": "9572299_T15",
"type": "CHEMICAL",
"text": [
"spermidine"
],
"offsets": [
[
479,
489
]
],
"normalized": []
},
{
"id": "9572299_T16",
"type": "CHEMICAL",
"text": [
"haloperidol"
],
"offsets": [
[
517,
528
]
],
"normalized": []
},
{
"id": "9572299_T17",
"type": "CHEMICAL",
"text": [
"amino acid"
],
"offsets": [
[
573,
583
]
],
"normalized": []
},
{
"id": "9572299_T18",
"type": "CHEMICAL",
"text": [
"asparagine"
],
"offsets": [
[
711,
721
]
],
"normalized": []
},
{
"id": "9572299_T19",
"type": "CHEMICAL",
"text": [
"arginine"
],
"offsets": [
[
725,
733
]
],
"normalized": []
},
{
"id": "9572299_T20",
"type": "CHEMICAL",
"text": [
"haloperidol"
],
"offsets": [
[
778,
789
]
],
"normalized": []
},
{
"id": "9572299_T21",
"type": "CHEMICAL",
"text": [
"125I-MK-801"
],
"offsets": [
[
801,
812
]
],
"normalized": []
},
{
"id": "9572299_T22",
"type": "CHEMICAL",
"text": [
"ifenprodil"
],
"offsets": [
[
871,
881
]
],
"normalized": []
},
{
"id": "9572299_T23",
"type": "CHEMICAL",
"text": [
"NMDA"
],
"offsets": [
[
177,
181
]
],
"normalized": []
},
{
"id": "9572299_T24",
"type": "CHEMICAL",
"text": [
"ifenprodil"
],
"offsets": [
[
959,
969
]
],
"normalized": []
},
{
"id": "9572299_T25",
"type": "CHEMICAL",
"text": [
"ifenprodil"
],
"offsets": [
[
1044,
1054
]
],
"normalized": []
},
{
"id": "9572299_T26",
"type": "CHEMICAL",
"text": [
"haloperidol"
],
"offsets": [
[
1090,
1101
]
],
"normalized": []
},
{
"id": "9572299_T27",
"type": "CHEMICAL",
"text": [
"N-methyl-D-aspartate"
],
"offsets": [
[
18,
38
]
],
"normalized": []
},
{
"id": "9572299_T28",
"type": "CHEMICAL",
"text": [
"haloperidol"
],
"offsets": [
[
51,
62
]
],
"normalized": []
},
{
"id": "9572299_T29",
"type": "GENE-Y",
"text": [
"NR2B (epsilon2)"
],
"offsets": [
[
207,
222
]
],
"normalized": []
},
{
"id": "9572299_T30",
"type": "GENE-N",
"text": [
"NMDA receptors"
],
"offsets": [
[
451,
465
]
],
"normalized": []
},
{
"id": "9572299_T31",
"type": "GENE-Y",
"text": [
"murine NR2A"
],
"offsets": [
[
620,
631
]
],
"normalized": []
},
{
"id": "9572299_T32",
"type": "GENE-Y",
"text": [
"NR2B"
],
"offsets": [
[
632,
636
]
],
"normalized": []
},
{
"id": "9572299_T33",
"type": "GENE-N",
"text": [
"(epislon1/epsilon2) receptors"
],
"offsets": [
[
637,
666
]
],
"normalized": []
},
{
"id": "9572299_T34",
"type": "GENE-N",
"text": [
"NMDA receptors"
],
"offsets": [
[
177,
191
]
],
"normalized": []
},
{
"id": "9572299_T35",
"type": "GENE-N",
"text": [
"N-methyl-D-aspartate receptor"
],
"offsets": [
[
18,
47
]
],
"normalized": []
},
{
"id": "9572299_T36",
"type": "GENE-Y",
"text": [
"NR2B"
],
"offsets": [
[
64,
68
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "9572299_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "9572299_T10",
"arg2_id": "9572299_T34",
"normalized": []
},
{
"id": "9572299_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "9572299_T10",
"arg2_id": "9572299_T29",
"normalized": []
},
{
"id": "9572299_2",
"type": "PART-OF",
"arg1_id": "9572299_T17",
"arg2_id": "9572299_T31",
"normalized": []
},
{
"id": "9572299_3",
"type": "PART-OF",
"arg1_id": "9572299_T17",
"arg2_id": "9572299_T32",
"normalized": []
},
{
"id": "9572299_4",
"type": "INHIBITOR",
"arg1_id": "9572299_T16",
"arg2_id": "9572299_T31",
"normalized": []
},
{
"id": "9572299_5",
"type": "INHIBITOR",
"arg1_id": "9572299_T16",
"arg2_id": "9572299_T32",
"normalized": []
},
{
"id": "9572299_6",
"type": "DIRECT-REGULATOR",
"arg1_id": "9572299_T16",
"arg2_id": "9572299_T31",
"normalized": []
},
{
"id": "9572299_7",
"type": "DIRECT-REGULATOR",
"arg1_id": "9572299_T16",
"arg2_id": "9572299_T32",
"normalized": []
}
] |
10494488 | 10494488 | [
{
"id": "10494488_title",
"type": "title",
"text": [
"Variations of progesterone receptor and c-fos gene expression in the rat uterus after treatment with norethisterone and its A-ring reduced metabolites."
],
"offsets": [
[
0,
151
]
]
},
{
"id": "10494488_abstract",
"type": "abstract",
"text": [
"It has been suggested that some contraceptive derivatives of 19-nor-testosterone possess estrogenic activity that may facilitate the development of breast cancer. The aim of this work was to investigate the estrogenic properties of norethisterone (NET) and its A-ring-reduced derivatives by determining progesterone receptor (PR) and c-fos mRNA content of two estrogen-regulated genes in the uterus of ovariectomized rats. mRNA content was evaluated by Northern blot 1-6 h after 17 beta-estradiol administration. The highest PR and c-fos mRNA content was observed 3 h and 2 h after 17 beta-estradiol administration, respectively. NET did not modify either PR or c-fos mRNA content. In contrast, 5 alpha- and 3 beta, 5 alpha-NET significantly increased mRNA content of both genes. The increase in c-fos mRNA content induced by these reduced compounds was lower than that found with estradiol treatment. The overall results indicate that NET administration can indirectly induce estrogenic effects through the action of its 5 alpha-dihydro and 3 beta, 5 alpha-tetrahydro derivatives."
],
"offsets": [
[
152,
1233
]
]
}
] | [
{
"id": "10494488_T1",
"type": "CHEMICAL",
"text": [
"5 alpha-dihydro"
],
"offsets": [
[
1174,
1189
]
],
"normalized": []
},
{
"id": "10494488_T2",
"type": "CHEMICAL",
"text": [
"3 beta, 5 alpha-tetrahydro"
],
"offsets": [
[
1194,
1220
]
],
"normalized": []
},
{
"id": "10494488_T3",
"type": "CHEMICAL",
"text": [
"norethisterone"
],
"offsets": [
[
384,
398
]
],
"normalized": []
},
{
"id": "10494488_T4",
"type": "CHEMICAL",
"text": [
"NET"
],
"offsets": [
[
400,
403
]
],
"normalized": []
},
{
"id": "10494488_T5",
"type": "CHEMICAL",
"text": [
"progesterone"
],
"offsets": [
[
455,
467
]
],
"normalized": []
},
{
"id": "10494488_T6",
"type": "CHEMICAL",
"text": [
"estrogen"
],
"offsets": [
[
512,
520
]
],
"normalized": []
},
{
"id": "10494488_T7",
"type": "CHEMICAL",
"text": [
"17 beta-estradiol"
],
"offsets": [
[
631,
648
]
],
"normalized": []
},
{
"id": "10494488_T8",
"type": "CHEMICAL",
"text": [
"17 beta-estradiol"
],
"offsets": [
[
734,
751
]
],
"normalized": []
},
{
"id": "10494488_T9",
"type": "CHEMICAL",
"text": [
"19-nor-testosterone"
],
"offsets": [
[
213,
232
]
],
"normalized": []
},
{
"id": "10494488_T10",
"type": "CHEMICAL",
"text": [
"NET"
],
"offsets": [
[
782,
785
]
],
"normalized": []
},
{
"id": "10494488_T11",
"type": "CHEMICAL",
"text": [
"5 alpha- and 3 beta, 5 alpha-NET"
],
"offsets": [
[
847,
879
]
],
"normalized": []
},
{
"id": "10494488_T12",
"type": "CHEMICAL",
"text": [
"estradiol"
],
"offsets": [
[
1033,
1042
]
],
"normalized": []
},
{
"id": "10494488_T13",
"type": "CHEMICAL",
"text": [
"NET"
],
"offsets": [
[
1088,
1091
]
],
"normalized": []
},
{
"id": "10494488_T14",
"type": "CHEMICAL",
"text": [
"norethisterone"
],
"offsets": [
[
101,
115
]
],
"normalized": []
},
{
"id": "10494488_T15",
"type": "CHEMICAL",
"text": [
"progesterone"
],
"offsets": [
[
14,
26
]
],
"normalized": []
},
{
"id": "10494488_T16",
"type": "GENE-Y",
"text": [
"progesterone receptor"
],
"offsets": [
[
455,
476
]
],
"normalized": []
},
{
"id": "10494488_T17",
"type": "GENE-Y",
"text": [
"PR"
],
"offsets": [
[
478,
480
]
],
"normalized": []
},
{
"id": "10494488_T18",
"type": "GENE-Y",
"text": [
"c-fos"
],
"offsets": [
[
486,
491
]
],
"normalized": []
},
{
"id": "10494488_T19",
"type": "GENE-Y",
"text": [
"PR"
],
"offsets": [
[
677,
679
]
],
"normalized": []
},
{
"id": "10494488_T20",
"type": "GENE-Y",
"text": [
"c-fos"
],
"offsets": [
[
684,
689
]
],
"normalized": []
},
{
"id": "10494488_T21",
"type": "GENE-Y",
"text": [
"PR"
],
"offsets": [
[
808,
810
]
],
"normalized": []
},
{
"id": "10494488_T22",
"type": "GENE-Y",
"text": [
"c-fos"
],
"offsets": [
[
814,
819
]
],
"normalized": []
},
{
"id": "10494488_T23",
"type": "GENE-Y",
"text": [
"c-fos"
],
"offsets": [
[
948,
953
]
],
"normalized": []
},
{
"id": "10494488_T24",
"type": "GENE-Y",
"text": [
"progesterone receptor"
],
"offsets": [
[
14,
35
]
],
"normalized": []
},
{
"id": "10494488_T25",
"type": "GENE-Y",
"text": [
"c-fos"
],
"offsets": [
[
40,
45
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "10494488_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "10494488_T8",
"arg2_id": "10494488_T19",
"normalized": []
},
{
"id": "10494488_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "10494488_T8",
"arg2_id": "10494488_T20",
"normalized": []
},
{
"id": "10494488_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "10494488_T12",
"arg2_id": "10494488_T23",
"normalized": []
}
] |
23535185 | 23535185 | [
{
"id": "23535185_title",
"type": "title",
"text": [
"Galangin attenuates mast cell-mediated allergic inflammation."
],
"offsets": [
[
0,
61
]
]
},
{
"id": "23535185_abstract",
"type": "abstract",
"text": [
"A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of galangin and underlying mechanisms of action using in vitro and in vivo models. Galangin inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). Galangin decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of galangin on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, galangin attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of galangin were more potent than cromolyn, a known anti-allergic drug. Our results showed that galangin down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, galangin could be a beneficial anti-allergic inflammatory agent."
],
"offsets": [
[
62,
1491
]
]
}
] | [
{
"id": "23535185_T1",
"type": "CHEMICAL",
"text": [
"galangin"
],
"offsets": [
[
1115,
1123
]
],
"normalized": []
},
{
"id": "23535185_T2",
"type": "CHEMICAL",
"text": [
"cromolyn"
],
"offsets": [
[
1146,
1154
]
],
"normalized": []
},
{
"id": "23535185_T3",
"type": "CHEMICAL",
"text": [
"galangin"
],
"offsets": [
[
1208,
1216
]
],
"normalized": []
},
{
"id": "23535185_T4",
"type": "CHEMICAL",
"text": [
"histamine"
],
"offsets": [
[
1294,
1303
]
],
"normalized": []
},
{
"id": "23535185_T5",
"type": "CHEMICAL",
"text": [
"galangin"
],
"offsets": [
[
1427,
1435
]
],
"normalized": []
},
{
"id": "23535185_T6",
"type": "CHEMICAL",
"text": [
"galangin"
],
"offsets": [
[
360,
368
]
],
"normalized": []
},
{
"id": "23535185_T7",
"type": "CHEMICAL",
"text": [
"Galangin"
],
"offsets": [
[
440,
448
]
],
"normalized": []
},
{
"id": "23535185_T8",
"type": "CHEMICAL",
"text": [
"histamine"
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459,
468
]
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"id": "23535185_T9",
"type": "CHEMICAL",
"text": [
"calcium"
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511,
518
]
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{
"id": "23535185_T10",
"type": "CHEMICAL",
"text": [
"phorbol 12-mystate 13-acetate"
],
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522,
551
]
],
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},
{
"id": "23535185_T11",
"type": "CHEMICAL",
"text": [
"calcium"
],
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557,
564
]
],
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},
{
"id": "23535185_T12",
"type": "CHEMICAL",
"text": [
"Galangin"
],
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619,
627
]
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},
{
"id": "23535185_T13",
"type": "CHEMICAL",
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"galangin"
],
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781,
789
]
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},
{
"id": "23535185_T14",
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"text": [
"N"
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850,
851
]
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},
{
"id": "23535185_T15",
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"galangin"
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959,
967
]
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"id": "23535185_T16",
"type": "CHEMICAL",
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"histamine"
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1044,
1053
]
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{
"id": "23535185_T17",
"type": "CHEMICAL",
"text": [
"Galangin"
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0,
8
]
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},
{
"id": "23535185_T18",
"type": "GENE-N",
"text": [
"cytokines"
],
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1347,
1356
]
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},
{
"id": "23535185_T19",
"type": "GENE-N",
"text": [
"cytokines"
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669,
678
]
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},
{
"id": "23535185_T20",
"type": "GENE-Y",
"text": [
"tumor necrosis factor (TNF)-α"
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688,
717
]
],
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},
{
"id": "23535185_T21",
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"text": [
"interleukin"
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719,
730
]
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{
"id": "23535185_T22",
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"(IL)-6"
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731,
737
]
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"id": "23535185_T23",
"type": "GENE-Y",
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"IL-1β"
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739,
744
]
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"id": "23535185_T24",
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"IL-8"
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750,
754
]
],
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},
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"id": "23535185_T25",
"type": "GENE-N",
"text": [
"cytokines"
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817,
826
]
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},
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"id": "23535185_T26",
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"text": [
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844,
849
]
],
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},
{
"id": "23535185_T27",
"type": "GENE-N",
"text": [
"N-terminal kinases"
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850,
868
]
],
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},
{
"id": "23535185_T28",
"type": "GENE-N",
"text": [
"p38"
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877
]
],
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},
{
"id": "23535185_T29",
"type": "GENE-N",
"text": [
"mitogen-activated protein kinase"
],
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878,
910
]
],
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},
{
"id": "23535185_T30",
"type": "GENE-N",
"text": [
"nuclear factor-κB"
],
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[
912,
929
]
],
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},
{
"id": "23535185_T31",
"type": "GENE-Y",
"text": [
"caspase-1"
],
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[
935,
944
]
],
"normalized": []
},
{
"id": "23535185_T32",
"type": "GENE-N",
"text": [
"IgE"
],
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[
979,
982
]
],
"normalized": []
},
{
"id": "23535185_T33",
"type": "GENE-Y",
"text": [
"histamine receptor 1"
],
"offsets": [
[
1044,
1064
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23535185_0",
"type": "INDIRECT-DOWNREGULATOR",
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"arg2_id": "23535185_T19",
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},
{
"id": "23535185_1",
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"arg1_id": "23535185_T12",
"arg2_id": "23535185_T20",
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},
{
"id": "23535185_2",
"type": "INDIRECT-DOWNREGULATOR",
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"arg2_id": "23535185_T21",
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},
{
"id": "23535185_3",
"type": "INDIRECT-DOWNREGULATOR",
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"arg2_id": "23535185_T22",
"normalized": []
},
{
"id": "23535185_4",
"type": "INDIRECT-DOWNREGULATOR",
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"arg2_id": "23535185_T23",
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},
{
"id": "23535185_5",
"type": "INDIRECT-DOWNREGULATOR",
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"arg2_id": "23535185_T24",
"normalized": []
},
{
"id": "23535185_6",
"type": "INDIRECT-DOWNREGULATOR",
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"arg2_id": "23535185_T25",
"normalized": []
},
{
"id": "23535185_7",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23535185_T15",
"arg2_id": "23535185_T33",
"normalized": []
},
{
"id": "23535185_8",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23535185_T3",
"arg2_id": "23535185_T18",
"normalized": []
}
] |
22977167 | 22977167 | [
{
"id": "22977167_title",
"type": "title",
"text": [
"Effects of ozone and particulate matter on cardiac mechanics: role of the atrial natriuretic peptide gene."
],
"offsets": [
[
0,
106
]
]
},
{
"id": "22977167_abstract",
"type": "abstract",
"text": [
"A positive association between air pollution exposure and increased human risk of chronic heart disease progression is well established. In the current study, we test two hypotheses: (1) the cardiac compensatory changes in response to air pollution are dependent on its composition and (2) specific cardiac adaptations are regulated by atrial natriuretic peptide (ANP). We address these hypotheses by initially examining the exposure effects of ozone (O(3)) and/or particulate matter (PM) on cardiac function in C57Bl/6J (B6) mice. Subsequently, the results are compared with cardiac functional changes to the same exposures in Nppa (the precursor gene for ANP) knockout (KO) mice. Separate groups of mice underwent 3 consecutive days of the same exposure sequence for 3h each consisting of the following: (1) 6h of filtered air (FAFA), (2) O(3) then FA (O(3)FA), (3) FA then carbon black (FACB), or (4) O(3) then CB. Cardiac function was assessed using a conductance catheter to generate cardiac pressure-volume loops 8-10h following each exposure sequence. As compared with FAFA, each sequence led to a substantial drop (as much as 33%) in stroke volume and cardiac output. However, these losses of cardiac function occurred by different compensatory mechanisms dependent on the pollutant composition. For example, O(3)FA exposure led to reductions in both end-systolic and end-diastolic left ventricular (LV) volumes, whereas FACB exposure led an increase in end-diastolic LV volume. These same cardiac compensatory changes were largely abolished in Nppa KO mice following O(3)FA or FACB exposure. These results suggest that cardiac functional changes in response to air pollution exposure are strongly dependent on the pollutant constituents, especially related to O(3) and/or PM. Furthermore, ANP regulation appears to be crucial to these cardiac compensatory mechanisms induced by air pollution."
],
"offsets": [
[
107,
2008
]
]
}
] | [
{
"id": "22977167_T1",
"type": "CHEMICAL",
"text": [
"O(3)"
],
"offsets": [
[
1424,
1428
]
],
"normalized": []
},
{
"id": "22977167_T2",
"type": "CHEMICAL",
"text": [
"O(3)"
],
"offsets": [
[
1683,
1687
]
],
"normalized": []
},
{
"id": "22977167_T3",
"type": "CHEMICAL",
"text": [
"O(3)"
],
"offsets": [
[
1876,
1880
]
],
"normalized": []
},
{
"id": "22977167_T4",
"type": "CHEMICAL",
"text": [
"ozone"
],
"offsets": [
[
552,
557
]
],
"normalized": []
},
{
"id": "22977167_T5",
"type": "CHEMICAL",
"text": [
"O(3)"
],
"offsets": [
[
559,
563
]
],
"normalized": []
},
{
"id": "22977167_T6",
"type": "CHEMICAL",
"text": [
"O(3)"
],
"offsets": [
[
948,
952
]
],
"normalized": []
},
{
"id": "22977167_T7",
"type": "CHEMICAL",
"text": [
"O(3)"
],
"offsets": [
[
962,
966
]
],
"normalized": []
},
{
"id": "22977167_T8",
"type": "CHEMICAL",
"text": [
"carbon black"
],
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[
983,
995
]
],
"normalized": []
},
{
"id": "22977167_T9",
"type": "CHEMICAL",
"text": [
"O(3)"
],
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[
1011,
1015
]
],
"normalized": []
},
{
"id": "22977167_T10",
"type": "CHEMICAL",
"text": [
"ozone"
],
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[
11,
16
]
],
"normalized": []
},
{
"id": "22977167_T11",
"type": "GENE-Y",
"text": [
"Nppa"
],
"offsets": [
[
1660,
1664
]
],
"normalized": []
},
{
"id": "22977167_T12",
"type": "GENE-Y",
"text": [
"ANP"
],
"offsets": [
[
1905,
1908
]
],
"normalized": []
},
{
"id": "22977167_T13",
"type": "GENE-Y",
"text": [
"atrial natriuretic peptide"
],
"offsets": [
[
443,
469
]
],
"normalized": []
},
{
"id": "22977167_T14",
"type": "GENE-Y",
"text": [
"ANP"
],
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[
471,
474
]
],
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},
{
"id": "22977167_T15",
"type": "GENE-Y",
"text": [
"Nppa"
],
"offsets": [
[
735,
739
]
],
"normalized": []
},
{
"id": "22977167_T16",
"type": "GENE-Y",
"text": [
"ANP"
],
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[
764,
767
]
],
"normalized": []
},
{
"id": "22977167_T17",
"type": "GENE-Y",
"text": [
"atrial natriuretic peptide"
],
"offsets": [
[
74,
100
]
],
"normalized": []
}
] | [] | [] | [] |
20222714 | 20222714 | [
{
"id": "20222714_title",
"type": "title",
"text": [
"Complexity in influenza virus targeted drug design: interaction with human sialidases."
],
"offsets": [
[
0,
86
]
]
},
{
"id": "20222714_abstract",
"type": "abstract",
"text": [
"With the global spread of the pandemic H1N1 and the ongoing pandemic potential of the H5N1 subtype, the influenza virus represents one of the most alarming viruses spreading worldwide. The influenza virus sialidase is an effective drug target, and a number of inhibitors are clinically effective against the virus (zanamivir, oseltamivir, peramivir). Here we report structural and biochemical studies of the human cytosolic sialidase Neu2 with influenza virus sialidase-targeting drugs and related compounds."
],
"offsets": [
[
87,
595
]
]
}
] | [
{
"id": "20222714_T1",
"type": "CHEMICAL",
"text": [
"zanamivir"
],
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[
402,
411
]
],
"normalized": []
},
{
"id": "20222714_T2",
"type": "CHEMICAL",
"text": [
"oseltamivir"
],
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[
413,
424
]
],
"normalized": []
},
{
"id": "20222714_T3",
"type": "CHEMICAL",
"text": [
"peramivir"
],
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[
426,
435
]
],
"normalized": []
},
{
"id": "20222714_T4",
"type": "GENE-N",
"text": [
"influenza virus sialidase"
],
"offsets": [
[
276,
301
]
],
"normalized": []
},
{
"id": "20222714_T5",
"type": "GENE-Y",
"text": [
"human cytosolic sialidase"
],
"offsets": [
[
495,
520
]
],
"normalized": []
},
{
"id": "20222714_T6",
"type": "GENE-Y",
"text": [
"Neu2"
],
"offsets": [
[
521,
525
]
],
"normalized": []
},
{
"id": "20222714_T7",
"type": "GENE-N",
"text": [
"influenza virus sialidase"
],
"offsets": [
[
531,
556
]
],
"normalized": []
},
{
"id": "20222714_T8",
"type": "GENE-N",
"text": [
"human sialidases"
],
"offsets": [
[
69,
85
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "20222714_0",
"type": "INHIBITOR",
"arg1_id": "20222714_T1",
"arg2_id": "20222714_T4",
"normalized": []
},
{
"id": "20222714_1",
"type": "INHIBITOR",
"arg1_id": "20222714_T2",
"arg2_id": "20222714_T4",
"normalized": []
},
{
"id": "20222714_2",
"type": "INHIBITOR",
"arg1_id": "20222714_T3",
"arg2_id": "20222714_T4",
"normalized": []
}
] |
23333576 | 23333576 | [
{
"id": "23333576_title",
"type": "title",
"text": [
"Areca nut procyanidins ameliorate streptozocin-induced hyperglycemia by regulating gluconeogenesis."
],
"offsets": [
[
0,
99
]
]
},
{
"id": "23333576_abstract",
"type": "abstract",
"text": [
"Hepatic gluconeogenesis is a major contributor to blood glucose in diabetes mellitus. Our previous study indicated that areca nut extract enriched with catechin-based procyanidins from oligomers to polymers gave rise to anti-inflammatory effects in vitro and in vivo. Here we have surveyed the molecular features of areca nut procyanidins (ANPs) using quadrupole time-of-flight liquid chromatography/mass spectrometry (Q-TOF LC/MS) and the resulting mass spectrum accurately described ANP from monomer to hexadecamer. Furthermore, the potential of ANP in terms of blood glucose homeostasis was explored using cyclic adenosine monophosphate (cAMP)/dexamethasone stimulated primary mouse hepatocytes and multiple low dose streptozocin (MLD-STZ) treated mice. With the primary hepatocytes, ANP dose-dependently inhibited gluconeogenesis and reduced the mRNA expression of two gluconeogenic key enzymes, phosphoenol-pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Intragastrically feeding of 10mg/kg ANP for 4weeks reduced the levels of fasting blood glucose, PEPCK and G6Pase in MLD-STZ mice. In additional, the level of 5'-AMP-activated protein kinase (AMPK) expression showed a trend towards being restored in the ANP treated MLD-STZ-mice. This study indicated that ANP has the potential to improve hyperglycemia by regulating gluconeogenic related kinases in MLD-STZ-mice."
],
"offsets": [
[
100,
1491
]
]
}
] | [
{
"id": "23333576_T1",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
1166,
1173
]
],
"normalized": []
},
{
"id": "23333576_T2",
"type": "CHEMICAL",
"text": [
"STZ"
],
"offsets": [
[
1199,
1202
]
],
"normalized": []
},
{
"id": "23333576_T3",
"type": "CHEMICAL",
"text": [
"5'-AMP"
],
"offsets": [
[
1237,
1243
]
],
"normalized": []
},
{
"id": "23333576_T4",
"type": "CHEMICAL",
"text": [
"STZ"
],
"offsets": [
[
1348,
1351
]
],
"normalized": []
},
{
"id": "23333576_T5",
"type": "CHEMICAL",
"text": [
"STZ"
],
"offsets": [
[
1482,
1485
]
],
"normalized": []
},
{
"id": "23333576_T6",
"type": "CHEMICAL",
"text": [
"catechin"
],
"offsets": [
[
252,
260
]
],
"normalized": []
},
{
"id": "23333576_T7",
"type": "CHEMICAL",
"text": [
"procyanidins"
],
"offsets": [
[
267,
279
]
],
"normalized": []
},
{
"id": "23333576_T8",
"type": "CHEMICAL",
"text": [
"procyanidins"
],
"offsets": [
[
426,
438
]
],
"normalized": []
},
{
"id": "23333576_T9",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
156,
163
]
],
"normalized": []
},
{
"id": "23333576_T10",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
670,
677
]
],
"normalized": []
},
{
"id": "23333576_T11",
"type": "CHEMICAL",
"text": [
"cyclic adenosine monophosphate"
],
"offsets": [
[
709,
739
]
],
"normalized": []
},
{
"id": "23333576_T12",
"type": "CHEMICAL",
"text": [
"cAMP"
],
"offsets": [
[
741,
745
]
],
"normalized": []
},
{
"id": "23333576_T13",
"type": "CHEMICAL",
"text": [
"dexamethasone"
],
"offsets": [
[
747,
760
]
],
"normalized": []
},
{
"id": "23333576_T14",
"type": "CHEMICAL",
"text": [
"streptozocin"
],
"offsets": [
[
820,
832
]
],
"normalized": []
},
{
"id": "23333576_T15",
"type": "CHEMICAL",
"text": [
"STZ"
],
"offsets": [
[
838,
841
]
],
"normalized": []
},
{
"id": "23333576_T16",
"type": "CHEMICAL",
"text": [
"phosphoenol-pyruvate"
],
"offsets": [
[
1000,
1020
]
],
"normalized": []
},
{
"id": "23333576_T17",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
1047,
1054
]
],
"normalized": []
},
{
"id": "23333576_T18",
"type": "CHEMICAL",
"text": [
"procyanidins"
],
"offsets": [
[
10,
22
]
],
"normalized": []
},
{
"id": "23333576_T19",
"type": "CHEMICAL",
"text": [
"streptozocin"
],
"offsets": [
[
34,
46
]
],
"normalized": []
},
{
"id": "23333576_T20",
"type": "GENE-Y",
"text": [
"PEPCK"
],
"offsets": [
[
1175,
1180
]
],
"normalized": []
},
{
"id": "23333576_T21",
"type": "GENE-Y",
"text": [
"G6Pase"
],
"offsets": [
[
1185,
1191
]
],
"normalized": []
},
{
"id": "23333576_T22",
"type": "GENE-N",
"text": [
"5'-AMP-activated protein kinase"
],
"offsets": [
[
1237,
1268
]
],
"normalized": []
},
{
"id": "23333576_T23",
"type": "GENE-N",
"text": [
"AMPK"
],
"offsets": [
[
1270,
1274
]
],
"normalized": []
},
{
"id": "23333576_T24",
"type": "GENE-N",
"text": [
"kinases"
],
"offsets": [
[
1467,
1474
]
],
"normalized": []
},
{
"id": "23333576_T25",
"type": "GENE-Y",
"text": [
"phosphoenol-pyruvate carboxykinase"
],
"offsets": [
[
1000,
1034
]
],
"normalized": []
},
{
"id": "23333576_T26",
"type": "GENE-Y",
"text": [
"PEPCK"
],
"offsets": [
[
1036,
1041
]
],
"normalized": []
},
{
"id": "23333576_T27",
"type": "GENE-Y",
"text": [
"glucose-6-phosphatase"
],
"offsets": [
[
1047,
1068
]
],
"normalized": []
},
{
"id": "23333576_T28",
"type": "GENE-Y",
"text": [
"G6Pase"
],
"offsets": [
[
1070,
1076
]
],
"normalized": []
}
] | [] | [] | [] |
23071294 | 23071294 | [
{
"id": "23071294_title",
"type": "title",
"text": [
"ApoE derived from adipose tissue does not suppress atherosclerosis or correct hyperlipidemia in apoE knockout mice."
],
"offsets": [
[
0,
115
]
]
},
{
"id": "23071294_abstract",
"type": "abstract",
"text": [
"The synthesis of apoE by adipocytes has profound effects on adipose tissue lipid flux and gene expression. Using adipose tissue transplantation from wild-type (WT) to apoE knockout (EKO) mice, we show that adipose tissue also contributes to circulating apoE. Different from circulating apoE produced by bone marrow transplantation (BMT), however, adipose tissue-derived apoE does not correct hyperlipidemia or suppress atherosclerosis. ApoE secreted by macrophages has a more acidic isoform distribution, and it increases binding of reconstituted VLDL particles to hepatocytes and fibroblasts more effectively than apoE secreted by adipocytes. The incremental binding can be entirely accounted for by binding to the LDL receptor. After BMT into EKO hosts, plasma cholesterol and macrophage-derived apoE are largely within IDL/LDL- and HDL-sized particles. After adipose tissue transplantation, most cholesterol and adipocyte apoE remain in VLDL. After BMT, circulating apoE no longer demonstrates predominance of acidic isoforms compared with that circulating after fat transplantation. In conclusion, fat transplantation provides circulating apoE levels similar to those provided by bone marrow transplantation, but it does not suppress hyperlipidemia or atherosclerosis. A potential mechanism contributing to this difference is differential binding to cell surface lipoprotein receptors."
],
"offsets": [
[
116,
1505
]
]
}
] | [
{
"id": "23071294_T1",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
879,
890
]
],
"normalized": []
},
{
"id": "23071294_T2",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
1015,
1026
]
],
"normalized": []
},
{
"id": "23071294_T3",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
1259,
1263
]
],
"normalized": []
},
{
"id": "23071294_T4",
"type": "GENE-N",
"text": [
"lipoprotein receptors"
],
"offsets": [
[
1483,
1504
]
],
"normalized": []
},
{
"id": "23071294_T5",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
283,
287
]
],
"normalized": []
},
{
"id": "23071294_T6",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
133,
137
]
],
"normalized": []
},
{
"id": "23071294_T7",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
369,
373
]
],
"normalized": []
},
{
"id": "23071294_T8",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
402,
406
]
],
"normalized": []
},
{
"id": "23071294_T9",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
486,
490
]
],
"normalized": []
},
{
"id": "23071294_T10",
"type": "GENE-Y",
"text": [
"ApoE"
],
"offsets": [
[
552,
556
]
],
"normalized": []
},
{
"id": "23071294_T11",
"type": "GENE-N",
"text": [
"VLDL"
],
"offsets": [
[
663,
667
]
],
"normalized": []
},
{
"id": "23071294_T12",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
731,
735
]
],
"normalized": []
},
{
"id": "23071294_T13",
"type": "GENE-Y",
"text": [
"LDL receptor"
],
"offsets": [
[
832,
844
]
],
"normalized": []
},
{
"id": "23071294_T14",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
914,
918
]
],
"normalized": []
},
{
"id": "23071294_T15",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
1041,
1045
]
],
"normalized": []
},
{
"id": "23071294_T16",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
1085,
1089
]
],
"normalized": []
},
{
"id": "23071294_T17",
"type": "GENE-Y",
"text": [
"ApoE"
],
"offsets": [
[
0,
4
]
],
"normalized": []
},
{
"id": "23071294_T18",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
96,
100
]
],
"normalized": []
}
] | [] | [] | [] |
22935610 | 22935610 | [
{
"id": "22935610_title",
"type": "title",
"text": [
"The prolyl-isomerase Pin1 activates the mitochondrial death program of p53."
],
"offsets": [
[
0,
75
]
]
},
{
"id": "22935610_abstract",
"type": "abstract",
"text": [
"In response to intense stress, the tumor protein p53 (p53) tumor suppressor rapidly mounts a direct mitochondrial death program that precedes transcription-mediated apoptosis. By eliminating severely damaged cells, this pathway contributes to tumor suppression as well as to cancer cell killing induced by both genotoxic drugs and non-genotoxic p53-reactivating molecules. Here we have explored the role had in this pathway by the prolyl-isomerase Pin1 (peptidylprolyl cis/trans isomerase, NIMA-interacting 1), a crucial transducer of p53's phosphorylation into conformational changes unleashing its pro-apoptotic activity. We show that Pin1 promotes stress-induced localization of p53 to mitochondria both in vitro and in vivo. In particular, we demonstrate that upon stress-induced phosphorylation of p53 on Ser46 by homeodomain interacting protein kinase 2, Pin1 stimulates its mitochondrial trafficking signal, that is, monoubiquitination. This pathway is induced also by the p53-activating molecule RITA, and we demonstrate the strong requirement of Pin1 for the induction of mitochondrial apoptosis by this compound. These findings have significant implications for treatment of p53-expressing tumors and for prospective use of p53-activating compounds in clinics."
],
"offsets": [
[
76,
1346
]
]
}
] | [
{
"id": "22935610_T1",
"type": "CHEMICAL",
"text": [
"prolyl"
],
"offsets": [
[
507,
513
]
],
"normalized": []
},
{
"id": "22935610_T2",
"type": "CHEMICAL",
"text": [
"Ser"
],
"offsets": [
[
886,
889
]
],
"normalized": []
},
{
"id": "22935610_T3",
"type": "CHEMICAL",
"text": [
"prolyl"
],
"offsets": [
[
4,
10
]
],
"normalized": []
},
{
"id": "22935610_T4",
"type": "GENE-Y",
"text": [
"Pin1"
],
"offsets": [
[
1131,
1135
]
],
"normalized": []
},
{
"id": "22935610_T5",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
1261,
1264
]
],
"normalized": []
},
{
"id": "22935610_T6",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
1310,
1313
]
],
"normalized": []
},
{
"id": "22935610_T7",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
421,
424
]
],
"normalized": []
},
{
"id": "22935610_T8",
"type": "GENE-Y",
"text": [
"tumor protein p53"
],
"offsets": [
[
111,
128
]
],
"normalized": []
},
{
"id": "22935610_T9",
"type": "GENE-Y",
"text": [
"prolyl-isomerase Pin1"
],
"offsets": [
[
507,
528
]
],
"normalized": []
},
{
"id": "22935610_T10",
"type": "GENE-Y",
"text": [
"peptidylprolyl cis/trans isomerase, NIMA-interacting 1"
],
"offsets": [
[
530,
584
]
],
"normalized": []
},
{
"id": "22935610_T11",
"type": "GENE-Y",
"text": [
"p53's"
],
"offsets": [
[
611,
616
]
],
"normalized": []
},
{
"id": "22935610_T12",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
130,
133
]
],
"normalized": []
},
{
"id": "22935610_T13",
"type": "GENE-Y",
"text": [
"Pin1"
],
"offsets": [
[
713,
717
]
],
"normalized": []
},
{
"id": "22935610_T14",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
758,
761
]
],
"normalized": []
},
{
"id": "22935610_T15",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
879,
882
]
],
"normalized": []
},
{
"id": "22935610_T16",
"type": "GENE-Y",
"text": [
"homeodomain interacting protein kinase 2"
],
"offsets": [
[
895,
935
]
],
"normalized": []
},
{
"id": "22935610_T17",
"type": "GENE-Y",
"text": [
"Pin1"
],
"offsets": [
[
937,
941
]
],
"normalized": []
},
{
"id": "22935610_T18",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
1056,
1059
]
],
"normalized": []
},
{
"id": "22935610_T19",
"type": "GENE-Y",
"text": [
"prolyl-isomerase Pin1"
],
"offsets": [
[
4,
25
]
],
"normalized": []
},
{
"id": "22935610_T20",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
71,
74
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "22935610_0",
"type": "PART-OF",
"arg1_id": "22935610_T2",
"arg2_id": "22935610_T15",
"normalized": []
}
] |
23132743 | 23132743 | [
{
"id": "23132743_title",
"type": "title",
"text": [
"Ligand-dependent actions of the vitamin D receptor are required for activation of TGF-β signaling during the inflammatory response to cutaneous injury."
],
"offsets": [
[
0,
151
]
]
},
{
"id": "23132743_abstract",
"type": "abstract",
"text": [
"The vitamin D receptor (VDR) has both 1,25-dihydroxyvitamin D-dependent and -independent actions in the epidermis. Ligand-dependent actions of the VDR have been shown to promote keratinocyte differentiation and to regulate formation of the epidermal barrier. In contrast, the actions of the VDR that regulate postmorphogenic hair cycling do not require 1,25-dihydroxyvitamin D. The VDR also has immunomodulatory actions that are dependent on its ligand, 1,25-dihydroxyvitamin D. To determine whether the ligand-dependent or -independent actions of the VDR regulate the inflammatory response to cutaneous injury, studies were performed in control, VDR knockout, and vitamin D-deficient mice. These investigations demonstrate that absence of receptor or ligand impairs the dermal response to cutaneous injury. Although neutrophil recruitment is not affected, the absence of VDR signaling leads to defects in macrophage recruitment and granulation tissue formation. Studies performed to identify the molecular basis for this phenotype demonstrate that absence of the VDR, or its ligand, impairs TGF-β signaling in the dermis, characterized by decreased expression of monocyte chemotactic protein-1 and reduced phosphorylation of phosphorylated Smad-3 as well as attenuated phosphorylated Smad-3 phosphorylation in response to TGF-β in primary dermal fibroblasts lacking the VDR. Thus, these data demonstrate that the liganded VDR interacts with the TGF-β signaling pathway to promote the normal inflammatory response to cutaneous injury."
],
"offsets": [
[
152,
1686
]
]
}
] | [
{
"id": "23132743_T1",
"type": "CHEMICAL",
"text": [
"1,25-dihydroxyvitamin D"
],
"offsets": [
[
505,
528
]
],
"normalized": []
},
{
"id": "23132743_T2",
"type": "CHEMICAL",
"text": [
"1,25-dihydroxyvitamin D"
],
"offsets": [
[
190,
213
]
],
"normalized": []
},
{
"id": "23132743_T3",
"type": "CHEMICAL",
"text": [
"vitamin D"
],
"offsets": [
[
156,
165
]
],
"normalized": []
},
{
"id": "23132743_T4",
"type": "CHEMICAL",
"text": [
"1,25-dihydroxyvitamin D"
],
"offsets": [
[
606,
629
]
],
"normalized": []
},
{
"id": "23132743_T5",
"type": "CHEMICAL",
"text": [
"vitamin D"
],
"offsets": [
[
817,
826
]
],
"normalized": []
},
{
"id": "23132743_T6",
"type": "CHEMICAL",
"text": [
"vitamin D"
],
"offsets": [
[
32,
41
]
],
"normalized": []
},
{
"id": "23132743_T7",
"type": "GENE-Y",
"text": [
"VDR"
],
"offsets": [
[
1216,
1219
]
],
"normalized": []
},
{
"id": "23132743_T8",
"type": "GENE-Y",
"text": [
"TGF-β"
],
"offsets": [
[
1244,
1249
]
],
"normalized": []
},
{
"id": "23132743_T9",
"type": "GENE-Y",
"text": [
"monocyte chemotactic protein-1"
],
"offsets": [
[
1316,
1346
]
],
"normalized": []
},
{
"id": "23132743_T10",
"type": "GENE-Y",
"text": [
"phosphorylated Smad-3"
],
"offsets": [
[
1378,
1399
]
],
"normalized": []
},
{
"id": "23132743_T11",
"type": "GENE-Y",
"text": [
"phosphorylated Smad-3"
],
"offsets": [
[
1422,
1443
]
],
"normalized": []
},
{
"id": "23132743_T12",
"type": "GENE-Y",
"text": [
"TGF-β"
],
"offsets": [
[
1475,
1480
]
],
"normalized": []
},
{
"id": "23132743_T13",
"type": "GENE-Y",
"text": [
"VDR"
],
"offsets": [
[
1523,
1526
]
],
"normalized": []
},
{
"id": "23132743_T14",
"type": "GENE-Y",
"text": [
"VDR"
],
"offsets": [
[
1575,
1578
]
],
"normalized": []
},
{
"id": "23132743_T15",
"type": "GENE-Y",
"text": [
"TGF-β"
],
"offsets": [
[
1598,
1603
]
],
"normalized": []
},
{
"id": "23132743_T16",
"type": "GENE-Y",
"text": [
"VDR"
],
"offsets": [
[
299,
302
]
],
"normalized": []
},
{
"id": "23132743_T17",
"type": "GENE-Y",
"text": [
"VDR"
],
"offsets": [
[
176,
179
]
],
"normalized": []
},
{
"id": "23132743_T18",
"type": "GENE-Y",
"text": [
"VDR"
],
"offsets": [
[
443,
446
]
],
"normalized": []
},
{
"id": "23132743_T19",
"type": "GENE-Y",
"text": [
"VDR"
],
"offsets": [
[
534,
537
]
],
"normalized": []
},
{
"id": "23132743_T20",
"type": "GENE-Y",
"text": [
"vitamin D receptor"
],
"offsets": [
[
156,
174
]
],
"normalized": []
},
{
"id": "23132743_T21",
"type": "GENE-Y",
"text": [
"VDR"
],
"offsets": [
[
704,
707
]
],
"normalized": []
},
{
"id": "23132743_T22",
"type": "GENE-Y",
"text": [
"VDR"
],
"offsets": [
[
799,
802
]
],
"normalized": []
},
{
"id": "23132743_T23",
"type": "GENE-Y",
"text": [
"VDR"
],
"offsets": [
[
1024,
1027
]
],
"normalized": []
},
{
"id": "23132743_T24",
"type": "GENE-Y",
"text": [
"vitamin D receptor"
],
"offsets": [
[
32,
50
]
],
"normalized": []
},
{
"id": "23132743_T25",
"type": "GENE-Y",
"text": [
"TGF-β"
],
"offsets": [
[
82,
87
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23132743_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "23132743_T4",
"arg2_id": "23132743_T19",
"normalized": []
}
] |
6706930 | 6706930 | [
{
"id": "6706930_title",
"type": "title",
"text": [
"Mechanism of iodide-dependent catalatic activity of thyroid peroxidase and lactoperoxidase."
],
"offsets": [
[
0,
91
]
]
},
{
"id": "6706930_abstract",
"type": "abstract",
"text": [
"Mechanisms that have been proposed for peroxidase-catalyzed iodination require the utilization of 1 mol of H2O2 for organic binding of 1 mol of iodide. When we measured the stoichiometry of this reaction using thyroid peroxidase or lactoperoxidase at pH 7.0, we consistently obtained a ratio less than 1.0. This was shown to be attributable to catalase-like activity of these enzymes, resulting in unproductive cleavage of H2O2. This catalatic activity was completely iodide-dependent. To elucidate the mechanism of the iodide-dependent catalatic activity, the effects of various agents were investigated. The major observations may be summarized as follows: 1) The catalatic activity was inhibited in the presence of an iodine acceptor such as tyrosine. 2) The pseudohalide, SCN-, could not replace I- as a promoter of catalatic activity. 3) The inhibitory effects of the thioureylene drugs, methimazole and carbimazole, on the iodide-dependent catalatic activity were very similar to those reported previously for thyroid peroxidase-catalyzed iodination. 4) High concentrations of I- inhibited the catalatic activity of thyroid peroxidase and lactoperoxidase in a manner similar to that described previously for peroxidase-catalyzed iodination. On the basis of these observations and other findings, we have proposed a scheme which offers a possible explanation for iodide-dependent catalatic activity of thyroid peroxidase and lactoperoxidase. Compound I of the peroxidases is represented as EO, and oxidation of I- by EO is postulated to form enzyme-bound hypoiodite, represented in our scheme as [EOI]-. We suggest that the latter can react with H2O2 in a catalase-like reaction, with evolution of O2. We postulate further that the same form of oxidized iodine is also involved in iodination of tyrosine, oxidation of thioureylene drugs, and oxidation of I-, and that inhibition of catalatic activity by these agents occurs through competition with H2O2 for oxidized iodine."
],
"offsets": [
[
92,
2071
]
]
}
] | [
{
"id": "6706930_T1",
"type": "CHEMICAL",
"text": [
"H2O2"
],
"offsets": [
[
199,
203
]
],
"normalized": []
},
{
"id": "6706930_T2",
"type": "CHEMICAL",
"text": [
"I-"
],
"offsets": [
[
1175,
1177
]
],
"normalized": []
},
{
"id": "6706930_T3",
"type": "CHEMICAL",
"text": [
"iodide"
],
"offsets": [
[
1460,
1466
]
],
"normalized": []
},
{
"id": "6706930_T4",
"type": "CHEMICAL",
"text": [
"iodide"
],
"offsets": [
[
236,
242
]
],
"normalized": []
},
{
"id": "6706930_T5",
"type": "CHEMICAL",
"text": [
"H2O2"
],
"offsets": [
[
1743,
1747
]
],
"normalized": []
},
{
"id": "6706930_T6",
"type": "CHEMICAL",
"text": [
"O2"
],
"offsets": [
[
1795,
1797
]
],
"normalized": []
},
{
"id": "6706930_T7",
"type": "CHEMICAL",
"text": [
"iodine"
],
"offsets": [
[
1851,
1857
]
],
"normalized": []
},
{
"id": "6706930_T8",
"type": "CHEMICAL",
"text": [
"tyrosine"
],
"offsets": [
[
1892,
1900
]
],
"normalized": []
},
{
"id": "6706930_T9",
"type": "CHEMICAL",
"text": [
"thioureylene"
],
"offsets": [
[
1915,
1927
]
],
"normalized": []
},
{
"id": "6706930_T10",
"type": "CHEMICAL",
"text": [
"I-"
],
"offsets": [
[
1952,
1954
]
],
"normalized": []
},
{
"id": "6706930_T11",
"type": "CHEMICAL",
"text": [
"H2O2"
],
"offsets": [
[
2046,
2050
]
],
"normalized": []
},
{
"id": "6706930_T12",
"type": "CHEMICAL",
"text": [
"iodine"
],
"offsets": [
[
2064,
2070
]
],
"normalized": []
},
{
"id": "6706930_T13",
"type": "CHEMICAL",
"text": [
"H2O2"
],
"offsets": [
[
515,
519
]
],
"normalized": []
},
{
"id": "6706930_T14",
"type": "CHEMICAL",
"text": [
"iodide"
],
"offsets": [
[
560,
566
]
],
"normalized": []
},
{
"id": "6706930_T15",
"type": "CHEMICAL",
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612,
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813,
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837,
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854,
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892,
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1001,
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1021,
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302,
320
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324,
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131,
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52,
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75,
90
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}
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}
] |
23265880 | 23265880 | [
{
"id": "23265880_title",
"type": "title",
"text": [
"A new single-photon emission computed tomography (SPECT) imaging agent for serotonin transporters: [(125)I]Flip-IDAM, (2-((2-((dimethylamino)methyl)-4-iodophenyl)thio)phenyl)methanol."
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0,
183
]
]
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{
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"text": [
"New ligands for in vivo brain imaging of serotonin transporter (SERT) with single photon emission tomography (SPECT) were prepared and evaluated. An efficient synthesis and radiolabeling of a biphenylthiol, FLIP-IDAM, 4, was accomplished. The affinity of FLIP-IDAM was evaluated by an in vitro inhibitory binding assay using [(125)I]-IDAM as radioligand in rat brain tissue homogenates (K(i) = 0.03 nM). New [(125)I]Flip-IDAM exhibited excellent binding affinity to SERT binding sites with a high hypothalamus to cerebellum ratio of 4 at 30 min post iv injection. The faster in vivo kinetics for brain uptake and a rapid washout from non-specific regions provide excellent signal to noise ratio. This new agent, when labeled with (123)I, may be a useful imaging agent for mapping SERT binding sites in the human brain."
],
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[
184,
1002
]
]
}
] | [
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376,
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]
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225,
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]
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914,
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75,
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]
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225,
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]
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"SERT"
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]
],
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},
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248,
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]
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]
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"id": "23265880_T15",
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],
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75,
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]
],
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}
] | [] | [] | [
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"arg2_id": "23265880_T15",
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}
] |
17434872 | 17434872 | [
{
"id": "17434872_title",
"type": "title",
"text": [
"Molecular determinants for the selective inhibition of cyclooxygenase-2 by lumiracoxib."
],
"offsets": [
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0,
87
]
]
},
{
"id": "17434872_abstract",
"type": "abstract",
"text": [
"Lumiracoxib is the first example of a marketed COX-2 inhibitor of the arylacetic acid class, and it is reported to be the most selective COXIB in vivo. However, the molecular basis of its COX-2 inhibition has not been completely defined. Using standard assays, lumiracoxib was found to be a poor inhibitor of purified ovine COX-1 and a relatively weak inhibitor of purified human COX-2. The extent of COX-2 inhibition plateaued at around 50% and suggested that the inhibitor may be reversibly bound to the enzyme. Kinetic studies with lumiracoxib demonstrated that it was a time-dependent and slowly reversible inhibitor of human COX-2 that exhibited at least two binding steps during inhibition. Derivatives of lumiracoxib were synthesized with or without the methyl group on the phenylacetic acid ring and with various substitutions on the lower aniline ring. Inhibition studies demonstrated that the methyl group on the phenylacetic acid ring is required for COX-2 selectivity. The chemical identity and position of the substituents on the lower aniline ring were important in determining the potency and extent of COX inhibition as well as COX-2 selectivity. Mutation of Ser-530 to Ala or Val-349 to Ala or Leu abolished the potent inhibition observed with wild-type human COX-2 and key lumiracoxib analogs. Interestingly, a Val-349 to Ile mutant was inhibited with equal potency to human COX-2 with 2,6-dichloro-, 2,6-dimethyl-, or 2-chloro-6-methyl-substituted inhibitors and, in the case of lumiracoxib, actually showed an increase in potency. Taken together with a recent crystal structure of a lumiracoxib-COX-2 complex, the kinetic analyses presented herein of the inhibition of mutant COX-2s by lumiracoxib allows the definition of the molecular basis of COX-2 inhibition."
],
"offsets": [
[
88,
1871
]
]
}
] | [
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],
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88,
99
]
],
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1137,
1144
]
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"Ser"
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1263,
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]
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"Ala"
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1274,
1277
]
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},
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"Val"
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1281,
1284
]
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"id": "17434872_T6",
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"Ala"
],
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1292,
1295
]
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"id": "17434872_T7",
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"Leu"
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1299,
1302
]
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"id": "17434872_T8",
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"lumiracoxib"
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1379,
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]
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"Val"
],
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1417,
1420
]
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},
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"id": "17434872_T10",
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"2,6-dichloro"
],
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[
1492,
1504
]
],
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},
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"id": "17434872_T11",
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"2,6-dimethyl"
],
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[
1507,
1519
]
],
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},
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"id": "17434872_T12",
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"2-chloro-6-methyl"
],
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1525,
1542
]
],
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"lumiracoxib"
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1586,
1597
]
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"lumiracoxib"
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1691,
1702
]
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"lumiracoxib"
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1794,
1805
]
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"lumiracoxib"
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349,
360
]
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"lumiracoxib"
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623,
634
]
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"arylacetic acid"
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158,
173
]
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"lumiracoxib"
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800,
811
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"methyl"
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849,
855
]
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"phenylacetic acid"
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[
869,
886
]
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"id": "17434872_T22",
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"aniline"
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[
936,
943
]
],
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"id": "17434872_T23",
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"text": [
"methyl"
],
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[
991,
997
]
],
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},
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"id": "17434872_T24",
"type": "CHEMICAL",
"text": [
"phenylacetic acid"
],
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[
1011,
1028
]
],
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"id": "17434872_T25",
"type": "CHEMICAL",
"text": [
"lumiracoxib"
],
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[
75,
86
]
],
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},
{
"id": "17434872_T26",
"type": "GENE-N",
"text": [
"COX"
],
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[
1206,
1209
]
],
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},
{
"id": "17434872_T27",
"type": "GENE-Y",
"text": [
"COX-2"
],
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[
1232,
1237
]
],
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},
{
"id": "17434872_T28",
"type": "GENE-N",
"text": [
"Ser-530 to Ala"
],
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[
1263,
1277
]
],
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},
{
"id": "17434872_T29",
"type": "GENE-N",
"text": [
"Val-349 to Ala or Leu"
],
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[
1281,
1302
]
],
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},
{
"id": "17434872_T30",
"type": "GENE-Y",
"text": [
"human COX-2"
],
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[
1359,
1370
]
],
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},
{
"id": "17434872_T31",
"type": "GENE-N",
"text": [
"Val-349 to Ile"
],
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[
1417,
1431
]
],
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},
{
"id": "17434872_T32",
"type": "GENE-Y",
"text": [
"human COX-2"
],
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[
1475,
1486
]
],
"normalized": []
},
{
"id": "17434872_T33",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
1703,
1708
]
],
"normalized": []
},
{
"id": "17434872_T34",
"type": "GENE-Y",
"text": [
"COX-2s"
],
"offsets": [
[
1784,
1790
]
],
"normalized": []
},
{
"id": "17434872_T35",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
1854,
1859
]
],
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},
{
"id": "17434872_T36",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
276,
281
]
],
"normalized": []
},
{
"id": "17434872_T37",
"type": "GENE-Y",
"text": [
"ovine COX-1"
],
"offsets": [
[
406,
417
]
],
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},
{
"id": "17434872_T38",
"type": "GENE-Y",
"text": [
"human COX-2"
],
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[
462,
473
]
],
"normalized": []
},
{
"id": "17434872_T39",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
489,
494
]
],
"normalized": []
},
{
"id": "17434872_T40",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
135,
140
]
],
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},
{
"id": "17434872_T41",
"type": "GENE-Y",
"text": [
"human COX-2"
],
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[
712,
723
]
],
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},
{
"id": "17434872_T42",
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] |
23602989 | 23602989 | [
{
"id": "23602989_title",
"type": "title",
"text": [
"Presynaptic CaMKIIα modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a Ca(2+) dependent manner."
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0,
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"CaMKIIα is expressed at high density in the nucleus accumbens where it binds to postsynaptic D3 receptors inhibiting their effects. In striatonigral projections, activation of presynaptic D3 receptors potentiates D1 receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by Ca(2+) activation of CaMKIIα. In SNr synaptosomes two procedures that increase cytoplasmic Ca(2+), ionomycin and K(+)-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and D1 dopamine receptors. The selective CaMKIIα inhibitor KN-62 reversed the blockade produced by ionomycin and K(+)-depolarization. Incubation in either Ca(2) -free solutions or with the selective Ca(2+) blocker nifedipine, also reversed the blocking effects of K(+)-depolarization. Immunoblot studies showed that K(+)-depolarization increased CaMKIIα phosphorylation in a KN-62 sensitive manner and promoted CaMKIIα binding to D3 receptors. In K(+)-depolarized tissues, D3 receptors potentiated D1 receptor-induced stimulation of [(3)H]GABA release only when CaMKIIα was blocked with KN-62. In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED50 for the D1 agonist SKF 38393 from 56 to 4 nM. KN-62 also enhanced the effects of dopamine on depolarization induced [(3)H]GABA release. KN-62 changed ED50 for dopamine from 584 to 56 nM. KN-62 did not affect D1 and D4 receptor responses. These experiments show that in striatonigral projections, CaMKIIα inhibits the action of D3 receptors in a Ca(2+) dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects."
],
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136,
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"KN-62"
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]
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"K(+)"
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1226,
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"[(3)H]GABA"
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"id": "23602989_T4",
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"KN-62"
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1366,
1371
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"PD 128,907"
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"SKF 38393"
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1542,
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"KN-62"
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2009,
2017
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"Ca(2+)"
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"nifedipine"
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30,
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]
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"CaMKIIα"
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136,
143
]
],
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"CaMKIIα"
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1190,
1197
]
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"id": "23602989_T34",
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"D3 receptors"
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1209,
1221
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"D3 receptors"
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1252,
1264
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"D1 receptor"
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1277,
1288
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"CaMKIIα"
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1341,
1348
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1422,
1424
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"D1"
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1469,
1471
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"D1 and D4 receptor"
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[
1669,
1687
]
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"CaMKIIα"
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1757,
1764
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"D3 receptors"
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1788,
1800
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"D3 receptors"
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324,
336
]
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"D1 receptor"
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349,
360
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"D3 receptor"
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479,
490
]
],
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"id": "23602989_T46",
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"CaMKIIα"
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[
582,
589
]
],
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},
{
"id": "23602989_T47",
"type": "GENE-N",
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"D3 and D1 dopamine receptors"
],
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[
776,
804
]
],
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"CaMKIIα"
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820,
827
]
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},
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"id": "23602989_T49",
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"D3 receptors"
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229,
241
]
],
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},
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"id": "23602989_T50",
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"CaMKIIα"
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[
1125,
1132
]
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"CaMKIIα"
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12,
19
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],
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},
{
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"text": [
"dopamine D3 receptor"
],
"offsets": [
[
30,
50
]
],
"normalized": []
}
] | [] | [] | [
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] |
9079657 | 9079657 | [
{
"id": "9079657_title",
"type": "title",
"text": [
"Activation-dependent exposure of the inter-EGF sequence Leu83-Leu88 in factor Xa mediates ligand binding to effector cell protease receptor-1."
],
"offsets": [
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0,
142
]
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},
{
"id": "9079657_abstract",
"type": "abstract",
"text": [
"Binding of factor Xa to human umbilical vein endothelial cells (HUVEC) is contributed by effector cell protease receptor-1 (EPR-1). The structural requirements of this recognition were investigated. Factor Xa or catalytically inactive 5-dimethylaminonaphthalene-1sulfonyl (dansyl) Glu-Gly-Arg-(DEGR)-chloromethylketone-factor Xa bound indistinguishably to HUVEC and EPR-1 transfectants, and inhibited equally well the binding of 125I-factor Xa to these cells. Similarly, factor Xa active site inhibitors TAP or NAP5 did not reduce ligand binding to EPR-1. A factor X peptide duplicating the inter-EGF sequence Leu83-Phe84-Thr85-Arg86-Lys87-Leu88- (Gly) inhibited factor V/Va-independent prothrombin activation by HUVEC and blocked binding of 125I-factor Xa to these cells in a dose-dependent manner (IC50 approximately 20-40 microM). In contrast, none of the other factor X peptides tested or a control peptide with the inter-EGF sequence in scrambled order was effective. A recombinant chimeric molecule expressing the factor X sequence Leu83-Leu88 within a factor IX backbone inhibited binding of 125I-factor Xa to HUVEC and EPR-1 transfectants in a dose-dependent fashion, while recombinant factor IX or plasma IXa had no effect. An antibody generated against the factor X peptide 83-88, and designated JC15, inhibited 125I-factor Xa binding to HUVEC. The JC15 antibody bound to factor Xa and the recombinant IX/X83-88 chimera in a concentration dependent manner, while no specific reactivity with factors X or IXa was observed. Furthermore, binding of 125I-factor Xa to immobilized JC15 was inhibited by molar excess of unlabeled factor Xa, but not by comparable concentrations of factors X or IXa. These findings identify the inter-EGF sequence Leu83-Leu88 in factor Xa as a novel recognition site for EPR-1, and suggest its potential role as a protease activation-dependent neo-epitope. This interacting motif may help elucidate the contribution of factor Xa to cellular assembly of coagulation and vascular injury."
],
"offsets": [
[
143,
2164
]
]
}
] | [
{
"id": "9079657_T1",
"type": "CHEMICAL",
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"125I"
],
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[
1242,
1246
]
],
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},
{
"id": "9079657_T2",
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"125I"
],
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[
1699,
1703
]
],
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},
{
"id": "9079657_T3",
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"5-dimethylaminonaphthalene-1sulfonyl (dansyl) Glu-Gly-Arg-(DEGR)-chloromethylketone"
],
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378,
461
]
],
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},
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"id": "9079657_T4",
"type": "CHEMICAL",
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"Gly"
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[
791,
794
]
],
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},
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"id": "9079657_T5",
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"125I"
],
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[
885,
889
]
],
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},
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"id": "9079657_T6",
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"factor X"
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1163,
1171
]
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},
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"id": "9079657_T7",
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"Leu83-Leu88"
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1181,
1192
]
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"id": "9079657_T8",
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"factor IX"
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1202,
1211
]
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"id": "9079657_T9",
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"factor Xa"
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1247,
1256
]
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},
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"id": "9079657_T10",
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"factor Xa"
],
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[
154,
163
]
],
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},
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"id": "9079657_T11",
"type": "GENE-Y",
"text": [
"EPR-1"
],
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[
1270,
1275
]
],
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},
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"id": "9079657_T12",
"type": "GENE-Y",
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"factor IX"
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1337,
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{
"id": "9079657_T13",
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"IXa"
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1357,
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"id": "9079657_T14",
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"EPR-1"
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267,
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1410,
1418
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1479
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1525,
1534
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1644,
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1704,
1713
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1777,
1786
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1828,
1844
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"id": "9079657_T22",
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"inter-EGF sequence"
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1874,
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},
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"id": "9079657_T23",
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"Leu83-Leu88"
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1893,
1904
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"factor Xa"
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1908,
1917
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"EPR-1"
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1950,
1955
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"factor Xa"
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2098,
2107
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342,
351
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462,
471
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"EPR-1"
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509,
514
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"factor Xa"
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577,
586
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"factor Xa"
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614,
623
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"EPR-1"
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692,
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"factor X"
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701,
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734,
752
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},
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"Leu83-Phe84-Thr85-Arg86-Lys87-Leu88- (Gly)"
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753,
795
]
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"normalized": []
},
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"factor V/Va"
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806,
817
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"prothrombin"
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830,
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890,
899
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"factor X"
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1008,
1016
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"effector cell protease receptor-1"
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232,
265
]
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"inter-EGF sequence"
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1063,
1081
]
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"normalized": []
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"type": "GENE-Y",
"text": [
"effector cell protease receptor-1"
],
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108,
141
]
],
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"id": "9079657_T43",
"type": "GENE-N",
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"inter-EGF sequence"
],
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37,
55
]
],
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},
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"id": "9079657_T44",
"type": "GENE-N",
"text": [
"Leu83-Leu88"
],
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[
56,
67
]
],
"normalized": []
},
{
"id": "9079657_T45",
"type": "GENE-Y",
"text": [
"factor Xa"
],
"offsets": [
[
71,
80
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "9079657_0",
"type": "PART-OF",
"arg1_id": "9079657_T4",
"arg2_id": "9079657_T33",
"normalized": []
}
] |
18568240 | 18568240 | [
{
"id": "18568240_title",
"type": "title",
"text": [
"Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition."
],
"offsets": [
[
0,
138
]
]
},
{
"id": "18568240_abstract",
"type": "abstract",
"text": [
"OBJECTIVE: The objective of this study was to determine the effect of nonspecific phosphodiesterase inhibition on transcription factor activation and tumor necrosis factor-alpha (TNF-alpha) production in lipopolysaccharide (LPS)-stimulated human mononuclear cells. INTRODUCTION: The production of TNF-alpha following LPS stimulation is one of the key steps in bacterial sepsis and inflammation. The mechanism by which phosphodiesterase inhibition alters TNF-alpha production in the presence of LPS remains unclear. METHODS: Human mononuclear cells were stimulated with LPS (1 microg/mL), in the presence and absence of Pentoxifylline (PTX; 20 mM), a nonspecific phosphodiesterase inhibitor. Western blotting of phosphorylated cytoplasmic I-kBalpha, nuclear factor-kB p65 (NF-kB), and nuclear cAMP-response element binding protein (CREB) was performed. DNA binding of NF-kB and CREB was verified by electrophoretic mobility shift assay. TNF-a levels were determined in the supernatant of stimulated cells in the presence and absence Protein kinase A inhibition by an enzyme-linked immunosorbent assay (ELISA). RESULTS: PTX was demonstrated to significantly reduce cytoplasmic I-kBalpha phosphorylation, nuclear p65 phosphorylation, and the DNA binding activity of NF-kB. In contrast, PTX markedly enhanced the phosphorylation and DNA binding activity of CREB. Cells concomitantly treated with PTX and LPS secreted similar levels of TNF-a in the presence and absence Protein kinase A inhibition. DISCUSSION: The increased level of cAMP that results from phosphodiesterase inhibition affects cytoplasmic and nuclear events, resulting in the attenuation of NF-kB and the activation of CREB transcriptional DNA binding through pathways that are partially Protein kinase A-independent. CONCLUSION: PTX-mediated phosphodiesterase inhibition occurs partially through a Protein kinase A-independent pathway and may serve as a useful tool in the attenuation of LPS-induced inflammation."
],
"offsets": [
[
139,
2115
]
]
}
] | [
{
"id": "18568240_T1",
"type": "CHEMICAL",
"text": [
"PTX"
],
"offsets": [
[
1257,
1260
]
],
"normalized": []
},
{
"id": "18568240_T2",
"type": "CHEMICAL",
"text": [
"PTX"
],
"offsets": [
[
1422,
1425
]
],
"normalized": []
},
{
"id": "18568240_T3",
"type": "CHEMICAL",
"text": [
"PTX"
],
"offsets": [
[
1531,
1534
]
],
"normalized": []
},
{
"id": "18568240_T4",
"type": "CHEMICAL",
"text": [
"cAMP"
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1668,
1672
]
],
"normalized": []
},
{
"id": "18568240_T5",
"type": "CHEMICAL",
"text": [
"PTX"
],
"offsets": [
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1931,
1934
]
],
"normalized": []
},
{
"id": "18568240_T6",
"type": "CHEMICAL",
"text": [
"Pentoxifylline"
],
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[
758,
772
]
],
"normalized": []
},
{
"id": "18568240_T7",
"type": "CHEMICAL",
"text": [
"PTX"
],
"offsets": [
[
774,
777
]
],
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},
{
"id": "18568240_T8",
"type": "CHEMICAL",
"text": [
"cAMP"
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931,
935
]
],
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},
{
"id": "18568240_T9",
"type": "GENE-N",
"text": [
"Protein kinase A"
],
"offsets": [
[
1171,
1187
]
],
"normalized": []
},
{
"id": "18568240_T10",
"type": "GENE-Y",
"text": [
"I-kBalpha"
],
"offsets": [
[
1314,
1323
]
],
"normalized": []
},
{
"id": "18568240_T11",
"type": "GENE-Y",
"text": [
"p65"
],
"offsets": [
[
1349,
1352
]
],
"normalized": []
},
{
"id": "18568240_T12",
"type": "GENE-N",
"text": [
"NF-kB"
],
"offsets": [
[
1402,
1407
]
],
"normalized": []
},
{
"id": "18568240_T13",
"type": "GENE-N",
"text": [
"CREB"
],
"offsets": [
[
1492,
1496
]
],
"normalized": []
},
{
"id": "18568240_T14",
"type": "GENE-Y",
"text": [
"TNF-a"
],
"offsets": [
[
1570,
1575
]
],
"normalized": []
},
{
"id": "18568240_T15",
"type": "GENE-N",
"text": [
"Protein kinase A"
],
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[
1604,
1620
]
],
"normalized": []
},
{
"id": "18568240_T16",
"type": "GENE-Y",
"text": [
"tumor necrosis factor-alpha"
],
"offsets": [
[
289,
316
]
],
"normalized": []
},
{
"id": "18568240_T17",
"type": "GENE-N",
"text": [
"phosphodiesterase"
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[
1691,
1708
]
],
"normalized": []
},
{
"id": "18568240_T18",
"type": "GENE-N",
"text": [
"NF-kB"
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1792,
1797
]
],
"normalized": []
},
{
"id": "18568240_T19",
"type": "GENE-N",
"text": [
"CREB"
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1820,
1824
]
],
"normalized": []
},
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"id": "18568240_T20",
"type": "GENE-N",
"text": [
"Protein kinase A"
],
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[
1889,
1905
]
],
"normalized": []
},
{
"id": "18568240_T21",
"type": "GENE-Y",
"text": [
"TNF-alpha"
],
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[
318,
327
]
],
"normalized": []
},
{
"id": "18568240_T22",
"type": "GENE-N",
"text": [
"phosphodiesterase"
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1944,
1961
]
],
"normalized": []
},
{
"id": "18568240_T23",
"type": "GENE-N",
"text": [
"Protein kinase A"
],
"offsets": [
[
2000,
2016
]
],
"normalized": []
},
{
"id": "18568240_T24",
"type": "GENE-Y",
"text": [
"TNF-alpha"
],
"offsets": [
[
436,
445
]
],
"normalized": []
},
{
"id": "18568240_T25",
"type": "GENE-Y",
"text": [
"TNF-alpha"
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"offsets": [
[
593,
602
]
],
"normalized": []
},
{
"id": "18568240_T26",
"type": "GENE-N",
"text": [
"phosphodiesterase"
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"offsets": [
[
801,
818
]
],
"normalized": []
},
{
"id": "18568240_T27",
"type": "GENE-Y",
"text": [
"I-kBalpha"
],
"offsets": [
[
877,
886
]
],
"normalized": []
},
{
"id": "18568240_T28",
"type": "GENE-N",
"text": [
"nuclear factor-kB"
],
"offsets": [
[
888,
905
]
],
"normalized": []
},
{
"id": "18568240_T29",
"type": "GENE-Y",
"text": [
"p65"
],
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[
906,
909
]
],
"normalized": []
},
{
"id": "18568240_T30",
"type": "GENE-N",
"text": [
"NF-kB"
],
"offsets": [
[
911,
916
]
],
"normalized": []
},
{
"id": "18568240_T31",
"type": "GENE-N",
"text": [
"cAMP-response element binding protein"
],
"offsets": [
[
931,
968
]
],
"normalized": []
},
{
"id": "18568240_T32",
"type": "GENE-N",
"text": [
"CREB"
],
"offsets": [
[
970,
974
]
],
"normalized": []
},
{
"id": "18568240_T33",
"type": "GENE-N",
"text": [
"NF-kB"
],
"offsets": [
[
1006,
1011
]
],
"normalized": []
},
{
"id": "18568240_T34",
"type": "GENE-N",
"text": [
"CREB"
],
"offsets": [
[
1016,
1020
]
],
"normalized": []
},
{
"id": "18568240_T35",
"type": "GENE-Y",
"text": [
"TNF-a"
],
"offsets": [
[
1075,
1080
]
],
"normalized": []
},
{
"id": "18568240_T36",
"type": "GENE-N",
"text": [
"phosphodiesterase"
],
"offsets": [
[
109,
126
]
],
"normalized": []
},
{
"id": "18568240_T37",
"type": "GENE-Y",
"text": [
"TNF-alpha"
],
"offsets": [
[
32,
41
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "18568240_0",
"type": "INHIBITOR",
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"arg2_id": "18568240_T26",
"normalized": []
},
{
"id": "18568240_1",
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},
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"id": "18568240_2",
"type": "INHIBITOR",
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"arg1_id": "18568240_T1",
"arg2_id": "18568240_T11",
"normalized": []
},
{
"id": "18568240_4",
"type": "INHIBITOR",
"arg1_id": "18568240_T1",
"arg2_id": "18568240_T12",
"normalized": []
},
{
"id": "18568240_5",
"type": "ACTIVATOR",
"arg1_id": "18568240_T2",
"arg2_id": "18568240_T13",
"normalized": []
},
{
"id": "18568240_6",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "18568240_T3",
"arg2_id": "18568240_T14",
"normalized": []
},
{
"id": "18568240_7",
"type": "SUBSTRATE",
"arg1_id": "18568240_T4",
"arg2_id": "18568240_T17",
"normalized": []
},
{
"id": "18568240_8",
"type": "INHIBITOR",
"arg1_id": "18568240_T4",
"arg2_id": "18568240_T18",
"normalized": []
},
{
"id": "18568240_9",
"type": "ACTIVATOR",
"arg1_id": "18568240_T4",
"arg2_id": "18568240_T19",
"normalized": []
},
{
"id": "18568240_10",
"type": "INHIBITOR",
"arg1_id": "18568240_T5",
"arg2_id": "18568240_T22",
"normalized": []
}
] |
16530878 | 16530878 | [
{
"id": "16530878_title",
"type": "title",
"text": [
"Direct molecular and spectroscopic evidence for increased ammonia removal capacity of skeletal muscle in acute liver failure."
],
"offsets": [
[
0,
125
]
]
},
{
"id": "16530878_abstract",
"type": "abstract",
"text": [
"BACKGROUND/AIMS: It has been proposed that, in acute liver failure, skeletal muscle adapts to become the principle organ responsible for removal of blood-borne ammonia by increasing glutamine synthesis, a reaction that is catalyzed by the cytosolic ATP-dependent enzyme glutamine synthetase. To address this issue, glutamine synthetase expression and activities were measured in skeletal muscle of rats with acute liver failure resulting from hepatic devascularization. METHODS: Glutamine synthetase protein and gene expression were investigated using immunoblotting and semi-quantitative RT-PCR analysis. Glutamine synthetase activity and glutamine de novo synthesis were measured using, respectively, a standard enzymatic assay and [13C]-nuclear magnetic resonance spectroscopy. RESULTS: Glutamine synthetase protein (but not gene) expression and enzyme activities were significantly up-regulated leading to increased de novo synthesis of glutamine and increased skeletal muscle capacity for ammonia removal in acute liver failure. In contrast to skeletal muscle, expression and activities of glutamine synthetase in the brain were significantly decreased. CONCLUSIONS: These findings demonstrate that skeletal muscle adapts, through a rapid induction of glutamine synthetase, to increase its capacity for removal of blood-borne ammonia in acute liver failure. Maintenance of muscle mass together with the development of agents with the capacity to stimulate muscle glutamine synthetase could provide effective ammonia-lowering strategies in this disorder."
],
"offsets": [
[
126,
1684
]
]
}
] | [
{
"id": "16530878_T1",
"type": "CHEMICAL",
"text": [
"glutamine"
],
"offsets": [
[
1221,
1230
]
],
"normalized": []
},
{
"id": "16530878_T2",
"type": "CHEMICAL",
"text": [
"glutamine"
],
"offsets": [
[
1383,
1392
]
],
"normalized": []
},
{
"id": "16530878_T3",
"type": "CHEMICAL",
"text": [
"ammonia"
],
"offsets": [
[
1457,
1464
]
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},
{
"id": "16530878_T4",
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"glutamine"
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1594,
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"id": "16530878_T5",
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"ammonia"
],
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1639,
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]
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{
"id": "16530878_T6",
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"ammonia"
],
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286,
293
]
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308,
317
]
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"id": "16530878_T8",
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"ATP"
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375,
378
]
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"id": "16530878_T9",
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"glutamine"
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396,
405
]
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"id": "16530878_T10",
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"glutamine"
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441,
450
]
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{
"id": "16530878_T11",
"type": "CHEMICAL",
"text": [
"Glutamine"
],
"offsets": [
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605,
614
]
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},
{
"id": "16530878_T12",
"type": "CHEMICAL",
"text": [
"Glutamine"
],
"offsets": [
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732,
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"Atomoxetine (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). Atomoxetine is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US. Atomoxetine is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in children and adolescents. The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex. Atomoxetine has a high affinity and selectivity for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors. Atomoxetine has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem. Atomoxetine was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected height and weight among atomoxetine recipients, this eventually returned to normal in the longer term. Data suggest that atomoxetine is unlikely to have any abuse potential. Atomoxetine appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD. Atomoxetine is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP) 2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination of atomoxetine than extensive metabolizers. Patients with hepatic insufficiency show an increase in atomoxetine exposure. CYP2D6 inhibitors, such as paroxetine, are associated with changes in atomoxetine pharmacokinetics similar to those observed among poor CYP2D6 metabolizers. Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials. Atomoxetine also demonstrated efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound. Atomoxetine efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded well to atomoxetine treatment. Atomoxetine did not differ significantly from or was noninferior to immediate-release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment). However, atomoxetine was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts. The efficacy of atomoxetine did not appear to be affected by the presence of co-morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration. Health-related quality of life (HR-QOL) appeared to be positively affected by atomoxetine in both short- and long-term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy. Atomoxetine was generally well tolerated in children and adolescents with ADHD. Common adverse events included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients discontinued atomoxetine treatment because of adverse events. Atomoxetine discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events. Atomoxetine appeared better tolerated among extensive CYP2D6 metabolizers than among poor metabolizers. Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both immediate- and extended-release. Somnolence appeared more common among atomoxetine recipients and insomnia appeared more common among stimulant recipients. A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of suicidal ideation than placebo. Rarely, atomoxetine may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to atomoxetine treatment. Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as shown in several Markov model analyses conducted from the perspective of various European countries, with a time horizon of 1 year."
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23348514 | 23348514 | [
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"id": "23348514_abstract",
"type": "abstract",
"text": [
"Severe burn injury causes hepatic dysfunction that results in major metabolic derangements including insulin resistance and hyperglycemia and is associated with hepatic endoplasmic reticulum (ER) stress. We have recently shown that insulin reduces ER stress and improves liver function and morphology; however, it is not clear whether these changes are directly insulin mediated or are due to glucose alterations. Metformin is an antidiabetic agent that decreases hyperglycemia by different pathways than insulin; therefore, we asked whether metformin affects postburn ER stress and hepatic metabolism. The aim of the present study is to determine the effects of metformin on postburn hepatic ER stress and metabolic markers. Male rats were randomized to sham, burn injury and burn injury plus metformin and were sacrificed at various time points. Outcomes measured were hepatic damage, function, metabolism and ER stress. Burn-induced decrease in albumin mRNA and increase in alanine transaminase (p < 0.01 versus sham) were not normalized by metformin treatment. In addition, ER stress markers were similarly increased in burn injury with or without metformin compared with sham (p < 0.05). We also found that gluconeogenesis and fatty acid metabolism gene expressions were upregulated with or without metformin compared with sham (p < 0.05). Our results indicate that, whereas thermal injury results in hepatic ER stress, metformin does not ameliorate postburn stress responses by correcting hepatic ER stress."
],
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88,
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}
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"metformin"
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"metformin"
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"fatty acid"
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"id": "23348514_T6",
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"glucose"
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481,
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"id": "23348514_T7",
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"Metformin"
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502,
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"id": "23348514_T8",
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"metformin"
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630,
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"id": "23348514_T9",
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"metformin"
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751,
760
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"type": "CHEMICAL",
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"metformin"
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882,
891
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"id": "23348514_T11",
"type": "CHEMICAL",
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"alanine"
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1065,
1072
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"id": "23348514_T12",
"type": "CHEMICAL",
"text": [
"metformin"
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11,
20
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"id": "23348514_T13",
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"text": [
"insulin"
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189,
196
]
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"id": "23348514_T14",
"type": "GENE-Y",
"text": [
"insulin"
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320,
327
]
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"id": "23348514_T15",
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"insulin"
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450,
457
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"id": "23348514_T16",
"type": "GENE-Y",
"text": [
"insulin"
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[
593,
600
]
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},
{
"id": "23348514_T17",
"type": "GENE-Y",
"text": [
"albumin"
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1036,
1043
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},
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"id": "23348514_T18",
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"text": [
"alanine transaminase"
],
"offsets": [
[
1065,
1085
]
],
"normalized": []
}
] | [] | [] | [] |
17273750 | 17273750 | [
{
"id": "17273750_title",
"type": "title",
"text": [
"Cimetidine induces apoptosis of human salivary gland tumor cells."
],
"offsets": [
[
0,
65
]
]
},
{
"id": "17273750_abstract",
"type": "abstract",
"text": [
"It has been reported that cimetidine, a histamine type-2 receptor (H2R) antagonist, inhibits the growth of glandular tumors such as colorectal cancer. However, its effects against salivary gland tumors are still unknown. We demonstrated previously that human salivary gland tumor (HSG) cells spontaneously express the neural cell adhesion molecule (NCAM) and also that HSG cell proliferation could be controlled via a homophilic (NCAM-NCAM) binding mechanism and that NCAM may be associated with perineural invasion by malignant salivary gland tumors. In the present study, we investigated the effects of cimetidine via the expression of NCAM on tumor growth and perineural/neural invasion in salivary gland tumor cells. Expression of both NCAM mRNA and protein was found to decrease in a dose-dependent manner upon treatment with cimetidine for 24 h. The MTT assay and confocal laser microscopy clearly showed that HSG cells underwent apoptosis after treatment with cimetidine. Activation of caspases 3, 7, 8 and 9 was observed in HSG cells after cimetidine treatment, thus confirming that the apoptosis was induced by the activated caspases. Apaf-1 activity was also detected in HSG cells in a dose-dependent manner after treatment with cimetidine. We also found that the cimetidine-mediated down-regulation of NCAM expression in HSG cells did not occur via blocking of the histamine receptor, even though H2R expression was observed on HSG cells, as two other H2R antagonists, famotidine and ranitidine, did not show similar effects. We demonstrated for the first time that cimetidine can induce significant apoptosis of salivary gland tumor cells, which express NCAM, at least in part by down-regulation of NCAM expression on the cells. These findings suggest that the growth, development and perineural/neural invasion of salivary gland tumor cells can be blocked by cimetidine administration through down-regulation of NCAM expression, as well as induction of apoptosis."
],
"offsets": [
[
66,
2042
]
]
}
] | [
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1124
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"cimetidine"
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1305,
1315
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"id": "17273750_T3",
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"text": [
"cimetidine"
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1340,
1350
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"id": "17273750_T4",
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"famotidine"
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1546,
1556
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"id": "17273750_T5",
"type": "CHEMICAL",
"text": [
"ranitidine"
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1561,
1571
]
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"id": "17273750_T6",
"type": "CHEMICAL",
"text": [
"cimetidine"
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1643,
1653
]
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"id": "17273750_T7",
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"text": [
"cimetidine"
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[
1938,
1948
]
],
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},
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"id": "17273750_T8",
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"text": [
"cimetidine"
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[
92,
102
]
],
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},
{
"id": "17273750_T9",
"type": "CHEMICAL",
"text": [
"histamine"
],
"offsets": [
[
106,
115
]
],
"normalized": []
},
{
"id": "17273750_T10",
"type": "CHEMICAL",
"text": [
"cimetidine"
],
"offsets": [
[
671,
681
]
],
"normalized": []
},
{
"id": "17273750_T11",
"type": "CHEMICAL",
"text": [
"cimetidine"
],
"offsets": [
[
897,
907
]
],
"normalized": []
},
{
"id": "17273750_T12",
"type": "CHEMICAL",
"text": [
"MTT"
],
"offsets": [
[
922,
925
]
],
"normalized": []
},
{
"id": "17273750_T13",
"type": "CHEMICAL",
"text": [
"cimetidine"
],
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[
1033,
1043
]
],
"normalized": []
},
{
"id": "17273750_T14",
"type": "CHEMICAL",
"text": [
"Cimetidine"
],
"offsets": [
[
0,
10
]
],
"normalized": []
},
{
"id": "17273750_T15",
"type": "GENE-N",
"text": [
"caspases"
],
"offsets": [
[
1200,
1208
]
],
"normalized": []
},
{
"id": "17273750_T16",
"type": "GENE-N",
"text": [
"Apaf-1"
],
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[
1210,
1216
]
],
"normalized": []
},
{
"id": "17273750_T17",
"type": "GENE-Y",
"text": [
"NCAM"
],
"offsets": [
[
1379,
1383
]
],
"normalized": []
},
{
"id": "17273750_T18",
"type": "GENE-N",
"text": [
"histamine receptor"
],
"offsets": [
[
1442,
1460
]
],
"normalized": []
},
{
"id": "17273750_T19",
"type": "GENE-Y",
"text": [
"H2R"
],
"offsets": [
[
1474,
1477
]
],
"normalized": []
},
{
"id": "17273750_T20",
"type": "GENE-Y",
"text": [
"H2R"
],
"offsets": [
[
1529,
1532
]
],
"normalized": []
},
{
"id": "17273750_T21",
"type": "GENE-Y",
"text": [
"NCAM"
],
"offsets": [
[
1732,
1736
]
],
"normalized": []
},
{
"id": "17273750_T22",
"type": "GENE-Y",
"text": [
"NCAM"
],
"offsets": [
[
1777,
1781
]
],
"normalized": []
},
{
"id": "17273750_T23",
"type": "GENE-Y",
"text": [
"NCAM"
],
"offsets": [
[
1991,
1995
]
],
"normalized": []
},
{
"id": "17273750_T24",
"type": "GENE-Y",
"text": [
"neural cell adhesion molecule"
],
"offsets": [
[
384,
413
]
],
"normalized": []
},
{
"id": "17273750_T25",
"type": "GENE-Y",
"text": [
"NCAM"
],
"offsets": [
[
415,
419
]
],
"normalized": []
},
{
"id": "17273750_T26",
"type": "GENE-Y",
"text": [
"histamine type-2 receptor"
],
"offsets": [
[
106,
131
]
],
"normalized": []
},
{
"id": "17273750_T27",
"type": "GENE-Y",
"text": [
"NCAM"
],
"offsets": [
[
496,
500
]
],
"normalized": []
},
{
"id": "17273750_T28",
"type": "GENE-Y",
"text": [
"NCAM"
],
"offsets": [
[
501,
505
]
],
"normalized": []
},
{
"id": "17273750_T29",
"type": "GENE-Y",
"text": [
"NCAM"
],
"offsets": [
[
534,
538
]
],
"normalized": []
},
{
"id": "17273750_T30",
"type": "GENE-Y",
"text": [
"NCAM"
],
"offsets": [
[
704,
708
]
],
"normalized": []
},
{
"id": "17273750_T31",
"type": "GENE-Y",
"text": [
"H2R"
],
"offsets": [
[
133,
136
]
],
"normalized": []
},
{
"id": "17273750_T32",
"type": "GENE-Y",
"text": [
"NCAM"
],
"offsets": [
[
806,
810
]
],
"normalized": []
},
{
"id": "17273750_T33",
"type": "GENE-N",
"text": [
"caspases 3, 7, 8 and 9"
],
"offsets": [
[
1059,
1081
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17273750_0",
"type": "ANTAGONIST",
"arg1_id": "17273750_T8",
"arg2_id": "17273750_T26",
"normalized": []
},
{
"id": "17273750_1",
"type": "ANTAGONIST",
"arg1_id": "17273750_T8",
"arg2_id": "17273750_T31",
"normalized": []
},
{
"id": "17273750_2",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "17273750_T11",
"arg2_id": "17273750_T32",
"normalized": []
},
{
"id": "17273750_3",
"type": "ACTIVATOR",
"arg1_id": "17273750_T1",
"arg2_id": "17273750_T15",
"normalized": []
},
{
"id": "17273750_4",
"type": "ACTIVATOR",
"arg1_id": "17273750_T2",
"arg2_id": "17273750_T16",
"normalized": []
},
{
"id": "17273750_5",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "17273750_T3",
"arg2_id": "17273750_T17",
"normalized": []
},
{
"id": "17273750_6",
"type": "ANTAGONIST",
"arg1_id": "17273750_T4",
"arg2_id": "17273750_T20",
"normalized": []
},
{
"id": "17273750_7",
"type": "ANTAGONIST",
"arg1_id": "17273750_T5",
"arg2_id": "17273750_T20",
"normalized": []
},
{
"id": "17273750_8",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "17273750_T6",
"arg2_id": "17273750_T22",
"normalized": []
},
{
"id": "17273750_9",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "17273750_T7",
"arg2_id": "17273750_T23",
"normalized": []
}
] |
17620346 | 17620346 | [
{
"id": "17620346_title",
"type": "title",
"text": [
"Covalent binding of rofecoxib, but not other cyclooxygenase-2 inhibitors, to allysine aldehyde in elastin of human aorta."
],
"offsets": [
[
0,
121
]
]
},
{
"id": "17620346_abstract",
"type": "abstract",
"text": [
"In rats, it has been reported that rofecoxib, a cyclooxygenase-2 (COX-2) inhibitor, reacts with the aldehyde group of allysine in elastin to give a condensation covalent adduct, thereby preventing the formation of cross-linkages in the elastin and causing degradation of the elastic fibers in aortas in vivo. Acid, organic solvent, and proteolytic enzyme treatments of human aortic homogenate after incubation with [(14)C]rofecoxib demonstrated that most of the radioactivity is covalently bound to elastin. The in vitro covalent binding was inhibited in the presence of beta-aminopropionitrile, D-penicillamine, and hydralazine, which suggested that the aldehyde group of allysine in human elastin was relevant to the covalent binding. The in vitro covalent binding of [(14)C]rofecoxib was significantly decreased by the addition of only nonradiolabeled rofecoxib but not the other COX-2 inhibitors, celecoxib, valdecoxib, etoricoxib, and CS-706 [2-(4-ethoxyphenyl)-4-methyl 1-(4-sulfamoylphenyl)-1H-pyrrole], a novel selective COX-2 inhibitor. All the above COX-2 inhibitors except for rofecoxib had no reactivity with the aldehyde group of benzaldehyde used as a model compound of allysine aldehyde under a physiological pH condition. On the other hand, no retention of the radioactivity of [(14)C]rofecoxib was observed in human aortic endothelial cells in vitro, suggesting that rofecoxib is not retained in aortic endothelial cells in vivo. These results suggest that rofecoxib, but not other COX-2 inhibitors, is capable of covalently binding to the aldehyde group of allysine in human elastin. This might be one of the main causes of cardiovascular events by rofecoxib in clinical situations."
],
"offsets": [
[
122,
1822
]
]
}
] | [
{
"id": "17620346_T1",
"type": "CHEMICAL",
"text": [
"aldehyde"
],
"offsets": [
[
222,
230
]
],
"normalized": []
},
{
"id": "17620346_T2",
"type": "CHEMICAL",
"text": [
"rofecoxib"
],
"offsets": [
[
1210,
1219
]
],
"normalized": []
},
{
"id": "17620346_T3",
"type": "CHEMICAL",
"text": [
"aldehyde"
],
"offsets": [
[
1247,
1255
]
],
"normalized": []
},
{
"id": "17620346_T4",
"type": "CHEMICAL",
"text": [
"allysine"
],
"offsets": [
[
240,
248
]
],
"normalized": []
},
{
"id": "17620346_T5",
"type": "CHEMICAL",
"text": [
"allysine aldehyde"
],
"offsets": [
[
1306,
1323
]
],
"normalized": []
},
{
"id": "17620346_T6",
"type": "CHEMICAL",
"text": [
"[(14)C]rofecoxib"
],
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[
1416,
1432
]
],
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},
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"id": "17620346_T7",
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"rofecoxib"
],
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[
1506,
1515
]
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},
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"rofecoxib"
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1596,
1605
]
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},
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"id": "17620346_T9",
"type": "CHEMICAL",
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"aldehyde"
],
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[
1679,
1687
]
],
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},
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"id": "17620346_T10",
"type": "CHEMICAL",
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"rofecoxib"
],
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[
1789,
1798
]
],
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},
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"id": "17620346_T11",
"type": "CHEMICAL",
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"rofecoxib"
],
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[
157,
166
]
],
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},
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"id": "17620346_T12",
"type": "CHEMICAL",
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"[(14)C]rofecoxib"
],
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[
537,
553
]
],
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},
{
"id": "17620346_T13",
"type": "CHEMICAL",
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"beta-aminopropionitrile"
],
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[
693,
716
]
],
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},
{
"id": "17620346_T14",
"type": "CHEMICAL",
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"D-penicillamine"
],
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[
718,
733
]
],
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},
{
"id": "17620346_T15",
"type": "CHEMICAL",
"text": [
"hydralazine"
],
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[
739,
750
]
],
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},
{
"id": "17620346_T16",
"type": "CHEMICAL",
"text": [
"aldehyde"
],
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[
777,
785
]
],
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},
{
"id": "17620346_T17",
"type": "CHEMICAL",
"text": [
"allysine"
],
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[
795,
803
]
],
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},
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"id": "17620346_T18",
"type": "CHEMICAL",
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"[(14)C]rofecoxib"
],
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[
892,
908
]
],
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},
{
"id": "17620346_T19",
"type": "CHEMICAL",
"text": [
"rofecoxib"
],
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[
977,
986
]
],
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},
{
"id": "17620346_T20",
"type": "CHEMICAL",
"text": [
"celecoxib"
],
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[
1023,
1032
]
],
"normalized": []
},
{
"id": "17620346_T21",
"type": "CHEMICAL",
"text": [
"valdecoxib"
],
"offsets": [
[
1034,
1044
]
],
"normalized": []
},
{
"id": "17620346_T22",
"type": "CHEMICAL",
"text": [
"etoricoxib"
],
"offsets": [
[
1046,
1056
]
],
"normalized": []
},
{
"id": "17620346_T23",
"type": "CHEMICAL",
"text": [
"CS-706"
],
"offsets": [
[
1062,
1068
]
],
"normalized": []
},
{
"id": "17620346_T24",
"type": "CHEMICAL",
"text": [
"2-(4-ethoxyphenyl)-4-methyl 1-(4-sulfamoylphenyl)-1H-pyrrole"
],
"offsets": [
[
1070,
1130
]
],
"normalized": []
},
{
"id": "17620346_T25",
"type": "CHEMICAL",
"text": [
"rofecoxib"
],
"offsets": [
[
20,
29
]
],
"normalized": []
},
{
"id": "17620346_T26",
"type": "CHEMICAL",
"text": [
"allysine aldehyde"
],
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1182,
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"elastin"
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252,
259
]
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1621,
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1709,
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358,
365
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170,
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"type": "GENE-Y",
"text": [
"elastin"
],
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[
98,
105
]
],
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}
] | [] | [] | [
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},
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}
] |
23477619 | 23477619 | [
{
"id": "23477619_title",
"type": "title",
"text": [
"DNA Adducts in Aldehyde Dehydrogenase-Positive Lung Stem Cells of A/J Mice Treated with the Tobacco Specific Lung Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)."
],
"offsets": [
[
0,
178
]
]
},
{
"id": "23477619_abstract",
"type": "abstract",
"text": [
"Lung cancer is the leading cause of cancer death in the world. Evidence suggests that lung cancer could originate from mutations accumulating in a subpopulation of self-renewing cells, lung stem cells. Aldehyde dehydrogenase (ALDH) is a marker of stem cells. To investigate the presence of DNA modifications in these cells, we isolated ALDH-positive lung cells from A/J mice exposed to the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Using LC-NSI-HRMS/MS-PRM, O(6)-methyl-G, 7-POB-G, and O(2)-POB-dT were positively identified in ALDH-positive cell DNA. This is the first example of detection of carcinogen-DNA adducts in lung stem cells, supporting the hypothesis of their role in lung carcinogenesis."
],
"offsets": [
[
179,
901
]
]
}
] | [
{
"id": "23477619_T1",
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],
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381,
389
]
],
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},
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"4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone"
],
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585,
631
]
],
"normalized": []
},
{
"id": "23477619_T3",
"type": "CHEMICAL",
"text": [
"O(6)-methyl-G"
],
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[
659,
672
]
],
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},
{
"id": "23477619_T4",
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"text": [
"7-POB-G"
],
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674,
681
]
],
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},
{
"id": "23477619_T5",
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"O(2)-POB-dT"
],
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687,
698
]
],
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},
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],
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125,
171
]
],
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},
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],
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15,
23
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],
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173,
176
]
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381,
403
]
],
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},
{
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"ALDH"
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405,
409
]
],
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},
{
"id": "23477619_T11",
"type": "GENE-N",
"text": [
"ALDH"
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515,
519
]
],
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},
{
"id": "23477619_T12",
"type": "GENE-N",
"text": [
"ALDH"
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729,
733
]
],
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},
{
"id": "23477619_T13",
"type": "GENE-N",
"text": [
"Aldehyde Dehydrogenase"
],
"offsets": [
[
15,
37
]
],
"normalized": []
}
] | [] | [] | [] |
18684057 | 18684057 | [
{
"id": "18684057_title",
"type": "title",
"text": [
"Optimizing denileukin diftitox (Ontak) therapy."
],
"offsets": [
[
0,
47
]
]
},
{
"id": "18684057_abstract",
"type": "abstract",
"text": [
"Denileukin diftitox (Ontak) is a novel recombinant fusion protein consisting of peptide sequences for the enzymatically active and membrane translocation domain of diphtheria toxin linked to human IL-2. Denileukin diftitox specifically binds to IL-2 receptors on the cell membrane, is internalized via receptor-mediated endocytosis and inhibits protein synthesis by ADP ribosylation of elongation factor 2, resulting in cell death. This article focuses on the clinical trial that led to the US FDA approval of the drug for cutaneous T-cell lymphoma in 1999, and other investigational studies for hematologic malignancies, recurrent and refractory chronic lymphocytic leukemia, non-Hodgkin B-cell lymphoma, graft-versus-host disease and autoimmune disease, demonstrating the activity and adverse effects of the drug."
],
"offsets": [
[
48,
863
]
]
}
] | [
{
"id": "18684057_T1",
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],
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414,
417
]
],
"normalized": []
},
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"Denileukin diftitox"
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48,
67
]
],
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},
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],
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212,
228
]
],
"normalized": []
},
{
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239,
249
]
],
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},
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"Denileukin diftitox"
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251,
270
]
],
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},
{
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69,
74
]
],
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},
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"id": "18684057_T7",
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"IL-2 receptors"
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293,
307
]
],
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},
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"id": "18684057_T8",
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"text": [
"elongation factor 2"
],
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434,
453
]
],
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},
{
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"type": "GENE-Y",
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"denileukin diftitox"
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11,
30
]
],
"normalized": []
},
{
"id": "18684057_T10",
"type": "GENE-Y",
"text": [
"Ontak"
],
"offsets": [
[
32,
37
]
],
"normalized": []
}
] | [] | [] | [] |
17181139 | 17181139 | [
{
"id": "17181139_title",
"type": "title",
"text": [
"Scaffold of the cyclooxygenase-2 (COX-2) inhibitor carprofen provides Alzheimer gamma-secretase modulators."
],
"offsets": [
[
0,
107
]
]
},
{
"id": "17181139_abstract",
"type": "abstract",
"text": [
"N-sulfonylated and N-alkylated carprofen derivatives were investigated for their inhibition and modulation of gamma-secretase, which is associated with Alzheimer's disease. The introduction of a lipophilic substituent transformed the COX-2 inhibitor carprofen into a potent gamma-secretase modulator. Several compounds (e.g., 9p, 11f) caused selective reduction of Abeta42 and an increase of Abeta38. The most active compounds displayed activities in the low micromolar range and no effect on the gamma-secretase cleavage at the e-site."
],
"offsets": [
[
108,
644
]
]
}
] | [
{
"id": "17181139_T1",
"type": "CHEMICAL",
"text": [
"N-sulfonylated"
],
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[
108,
122
]
],
"normalized": []
},
{
"id": "17181139_T2",
"type": "CHEMICAL",
"text": [
"N-alkylated"
],
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[
127,
138
]
],
"normalized": []
},
{
"id": "17181139_T3",
"type": "CHEMICAL",
"text": [
"carprofen"
],
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[
358,
367
]
],
"normalized": []
},
{
"id": "17181139_T4",
"type": "CHEMICAL",
"text": [
"carprofen"
],
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[
139,
148
]
],
"normalized": []
},
{
"id": "17181139_T5",
"type": "CHEMICAL",
"text": [
"carprofen"
],
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[
51,
60
]
],
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},
{
"id": "17181139_T6",
"type": "GENE-N",
"text": [
"gamma-secretase"
],
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218,
233
]
],
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},
{
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"COX-2"
],
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342,
347
]
],
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},
{
"id": "17181139_T8",
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"gamma-secretase"
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382,
397
]
],
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},
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"Abeta42"
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473,
480
]
],
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},
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"Abeta38"
],
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500,
507
]
],
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},
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605,
620
]
],
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},
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"type": "GENE-N",
"text": [
"e-site"
],
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[
637,
643
]
],
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},
{
"id": "17181139_T13",
"type": "GENE-Y",
"text": [
"cyclooxygenase-2"
],
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[
16,
32
]
],
"normalized": []
},
{
"id": "17181139_T14",
"type": "GENE-Y",
"text": [
"COX-2"
],
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34,
39
]
],
"normalized": []
},
{
"id": "17181139_T15",
"type": "GENE-N",
"text": [
"gamma-secretase"
],
"offsets": [
[
80,
95
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17181139_0",
"type": "INHIBITOR",
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"arg2_id": "17181139_T13",
"normalized": []
},
{
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"arg2_id": "17181139_T14",
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},
{
"id": "17181139_2",
"type": "INHIBITOR",
"arg1_id": "17181139_T3",
"arg2_id": "17181139_T7",
"normalized": []
}
] |
16973729 | 16973729 | [
{
"id": "16973729_title",
"type": "title",
"text": [
"Hyperphagia alters expression of hypothalamic 5-HT2C and 5-HT1B receptor genes and plasma des-acyl ghrelin levels in Ay mice."
],
"offsets": [
[
0,
125
]
]
},
{
"id": "16973729_abstract",
"type": "abstract",
"text": [
"The central melanocortin (MC) pathway is suggested to mediate satiety signaling downstream of serotonin (5-HT)2C receptors. 5-HT2C receptor mutant mice consume more food, which leads to late-onset obesity and impaired glucose tolerance. Ay mice with ectopic expression of the agouti peptide, which leads to a perturbation of the central MC pathway, develop obesity and diabetes, associated with low levels of plasma total ghrelin. Here, we report that 5-wk-old Ay mice consumed more food in association with decreases in levels of plasma des-acyl ghrelin, but not active ghrelin, and increases in hypothalamic 5-HT2C and 5-HT1B receptor gene expression compared with wild-type mice matched for age and body weight. These alterations were also observed in 8-wk-old obese Ay mice. Restricted feeding significantly decreased hypothalamic 5-HT2C and 5-HT1B receptor gene expression in association with a reversal of the decreases in plasma des-acyl ghrelin levels in 5-wk-old Ay mice. Moreover, restricted feeding reduced body weight, hyperinsulinemia, and hyperglycemia in association with increases in plasma des-acyl ghrelin levels in 8-wk-old obese Ay mice. Administration of m-chlorophenylpiperazine and fenfluramine, both of which induce anorexic effects via 5-HT2C receptors and/or 5-HT1B receptors, suppressed food intake in 5- and 8-wk-old Ay mice, whereas the anorexic effects were attenuated in food-restricted Ay mice. These findings suggest that the agouti peptide down-regulates hypothalamic 5-HT2C and 5-HT1B receptor gene expression under restricted feeding conditions, whereas chronic hyperphagia increases the expression of these genes and decreases plasma des-acyl ghrelin levels in Ay mice."
],
"offsets": [
[
126,
1832
]
]
}
] | [
{
"id": "16973729_T1",
"type": "CHEMICAL",
"text": [
"m-chlorophenylpiperazine"
],
"offsets": [
[
1302,
1326
]
],
"normalized": []
},
{
"id": "16973729_T2",
"type": "CHEMICAL",
"text": [
"fenfluramine"
],
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[
1331,
1343
]
],
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},
{
"id": "16973729_T3",
"type": "CHEMICAL",
"text": [
"glucose"
],
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[
344,
351
]
],
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},
{
"id": "16973729_T4",
"type": "GENE-Y",
"text": [
"des-acyl ghrelin"
],
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[
1233,
1249
]
],
"normalized": []
},
{
"id": "16973729_T5",
"type": "GENE-Y",
"text": [
"melanocortin"
],
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[
138,
150
]
],
"normalized": []
},
{
"id": "16973729_T6",
"type": "GENE-Y",
"text": [
"5-HT2C"
],
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[
250,
256
]
],
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},
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"id": "16973729_T7",
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"5-HT2C"
],
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[
1387,
1393
]
],
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},
{
"id": "16973729_T8",
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"text": [
"5-HT1B"
],
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[
1411,
1417
]
],
"normalized": []
},
{
"id": "16973729_T9",
"type": "GENE-Y",
"text": [
"agouti peptide"
],
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[
1585,
1599
]
],
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},
{
"id": "16973729_T10",
"type": "GENE-Y",
"text": [
"5-HT2C"
],
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[
1628,
1634
]
],
"normalized": []
},
{
"id": "16973729_T11",
"type": "GENE-Y",
"text": [
"5-HT1B"
],
"offsets": [
[
1639,
1645
]
],
"normalized": []
},
{
"id": "16973729_T12",
"type": "GENE-Y",
"text": [
"des-acyl ghrelin"
],
"offsets": [
[
1797,
1813
]
],
"normalized": []
},
{
"id": "16973729_T13",
"type": "GENE-Y",
"text": [
"MC"
],
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[
152,
154
]
],
"normalized": []
},
{
"id": "16973729_T14",
"type": "GENE-Y",
"text": [
"agouti peptide"
],
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[
402,
416
]
],
"normalized": []
},
{
"id": "16973729_T15",
"type": "GENE-Y",
"text": [
"MC"
],
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[
463,
465
]
],
"normalized": []
},
{
"id": "16973729_T16",
"type": "GENE-Y",
"text": [
"ghrelin"
],
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[
548,
555
]
],
"normalized": []
},
{
"id": "16973729_T17",
"type": "GENE-Y",
"text": [
"des-acyl ghrelin"
],
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"ghrelin"
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] | [] | [] | [] |
23376438 | 23376438 | [
{
"id": "23376438_title",
"type": "title",
"text": [
"Cellular mechanisms of the cytotoxic effects of the zearalenone metabolites α-zearalenol and β-zearalenol on RAW264.7 macrophages."
],
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0,
130
]
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"id": "23376438_abstract",
"type": "abstract",
"text": [
"Zearalenone (ZEN) and its metabolites are commonly found in many food commodities and are known to cause reproductive disorders and genotoxic effects. The major ZEN metabolites are α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL). Although many studies have demonstrated the cytotoxic effects of these metabolites, the mechanisms by which α-ZOL or β-ZOL mediates their cytotoxic effects appear to differ according to cell type and the exposed toxins. We evaluated the toxicity of α-ZOL and β-ZOL on RAW264.7 macrophages and investigated the underlying mechanisms. β-ZOL not only more strongly reduced the viability of cells than did α-ZOL, but it also induced cell death mainly by apoptosis rather than necrosis. The ZEN metabolites induced loss of mitochondrial membrane potential (MMP), mitochondrial changes in Bcl-2 and Bax proteins, and cytoplasmic release of cytochrome c and apoptosis-inducing factor (AIF). Use of an inhibitor specific to c-Jun N-terminal kinase (JNK), p38 kinase or p53, but not pan-caspase or caspase-8, decreased the toxin-induced generation of reactive oxygen species (ROS) and also attenuated the α-ZOL- or β-ZOL-induced decrease of cell viability. Antioxidative enzyme or compounds such as catalase, acteoside, and (E)-1-(3,4-dihydroxyphenethyl)-3-(4-hydroxystyryl)urea suppressed the ZEN metabolite-mediated reduction of cell viability. Further, knockdown of AIF via siRNA transfection diminished the ZEN metabolite-induced cell death. Collectively, these results suggest that the activation of p53, JNK or p38 kinase by ZEN metabolites is the main upstream signal required for the mitochondrial alteration of Bcl-2/Bax signaling pathways and intracellular ROS generation, while MMP loss and nuclear translocation of AIF are the critical downstream events for ZEN metabolite-mediated apoptosis in macrophages."
],
"offsets": [
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131,
1969
]
]
}
] | [
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"id": "23376438_T1",
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]
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"id": "23376438_T2",
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1210,
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]
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"id": "23376438_T3",
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"α-ZOL"
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1255,
1260
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"id": "23376438_T4",
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"id": "23376438_T5",
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1359,
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{
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]
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"ZEN"
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1444,
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"ZEN"
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"ZEN"
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"ZEN"
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]
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"ZEN"
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292,
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]
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"id": "23376438_T12",
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"ZEN"
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1920,
1923
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312,
324
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326,
331
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351,
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467,
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476,
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692,
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761,
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{
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"ZEN"
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845,
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"N"
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1082
]
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52,
63
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76,
88
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93,
105
]
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"caspase"
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"caspase-8"
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1157
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},
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"p53"
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1655,
1658
]
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},
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"JNK"
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1660,
1663
]
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},
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"id": "23376438_T32",
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"p38"
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1667,
1670
]
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},
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"id": "23376438_T33",
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"kinase"
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1671,
1677
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},
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"Bcl-2"
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1770,
1775
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"Bax"
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1776,
1779
]
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},
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"AIF"
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1877,
1880
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],
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},
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"Bcl-2"
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942,
947
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"Bax"
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952,
955
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"cytochrome c"
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993,
1005
]
],
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},
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"id": "23376438_T40",
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"apoptosis-inducing factor"
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1010,
1035
]
],
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},
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"id": "23376438_T41",
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"AIF"
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1037,
1040
]
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},
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"id": "23376438_T42",
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"c-Jun N-terminal kinase"
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1075,
1098
]
],
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},
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"JNK"
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1100,
1103
]
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},
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"id": "23376438_T44",
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"p38"
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1106,
1109
]
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},
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"kinase"
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1110,
1116
]
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},
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"type": "GENE-Y",
"text": [
"p53"
],
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[
1120,
1123
]
],
"normalized": []
}
] | [] | [] | [
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"arg2_id": "23376438_T39",
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},
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},
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},
{
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},
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"type": "ACTIVATOR",
"arg1_id": "23376438_T10",
"arg2_id": "23376438_T33",
"normalized": []
}
] |
11146120 | 11146120 | [
{
"id": "11146120_title",
"type": "title",
"text": [
"Pharmacological modulation of nerve growth factor synthesis: a mechanistic comparison of vitamin D receptor and beta(2)-adrenoceptor agonists."
],
"offsets": [
[
0,
142
]
]
},
{
"id": "11146120_abstract",
"type": "abstract",
"text": [
"Increasing nerve growth factor (NGF) in the PNS is a rational strategy for treating certain neurodegenerative disorders. The present studies were undertaken to compare two compounds, a vitamin D(3) analogue (CB1093) with minimal calcaemic effects, and clenbuterol, a long-acting beta(2)-adrenoceptor agonist, both of which induce NGF synthesis in vivo. Clenbuterol caused significant increases in both NGF mRNA and protein in 3T3 cells; with maxima at 10 nM and at 8-12 h exposure. Effects of clenbuterol on NGF mRNA were antagonized by propranolol. Mobility shift assays on whole cell extracts showed that clenbuterol increased AP1 binding in 3T3 cells prior to increasing NGF synthesis. Clenbuterol was without effect on NGF mRNA levels in L929 cells, whereas CB1093 caused significant increases in both NGF mRNA and protein levels in both 3T3 and L929 cells. Stimulation was almost maximal at 24 h exposure and was sustained for at least 72 h. The magnitude of the increase was much greater in L929 (700% increase) than in 3T3 cells (80%). Binding to the vitamin D nuclear receptor (VDR), which acts as a transcription factor itself, was increased as early as 30 min after exposure to of CB1093 and maintained up to 24 h. Increased VDR binding preceded increased NGF mRNA. A 150% increase in AP-1 binding was also evident. This study demonstrates that CB1093 and clenbuterol stimulate NGF levels in vitro and that AP-1 binding could be a commonality between the mechanism of NGF induction of these two compounds."
],
"offsets": [
[
143,
1658
]
]
}
] | [
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1201,
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351,
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]
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750,
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832,
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905,
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"vitamin D"
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89,
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]
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1201,
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]
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"VDR"
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1229,
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"id": "11146120_T17",
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"nerve growth factor"
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154,
173
]
],
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},
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"VDR"
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1378,
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]
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},
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"id": "11146120_T19",
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"NGF"
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},
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]
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},
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"id": "11146120_T21",
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},
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"id": "11146120_T22",
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"AP-1"
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1560,
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]
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},
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"id": "11146120_T23",
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"NGF"
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]
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},
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"id": "11146120_T24",
"type": "GENE-Y",
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"beta(2)-adrenoceptor"
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422,
442
]
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},
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"id": "11146120_T25",
"type": "GENE-Y",
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"NGF"
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175,
178
]
],
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},
{
"id": "11146120_T26",
"type": "GENE-Y",
"text": [
"NGF"
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473,
476
]
],
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},
{
"id": "11146120_T27",
"type": "GENE-Y",
"text": [
"NGF"
],
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545,
548
]
],
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},
{
"id": "11146120_T28",
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] |
23300056 | 23300056 | [
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15299009 | 15299009 | [
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],
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"Retinaldehyde dehydrogenase II (RalDH2) converts retinal to the transcriptional regulator retinoic acid in the developing embryo. The x-ray structure of the enzyme revealed an important structural difference between this protein and other aldehyde dehydrogenases of the same enzyme superfamily; a 20-amino acid span in the substrate access channel in retinaldehyde dehydrogenase II is disordered, whereas in other aldehyde dehydrogenases this region forms a well defined wall of the substrate access channel. We asked whether this disordered loop might order during the course of catalysis and provide a means for an enzyme that requires a large substrate access channel to restrict access to the catalytic machinery by smaller compounds that might potentially enter the active site and be metabolized. Our experiments, a combination of kinetic, spectroscopic, and crystallographic techniques, suggest that a disorder to order transition is linked to catalytic activity."
],
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] |
10740137 | 10740137 | [
{
"id": "10740137_title",
"type": "title",
"text": [
"Statins: effective antiatherosclerotic therapy."
],
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0,
47
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]
},
{
"id": "10740137_abstract",
"type": "abstract",
"text": [
"BACKGROUND: Statins are the most effective agents currently available for lowering plasma levels of low-density lipoprotein cholesterol (LDL-C) and are the mainstay of therapy for hyperlipidemia. The statins are highly liver-selective, inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a key enzyme in the synthesis of cholesterol. Several large, controlled clinical trials have confirmed significant reductions in rates of coronary heart disease morbidity and death with long-term statin therapy in patients with mild to severe hypercholesterolemia. METHODS AND RESULTS: This review article is based on a literature search of more than 60 relevant articles from peer-reviewed journals. Search engines included Medline and Embase. In surveying clinical and angiographic evidence, we found that statins appear to reduce the incidence of coronary events by slowing the progression of atherosclerosis and preventing atheromatous lesion formation. We found that the 6 statins currently marketed-atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin-differ in their inhibitory action on the HMG-CoA reductase enzyme. CONCLUSIONS: The use of more potent statins such as atorvastatin and simvastatin affords greater lowering of LDL-C and triglyceride levels, allowing more patients to achieve target goals. The question of how low LDL-C levels should be lowered will be answered by ongoing clinical trials."
],
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48,
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}
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172,
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248,
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295,
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334,
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387,
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148,
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1182,
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1317,
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185,
188
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1420,
1423
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295,
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]
],
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}
] | [] | [] | [
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{
"id": "10740137_10",
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},
{
"id": "10740137_11",
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{
"id": "10740137_12",
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"arg1_id": "10740137_T10",
"arg2_id": "10740137_T21",
"normalized": []
}
] |
23558236 | 23558236 | [
{
"id": "23558236_title",
"type": "title",
"text": [
"Design, synthesis and cytotoxicity of cell death mechanism of rotundic acid derivatives."
],
"offsets": [
[
0,
88
]
]
},
{
"id": "23558236_abstract",
"type": "abstract",
"text": [
"In the present investigation, 16 new rotundic acid (RA) derivatives modified at the C-3, C-23 and C-28 positions were synthesized. The cytotoxicities of the derivatives were evaluated against HeLa, A375, HepG2, SPC-A1 and NCI-H446 human tumor cell lines by MTT assay. Among these derivatives, compounds 4-7 exhibited stronger cell growth inhibitory than RA and compound 4 was found to be the best inhibition activity on five human tumor cell lines with IC50 <10μM. The apoptosis mechanism of compound 4 in HeLa cells was investigated by western blot analysis. The results indicated that compound 4 could induce apoptosis through increasing protein expression of cleaved caspase-3 and Bax, and decreasing protein expression of Bcl-2. In summary, the present work suggests that compound 4 might serve as an effective chemotherapeutic candidate."
],
"offsets": [
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89,
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]
}
] | [
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"id": "23558236_T1",
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346,
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126,
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62,
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{
"id": "23558236_T4",
"type": "GENE-Y",
"text": [
"caspase-3"
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768
]
],
"normalized": []
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{
"id": "23558236_T5",
"type": "GENE-Y",
"text": [
"Bax"
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773,
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]
],
"normalized": []
},
{
"id": "23558236_T6",
"type": "GENE-Y",
"text": [
"Bcl-2"
],
"offsets": [
[
815,
820
]
],
"normalized": []
}
] | [] | [] | [] |
23391443 | 23391443 | [
{
"id": "23391443_title",
"type": "title",
"text": [
"An intra-articular salmon calcitonin-based nanocomplex reduces experimental inflammatory arthritis."
],
"offsets": [
[
0,
99
]
]
},
{
"id": "23391443_abstract",
"type": "abstract",
"text": [
"Prolonged inappropriate inflammatory responses contribute to the pathogenesis of rheumatoid arthritis (RA) and to aspects of osteoarthritis (OA). The orphan nuclear receptor, NR4A2, is a key regulator and potential biomarker for inflammation and represents a potentially valuable therapeutic target. Both salmon calcitonin (sCT) and hyaluronic acid (HA) attenuated activated mRNA expression of NR4A1, NR4A2, NR4A3, and matrix metalloproteinases (MMPs) 1, 3 and 13 in three human cell lines: SW1353 chondrocytes, U937 and THP-1 monocytes. Ad-mixtures of sCT and HA further down-regulated expression of NR4A2 compared to either agent alone at specific concentrations, hence the rationale for their formulation in nanocomplexes (NPs) using chitosan. The sCT released from NP stimulated cAMP production in human T47D breast cancer cells expressing sCT receptors. When NP were injected by the intra-articular (I.A.) route to the mouse knee during on-going inflammatory arthritis of the K/BxN serum transfer model, joint inflammation was reduced together with NR4A2 expression, and local bone architecture was preserved. These data highlight remarkable anti-inflammatory effects of sCT and HA at the level of reducing NR4A2 mRNA expression in vitro. Combining them in NP elicits anti-arthritic effects in vivo following I.A. delivery."
],
"offsets": [
[
100,
1428
]
]
}
] | [
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"id": "23391443_T1",
"type": "CHEMICAL",
"text": [
"cAMP"
],
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883,
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]
],
"normalized": []
},
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"id": "23391443_T2",
"type": "GENE-Y",
"text": [
"NR4A2"
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1154,
1159
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"id": "23391443_T3",
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"text": [
"NR4A2"
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1312,
1317
]
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},
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"id": "23391443_T4",
"type": "GENE-Y",
"text": [
"orphan nuclear receptor, NR4A2"
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250,
280
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"id": "23391443_T5",
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"NR4A1"
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494,
499
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"id": "23391443_T6",
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"text": [
"NR4A2"
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501,
506
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"id": "23391443_T7",
"type": "GENE-Y",
"text": [
"NR4A3"
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508,
513
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"id": "23391443_T8",
"type": "GENE-N",
"text": [
"matrix metalloproteinases (MMPs) 1, 3 and 13"
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519,
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]
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"id": "23391443_T9",
"type": "GENE-Y",
"text": [
"NR4A2"
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701,
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"id": "23391443_T10",
"type": "GENE-Y",
"text": [
"sCT receptors"
],
"offsets": [
[
944,
957
]
],
"normalized": []
}
] | [] | [] | [] |
23533219 | 23533219 | [
{
"id": "23533219_title",
"type": "title",
"text": [
"Increased activin bioavailability enhances hepatic insulin sensitivity while inducing hepatic steatosis in male mice."
],
"offsets": [
[
0,
117
]
]
},
{
"id": "23533219_abstract",
"type": "abstract",
"text": [
"The development of insulin resistance is tightly linked to fatty liver disease and is considered a major health concern worldwide, although their mechanistic relationship remains controversial. Activin has emerging roles in nutrient homeostasis but its metabolic effects on hepatocytes remain unknown. In this study, we investigated the effects of increased endogenous activin bioactivity on hepatic nutrient homeostasis by creating mice with inactivating mutations that deplete the circulating activin antagonists, follistatin like-3 (FSTL3) or the follistatin 315 isoform (FST315; FST288-only mice). We investigated liver histology and lipid content, hepatic insulin sensitivity, and metabolic gene expression including the HepG2 cell and primary hepatocyte response to activin treatment. Both FSTL3KO and FST288-only mice had extensive hepatic steatosis and elevated hepatic triglyceride (TG) content. Unexpectedly, insulin signaling, as assessed by phospho-AKT, was enhanced in both mouse models. Pretreatment of HepG2 cells with activin A increased their response to subsequent insulin challenge. Gene expression analysis suggests that increased lipid uptake, enhanced de novo lipid synthesis, decreased lipolysis and/or enhanced glucose uptake contribute to increased hepatic TG content in these models. However, activin treatment recapitulated only some of these gene changes suggesting that increased activin bioactivity may be only partially responsible for this phenotype. Nevertheless, our results indicate that activin enhances hepatocyte insulin response which ultimately leads to hepatic steatosis despite the increased insulin sensitivity. Thus, regulation of activin bioactivity is critical for maintaining normal liver lipid homeostasis and response to insulin while activin agonists may be useful for increasing liver insulin sensitivity."
],
"offsets": [
[
118,
1974
]
]
}
] | [
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"id": "23533219_T1",
"type": "CHEMICAL",
"text": [
"glucose"
],
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1353,
1360
]
],
"normalized": []
},
{
"id": "23533219_T2",
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"text": [
"triglyceride"
],
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[
996,
1008
]
],
"normalized": []
},
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"id": "23533219_T3",
"type": "GENE-Y",
"text": [
"activin A"
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1152,
1161
]
],
"normalized": []
},
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"id": "23533219_T4",
"type": "GENE-N",
"text": [
"insulin"
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1208
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"id": "23533219_T5",
"type": "GENE-N",
"text": [
"activin"
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1437,
1444
]
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"id": "23533219_T6",
"type": "GENE-N",
"text": [
"activin"
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1527,
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]
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"id": "23533219_T7",
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"text": [
"insulin"
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"id": "23533219_T8",
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"text": [
"insulin"
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"id": "23533219_T9",
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"insulin"
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"text": [
"insulin"
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1954,
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]
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},
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"id": "23533219_T13",
"type": "GENE-Y",
"text": [
"insulin"
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137,
144
]
],
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},
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"id": "23533219_T14",
"type": "GENE-N",
"text": [
"Activin"
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312,
319
]
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},
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"id": "23533219_T15",
"type": "GENE-N",
"text": [
"activin"
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487,
494
]
],
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},
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"id": "23533219_T16",
"type": "GENE-N",
"text": [
"activin"
],
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613,
620
]
],
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},
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"id": "23533219_T17",
"type": "GENE-Y",
"text": [
"follistatin like-3"
],
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[
634,
652
]
],
"normalized": []
},
{
"id": "23533219_T18",
"type": "GENE-Y",
"text": [
"FSTL3"
],
"offsets": [
[
654,
659
]
],
"normalized": []
},
{
"id": "23533219_T19",
"type": "GENE-Y",
"text": [
"follistatin 315"
],
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[
668,
683
]
],
"normalized": []
},
{
"id": "23533219_T20",
"type": "GENE-Y",
"text": [
"FST315"
],
"offsets": [
[
693,
699
]
],
"normalized": []
},
{
"id": "23533219_T21",
"type": "GENE-Y",
"text": [
"FST288"
],
"offsets": [
[
701,
707
]
],
"normalized": []
},
{
"id": "23533219_T22",
"type": "GENE-N",
"text": [
"insulin"
],
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[
779,
786
]
],
"normalized": []
},
{
"id": "23533219_T23",
"type": "GENE-N",
"text": [
"activin"
],
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[
890,
897
]
],
"normalized": []
},
{
"id": "23533219_T24",
"type": "GENE-Y",
"text": [
"FSTL3"
],
"offsets": [
[
914,
919
]
],
"normalized": []
},
{
"id": "23533219_T25",
"type": "GENE-Y",
"text": [
"FST288"
],
"offsets": [
[
926,
932
]
],
"normalized": []
},
{
"id": "23533219_T26",
"type": "GENE-N",
"text": [
"insulin"
],
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[
1037,
1044
]
],
"normalized": []
},
{
"id": "23533219_T27",
"type": "GENE-N",
"text": [
"phospho-AKT"
],
"offsets": [
[
1071,
1082
]
],
"normalized": []
},
{
"id": "23533219_T28",
"type": "GENE-N",
"text": [
"activin"
],
"offsets": [
[
10,
17
]
],
"normalized": []
},
{
"id": "23533219_T29",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
51,
58
]
],
"normalized": []
}
] | [] | [] | [] |
17929831 | 17929831 | [
{
"id": "17929831_title",
"type": "title",
"text": [
"Kinetic characterization of adenylosuccinate synthetase from the thermophilic archaea Methanocaldococcus jannaschii."
],
"offsets": [
[
0,
116
]
]
},
{
"id": "17929831_abstract",
"type": "abstract",
"text": [
"Adenylosuccinate synthetase (AdSS) catalyzes the Mg2+ dependent condensation of a molecule of IMP with aspartate to form adenylosuccinate, in a reaction driven by the hydrolysis of GTP to GDP. AdSS from the thermophilic archaea, Methanocaldococcus jannaschii (MjAdSS) is 345 amino acids long against an average length of 430-457 amino acids for most mesophilic AdSS. This short AdSS has two large deletions that map to the middle and C-terminus of the protein. This article discusses the detailed kinetic characterization of MjAdSS. Initial velocity and product inhibition studies, carried out at 70 degrees C, suggest a rapid equilibrium random AB steady-state ordered C kinetic mechanism for the MjAdSS catalyzed reaction. AdSS are known to exhibit monomer-dimer equilibrium with the dimer being implicated in catalysis. In contrast, our studies show that MjAdSS is an equilibrium mixture of dimers and tetramers with the tetramer being the catalytically active form. The tetramer dissociates into dimers with a minor increase in ionic strength of the buffer, while the dimer is extremely stable and does not dissociate even at 1.2 M NaCl. Phosphate, a product of the reaction, was found to be a potent inhibitor of MjAdSS showing biphasic inhibition of enzyme activity. The inhibition was competitive with IMP and noncompetitive with GTP. MjAdSS, like the mouse acidic isozyme, exhibits substrate inhibition, with IMP inhibiting enzyme activity at subsaturating GTP concentrations. Regulation of enzyme activity by the glycolytic intermediate, fructose 1,6 bisphosphate, was also observed with the inhibition being competitive with IMP and noncompetitive against GTP."
],
"offsets": [
[
117,
1787
]
]
}
] | [
{
"id": "17929831_T1",
"type": "CHEMICAL",
"text": [
"Adenylosuccinate"
],
"offsets": [
[
117,
133
]
],
"normalized": []
},
{
"id": "17929831_T2",
"type": "CHEMICAL",
"text": [
"aspartate"
],
"offsets": [
[
220,
229
]
],
"normalized": []
},
{
"id": "17929831_T3",
"type": "CHEMICAL",
"text": [
"NaCl"
],
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[
1253,
1257
]
],
"normalized": []
},
{
"id": "17929831_T4",
"type": "CHEMICAL",
"text": [
"Phosphate"
],
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[
1259,
1268
]
],
"normalized": []
},
{
"id": "17929831_T5",
"type": "CHEMICAL",
"text": [
"adenylosuccinate"
],
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[
238,
254
]
],
"normalized": []
},
{
"id": "17929831_T6",
"type": "CHEMICAL",
"text": [
"GTP"
],
"offsets": [
[
1454,
1457
]
],
"normalized": []
},
{
"id": "17929831_T7",
"type": "CHEMICAL",
"text": [
"acidic"
],
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[
1482,
1488
]
],
"normalized": []
},
{
"id": "17929831_T8",
"type": "CHEMICAL",
"text": [
"GTP"
],
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[
1582,
1585
]
],
"normalized": []
},
{
"id": "17929831_T9",
"type": "CHEMICAL",
"text": [
"fructose"
],
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[
1664,
1672
]
],
"normalized": []
},
{
"id": "17929831_T10",
"type": "CHEMICAL",
"text": [
"1,6 bisphosphate"
],
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[
1673,
1689
]
],
"normalized": []
},
{
"id": "17929831_T11",
"type": "CHEMICAL",
"text": [
"GTP"
],
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[
1783,
1786
]
],
"normalized": []
},
{
"id": "17929831_T12",
"type": "CHEMICAL",
"text": [
"GTP"
],
"offsets": [
[
298,
301
]
],
"normalized": []
},
{
"id": "17929831_T13",
"type": "CHEMICAL",
"text": [
"GDP"
],
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[
305,
308
]
],
"normalized": []
},
{
"id": "17929831_T14",
"type": "CHEMICAL",
"text": [
"amino acids"
],
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[
392,
403
]
],
"normalized": []
},
{
"id": "17929831_T15",
"type": "CHEMICAL",
"text": [
"amino acids"
],
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[
446,
457
]
],
"normalized": []
},
{
"id": "17929831_T16",
"type": "CHEMICAL",
"text": [
"C"
],
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[
551,
552
]
],
"normalized": []
},
{
"id": "17929831_T17",
"type": "CHEMICAL",
"text": [
"Mg2+"
],
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[
166,
170
]
],
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},
{
"id": "17929831_T18",
"type": "CHEMICAL",
"text": [
"adenylosuccinate"
],
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[
28,
44
]
],
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},
{
"id": "17929831_T19",
"type": "GENE-Y",
"text": [
"Adenylosuccinate synthetase"
],
"offsets": [
[
117,
144
]
],
"normalized": []
},
{
"id": "17929831_T20",
"type": "GENE-Y",
"text": [
"MjAdSS"
],
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[
1335,
1341
]
],
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},
{
"id": "17929831_T21",
"type": "GENE-Y",
"text": [
"MjAdSS"
],
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[
1459,
1465
]
],
"normalized": []
},
{
"id": "17929831_T22",
"type": "GENE-N",
"text": [
"mouse acidic isozyme"
],
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[
1476,
1496
]
],
"normalized": []
},
{
"id": "17929831_T23",
"type": "GENE-Y",
"text": [
"AdSS"
],
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[
310,
314
]
],
"normalized": []
},
{
"id": "17929831_T24",
"type": "GENE-Y",
"text": [
"MjAdSS"
],
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[
377,
383
]
],
"normalized": []
},
{
"id": "17929831_T25",
"type": "GENE-Y",
"text": [
"AdSS"
],
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[
146,
150
]
],
"normalized": []
},
{
"id": "17929831_T26",
"type": "GENE-Y",
"text": [
"AdSS"
],
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[
478,
482
]
],
"normalized": []
},
{
"id": "17929831_T27",
"type": "GENE-Y",
"text": [
"AdSS"
],
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[
495,
499
]
],
"normalized": []
},
{
"id": "17929831_T28",
"type": "GENE-Y",
"text": [
"MjAdSS"
],
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[
642,
648
]
],
"normalized": []
},
{
"id": "17929831_T29",
"type": "GENE-Y",
"text": [
"MjAdSS"
],
"offsets": [
[
815,
821
]
],
"normalized": []
},
{
"id": "17929831_T30",
"type": "GENE-Y",
"text": [
"AdSS"
],
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[
842,
846
]
],
"normalized": []
},
{
"id": "17929831_T31",
"type": "GENE-Y",
"text": [
"MjAdSS"
],
"offsets": [
[
975,
981
]
],
"normalized": []
},
{
"id": "17929831_T32",
"type": "GENE-Y",
"text": [
"adenylosuccinate synthetase"
],
"offsets": [
[
28,
55
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17929831_0",
"type": "PRODUCT-OF",
"arg1_id": "17929831_T5",
"arg2_id": "17929831_T19",
"normalized": []
},
{
"id": "17929831_1",
"type": "PRODUCT-OF",
"arg1_id": "17929831_T5",
"arg2_id": "17929831_T25",
"normalized": []
},
{
"id": "17929831_2",
"type": "SUBSTRATE",
"arg1_id": "17929831_T17",
"arg2_id": "17929831_T25",
"normalized": []
},
{
"id": "17929831_3",
"type": "PART-OF",
"arg1_id": "17929831_T14",
"arg2_id": "17929831_T24",
"normalized": []
},
{
"id": "17929831_4",
"type": "PART-OF",
"arg1_id": "17929831_T14",
"arg2_id": "17929831_T23",
"normalized": []
},
{
"id": "17929831_5",
"type": "PART-OF",
"arg1_id": "17929831_T15",
"arg2_id": "17929831_T26",
"normalized": []
},
{
"id": "17929831_6",
"type": "PART-OF",
"arg1_id": "17929831_T16",
"arg2_id": "17929831_T27",
"normalized": []
},
{
"id": "17929831_7",
"type": "INHIBITOR",
"arg1_id": "17929831_T4",
"arg2_id": "17929831_T20",
"normalized": []
}
] |
23265904 | 23265904 | [
{
"id": "23265904_title",
"type": "title",
"text": [
"Discovery of liver-targeted inhibitors of stearoyl-CoA desaturase (SCD1)."
],
"offsets": [
[
0,
73
]
]
},
{
"id": "23265904_abstract",
"type": "abstract",
"text": [
"Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies."
],
"offsets": [
[
74,
1201
]
]
}
] | [
{
"id": "23265904_T1",
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"text": [
"spirocyclic piperidine"
],
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1075,
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],
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{
"id": "23265904_T2",
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"CoA"
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180,
183
]
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},
{
"id": "23265904_T3",
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96,
129
]
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{
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424,
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443,
451
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489,
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159,
178
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1025,
1045
]
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42,
54
]
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199,
203
]
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159,
197
]
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42,
65
]
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},
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"type": "GENE-Y",
"text": [
"SCD1"
],
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[
67,
71
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23265904_0",
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"arg2_id": "23265904_T16",
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},
{
"id": "23265904_1",
"type": "INHIBITOR",
"arg1_id": "23265904_T3",
"arg2_id": "23265904_T15",
"normalized": []
}
] |
23231967 | 23231967 | [
{
"id": "23231967_title",
"type": "title",
"text": [
"Selective and potent adenosine A3 receptor antagonists by methoxyaryl substitution on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold."
],
"offsets": [
[
0,
137
]
]
},
{
"id": "23231967_abstract",
"type": "abstract",
"text": [
"The influence of diverse methoxyphenyl substitution patterns on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold is herein explored in order to modulate the A(3) adenosine receptor antagonistic profile. As a result, novel ligands exhibiting excellent potency (K(i) on A(3) AR < 20 nM) and selectivity profiles (above 100-fold within the adenosine receptors family) are reported. Moreover, our joint theoretical and experimental approach allows the identification of novel pharmacophoric elements conferring A(3)AR selectivity, first established by a robust computational model and thereafter characterizing the most salient features of the structure-activity and structure-selectivity relationships in this series."
],
"offsets": [
[
138,
854
]
]
}
] | [
{
"id": "23231967_T1",
"type": "CHEMICAL",
"text": [
"adenosine"
],
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[
302,
311
]
],
"normalized": []
},
{
"id": "23231967_T2",
"type": "CHEMICAL",
"text": [
"methoxyphenyl"
],
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[
163,
176
]
],
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},
{
"id": "23231967_T3",
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"text": [
"adenosine"
],
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477,
486
]
],
"normalized": []
},
{
"id": "23231967_T4",
"type": "CHEMICAL",
"text": [
"N-(2,6-diarylpyrimidin-4-yl)acetamide"
],
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[
206,
243
]
],
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},
{
"id": "23231967_T5",
"type": "CHEMICAL",
"text": [
"adenosine"
],
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[
21,
30
]
],
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},
{
"id": "23231967_T6",
"type": "CHEMICAL",
"text": [
"methoxyaryl"
],
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[
58,
69
]
],
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},
{
"id": "23231967_T7",
"type": "CHEMICAL",
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],
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90,
127
]
],
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},
{
"id": "23231967_T8",
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"A(3) adenosine receptor"
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[
297,
320
]
],
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},
{
"id": "23231967_T9",
"type": "GENE-N",
"text": [
"adenosine receptors"
],
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[
477,
496
]
],
"normalized": []
},
{
"id": "23231967_T10",
"type": "GENE-Y",
"text": [
"A(3)AR"
],
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[
647,
653
]
],
"normalized": []
},
{
"id": "23231967_T11",
"type": "GENE-Y",
"text": [
"adenosine A3 receptor"
],
"offsets": [
[
21,
42
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23231967_0",
"type": "ANTAGONIST",
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"arg2_id": "23231967_T11",
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},
{
"id": "23231967_1",
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},
{
"id": "23231967_2",
"type": "ANTAGONIST",
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"arg2_id": "23231967_T8",
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},
{
"id": "23231967_3",
"type": "ANTAGONIST",
"arg1_id": "23231967_T4",
"arg2_id": "23231967_T8",
"normalized": []
}
] |
23505146 | 23505146 | [
{
"id": "23505146_title",
"type": "title",
"text": [
"Diverse effects of macromolecular crowding on the sequential glycan-processing pathway involved in glycoprotein quality control."
],
"offsets": [
[
0,
128
]
]
},
{
"id": "23505146_abstract",
"type": "abstract",
"text": [
"Compared with in vitro conditions, the intracellular environment is highly crowded with biomolecules; this has numerous effects on protein functions, including enzymatic activity. We examined the effects of macromolecular crowding on glycan processing of N-glycoprotein in the endoplasmic reticulum as a model sequential metabolic pathway. Experiments with synthetic substrates of physiological glycan structure clearly showed that the first half of the pathway (glucose trimming) was accelerated, whereas the second (mannose trimming) was decelerated under molecular crowding conditions. Furthermore, calreticulin, a lectin-like molecular chaperone, bound more strongly to a glycan-processing intermediate under these conditions. This study demonstrates the diverse effects of molecular crowding on sequential enzymatic processing, and the importance of the effects of macromolecular crowding on in vitro assays for understanding sequential metabolic pathways."
],
"offsets": [
[
129,
1090
]
]
}
] | [
{
"id": "23505146_T1",
"type": "CHEMICAL",
"text": [
"N"
],
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[
384,
385
]
],
"normalized": []
},
{
"id": "23505146_T2",
"type": "CHEMICAL",
"text": [
"glucose"
],
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[
592,
599
]
],
"normalized": []
},
{
"id": "23505146_T3",
"type": "CHEMICAL",
"text": [
"mannose"
],
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[
647,
654
]
],
"normalized": []
},
{
"id": "23505146_T4",
"type": "GENE-Y",
"text": [
"calreticulin"
],
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[
731,
743
]
],
"normalized": []
},
{
"id": "23505146_T5",
"type": "GENE-N",
"text": [
"lectin"
],
"offsets": [
[
747,
753
]
],
"normalized": []
}
] | [] | [] | [] |
23508961 | 23508961 | [
{
"id": "23508961_title",
"type": "title",
"text": [
"Agonist-induced Down-regulation of Endogenous Protein Kinase C α through an Endolysosomal Mechanism."
],
"offsets": [
[
0,
100
]
]
},
{
"id": "23508961_abstract",
"type": "abstract",
"text": [
"Protein kinase C (PKC) isozymes undergo down-regulation upon sustained stimulation. Previous studies have pointed to the existence of both proteasome-dependent and -independent pathways of PKCα processing. Here we demonstrate that these down-regulation pathways are engaged in different subcellular compartments; proteasomal degradation occurs mainly at the plasma membrane, whereas non-proteasomal processing occurs in the perinuclear region. Using cholesterol depletion, pharmacological inhibitors, RNA interference, and dominant-negative mutants, we define the mechanisms involved in perinuclear accumulation of PKCα and identify the non-proteasomal mechanism mediating its degradation. We show that intracellular accumulation of PKCα involves at least two clathrin-independent, cholesterol/lipid raft-mediated pathways that do not require ubiquitination of the protein; one is dynamin-dependent and likely involves caveolae, whereas the other is dynamin- and small GTPase-independent. Internalized PKCα traffics through endosomes and is delivered to the lysosome for degradation. Supportive evidence includes (a) detection of the enzyme in EEA1-positive early endosomes, Rab7-positive late endosomes/multivesicular bodies, and LAMP1-positive lysosomes and (b) inhibition of its down-regulation by lysosome-disrupting agents and leupeptin. Only limited dephosphorylation of PKCα occurs during trafficking, with fully mature enzyme being the main target for lysosomal degradation. These studies define a novel and widespread mechanism of desensitization of PKCα signaling that involves endocytic trafficking and lysosome-mediated degradation of the mature, fully phosphorylated protein."
],
"offsets": [
[
101,
1789
]
]
}
] | [
{
"id": "23508961_T1",
"type": "CHEMICAL",
"text": [
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],
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[
1433,
1442
]
],
"normalized": []
},
{
"id": "23508961_T2",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
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[
551,
562
]
],
"normalized": []
},
{
"id": "23508961_T3",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
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[
883,
894
]
],
"normalized": []
},
{
"id": "23508961_T4",
"type": "GENE-N",
"text": [
"Protein kinase C"
],
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[
101,
117
]
],
"normalized": []
},
{
"id": "23508961_T5",
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"text": [
"PKCα"
],
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[
1103,
1107
]
],
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},
{
"id": "23508961_T6",
"type": "GENE-Y",
"text": [
"EEA1"
],
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[
1245,
1249
]
],
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},
{
"id": "23508961_T7",
"type": "GENE-Y",
"text": [
"Rab7"
],
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[
1276,
1280
]
],
"normalized": []
},
{
"id": "23508961_T8",
"type": "GENE-Y",
"text": [
"LAMP1"
],
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[
1332,
1337
]
],
"normalized": []
},
{
"id": "23508961_T9",
"type": "GENE-Y",
"text": [
"PKCα"
],
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[
1478,
1482
]
],
"normalized": []
},
{
"id": "23508961_T10",
"type": "GENE-N",
"text": [
"proteasome"
],
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[
240,
250
]
],
"normalized": []
},
{
"id": "23508961_T11",
"type": "GENE-Y",
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"PKCα"
],
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[
1660,
1664
]
],
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},
{
"id": "23508961_T12",
"type": "GENE-N",
"text": [
"PKC"
],
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[
119,
122
]
],
"normalized": []
},
{
"id": "23508961_T13",
"type": "GENE-Y",
"text": [
"PKCα"
],
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[
290,
294
]
],
"normalized": []
},
{
"id": "23508961_T14",
"type": "GENE-Y",
"text": [
"PKCα"
],
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[
716,
720
]
],
"normalized": []
},
{
"id": "23508961_T15",
"type": "GENE-Y",
"text": [
"PKCα"
],
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[
834,
838
]
],
"normalized": []
},
{
"id": "23508961_T16",
"type": "GENE-N",
"text": [
"clathrin"
],
"offsets": [
[
861,
869
]
],
"normalized": []
},
{
"id": "23508961_T17",
"type": "GENE-N",
"text": [
"dynamin"
],
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[
982,
989
]
],
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},
{
"id": "23508961_T18",
"type": "GENE-N",
"text": [
"dynamin"
],
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[
1051,
1058
]
],
"normalized": []
},
{
"id": "23508961_T19",
"type": "GENE-N",
"text": [
"GTPase"
],
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[
1070,
1076
]
],
"normalized": []
},
{
"id": "23508961_T20",
"type": "GENE-Y",
"text": [
"Protein Kinase C α"
],
"offsets": [
[
46,
64
]
],
"normalized": []
}
] | [] | [] | [] |
15686475 | 15686475 | [
{
"id": "15686475_title",
"type": "title",
"text": [
"Effect of apocalmodulin on recombinant human brain glutamic acid decarboxylase."
],
"offsets": [
[
0,
79
]
]
},
{
"id": "15686475_abstract",
"type": "abstract",
"text": [
"In this work, we report that the recombinant glutathione S-transferase (GST)-human L-glutamic acid decarboxylase (HGAD) isoforms, 65-kDa L-glutamic acid decarboxylase (GAD) (GST-HGAD65) fusion protein or free truncated HGAD65, were activated by apocalmodulin (ApoCaM) to an extent of 60%. Both truncated forms of GAD67 (tGAD67), HGAD67(Delta1-70) and HGAD67(Delta1-90), were markedly activated by ApoCaM to an extent of 141 and 85%, respectively, while GST-HGAD67 was not significantly affected. The activation appears to be due to an increase of GAD affinity for its cofactor, pyridoxal phosphate (PLP). This conclusion is based on the following observations. Firstly, the V(max) of GAD was increased when ApoCaM was present whereas the affinity for the substrate, glutamate, was not affected. Secondly, the affinity of GAD for PLP was increased in the presence of ApoCaM. Thirdly, results from calmodulin-agarose affinity column chromatography studies indicated a direct interaction or binding between ApoCaM and GAD. Fourthly, ApoCaM was found to be copurified with GAD65/GAD67 by anti-GAD65/67 immunoaffinity column using rat brain extract. Hence, it is proposed that a conformational change is induced when ApoCaM interacts with GAD65 or tGAD67, resulting in an increase of GAD affinity for PLP and the activation of GAD. The physiological significance of the interaction between GAD and ApoCaM is discussed."
],
"offsets": [
[
80,
1493
]
]
}
] | [
{
"id": "15686475_T1",
"type": "CHEMICAL",
"text": [
"PLP"
],
"offsets": [
[
1376,
1379
]
],
"normalized": []
},
{
"id": "15686475_T2",
"type": "CHEMICAL",
"text": [
"L-glutamic acid"
],
"offsets": [
[
217,
232
]
],
"normalized": []
},
{
"id": "15686475_T3",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
125,
136
]
],
"normalized": []
},
{
"id": "15686475_T4",
"type": "CHEMICAL",
"text": [
"S"
],
"offsets": [
[
137,
138
]
],
"normalized": []
},
{
"id": "15686475_T5",
"type": "CHEMICAL",
"text": [
"pyridoxal phosphate"
],
"offsets": [
[
658,
677
]
],
"normalized": []
},
{
"id": "15686475_T6",
"type": "CHEMICAL",
"text": [
"PLP"
],
"offsets": [
[
679,
682
]
],
"normalized": []
},
{
"id": "15686475_T7",
"type": "CHEMICAL",
"text": [
"glutamate"
],
"offsets": [
[
846,
855
]
],
"normalized": []
},
{
"id": "15686475_T8",
"type": "CHEMICAL",
"text": [
"PLP"
],
"offsets": [
[
909,
912
]
],
"normalized": []
},
{
"id": "15686475_T9",
"type": "CHEMICAL",
"text": [
"L-glutamic acid"
],
"offsets": [
[
163,
178
]
],
"normalized": []
},
{
"id": "15686475_T10",
"type": "CHEMICAL",
"text": [
"glutamic acid"
],
"offsets": [
[
51,
64
]
],
"normalized": []
},
{
"id": "15686475_T11",
"type": "GENE-Y",
"text": [
"ApoCaM"
],
"offsets": [
[
1084,
1090
]
],
"normalized": []
},
{
"id": "15686475_T12",
"type": "GENE-Y",
"text": [
"GAD"
],
"offsets": [
[
1095,
1098
]
],
"normalized": []
},
{
"id": "15686475_T13",
"type": "GENE-Y",
"text": [
"ApoCaM"
],
"offsets": [
[
1110,
1116
]
],
"normalized": []
},
{
"id": "15686475_T14",
"type": "GENE-Y",
"text": [
"GAD65"
],
"offsets": [
[
1149,
1154
]
],
"normalized": []
},
{
"id": "15686475_T15",
"type": "GENE-Y",
"text": [
"GAD67"
],
"offsets": [
[
1155,
1160
]
],
"normalized": []
},
{
"id": "15686475_T16",
"type": "GENE-N",
"text": [
"GAD65/67"
],
"offsets": [
[
1169,
1177
]
],
"normalized": []
},
{
"id": "15686475_T17",
"type": "GENE-Y",
"text": [
"HGAD"
],
"offsets": [
[
194,
198
]
],
"normalized": []
},
{
"id": "15686475_T18",
"type": "GENE-Y",
"text": [
"ApoCaM"
],
"offsets": [
[
1292,
1298
]
],
"normalized": []
},
{
"id": "15686475_T19",
"type": "GENE-Y",
"text": [
"GAD65"
],
"offsets": [
[
1314,
1319
]
],
"normalized": []
},
{
"id": "15686475_T20",
"type": "GENE-Y",
"text": [
"tGAD67"
],
"offsets": [
[
1323,
1329
]
],
"normalized": []
},
{
"id": "15686475_T21",
"type": "GENE-Y",
"text": [
"GAD"
],
"offsets": [
[
1359,
1362
]
],
"normalized": []
},
{
"id": "15686475_T22",
"type": "GENE-Y",
"text": [
"65-kDa L-glutamic acid decarboxylase"
],
"offsets": [
[
210,
246
]
],
"normalized": []
},
{
"id": "15686475_T23",
"type": "GENE-Y",
"text": [
"GAD"
],
"offsets": [
[
1402,
1405
]
],
"normalized": []
},
{
"id": "15686475_T24",
"type": "GENE-Y",
"text": [
"GAD"
],
"offsets": [
[
1465,
1468
]
],
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39,
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}
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}
] |
23281613 | 23281613 | [
{
"id": "23281613_title",
"type": "title",
"text": [
"Two new ent-3,4-seco-labdane diterpenoids from Callicarpa nudiflora."
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0,
68
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]
},
{
"id": "23281613_abstract",
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"Two new ent-3,4-seco-labdane diterpenoids, methylcallicarpate (1) and callicarpic acid (2), were isolated from the leaves of Callicarpa nudiflora Hook et Arn. Their structures and relative configurations were established by analysis of spectroscopic data. Their absolute configurations were assigned by the application of the CD technique for the first time among the ent-3,4-seco-labdane-type diterpenes."
],
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69,
474
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]
}
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]
],
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}
] | [] | [] | [] |
10208491 | 10208491 | [
{
"id": "10208491_title",
"type": "title",
"text": [
"Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases."
],
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]
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"id": "10208491_abstract",
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"text": [
"Elevated plasma homocysteine is increasingly being recognized as a risk factor for coronary artery disease (CAD). Although there is general agreement on the importance of micronutrients and genetic predisposition to elevated plasma homocysteine, the exact influence of the known prevalent mutations in genes which regulate homocysteine metabolism is not clear. We studied 376 cases of individuals with premature CAD with respect to their fasting and post-methionine load (PML) total homocysteine (tHcy) concentrations. We also determined the presence or absence of the T833C and G919A mutations of the cystathionine-beta-synthase (CBS) gene, the C677T mutation of the methylene tetrahydrofolate reductase (MTHFR) gene, and the A2756G transition of the B12 dependent methionine synthase (MS) gene. Our objectives were therefore both to confirm the relationship of plasma homocysteine with premature CAD and to examine the importance of genetic influence on both fasting and PML homocysteine. Approximately 32% of the CAD patients had fasting hyperhomocysteinemia and 16% had PML hyperhomocysteinemia. Of these, 8.5% had both forms of hyperhomocysteinemia (combined hyperhomocysteinemia). The T133C mutation in the CBS gene and the thermolabile C677T mutation in the MTHFR gene seem to play an important role in the subset of individuals with combined hyperhomocysteinemia. The A2756G transition in the MS gene is not associated with elevated plasma tHcy. Many cases (47%) of hyperhomocysteinemia are not associated with micronutrient deficiencies, impaired renal function, and/or currently known genetic mutations. Further work is needed to study whether unknown mutations, particularly those residing in the intronic sequences of the genes involved in homocysteine metabolism, other environmental factors, or interaction of gene, nutrient, and environmental factors may be the cause of currently unexplained cases of mild hyperhomocysteinemia."
],
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107,
2050
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]
}
] | [
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]
],
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123,
135
]
],
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1859,
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430,
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]
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562,
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]
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"homocysteine"
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590,
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]
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"tHcy"
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604,
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]
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"cystathionine"
],
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709,
722
]
],
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"id": "10208491_T10",
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775,
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]
],
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"methionine"
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]
],
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"homocysteine"
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977,
989
]
],
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},
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"homocysteine"
],
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[
1084,
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]
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},
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"T133C"
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1298,
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]
],
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]
],
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1355
]
],
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},
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"MTHFR"
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1372,
1377
]
],
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]
],
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},
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"MS"
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1510
]
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"T833C"
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676,
681
]
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"G919A"
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686,
691
]
],
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},
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"cystathionine-beta-synthase"
],
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[
709,
736
]
],
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},
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"id": "10208491_T23",
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"CBS"
],
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[
738,
741
]
],
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},
{
"id": "10208491_T24",
"type": "GENE-N",
"text": [
"C677T"
],
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[
753,
758
]
],
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},
{
"id": "10208491_T25",
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"methylene tetrahydrofolate reductase"
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[
775,
811
]
],
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},
{
"id": "10208491_T26",
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"MTHFR"
],
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[
813,
818
]
],
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},
{
"id": "10208491_T27",
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"A2756G"
],
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[
834,
840
]
],
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},
{
"id": "10208491_T28",
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"text": [
"methionine synthase"
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[
873,
892
]
],
"normalized": []
},
{
"id": "10208491_T29",
"type": "GENE-Y",
"text": [
"MS"
],
"offsets": [
[
894,
896
]
],
"normalized": []
}
] | [] | [] | [] |
23312283 | 23312283 | [
{
"id": "23312283_title",
"type": "title",
"text": [
"Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation."
],
"offsets": [
[
0,
118
]
]
},
{
"id": "23312283_abstract",
"type": "abstract",
"text": [
"Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis."
],
"offsets": [
[
119,
1171
]
]
}
] | [
{
"id": "23312283_T1",
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"trimethylamine-N-oxide"
],
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[
131,
153
]
],
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},
{
"id": "23312283_T2",
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"TMAO"
],
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[
279,
283
]
],
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},
{
"id": "23312283_T3",
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"flavin"
],
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[
316,
322
]
],
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},
{
"id": "23312283_T4",
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],
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377,
391
]
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},
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"id": "23312283_T5",
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393,
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]
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"id": "23312283_T6",
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"choline"
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436,
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]
],
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],
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448,
452
]
],
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},
{
"id": "23312283_T8",
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"TMAO"
],
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[
155,
159
]
],
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},
{
"id": "23312283_T9",
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"TMAO"
],
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[
593,
597
]
],
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},
{
"id": "23312283_T10",
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"TMAO"
],
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636,
640
]
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},
{
"id": "23312283_T11",
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"androgens"
],
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[
820,
829
]
],
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},
{
"id": "23312283_T12",
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"bile acids"
],
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[
869,
879
]
],
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},
{
"id": "23312283_T13",
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"text": [
"bile acid"
],
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[
943,
952
]
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{
"id": "23312283_T14",
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"TMAO"
],
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1072,
1076
]
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{
"id": "23312283_T15",
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"TMAO"
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1111,
1115
]
],
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{
"id": "23312283_T16",
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"text": [
"Trimethylamine-N-oxide"
],
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[
0,
22
]
],
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"id": "23312283_T17",
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316,
337
]
],
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},
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"id": "23312283_T18",
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"FMO1"
],
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354,
358
]
],
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},
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"id": "23312283_T19",
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"FMO3"
],
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363,
367
]
],
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},
{
"id": "23312283_T20",
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"FMO3"
],
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[
476,
480
]
],
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},
{
"id": "23312283_T21",
"type": "GENE-Y",
"text": [
"FMO1"
],
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[
528,
532
]
],
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},
{
"id": "23312283_T22",
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"text": [
"FMO3"
],
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[
534,
538
]
],
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},
{
"id": "23312283_T23",
"type": "GENE-Y",
"text": [
"FMO3"
],
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[
621,
625
]
],
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},
{
"id": "23312283_T24",
"type": "GENE-Y",
"text": [
"FMO3"
],
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[
682,
686
]
],
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},
{
"id": "23312283_T25",
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"text": [
"FMO3"
],
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766,
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},
{
"id": "23312283_T26",
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"text": [
"FMO3"
],
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831,
835
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],
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},
{
"id": "23312283_T27",
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913,
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935,
938
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"text": [
"FMO3"
],
"offsets": [
[
1063,
1067
]
],
"normalized": []
}
] | [] | [] | [
{
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}
] |
9670923 | 9670923 | [
{
"id": "9670923_title",
"type": "title",
"text": [
"Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family."
],
"offsets": [
[
0,
106
]
]
},
{
"id": "9670923_abstract",
"type": "abstract",
"text": [
"Voltage-activated Ca2+ channels exist as multigene families that share common structural features. Different Ca2+ channels are distinguished by their electrophysiology and pharmacology and can be classified as either low or high voltage-activated channels. Six alpha1 subunit genes cloned previously code for high voltage-activated Ca2+ channels; therefore, we have used a database search strategy to identify new Ca2+ channel genes, possibly including low voltage-activated (T-type) channels. A novel expressed sequence-tagged cDNA clone of alpha1G was used to screen a cDNA library, and in the present study, we report the cloning of alpha1H (or CavT.2), a low voltage-activated Ca2+ channel from human heart. Northern blots of human mRNA detected more alpha1H expression in peripheral tissues, such as kidney and heart, than in brain. We mapped the gene, CACNA1H, to human chromosome 16p13.3 and mouse chromosome 17. Expression of alpha1H in HEK-293 cells resulted in Ca2+ channel currents displaying voltage dependence, kinetics, and unitary conductance characteristic of native T-type Ca2+ channels. The alpha1H channel is sensitive to mibefradil, a nondihydropyridine Ca2+ channel blocker, with an IC50 of 1.4 micromol/L, consistent with the reported potency of mibefradil for T-type Ca2+ channels. Together with alpha1G, a rat brain T-type Ca2+ channel also cloned in our laboratory, these genes define a unique family of Ca2+ channels."
],
"offsets": [
[
107,
1550
]
]
}
] | [
{
"id": "9670923_T1",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
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[
1197,
1201
]
],
"normalized": []
},
{
"id": "9670923_T2",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
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[
216,
220
]
],
"normalized": []
},
{
"id": "9670923_T3",
"type": "CHEMICAL",
"text": [
"mibefradil"
],
"offsets": [
[
1248,
1258
]
],
"normalized": []
},
{
"id": "9670923_T4",
"type": "CHEMICAL",
"text": [
"nondihydropyridine Ca2+"
],
"offsets": [
[
1262,
1285
]
],
"normalized": []
},
{
"id": "9670923_T5",
"type": "CHEMICAL",
"text": [
"mibefradil"
],
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[
1375,
1385
]
],
"normalized": []
},
{
"id": "9670923_T6",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
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[
1397,
1401
]
],
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},
{
"id": "9670923_T7",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
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[
1454,
1458
]
],
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},
{
"id": "9670923_T8",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
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[
1536,
1540
]
],
"normalized": []
},
{
"id": "9670923_T9",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
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[
125,
129
]
],
"normalized": []
},
{
"id": "9670923_T10",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
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[
439,
443
]
],
"normalized": []
},
{
"id": "9670923_T11",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
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[
521,
525
]
],
"normalized": []
},
{
"id": "9670923_T12",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
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[
788,
792
]
],
"normalized": []
},
{
"id": "9670923_T13",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
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[
1078,
1082
]
],
"normalized": []
},
{
"id": "9670923_T14",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
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[
81,
85
]
],
"normalized": []
},
{
"id": "9670923_T15",
"type": "GENE-N",
"text": [
"Voltage-activated Ca2+ channels"
],
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[
107,
138
]
],
"normalized": []
},
{
"id": "9670923_T16",
"type": "GENE-N",
"text": [
"T-type Ca2+ channels"
],
"offsets": [
[
1190,
1210
]
],
"normalized": []
},
{
"id": "9670923_T17",
"type": "GENE-N",
"text": [
"Ca2+ channels"
],
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[
216,
229
]
],
"normalized": []
},
{
"id": "9670923_T18",
"type": "GENE-N",
"text": [
"alpha1H channel"
],
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[
1216,
1231
]
],
"normalized": []
},
{
"id": "9670923_T19",
"type": "GENE-N",
"text": [
"Ca2+ channel"
],
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[
1281,
1293
]
],
"normalized": []
},
{
"id": "9670923_T20",
"type": "GENE-Y",
"text": [
"T-type Ca2+ channels"
],
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[
1390,
1410
]
],
"normalized": []
},
{
"id": "9670923_T21",
"type": "GENE-Y",
"text": [
"alpha1G"
],
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[
1426,
1433
]
],
"normalized": []
},
{
"id": "9670923_T22",
"type": "GENE-N",
"text": [
"rat brain T-type Ca2+ channel"
],
"offsets": [
[
1437,
1466
]
],
"normalized": []
},
{
"id": "9670923_T23",
"type": "GENE-N",
"text": [
"Ca2+ channels"
],
"offsets": [
[
1536,
1549
]
],
"normalized": []
},
{
"id": "9670923_T24",
"type": "GENE-N",
"text": [
"low or high voltage-activated channels"
],
"offsets": [
[
324,
362
]
],
"normalized": []
},
{
"id": "9670923_T25",
"type": "GENE-N",
"text": [
"alpha1"
],
"offsets": [
[
368,
374
]
],
"normalized": []
},
{
"id": "9670923_T26",
"type": "GENE-N",
"text": [
"high voltage-activated Ca2+ channels"
],
"offsets": [
[
416,
452
]
],
"normalized": []
},
{
"id": "9670923_T27",
"type": "GENE-N",
"text": [
"Ca2+ channel"
],
"offsets": [
[
521,
533
]
],
"normalized": []
},
{
"id": "9670923_T28",
"type": "GENE-N",
"text": [
"low voltage-activated (T-type) channels"
],
"offsets": [
[
560,
599
]
],
"normalized": []
},
{
"id": "9670923_T29",
"type": "GENE-Y",
"text": [
"alpha1G"
],
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[
649,
656
]
],
"normalized": []
},
{
"id": "9670923_T30",
"type": "GENE-Y",
"text": [
"alpha1H"
],
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[
743,
750
]
],
"normalized": []
},
{
"id": "9670923_T31",
"type": "GENE-Y",
"text": [
"CavT.2"
],
"offsets": [
[
755,
761
]
],
"normalized": []
},
{
"id": "9670923_T32",
"type": "GENE-N",
"text": [
"low voltage-activated Ca2+ channel"
],
"offsets": [
[
766,
800
]
],
"normalized": []
},
{
"id": "9670923_T33",
"type": "GENE-Y",
"text": [
"alpha1H"
],
"offsets": [
[
862,
869
]
],
"normalized": []
},
{
"id": "9670923_T34",
"type": "GENE-N",
"text": [
"CACNA1H"
],
"offsets": [
[
965,
972
]
],
"normalized": []
},
{
"id": "9670923_T35",
"type": "GENE-Y",
"text": [
"alpha1H"
],
"offsets": [
[
1041,
1048
]
],
"normalized": []
},
{
"id": "9670923_T36",
"type": "GENE-N",
"text": [
"Ca2+ channel"
],
"offsets": [
[
1078,
1090
]
],
"normalized": []
},
{
"id": "9670923_T37",
"type": "GENE-Y",
"text": [
"alpha1H"
],
"offsets": [
[
32,
39
]
],
"normalized": []
},
{
"id": "9670923_T38",
"type": "GENE-N",
"text": [
"T-type Ca2+ channel"
],
"offsets": [
[
74,
93
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "9670923_0",
"type": "INHIBITOR",
"arg1_id": "9670923_T3",
"arg2_id": "9670923_T19",
"normalized": []
}
] |
23541982 | 23541982 | [
{
"id": "23541982_title",
"type": "title",
"text": [
"Potential diagnostic applications of side chain oxysterols analysis in plasma and cerebrospinal fluid."
],
"offsets": [
[
0,
102
]
]
},
{
"id": "23541982_abstract",
"type": "abstract",
"text": [
"The neurospecific cholesterol 24-hydroxylase converts excess brain cholesterol into 24S-hydroxycholesterol (24OHC) which, via the liver X receptor (LXR), can increase the expression and synthesis of astrocyte ApoE. 24OHC effluxes directly from brain into plasma where it is considered an indicator of brain cholesterol turnover. It is reduced in neurodegenerative disease states proportionally to the severity of disease and the degree of brain atrophy. In the early phases of active disease, a higher rate of turnover may result in transitory increases in plasma 24OHC. Less than 1% of the total brain excretion of 24OHC occurs via the cerebrospinal fluid (CSF) whereas almost all 27-hydroxycholesterol (27OHC) excretion is dependent on the function of the blood-cerebrospinal fluid barrier. Iincreased CSF oxysterols were found in patients with neurodegenerative and neuroinflammatory diseases in the presence of barrier dysfunction. In neurodegeneration, free cholesterol released from dying cells may engulf neurons. Cholesterol also increases Amyloid β (Aβ) deposition and tau pathology. ApoE, 24OHC, tau and soluble APP were correlated in Alzheimer disease (AD) samples. Excess of cholesterol converted into 24OHC may up-regulate ApoE synthesis which is a scavenger for Aβ and Tau. In AD this protective mechanism seems to be inefficient, probably due to the presence of high concentrations of 27OHC, microvascular dysfunction and the decreased efficiency of ApoE4 as lipid transporter and Aβ scavenger. 24OHC itself was cytotoxic. Analysis of side chain oxysterols in the CSF is likely to provided useful information about cholesterol metabolism and ApoE function in the pathogenesis of AD."
],
"offsets": [
[
103,
1800
]
]
}
] | [
{
"id": "23541982_T1",
"type": "CHEMICAL",
"text": [
"Cholesterol"
],
"offsets": [
[
1124,
1135
]
],
"normalized": []
},
{
"id": "23541982_T2",
"type": "CHEMICAL",
"text": [
"24OHC"
],
"offsets": [
[
211,
216
]
],
"normalized": []
},
{
"id": "23541982_T3",
"type": "CHEMICAL",
"text": [
"24OHC"
],
"offsets": [
[
1202,
1207
]
],
"normalized": []
},
{
"id": "23541982_T4",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
1290,
1301
]
],
"normalized": []
},
{
"id": "23541982_T5",
"type": "CHEMICAL",
"text": [
"24OHC"
],
"offsets": [
[
1317,
1322
]
],
"normalized": []
},
{
"id": "23541982_T6",
"type": "CHEMICAL",
"text": [
"27OHC"
],
"offsets": [
[
1503,
1508
]
],
"normalized": []
},
{
"id": "23541982_T7",
"type": "CHEMICAL",
"text": [
"24OHC"
],
"offsets": [
[
1613,
1618
]
],
"normalized": []
},
{
"id": "23541982_T8",
"type": "CHEMICAL",
"text": [
"oxysterols"
],
"offsets": [
[
1664,
1674
]
],
"normalized": []
},
{
"id": "23541982_T9",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
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[
1733,
1744
]
],
"normalized": []
},
{
"id": "23541982_T10",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
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[
121,
132
]
],
"normalized": []
},
{
"id": "23541982_T11",
"type": "CHEMICAL",
"text": [
"24OHC"
],
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[
318,
323
]
],
"normalized": []
},
{
"id": "23541982_T12",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
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[
410,
421
]
],
"normalized": []
},
{
"id": "23541982_T13",
"type": "CHEMICAL",
"text": [
"24OHC"
],
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[
667,
672
]
],
"normalized": []
},
{
"id": "23541982_T14",
"type": "CHEMICAL",
"text": [
"24OHC"
],
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[
719,
724
]
],
"normalized": []
},
{
"id": "23541982_T15",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
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[
170,
181
]
],
"normalized": []
},
{
"id": "23541982_T16",
"type": "CHEMICAL",
"text": [
"27-hydroxycholesterol"
],
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[
785,
806
]
],
"normalized": []
},
{
"id": "23541982_T17",
"type": "CHEMICAL",
"text": [
"27OHC"
],
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[
808,
813
]
],
"normalized": []
},
{
"id": "23541982_T18",
"type": "CHEMICAL",
"text": [
"oxysterols"
],
"offsets": [
[
911,
921
]
],
"normalized": []
},
{
"id": "23541982_T19",
"type": "CHEMICAL",
"text": [
"24S-hydroxycholesterol"
],
"offsets": [
[
187,
209
]
],
"normalized": []
},
{
"id": "23541982_T20",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
1066,
1077
]
],
"normalized": []
},
{
"id": "23541982_T21",
"type": "CHEMICAL",
"text": [
"oxysterols"
],
"offsets": [
[
48,
58
]
],
"normalized": []
},
{
"id": "23541982_T22",
"type": "GENE-Y",
"text": [
"Amyloid β"
],
"offsets": [
[
1151,
1160
]
],
"normalized": []
},
{
"id": "23541982_T23",
"type": "GENE-Y",
"text": [
"Aβ"
],
"offsets": [
[
1162,
1164
]
],
"normalized": []
},
{
"id": "23541982_T24",
"type": "GENE-Y",
"text": [
"tau"
],
"offsets": [
[
1181,
1184
]
],
"normalized": []
},
{
"id": "23541982_T25",
"type": "GENE-Y",
"text": [
"ApoE"
],
"offsets": [
[
1196,
1200
]
],
"normalized": []
},
{
"id": "23541982_T26",
"type": "GENE-Y",
"text": [
"tau"
],
"offsets": [
[
1209,
1212
]
],
"normalized": []
},
{
"id": "23541982_T27",
"type": "GENE-Y",
"text": [
"soluble APP"
],
"offsets": [
[
1217,
1228
]
],
"normalized": []
},
{
"id": "23541982_T28",
"type": "GENE-Y",
"text": [
"ApoE"
],
"offsets": [
[
1339,
1343
]
],
"normalized": []
},
{
"id": "23541982_T29",
"type": "GENE-Y",
"text": [
"Aβ"
],
"offsets": [
[
1379,
1381
]
],
"normalized": []
},
{
"id": "23541982_T30",
"type": "GENE-Y",
"text": [
"Tau"
],
"offsets": [
[
1386,
1389
]
],
"normalized": []
},
{
"id": "23541982_T31",
"type": "GENE-N",
"text": [
"liver X receptor"
],
"offsets": [
[
233,
249
]
],
"normalized": []
},
{
"id": "23541982_T32",
"type": "GENE-Y",
"text": [
"ApoE4"
],
"offsets": [
[
1568,
1573
]
],
"normalized": []
},
{
"id": "23541982_T33",
"type": "GENE-N",
"text": [
"LXR"
],
"offsets": [
[
251,
254
]
],
"normalized": []
},
{
"id": "23541982_T34",
"type": "GENE-Y",
"text": [
"Aβ"
],
"offsets": [
[
1599,
1601
]
],
"normalized": []
},
{
"id": "23541982_T35",
"type": "GENE-Y",
"text": [
"ApoE"
],
"offsets": [
[
1760,
1764
]
],
"normalized": []
},
{
"id": "23541982_T36",
"type": "GENE-Y",
"text": [
"ApoE"
],
"offsets": [
[
312,
316
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23541982_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23541982_T5",
"arg2_id": "23541982_T28",
"normalized": []
},
{
"id": "23541982_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23541982_T4",
"arg2_id": "23541982_T28",
"normalized": []
}
] |
23411217 | 23411217 | [
{
"id": "23411217_title",
"type": "title",
"text": [
"Peyer's patch-mediated intestinal immune system modulating activity of pectic-type polysaccharide from peel of Citrus unshiu."
],
"offsets": [
[
0,
125
]
]
},
{
"id": "23411217_abstract",
"type": "abstract",
"text": [
"An intestinal immune system modulating polysaccharide (CUI-3IIb-3-2, 18kDa) was purified from Citrus unshiu peel. CUI-3IIb-3-2 mainly comprised GalA, GlcA, Ara, Gal and Rha, and it consisted of 4-linked GalA, terminal Araf, 4- or 5-linked/3,4- or 3,5-branched Ara, terminal Gal, and 2-linked/2,4-branched Rha. After CUI-3IIb-3-2 digestion by endo-α-d-(1→4)-polygalacturonase, its hydrolysate was fractionated into PG-1 and PG-2. Methylation analyses of PG-1 and PG-2 using base-catalysed β-elimination suggested that CUI-3IIb-3-2 be assumed as pectic-type polysaccharide. Since the activities of PG-1 and PG-2 were potently decreased, the whole polysaccharide structure of CUI-3IIb-3-2 would be essential to maintain the activity. Meanwhile, when CUI-3IIb was orally administered in mice, bone marrow cell proliferation and GM-CSF/IL-6 production from Peyer's patch cell were significantly higher (1.76- and 2.03/2.51-fold, respectively) than a saline. Therefore, a pectic-type polysaccharide from citrus peel could stimulate Peyer's patches and produce hematopoietic growth factors resulted in bone marrow cell proliferation."
],
"offsets": [
[
126,
1252
]
]
}
] | [
{
"id": "23411217_T1",
"type": "CHEMICAL",
"text": [
"GalA"
],
"offsets": [
[
270,
274
]
],
"normalized": []
},
{
"id": "23411217_T2",
"type": "CHEMICAL",
"text": [
"GlcA"
],
"offsets": [
[
276,
280
]
],
"normalized": []
},
{
"id": "23411217_T3",
"type": "CHEMICAL",
"text": [
"Ara"
],
"offsets": [
[
282,
285
]
],
"normalized": []
},
{
"id": "23411217_T4",
"type": "CHEMICAL",
"text": [
"Gal"
],
"offsets": [
[
287,
290
]
],
"normalized": []
},
{
"id": "23411217_T5",
"type": "CHEMICAL",
"text": [
"Rha"
],
"offsets": [
[
295,
298
]
],
"normalized": []
},
{
"id": "23411217_T6",
"type": "CHEMICAL",
"text": [
"GalA"
],
"offsets": [
[
329,
333
]
],
"normalized": []
},
{
"id": "23411217_T7",
"type": "CHEMICAL",
"text": [
"Araf"
],
"offsets": [
[
344,
348
]
],
"normalized": []
},
{
"id": "23411217_T8",
"type": "CHEMICAL",
"text": [
"Ara"
],
"offsets": [
[
386,
389
]
],
"normalized": []
},
{
"id": "23411217_T9",
"type": "CHEMICAL",
"text": [
"Gal"
],
"offsets": [
[
400,
403
]
],
"normalized": []
},
{
"id": "23411217_T10",
"type": "CHEMICAL",
"text": [
"Rha"
],
"offsets": [
[
431,
434
]
],
"normalized": []
},
{
"id": "23411217_T11",
"type": "GENE-N",
"text": [
"polygalacturonase"
],
"offsets": [
[
483,
500
]
],
"normalized": []
},
{
"id": "23411217_T12",
"type": "GENE-Y",
"text": [
"IL-6"
],
"offsets": [
[
957,
961
]
],
"normalized": []
}
] | [] | [] | [] |
18549347 | 18549347 | [
{
"id": "18549347_title",
"type": "title",
"text": [
"An expert opinion on safinamide in Parkinson's disease."
],
"offsets": [
[
0,
55
]
]
},
{
"id": "18549347_abstract",
"type": "abstract",
"text": [
"BACKGROUND: Dopamine replacement therapies (levodopa, dopamine receptor agonists, anticholinergics, monoamine oxidase B inhibitors, and catechol-O-methyltransferase inhibitors) remain the cornerstones of therapeutic interventions for Parkinson's disease (PD). Despite the treatment options for PD symptoms, a cure remains elusive. An optimal treatment would be one that combined relief in both motor and nonmotor symptoms with neuroprotective properties. Safinamide is an investigational drug for PD currently in development as add-on therapy to both dopamine agonists and levodopa. Safinamide is a unique molecule with a novel mode of action, targeting both dopaminergic and glutaminergic systems, and potentially provides motor symptom control. Preliminary results from experimental models suggest potential neuroprotective effects. Studies on the potential effects on nonmotor symptoms are ongoing. OBJECTIVE: To review the mechanism of action and pharmacokinetics, and to evaluate the available clinical safety and efficacy results of safinamide. METHODS: A search of the electronic database MEDLINE (PubMed, no time limits) was performed on 14 December 2007. The full text of all citations was obtained for review. Furthermore, two abstracts on safinamide published as proceedings of a European conference were reviewed. RESULTS/CONCLUSION: Safinamide is a promising investigational drug for PD with a novel mode of action. Early reports confirm the potential efficacy of safinamide in PD. Further studies on potential effects on cognition and neuroprotection are needed."
],
"offsets": [
[
56,
1632
]
]
}
] | [
{
"id": "18549347_T1",
"type": "CHEMICAL",
"text": [
"monoamine"
],
"offsets": [
[
156,
165
]
],
"normalized": []
},
{
"id": "18549347_T2",
"type": "CHEMICAL",
"text": [
"safinamide"
],
"offsets": [
[
1095,
1105
]
],
"normalized": []
},
{
"id": "18549347_T3",
"type": "CHEMICAL",
"text": [
"Dopamine"
],
"offsets": [
[
68,
76
]
],
"normalized": []
},
{
"id": "18549347_T4",
"type": "CHEMICAL",
"text": [
"safinamide"
],
"offsets": [
[
1306,
1316
]
],
"normalized": []
},
{
"id": "18549347_T5",
"type": "CHEMICAL",
"text": [
"Safinamide"
],
"offsets": [
[
1402,
1412
]
],
"normalized": []
},
{
"id": "18549347_T6",
"type": "CHEMICAL",
"text": [
"catechol"
],
"offsets": [
[
192,
200
]
],
"normalized": []
},
{
"id": "18549347_T7",
"type": "CHEMICAL",
"text": [
"safinamide"
],
"offsets": [
[
1533,
1543
]
],
"normalized": []
},
{
"id": "18549347_T8",
"type": "CHEMICAL",
"text": [
"levodopa"
],
"offsets": [
[
100,
108
]
],
"normalized": []
},
{
"id": "18549347_T9",
"type": "CHEMICAL",
"text": [
"Safinamide"
],
"offsets": [
[
511,
521
]
],
"normalized": []
},
{
"id": "18549347_T10",
"type": "CHEMICAL",
"text": [
"dopamine"
],
"offsets": [
[
110,
118
]
],
"normalized": []
},
{
"id": "18549347_T11",
"type": "CHEMICAL",
"text": [
"dopamine"
],
"offsets": [
[
607,
615
]
],
"normalized": []
},
{
"id": "18549347_T12",
"type": "CHEMICAL",
"text": [
"levodopa"
],
"offsets": [
[
629,
637
]
],
"normalized": []
},
{
"id": "18549347_T13",
"type": "CHEMICAL",
"text": [
"Safinamide"
],
"offsets": [
[
639,
649
]
],
"normalized": []
},
{
"id": "18549347_T14",
"type": "CHEMICAL",
"text": [
"safinamide"
],
"offsets": [
[
21,
31
]
],
"normalized": []
},
{
"id": "18549347_T15",
"type": "GENE-Y",
"text": [
"monoamine oxidase B"
],
"offsets": [
[
156,
175
]
],
"normalized": []
},
{
"id": "18549347_T16",
"type": "GENE-Y",
"text": [
"catechol-O-methyltransferase"
],
"offsets": [
[
192,
220
]
],
"normalized": []
},
{
"id": "18549347_T17",
"type": "GENE-N",
"text": [
"dopamine receptor"
],
"offsets": [
[
110,
127
]
],
"normalized": []
}
] | [] | [] | [] |
10368299 | 10368299 | [
{
"id": "10368299_title",
"type": "title",
"text": [
"Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs."
],
"offsets": [
[
0,
122
]
]
},
{
"id": "10368299_abstract",
"type": "abstract",
"text": [
"BACKGROUND: Several cholinesterase inhibitors are either being utilized for symptomatic treatment of Alzheimer's disease or are in advanced clinical trials. E2020, marketed as Aricept, is a member of a large family of N-benzylpiperidine-based acetylcholinesterase (AChE) inhibitors developed, synthesized and evaluated by the Eisai Company in Japan. These inhibitors were designed on the basis of QSAR studies, prior to elucidation of the three-dimensional structure of Torpedo californica AChE (TcAChE). It significantly enhances performance in animal models of cholinergic hypofunction and has a high affinity for AChE, binding to both electric eel and mouse AChE in the nanomolar range. RESULTS: Our experimental structure of the E2020-TcAChE complex pinpoints specific interactions responsible for the high affinity and selectivity demonstrated previously. It shows that E2020 has a unique orientation along the active-site gorge, extending from the anionic subsite of the active site, at the bottom, to the peripheral anionic site, at the top, via aromatic stacking interactions with conserved aromatic acid residues. E2020 does not, however, interact directly with either the catalytic triad or the 'oxyanion hole', but only indirectly via solvent molecules. CONCLUSIONS: Our study shows, a posteriori, that the design of E2020 took advantage of several important features of the active-site gorge of AChE to produce a drug with both high affinity for AChE and a high degree of selectivity for AChE versus butyrylcholinesterase (BChE). It also delineates voids within the gorge that are not occupied by E2020 and could provide sites for potential modification of E2020 to produce drugs with improved pharmacological profiles."
],
"offsets": [
[
123,
1854
]
]
}
] | [
{
"id": "10368299_T1",
"type": "CHEMICAL",
"text": [
"aromatic acid"
],
"offsets": [
[
1222,
1235
]
],
"normalized": []
},
{
"id": "10368299_T2",
"type": "CHEMICAL",
"text": [
"E2020"
],
"offsets": [
[
1246,
1251
]
],
"normalized": []
},
{
"id": "10368299_T3",
"type": "CHEMICAL",
"text": [
"E2020"
],
"offsets": [
[
1451,
1456
]
],
"normalized": []
},
{
"id": "10368299_T4",
"type": "CHEMICAL",
"text": [
"E2020"
],
"offsets": [
[
1732,
1737
]
],
"normalized": []
},
{
"id": "10368299_T5",
"type": "CHEMICAL",
"text": [
"E2020"
],
"offsets": [
[
1792,
1797
]
],
"normalized": []
},
{
"id": "10368299_T6",
"type": "CHEMICAL",
"text": [
"Aricept"
],
"offsets": [
[
299,
306
]
],
"normalized": []
},
{
"id": "10368299_T7",
"type": "CHEMICAL",
"text": [
"N-benzylpiperidine"
],
"offsets": [
[
341,
359
]
],
"normalized": []
},
{
"id": "10368299_T8",
"type": "CHEMICAL",
"text": [
"E2020"
],
"offsets": [
[
856,
861
]
],
"normalized": []
},
{
"id": "10368299_T9",
"type": "CHEMICAL",
"text": [
"E2020"
],
"offsets": [
[
998,
1003
]
],
"normalized": []
},
{
"id": "10368299_T10",
"type": "CHEMICAL",
"text": [
"E2020"
],
"offsets": [
[
49,
54
]
],
"normalized": []
},
{
"id": "10368299_T11",
"type": "CHEMICAL",
"text": [
"Aricept"
],
"offsets": [
[
56,
63
]
],
"normalized": []
},
{
"id": "10368299_T12",
"type": "GENE-Y",
"text": [
"AChE"
],
"offsets": [
[
1530,
1534
]
],
"normalized": []
},
{
"id": "10368299_T13",
"type": "GENE-Y",
"text": [
"AChE"
],
"offsets": [
[
1581,
1585
]
],
"normalized": []
},
{
"id": "10368299_T14",
"type": "GENE-Y",
"text": [
"AChE"
],
"offsets": [
[
1623,
1627
]
],
"normalized": []
},
{
"id": "10368299_T15",
"type": "GENE-Y",
"text": [
"butyrylcholinesterase"
],
"offsets": [
[
1635,
1656
]
],
"normalized": []
},
{
"id": "10368299_T16",
"type": "GENE-Y",
"text": [
"BChE"
],
"offsets": [
[
1658,
1662
]
],
"normalized": []
},
{
"id": "10368299_T17",
"type": "GENE-Y",
"text": [
"cholinesterase"
],
"offsets": [
[
143,
157
]
],
"normalized": []
},
{
"id": "10368299_T18",
"type": "GENE-Y",
"text": [
"acetylcholinesterase"
],
"offsets": [
[
366,
386
]
],
"normalized": []
},
{
"id": "10368299_T19",
"type": "GENE-Y",
"text": [
"AChE"
],
"offsets": [
[
388,
392
]
],
"normalized": []
},
{
"id": "10368299_T20",
"type": "GENE-Y",
"text": [
"Torpedo californica AChE"
],
"offsets": [
[
593,
617
]
],
"normalized": []
},
{
"id": "10368299_T21",
"type": "GENE-Y",
"text": [
"TcAChE"
],
"offsets": [
[
619,
625
]
],
"normalized": []
},
{
"id": "10368299_T22",
"type": "GENE-Y",
"text": [
"AChE"
],
"offsets": [
[
739,
743
]
],
"normalized": []
},
{
"id": "10368299_T23",
"type": "GENE-N",
"text": [
"electric eel and mouse AChE"
],
"offsets": [
[
761,
788
]
],
"normalized": []
},
{
"id": "10368299_T24",
"type": "GENE-Y",
"text": [
"TcAChE"
],
"offsets": [
[
862,
868
]
],
"normalized": []
},
{
"id": "10368299_T25",
"type": "GENE-Y",
"text": [
"acetylcholinesterase"
],
"offsets": [
[
13,
33
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "10368299_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "10368299_T10",
"arg2_id": "10368299_T25",
"normalized": []
},
{
"id": "10368299_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "10368299_T11",
"arg2_id": "10368299_T25",
"normalized": []
},
{
"id": "10368299_2",
"type": "INHIBITOR",
"arg1_id": "10368299_T6",
"arg2_id": "10368299_T18",
"normalized": []
},
{
"id": "10368299_3",
"type": "INHIBITOR",
"arg1_id": "10368299_T6",
"arg2_id": "10368299_T19",
"normalized": []
},
{
"id": "10368299_4",
"type": "INHIBITOR",
"arg1_id": "10368299_T7",
"arg2_id": "10368299_T18",
"normalized": []
},
{
"id": "10368299_5",
"type": "INHIBITOR",
"arg1_id": "10368299_T7",
"arg2_id": "10368299_T19",
"normalized": []
},
{
"id": "10368299_6",
"type": "DIRECT-REGULATOR",
"arg1_id": "10368299_T8",
"arg2_id": "10368299_T24",
"normalized": []
},
{
"id": "10368299_7",
"type": "DIRECT-REGULATOR",
"arg1_id": "10368299_T3",
"arg2_id": "10368299_T12",
"normalized": []
},
{
"id": "10368299_8",
"type": "DIRECT-REGULATOR",
"arg1_id": "10368299_T3",
"arg2_id": "10368299_T13",
"normalized": []
},
{
"id": "10368299_9",
"type": "DIRECT-REGULATOR",
"arg1_id": "10368299_T3",
"arg2_id": "10368299_T14",
"normalized": []
}
] |
23271742 | 23271742 | [
{
"id": "23271742_title",
"type": "title",
"text": [
"Arsenic suppresses cell survival via Pirh2-mediated proteasomal degradation of ΔNp63 protein."
],
"offsets": [
[
0,
93
]
]
},
{
"id": "23271742_abstract",
"type": "abstract",
"text": [
"Transcription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53. Because of transcription from two distinct promoters, the p63 gene encodes two isoforms, TAp63 and ΔNp63. Although TAp63 acts as a tumor suppressor, ΔNp63 functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting ΔNp63 might be used to manage tumors that overexpress ΔNp63. Here we found that arsenic trioxide, a frontline agent for acute promyelocytic leukemia, inhibits ΔNp63 but not TAp63 expression in time- and dose-dependent manners. In addition, we found that arsenic trioxide decreases the stability of ΔNp63 protein via a proteasome-dependent pathway but has little effect on the level of ΔNp63 transcript. Furthermore, we found that arsenic trioxide activates the Pirh2 promoter and consequently induces Pirh2 expression. Consistent with this, we found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, arsenic-induced degradation of ΔNp63 protein. Importantly, we found that knockdown of ΔNp63 sensitizes, whereas ectopic expression of ΔNp63 inhibits, growth suppression induced by arsenic. Together, these data suggest that arsenic degrades ΔNp63 protein at least in part via Pirh2-dependent proteolysis and that inhibition of ΔNp63 expression facilitates tumor cells to arsenic-induced death."
],
"offsets": [
[
94,
1495
]
]
}
] | [
{
"id": "23271742_T1",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1103,
1110
]
],
"normalized": []
},
{
"id": "23271742_T2",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1283,
1290
]
],
"normalized": []
},
{
"id": "23271742_T3",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1326,
1333
]
],
"normalized": []
},
{
"id": "23271742_T4",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1473,
1480
]
],
"normalized": []
},
{
"id": "23271742_T5",
"type": "CHEMICAL",
"text": [
"arsenic trioxide"
],
"offsets": [
[
553,
569
]
],
"normalized": []
},
{
"id": "23271742_T6",
"type": "CHEMICAL",
"text": [
"arsenic trioxide"
],
"offsets": [
[
727,
743
]
],
"normalized": []
},
{
"id": "23271742_T7",
"type": "CHEMICAL",
"text": [
"arsenic trioxide"
],
"offsets": [
[
903,
919
]
],
"normalized": []
},
{
"id": "23271742_T8",
"type": "CHEMICAL",
"text": [
"Arsenic"
],
"offsets": [
[
0,
7
]
],
"normalized": []
},
{
"id": "23271742_T9",
"type": "GENE-Y",
"text": [
"Transcription factor p63"
],
"offsets": [
[
94,
118
]
],
"normalized": []
},
{
"id": "23271742_T10",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
197,
200
]
],
"normalized": []
},
{
"id": "23271742_T11",
"type": "GENE-Y",
"text": [
"ΔNp63"
],
"offsets": [
[
1134,
1139
]
],
"normalized": []
},
{
"id": "23271742_T12",
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] |
23639249 | 23639249 | [
{
"id": "23639249_title",
"type": "title",
"text": [
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],
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}
] | [] | [] | [
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},
{
"id": "23639249_4",
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},
{
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{
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},
{
"id": "23639249_7",
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},
{
"id": "23639249_8",
"type": "DIRECT-REGULATOR",
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},
{
"id": "23639249_9",
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},
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},
{
"id": "23639249_13",
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},
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"id": "23639249_15",
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},
{
"id": "23639249_20",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23639249_T3",
"arg2_id": "23639249_T17",
"normalized": []
}
] |
12569076 | 12569076 | [
{
"id": "12569076_title",
"type": "title",
"text": [
"Desensitization of beta2-adrenoceptor-mediated responses by short-acting beta2-adrenoceptor agonists in human lung mast cells."
],
"offsets": [
[
0,
126
]
]
},
{
"id": "12569076_abstract",
"type": "abstract",
"text": [
"1 The principal aim of the present study was to determine whether long-term treatment of human lung mast cells (HLMC) with the clinically-relevant beta(2)-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of beta(2)-adrenoceptor-mediated responses in these cells. 2 The non-selective beta-adrenoceptor agonist, isoprenaline, and the selective beta(2)-adrenoceptor agonists, salbutamol and terbutaline, inhibited the IgE-mediated release of histamine from HLMC. Salbutamol (pD(2); 7.7+/-0.3) and terbutaline (pD(2); 7.3+/-0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD(2); 8.6+/-0.2). 3 Isoprenaline (10(-5) M), salbutamol (10(-5) M) and terbutaline (10(-5) M) enhanced total cell cAMP levels in HLMC over basal by 361+/-90, 150+/-38 and 165+/-35%, respectively. 4 Long-term exposure (24 h) of HLMC to either salbutamol (10(-7) M) or terbutaline (10(-7) M) led to a subsequent reduction in the effectiveness of salbutamol and terbutaline (both 10(-9)-10(-4) M) to inhibit histamine release. However, salbutamol was significantly (P<0.05) more effective than terbutaline at promoting the functional desensitization. 5 Radioligand binding studies, using iodinated cyanopindolol, were performed to determine beta(2)-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with either salbutamol (10(-6) M) or terbutaline (10(-6) M). Both agonists reduced beta(2)-adrenoceptor density in membranes to about the same extent (approximately 25% reduction) but these changes in receptor density were not statistically significant (P>0.05). 6 These data indicate that long-term exposure of mast cells to salbutamol causes greater levels of desensitization to beta(2)-adrenoceptor-mediated responses in HLMC than terbutaline. These findings may have wider clinical significance in the context of asthma treatment as compromised mast cell inhibition could result following long-term exposure of mast cells to short-acting bronchodilators."
],
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127,
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}
] | [
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"id": "12569076_T1",
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"terbutaline"
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"histamine"
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"id": "12569076_T12",
"type": "CHEMICAL",
"text": [
"terbutaline"
],
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320,
331
]
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{
"id": "12569076_T13",
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"text": [
"isoprenaline"
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464,
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]
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"id": "12569076_T14",
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"salbutamol"
],
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527,
537
]
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{
"id": "12569076_T15",
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"text": [
"terbutaline"
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542,
553
]
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{
"id": "12569076_T16",
"type": "CHEMICAL",
"text": [
"histamine"
],
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593,
602
]
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{
"id": "12569076_T17",
"type": "CHEMICAL",
"text": [
"Salbutamol"
],
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614,
624
]
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{
"id": "12569076_T18",
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"terbutaline"
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648,
659
]
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"histamine"
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720,
729
]
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{
"id": "12569076_T20",
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"isoprenaline"
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783,
795
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"Isoprenaline"
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818,
830
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"salbutamol"
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843,
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"terbutaline"
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869,
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]
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"cAMP"
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912,
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"terbutaline"
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1065,
1076
]
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"id": "12569076_T27",
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"beta(2)-adrenoceptor"
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1436,
1456
]
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274,
294
]
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1601,
1621
]
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"beta(2)-adrenoceptor"
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1899,
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]
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"id": "12569076_T31",
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"beta(2)-adrenoceptor"
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361,
381
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"id": "12569076_T32",
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]
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496,
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]
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"id": "12569076_T34",
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"text": [
"IgE"
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569,
572
]
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"id": "12569076_T35",
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"beta2-adrenoceptor"
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19,
37
]
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},
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"id": "12569076_T36",
"type": "GENE-Y",
"text": [
"beta2-adrenoceptor"
],
"offsets": [
[
73,
91
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12569076_0",
"type": "AGONIST",
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"arg2_id": "12569076_T28",
"normalized": []
},
{
"id": "12569076_1",
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},
{
"id": "12569076_2",
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},
{
"id": "12569076_4",
"type": "AGONIST",
"arg1_id": "12569076_T15",
"arg2_id": "12569076_T33",
"normalized": []
}
] |
16495723 | 16495723 | [
{
"id": "16495723_title",
"type": "title",
"text": [
"Effects of monoamine oxidase inhibitors on cocaine discrimination in rats."
],
"offsets": [
[
0,
74
]
]
},
{
"id": "16495723_abstract",
"type": "abstract",
"text": [
"This study tested the time course of the discriminative stimulus effects of inhibitors of monoamine oxidase alone or in combination with cocaine. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg, intraperitoneal) from saline using a two-lever choice methodology. The nonselective monoamine oxidase inhibitors tranylcypromine (0.01-5 mg/kg) and phenelzine (1-25 mg/kg), the monoamine oxidase-A selective compound clorgyline (1-25 mg/kg), and the monoamine oxidase-B selective compounds pargyline (0.005-50 mg/kg) and selegiline (1-25 mg/kg) were tested for substitution 15 min or 24 h following administration, and in combination with 10 mg/kg of cocaine 24 and 48 h after administration. At 15 min, selegiline fully substituted for the discriminative stimulus effects of cocaine, whereas all other compounds partially substituted. At 24 h, substitution of cocaine was diminished for all compounds except phenelzine, which produced a greater amount of substitution at 24 h than at 15 min. When cocaine was administered 24 h after clorgyline, selegiline, pargyline, and phenelzine, cocaine-appropriate responding was attenuated at intermediate doses of these drugs, whereas the highest doses did not alter cocaine-lever responding. All compounds except selegiline substantially decreased response rate and produced various adverse effects. At 48 h, the effects of all compounds except phenelzine were markedly reduced. Selectivity for monoamine oxidase-A or monoamine oxidase-B did not predict the ability to substitute for or attenuate the subjective effects of cocaine. These findings suggest that monoamine oxidase inhibitors can modulate the discriminative stimulus effects of cocaine for at least 24 h, and may be useful for treatment of cocaine abuse."
],
"offsets": [
[
75,
1853
]
]
}
] | [
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"id": "16495723_T1",
"type": "CHEMICAL",
"text": [
"cocaine"
],
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[
1091,
1098
]
],
"normalized": []
},
{
"id": "16495723_T2",
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"text": [
"clorgyline"
],
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[
1127,
1137
]
],
"normalized": []
},
{
"id": "16495723_T3",
"type": "CHEMICAL",
"text": [
"selegiline"
],
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[
1139,
1149
]
],
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},
{
"id": "16495723_T4",
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"pargyline"
],
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[
1151,
1160
]
],
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},
{
"id": "16495723_T5",
"type": "CHEMICAL",
"text": [
"phenelzine"
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[
1166,
1176
]
],
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},
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"id": "16495723_T6",
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"text": [
"cocaine"
],
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1178,
1185
]
],
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{
"id": "16495723_T7",
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"text": [
"cocaine"
],
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[
1302,
1309
]
],
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},
{
"id": "16495723_T8",
"type": "CHEMICAL",
"text": [
"selegiline"
],
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[
1349,
1359
]
],
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},
{
"id": "16495723_T9",
"type": "CHEMICAL",
"text": [
"cocaine"
],
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[
212,
219
]
],
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},
{
"id": "16495723_T10",
"type": "CHEMICAL",
"text": [
"phenelzine"
],
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[
1481,
1491
]
],
"normalized": []
},
{
"id": "16495723_T11",
"type": "CHEMICAL",
"text": [
"monoamine"
],
"offsets": [
[
1531,
1540
]
],
"normalized": []
},
{
"id": "16495723_T12",
"type": "CHEMICAL",
"text": [
"monoamine"
],
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[
1554,
1563
]
],
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},
{
"id": "16495723_T13",
"type": "CHEMICAL",
"text": [
"cocaine"
],
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[
1659,
1666
]
],
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},
{
"id": "16495723_T14",
"type": "CHEMICAL",
"text": [
"monoamine"
],
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[
1696,
1705
]
],
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},
{
"id": "16495723_T15",
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"text": [
"cocaine"
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1777,
1784
]
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"id": "16495723_T16",
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"text": [
"cocaine"
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1839,
1846
]
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"id": "16495723_T17",
"type": "CHEMICAL",
"text": [
"cocaine"
],
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275,
282
]
],
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"id": "16495723_T18",
"type": "CHEMICAL",
"text": [
"monoamine"
],
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[
378,
387
]
],
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},
{
"id": "16495723_T19",
"type": "CHEMICAL",
"text": [
"tranylcypromine"
],
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[
407,
422
]
],
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},
{
"id": "16495723_T20",
"type": "CHEMICAL",
"text": [
"phenelzine"
],
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[
442,
452
]
],
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"id": "16495723_T21",
"type": "CHEMICAL",
"text": [
"monoamine"
],
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471,
480
]
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},
{
"id": "16495723_T22",
"type": "CHEMICAL",
"text": [
"monoamine"
],
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[
543,
552
]
],
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},
{
"id": "16495723_T23",
"type": "CHEMICAL",
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"pargyline"
],
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[
583,
592
]
],
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},
{
"id": "16495723_T24",
"type": "CHEMICAL",
"text": [
"selegiline"
],
"offsets": [
[
614,
624
]
],
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},
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"id": "16495723_T25",
"type": "CHEMICAL",
"text": [
"cocaine"
],
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[
744,
751
]
],
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},
{
"id": "16495723_T26",
"type": "CHEMICAL",
"text": [
"selegiline"
],
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[
797,
807
]
],
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},
{
"id": "16495723_T27",
"type": "CHEMICAL",
"text": [
"cocaine"
],
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[
869,
876
]
],
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"id": "16495723_T28",
"type": "CHEMICAL",
"text": [
"cocaine"
],
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[
954,
961
]
],
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},
{
"id": "16495723_T29",
"type": "CHEMICAL",
"text": [
"monoamine"
],
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[
165,
174
]
],
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},
{
"id": "16495723_T30",
"type": "CHEMICAL",
"text": [
"phenelzine"
],
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[
1002,
1012
]
],
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},
{
"id": "16495723_T31",
"type": "CHEMICAL",
"text": [
"monoamine"
],
"offsets": [
[
11,
20
]
],
"normalized": []
},
{
"id": "16495723_T32",
"type": "CHEMICAL",
"text": [
"cocaine"
],
"offsets": [
[
43,
50
]
],
"normalized": []
},
{
"id": "16495723_T33",
"type": "GENE-Y",
"text": [
"monoamine oxidase-A"
],
"offsets": [
[
1531,
1550
]
],
"normalized": []
},
{
"id": "16495723_T34",
"type": "GENE-Y",
"text": [
"monoamine oxidase-B"
],
"offsets": [
[
1554,
1573
]
],
"normalized": []
},
{
"id": "16495723_T35",
"type": "GENE-N",
"text": [
"monoamine oxidase"
],
"offsets": [
[
1696,
1713
]
],
"normalized": []
},
{
"id": "16495723_T36",
"type": "GENE-N",
"text": [
"monoamine oxidase"
],
"offsets": [
[
378,
395
]
],
"normalized": []
},
{
"id": "16495723_T37",
"type": "GENE-Y",
"text": [
"monoamine oxidase-A"
],
"offsets": [
[
471,
490
]
],
"normalized": []
},
{
"id": "16495723_T38",
"type": "GENE-Y",
"text": [
"monoamine oxidase-B"
],
"offsets": [
[
543,
562
]
],
"normalized": []
},
{
"id": "16495723_T39",
"type": "GENE-N",
"text": [
"monoamine oxidase"
],
"offsets": [
[
165,
182
]
],
"normalized": []
},
{
"id": "16495723_T40",
"type": "GENE-N",
"text": [
"monoamine oxidase"
],
"offsets": [
[
11,
28
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16495723_0",
"type": "INHIBITOR",
"arg1_id": "16495723_T19",
"arg2_id": "16495723_T36",
"normalized": []
},
{
"id": "16495723_1",
"type": "INHIBITOR",
"arg1_id": "16495723_T20",
"arg2_id": "16495723_T36",
"normalized": []
},
{
"id": "16495723_2",
"type": "INHIBITOR",
"arg1_id": "16495723_T23",
"arg2_id": "16495723_T38",
"normalized": []
},
{
"id": "16495723_3",
"type": "INHIBITOR",
"arg1_id": "16495723_T24",
"arg2_id": "16495723_T38",
"normalized": []
}
] |
23552260 | 23552260 | [
{
"id": "23552260_title",
"type": "title",
"text": [
"Histological, ultrastructural and immunohistochemical studies on the protective effect of ginger extract against cisplatin-induced nephrotoxicity in male rats."
],
"offsets": [
[
0,
159
]
]
},
{
"id": "23552260_abstract",
"type": "abstract",
"text": [
"Cisplatin (CP) is a widely used anticancer drug; however, it has several side effects such as nephrotoxicity. Ginger, the rhizome of Zingiber officinale, consumed since ancient times has numerous health benefits. The objective of this work was to evaluate the protective effect of ginger extract (GE) against CP-induced nephrotoxicity. CP group displayed a marked renal failure characterized by a significant increase in serum creatinine and blood urea nitrogen (BUN) levels in addition to severe histopathological and ultrastructural renal alterations. Also, CP group showed an increase in the immunohistochemical expression of Bax proapoptotic protein. In contrast, GE+CP group showed significant decrease in the elevated serum creatinine and BUN levels and an improvement in the histopathological and ultrastructural renal injury induced by CP. The overexpression of Bax proapoptotic protein was significantly decreased in the GE+CP group. Hence, the present results indicated that GE has a protective effect against CP-induced renal damage in rats. Thereby, such findings recommended the usage of GE to prevent and/or decrease the renal damage induced by CP chemotherapeutic treatment."
],
"offsets": [
[
160,
1349
]
]
}
] | [
{
"id": "23552260_T1",
"type": "CHEMICAL",
"text": [
"Cisplatin"
],
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[
160,
169
]
],
"normalized": []
},
{
"id": "23552260_T2",
"type": "CHEMICAL",
"text": [
"creatinine"
],
"offsets": [
[
587,
597
]
],
"normalized": []
},
{
"id": "23552260_T3",
"type": "CHEMICAL",
"text": [
"urea"
],
"offsets": [
[
608,
612
]
],
"normalized": []
},
{
"id": "23552260_T4",
"type": "CHEMICAL",
"text": [
"nitrogen"
],
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[
613,
621
]
],
"normalized": []
},
{
"id": "23552260_T5",
"type": "CHEMICAL",
"text": [
"creatinine"
],
"offsets": [
[
890,
900
]
],
"normalized": []
},
{
"id": "23552260_T6",
"type": "CHEMICAL",
"text": [
"cisplatin"
],
"offsets": [
[
113,
122
]
],
"normalized": []
},
{
"id": "23552260_T7",
"type": "GENE-Y",
"text": [
"Bax"
],
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[
789,
792
]
],
"normalized": []
},
{
"id": "23552260_T8",
"type": "GENE-Y",
"text": [
"Bax"
],
"offsets": [
[
1030,
1033
]
],
"normalized": []
}
] | [] | [] | [] |
11342438 | 11342438 | [
{
"id": "11342438_title",
"type": "title",
"text": [
"Model for a factor IX activation complex on blood platelets: dimeric conformation of factor XIa is essential."
],
"offsets": [
[
0,
109
]
]
},
{
"id": "11342438_abstract",
"type": "abstract",
"text": [
"Human coagulation factor XI (FXI) is a plasma serine protease composed of 2 identical 80-kd polypeptides connected by a disulfide bond. This dimeric structure is unique among blood coagulation enzymes. The hypothesis was tested that dimeric conformation is required for normal FXI function by generating a monomeric version of FXI (FXI/PKA4) and comparing it to wild-type FXI in assays requiring factor IX activation by activated FXI (FXIa). FXI/PKA4 was made by replacing the FXI A4 domain with the A4 domain from prekallikrein (PK). A dimeric version of FXI/PKA4 (FXI/PKA4-Gly326) was prepared as a control. Activated FXI/PKA4 and FXI/PKA4-Gly326 activate factor IX with kinetic parameters similar to those of FXIa. In kaolin-triggered plasma clotting assays containing purified phospholipid, FXI/PKA4 and FXI/PKA4-Gly326 have coagulant activity similar to FXI. The surface of activated platelets is likely to be a physiologic site for reactions involving FXI/FXIa. In competition binding assays FXI/PKA4, FXI/PKA4-Gly326, and FXI have similar affinities for activated platelets (K(i) = 12-16 nM). In clotting assays in which phospholipid is replaced by activated platelets, the dimeric proteins FXI and FXI/PKA4-Gly326 promote coagulation similarly; however, monomeric FXI/PKA4 has greatly reduced activity. Western immunoblot analysis confirmed that activated monomeric FXI/PKA4 activates factor IX poorly in the presence of activated platelets. These findings demonstrate the importance of the dimeric state to FXI activity and suggest a novel model for factor IX activation in which FXIa binds to activated platelets by one chain of the dimer, while binding to factor IX through the other."
],
"offsets": [
[
110,
1805
]
]
}
] | [
{
"id": "11342438_T1",
"type": "CHEMICAL",
"text": [
"Gly326"
],
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[
1127,
1133
]
],
"normalized": []
},
{
"id": "11342438_T2",
"type": "CHEMICAL",
"text": [
"phospholipid"
],
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[
1238,
1250
]
],
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},
{
"id": "11342438_T3",
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"text": [
"disulfide"
],
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[
230,
239
]
],
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},
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"id": "11342438_T4",
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"Gly326"
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[
1325,
1331
]
],
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},
{
"id": "11342438_T5",
"type": "CHEMICAL",
"text": [
"serine"
],
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[
156,
162
]
],
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},
{
"id": "11342438_T6",
"type": "CHEMICAL",
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556,
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156,
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85,
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}
] |
15871445 | 15871445 | [
{
"id": "15871445_title",
"type": "title",
"text": [
"Tolerability of selective cyclooxygenase inhibitor, celecoxib, in patients with analgesic intolerance."
],
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0,
102
]
]
},
{
"id": "15871445_abstract",
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"text": [
"Intolerance reactions to acetyl salicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) are common and caused by inhibition of COX-1 enzyme. Therefore, drugs that selectively inhibit COX-2 enzyme may be safe in these subjects. In this study, we evaluated the tolerability of celecoxib, a selective COX-2 inhibitor, in patients with analgesic intolerance. The eligible study population consisted of patients with a history of urticaria/angioedema, naso-ocular symptoms, bronchospasm, and/or anaphylactoid reaction induced by ASA and/or NSAIDs. A single-blind, placebo-controlled oral challenge test was performed in the hospital setting. On 2 separate days, 1/4 and 3/4 divided doses of placebo and celecoxib (Celebrex 200 mg, Pfizer, Turkey) were given with 2-hour intervals. Seventy-five subjects (mean age: 38.2 +/- 1.4 years; F:M: 55:20) were included in the study. Twenty-one subjects had asthma. No reaction was observed with placebo or celecoxib provocation. Although celecoxib seems to be a safe alternative drug in our study group, considering its serious adverse events reported in the literature, the drug should be recommended for patients with analgesic intolerance only after being tested by an experienced allergist."
],
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103,
1348
]
]
}
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151,
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]
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642,
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"cyclooxygenase"
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26,
40
]
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}
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}
] |
23536271 | 23536271 | [
{
"id": "23536271_title",
"type": "title",
"text": [
"β-Ionone arrests cell cycle of gastric carcinoma cancer cells by a MAPK pathway."
],
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0,
80
]
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{
"id": "23536271_abstract",
"type": "abstract",
"text": [
"β-Ionone is an end ring analog of β-carotenoid which has been shown to possess potent anti-proliferative activity both in vitro and in vivo. To investigate the possible inhibitory effects of β-ionone, we studied cell growth characteristics, DNA synthesis, cell cycle progression, as well as mitogen-activated protein kinases (MAPKs) pathways in the human gastric adenocarcinoma cancer cell line (SGC-7901). Our results show that cell growth and DNA synthesis were inhibited, and the cell cycle was arrested at the G0/G1 phase in a dose-dependent manner in cells treated with β-ionone (25, 50, 100 and 200 μmol/L) for 24 h. We found that the β-ionone significantly decreased the extracellular signal-regulated kinase protein expression and significantly increased the levels of p38 and Jun-amino-terminal kinase protein expression (P < 0.01). β-Ionone also inhibited cell cycle-related proteins of Cdk4, Cyclin B1, D1 and increased p27 protein expression in SGC-7901 cells. These results suggested that the cell cycle arrest observed may be regulated through a MAPK pathway by transcriptional down-regulation of cell cycle proteins. These results demonstrate potent ability of β-ionone to arrest cell cycle of SGC-7901 cells and decrease proliferation."
],
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81,
1332
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]
}
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0,
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1141,
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372,
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407,
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]
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"extracellular signal-regulated kinase"
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759,
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]
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"p38"
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858,
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]
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"Jun-amino-terminal kinase"
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866,
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"id": "23536271_T15",
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"cell cycle-related proteins"
],
"offsets": [
[
947,
974
]
],
"normalized": []
},
{
"id": "23536271_T16",
"type": "GENE-Y",
"text": [
"Cdk4"
],
"offsets": [
[
978,
982
]
],
"normalized": []
},
{
"id": "23536271_T17",
"type": "GENE-N",
"text": [
"Cyclin B1, D1"
],
"offsets": [
[
984,
997
]
],
"normalized": []
},
{
"id": "23536271_T18",
"type": "GENE-Y",
"text": [
"p27"
],
"offsets": [
[
1012,
1015
]
],
"normalized": []
},
{
"id": "23536271_T19",
"type": "GENE-N",
"text": [
"MAPK"
],
"offsets": [
[
67,
71
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23536271_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23536271_T5",
"arg2_id": "23536271_T12",
"normalized": []
},
{
"id": "23536271_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23536271_T5",
"arg2_id": "23536271_T13",
"normalized": []
},
{
"id": "23536271_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23536271_T5",
"arg2_id": "23536271_T14",
"normalized": []
},
{
"id": "23536271_3",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23536271_T7",
"arg2_id": "23536271_T15",
"normalized": []
},
{
"id": "23536271_4",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23536271_T7",
"arg2_id": "23536271_T16",
"normalized": []
},
{
"id": "23536271_5",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23536271_T7",
"arg2_id": "23536271_T18",
"normalized": []
}
] |
23510510 | 23510510 | [
{
"id": "23510510_title",
"type": "title",
"text": [
"Dendrimer Driven Self-Assembly of SPR Active Silver-Gold Nanohybrids."
],
"offsets": [
[
0,
69
]
]
},
{
"id": "23510510_abstract",
"type": "abstract",
"text": [
"A fourth generation PAMAM dendrimer has been successfully employed for the development of a single step synthesis strategy for self-assembled Ag-Au nanohybrid structures. The surface plasmon resonance properties and the degree of self-assembly of the nanohybrid are strongly correlated with the stoichiometry of the metals which gives rise to enhanced plasmonic properties. The enhanced plasmonic response of the nanohybrids is modeled and is validated experimentally in a model HRP (horseradish peroxidise) bioassay carried out on an SPR-based biochip platform."
],
"offsets": [
[
70,
632
]
]
}
] | [
{
"id": "23510510_T1",
"type": "CHEMICAL",
"text": [
"Ag"
],
"offsets": [
[
212,
214
]
],
"normalized": []
},
{
"id": "23510510_T2",
"type": "CHEMICAL",
"text": [
"Au"
],
"offsets": [
[
215,
217
]
],
"normalized": []
},
{
"id": "23510510_T3",
"type": "CHEMICAL",
"text": [
"PAMAM"
],
"offsets": [
[
90,
95
]
],
"normalized": []
},
{
"id": "23510510_T4",
"type": "CHEMICAL",
"text": [
"Silver"
],
"offsets": [
[
45,
51
]
],
"normalized": []
},
{
"id": "23510510_T5",
"type": "GENE-Y",
"text": [
"HRP"
],
"offsets": [
[
549,
552
]
],
"normalized": []
},
{
"id": "23510510_T6",
"type": "GENE-Y",
"text": [
"horseradish peroxidise"
],
"offsets": [
[
554,
576
]
],
"normalized": []
}
] | [] | [] | [] |
23192339 | 23192339 | [
{
"id": "23192339_title",
"type": "title",
"text": [
"Transcriptional regulatory factor X6 (Rfx6) increases gastric inhibitory polypeptide (GIP) expression in enteroendocrine K-cells and is involved in GIP hypersecretion in high fat diet-induced obesity."
],
"offsets": [
[
0,
200
]
]
},
{
"id": "23192339_abstract",
"type": "abstract",
"text": [
"Gastric inhibitory polypeptide (GIP) is an incretin released from enteroendocrine K-cells in response to nutrient ingestion. GIP potentiates glucose-stimulated insulin secretion and induces energy accumulation into adipose tissue, resulting in obesity. Plasma GIP levels are reported to be increased in the obese state. However, the molecular mechanisms of GIP secretion and high fat diet (HFD)-induced GIP hypersecretion remain unclear, primarily due to difficulties in separating K-cells from other intestinal epithelial cells in vivo. In this study, GIP-GFP knock-in mice that enable us to visualize K-cells by enhanced GFP were established. Microarray analysis of isolated K-cells from these mice revealed that transcriptional regulatory factor X6 (Rfx6) is expressed exclusively in K-cells. In vitro experiments using the mouse intestinal cell line STC-1 showed that knockdown of Rfx6 decreased mRNA expression, cellular content, and secretion of GIP. Rfx6 bound to the region in the gip promoter that regulates gip promoter activity, and overexpression of Rfx6 increased GIP mRNA expression. HFD induced obesity and GIP hypersecretion in GIP-GFP heterozygous mice in vivo. Immunohistochemical and flow cytometry analysis showed no significant difference in K-cell number between control fat diet-fed (CFD) and HFD-fed mice. However, GIP content in the upper small intestine and GIP mRNA expression in K-cells were significantly increased in HFD-fed mice compared with those in CFD-fed mice. Furthermore, expression levels of Rfx6 mRNA were increased in K-cells of HFD-fed mice. These results suggest that Rfx6 increases GIP expression and content in K-cells and is involved in GIP hypersecretion in HFD-induced obesity."
],
"offsets": [
[
201,
1926
]
]
}
] | [
{
"id": "23192339_T1",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
342,
349
]
],
"normalized": []
},
{
"id": "23192339_T2",
"type": "GENE-Y",
"text": [
"Gastric inhibitory polypeptide"
],
"offsets": [
[
201,
231
]
],
"normalized": []
},
{
"id": "23192339_T3",
"type": "GENE-N",
"text": [
"gip promoter"
],
"offsets": [
[
1218,
1230
]
],
"normalized": []
},
{
"id": "23192339_T4",
"type": "GENE-Y",
"text": [
"Rfx6"
],
"offsets": [
[
1263,
1267
]
],
"normalized": []
},
{
"id": "23192339_T5",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
1278,
1281
]
],
"normalized": []
},
{
"id": "23192339_T6",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
1323,
1326
]
],
"normalized": []
},
{
"id": "23192339_T7",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
1345,
1348
]
],
"normalized": []
},
{
"id": "23192339_T8",
"type": "GENE-N",
"text": [
"GFP"
],
"offsets": [
[
1349,
1352
]
],
"normalized": []
},
{
"id": "23192339_T9",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
326,
329
]
],
"normalized": []
},
{
"id": "23192339_T10",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
1540,
1543
]
],
"normalized": []
},
{
"id": "23192339_T11",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
1585,
1588
]
],
"normalized": []
},
{
"id": "23192339_T12",
"type": "GENE-Y",
"text": [
"Rfx6"
],
"offsets": [
[
1732,
1736
]
],
"normalized": []
},
{
"id": "23192339_T13",
"type": "GENE-Y",
"text": [
"insulin"
],
"offsets": [
[
361,
368
]
],
"normalized": []
},
{
"id": "23192339_T14",
"type": "GENE-Y",
"text": [
"Rfx6"
],
"offsets": [
[
1812,
1816
]
],
"normalized": []
},
{
"id": "23192339_T15",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
1827,
1830
]
],
"normalized": []
},
{
"id": "23192339_T16",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
1884,
1887
]
],
"normalized": []
},
{
"id": "23192339_T17",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
461,
464
]
],
"normalized": []
},
{
"id": "23192339_T18",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
233,
236
]
],
"normalized": []
},
{
"id": "23192339_T19",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
558,
561
]
],
"normalized": []
},
{
"id": "23192339_T20",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
604,
607
]
],
"normalized": []
},
{
"id": "23192339_T21",
"type": "GENE-Y",
"text": [
"incretin"
],
"offsets": [
[
244,
252
]
],
"normalized": []
},
{
"id": "23192339_T22",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
754,
757
]
],
"normalized": []
},
{
"id": "23192339_T23",
"type": "GENE-N",
"text": [
"GFP"
],
"offsets": [
[
758,
761
]
],
"normalized": []
},
{
"id": "23192339_T24",
"type": "GENE-Y",
"text": [
"GFP"
],
"offsets": [
[
824,
827
]
],
"normalized": []
},
{
"id": "23192339_T25",
"type": "GENE-Y",
"text": [
"transcriptional regulatory factor X6"
],
"offsets": [
[
916,
952
]
],
"normalized": []
},
{
"id": "23192339_T26",
"type": "GENE-Y",
"text": [
"Rfx6"
],
"offsets": [
[
954,
958
]
],
"normalized": []
},
{
"id": "23192339_T27",
"type": "GENE-Y",
"text": [
"Rfx6"
],
"offsets": [
[
1086,
1090
]
],
"normalized": []
},
{
"id": "23192339_T28",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
1153,
1156
]
],
"normalized": []
},
{
"id": "23192339_T29",
"type": "GENE-Y",
"text": [
"Rfx6"
],
"offsets": [
[
1158,
1162
]
],
"normalized": []
},
{
"id": "23192339_T30",
"type": "GENE-N",
"text": [
"gip promoter"
],
"offsets": [
[
1190,
1202
]
],
"normalized": []
},
{
"id": "23192339_T31",
"type": "GENE-Y",
"text": [
"Transcriptional regulatory factor X6"
],
"offsets": [
[
0,
36
]
],
"normalized": []
},
{
"id": "23192339_T32",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
148,
151
]
],
"normalized": []
},
{
"id": "23192339_T33",
"type": "GENE-Y",
"text": [
"Rfx6"
],
"offsets": [
[
38,
42
]
],
"normalized": []
},
{
"id": "23192339_T34",
"type": "GENE-Y",
"text": [
"gastric inhibitory polypeptide"
],
"offsets": [
[
54,
84
]
],
"normalized": []
},
{
"id": "23192339_T35",
"type": "GENE-Y",
"text": [
"GIP"
],
"offsets": [
[
86,
89
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23192339_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23192339_T1",
"arg2_id": "23192339_T13",
"normalized": []
}
] |
10363282 | 10363282 | [
{
"id": "10363282_title",
"type": "title",
"text": [
"Role of acetylcholinesterase (AChE) secreted by parasitic nematodes on the growth of the cell line from epithelial origin HT29-D4."
],
"offsets": [
[
0,
130
]
]
},
{
"id": "10363282_abstract",
"type": "abstract",
"text": [
"The excretory-secretory (E-S) products of the parasitic nematodes Trichostrongylus colubriformis and Nematodirus battus were found to modify the in vitro proliferation of the tumorous colic HT29-D4 cell line of epithelial origin. A characteristic feature of these E-S products is the presence of a high level of acetylcholinesterase (AChE) activity, the biological significance of which remains unclear. To determine a possible role of AChE on cell growth, the enzyme was purified from E-S products using edrophonium chloride. Purity was confirmed by polyacrylamide gel electrophoresis, using silver and Karnovsky stains, before assessing its effects on cell proliferation. The purified AChE was incorporated at different concentrations in a culture medium of HT29-D4 cells. A mitogenic effect was shown for low concentrations (0.1-14 units). By contrast, an inhibitory effect was noted at high concentrations (35-1400 units). Furthermore, polyclonal antibodies were prepared and depletion of AChE in E-S products by immunoprecipitation or affinity chromatography resulted in a partial or total disappearance of the stimulatory effect of cell growth. Thus, the results form this in vitro study suggest a modulatory role for AChE secreted by nematode parasites on the proliferation of epithelial cells of the host."
],
"offsets": [
[
131,
1444
]
]
}
] | [
{
"id": "10363282_T1",
"type": "CHEMICAL",
"text": [
"edrophonium chloride"
],
"offsets": [
[
636,
656
]
],
"normalized": []
},
{
"id": "10363282_T2",
"type": "GENE-N",
"text": [
"AChE"
],
"offsets": [
[
1355,
1359
]
],
"normalized": []
},
{
"id": "10363282_T3",
"type": "GENE-N",
"text": [
"acetylcholinesterase"
],
"offsets": [
[
443,
463
]
],
"normalized": []
},
{
"id": "10363282_T4",
"type": "GENE-N",
"text": [
"AChE"
],
"offsets": [
[
465,
469
]
],
"normalized": []
},
{
"id": "10363282_T5",
"type": "GENE-N",
"text": [
"AChE"
],
"offsets": [
[
567,
571
]
],
"normalized": []
},
{
"id": "10363282_T6",
"type": "GENE-N",
"text": [
"AChE"
],
"offsets": [
[
818,
822
]
],
"normalized": []
},
{
"id": "10363282_T7",
"type": "GENE-N",
"text": [
"AChE"
],
"offsets": [
[
1124,
1128
]
],
"normalized": []
}
] | [] | [] | [] |
23353821 | 23353821 | [
{
"id": "23353821_title",
"type": "title",
"text": [
"Cystathionase mediates senescence evasion in melanocytes and melanoma cells."
],
"offsets": [
[
0,
76
]
]
},
{
"id": "23353821_abstract",
"type": "abstract",
"text": [
"The development of malignant melanoma is a highly complex process, which is still poorly understood. A majority of human melanomas are found to express a few oncogenic proteins, such as mutant RAS and BRAF variants. However, these oncogenes are also found in nevi, and it is now a well-accepted fact that their expression alone leads to senescence. This renders the understanding of senescence escape mechanisms an important point to understand tumor development. Here, we approached the question of senescence evasion by expressing the transcription factor v-myc myelocytomatosis viral oncogene homolog (c-MYC), which is known to act synergistically with many oncogenes, in melanocytes. We observed that MYC drives the evasion of reactive-oxygen stress-induced melanocyte senescence, caused by activated receptor tyrosine kinase signaling. Conversely, MIZ1, the growth suppressing interaction partner of MYC, is involved in mediating melanocyte senescence. Both, MYC overexpression and Miz1 knockdown led to a strong reduction of endogenous reactive-oxygen species (ROS), DNA damage and senescence. We identified the cystathionase (CTH) gene product as mediator of the ROS-related MYC and MIZ1 effects. Blocking CTH enzymatic activity in MYC-overexpressing and Miz1 knockdown cells increased intracellular stress and senescence. Importantly, pharmacological inhibition of CTH in human melanoma cells also reconstituted senescence in the majority of cell lines, and CTH knockdown reduced tumorigenic effects such as proliferation, H(2)O(2) resistance and soft agar growth. Thus, we identified CTH as new MYC target gene with an important function in senescence evasion.Oncogene advance online publication, 28 January 2013; doi:10.1038/onc.2012.641."
],
"offsets": [
[
77,
1825
]
]
}
] | [
{
"id": "23353821_T1",
"type": "CHEMICAL",
"text": [
"oxygen"
],
"offsets": [
[
1128,
1134
]
],
"normalized": []
},
{
"id": "23353821_T2",
"type": "CHEMICAL",
"text": [
"H(2)O(2)"
],
"offsets": [
[
1608,
1616
]
],
"normalized": []
},
{
"id": "23353821_T3",
"type": "CHEMICAL",
"text": [
"oxygen"
],
"offsets": [
[
817,
823
]
],
"normalized": []
},
{
"id": "23353821_T4",
"type": "CHEMICAL",
"text": [
"tyrosine"
],
"offsets": [
[
891,
899
]
],
"normalized": []
},
{
"id": "23353821_T5",
"type": "GENE-Y",
"text": [
"cystathionase"
],
"offsets": [
[
1195,
1208
]
],
"normalized": []
},
{
"id": "23353821_T6",
"type": "GENE-Y",
"text": [
"CTH"
],
"offsets": [
[
1210,
1213
]
],
"normalized": []
},
{
"id": "23353821_T7",
"type": "GENE-Y",
"text": [
"MYC"
],
"offsets": [
[
1259,
1262
]
],
"normalized": []
},
{
"id": "23353821_T8",
"type": "GENE-Y",
"text": [
"MIZ1"
],
"offsets": [
[
1267,
1271
]
],
"normalized": []
},
{
"id": "23353821_T9",
"type": "GENE-Y",
"text": [
"CTH"
],
"offsets": [
[
1290,
1293
]
],
"normalized": []
},
{
"id": "23353821_T10",
"type": "GENE-Y",
"text": [
"MYC"
],
"offsets": [
[
1316,
1319
]
],
"normalized": []
},
{
"id": "23353821_T11",
"type": "GENE-Y",
"text": [
"Miz1"
],
"offsets": [
[
1339,
1343
]
],
"normalized": []
},
{
"id": "23353821_T12",
"type": "GENE-Y",
"text": [
"CTH"
],
"offsets": [
[
1450,
1453
]
],
"normalized": []
},
{
"id": "23353821_T13",
"type": "GENE-Y",
"text": [
"CTH"
],
"offsets": [
[
1543,
1546
]
],
"normalized": []
},
{
"id": "23353821_T14",
"type": "GENE-Y",
"text": [
"CTH"
],
"offsets": [
[
1670,
1673
]
],
"normalized": []
},
{
"id": "23353821_T15",
"type": "GENE-Y",
"text": [
"MYC"
],
"offsets": [
[
1681,
1684
]
],
"normalized": []
},
{
"id": "23353821_T16",
"type": "GENE-N",
"text": [
"RAS"
],
"offsets": [
[
270,
273
]
],
"normalized": []
},
{
"id": "23353821_T17",
"type": "GENE-Y",
"text": [
"BRAF"
],
"offsets": [
[
278,
282
]
],
"normalized": []
},
{
"id": "23353821_T18",
"type": "GENE-Y",
"text": [
"v-myc myelocytomatosis viral oncogene homolog"
],
"offsets": [
[
635,
680
]
],
"normalized": []
},
{
"id": "23353821_T19",
"type": "GENE-Y",
"text": [
"c-MYC"
],
"offsets": [
[
682,
687
]
],
"normalized": []
},
{
"id": "23353821_T20",
"type": "GENE-Y",
"text": [
"MYC"
],
"offsets": [
[
782,
785
]
],
"normalized": []
},
{
"id": "23353821_T21",
"type": "GENE-N",
"text": [
"receptor tyrosine kinase"
],
"offsets": [
[
882,
906
]
],
"normalized": []
},
{
"id": "23353821_T22",
"type": "GENE-Y",
"text": [
"MIZ1"
],
"offsets": [
[
930,
934
]
],
"normalized": []
},
{
"id": "23353821_T23",
"type": "GENE-Y",
"text": [
"MYC"
],
"offsets": [
[
982,
985
]
],
"normalized": []
},
{
"id": "23353821_T24",
"type": "GENE-Y",
"text": [
"MYC"
],
"offsets": [
[
1041,
1044
]
],
"normalized": []
},
{
"id": "23353821_T25",
"type": "GENE-Y",
"text": [
"Miz1"
],
"offsets": [
[
1064,
1068
]
],
"normalized": []
},
{
"id": "23353821_T26",
"type": "GENE-Y",
"text": [
"Cystathionase"
],
"offsets": [
[
0,
13
]
],
"normalized": []
}
] | [] | [] | [] |
12416991 | 12416991 | [
{
"id": "12416991_title",
"type": "title",
"text": [
"Kinetics of allopregnanolone formation catalyzed by human 3 alpha-hydroxysteroid dehydrogenase type III (AKR1C2)."
],
"offsets": [
[
0,
113
]
]
},
{
"id": "12416991_abstract",
"type": "abstract",
"text": [
"Allopregnanolone is a neurosteroid which exhibits anxiolytic and anticonvulsant activities through potentiation of the GABA(A) receptor. The reduction of 5alpha-dihydroprogesterone (5alpha-DHP), the last step in allopregnanolone biosynthesis, is catalyzed by 3alpha-hydroxysteroid dehydrogenases (3alpha-HSDs). While the mechanism of action of allopregnanolone and the physiological and pharmacological modulation of allopregnanolone concentrations in vivo have been extensively studied, there has been little characterization of the kinetics of human 3alpha-HSD catalyzed allopregnanolone formation. We report here determination of the kinetic mechanism for 5alpha-DHP reduction catalyzed by human 3alpha-HSD type III by using steady-state kinetics studies and assessment of the ability of fluoxetine and various other small molecules to activate 3alpha-HSD type III catalyzed allopregnanolone formation. Enzyme-catalyzed 5alpha-DHP reduction yielded two products, allopregnanolone and 5alpha,20alpha-tetrahydroprogesterone, as measured by using a radiometric thin-layer chromatography assay, while 5beta-DHP reduction yielded the neurosteroid pregnanolone as the only product. 5Beta-DHP reduction proceeded with a catalytic efficiency 10 times higher than that of 5alpha-DHP reduction. Two-substrate kinetic analysis and dead-end inhibition studies for 5alpha-DHP reduction and allopregnanolone oxidation indicated that 3alpha-HSD type III utilized a ternary complex (sequential) kinetic mechanism, with nicotinamide adenine dinucleotide cofactor binding before steroid substrate and leaving after steroid product. Since previous reports suggested that fluoxetine and certain other small molecules increased allopregnanolone concentrations in vivo by activating 3alpha-HSD type III, we investigated whether these small molecules were able to activate human 3alpha-HSD type III. Our results showed that, at concentrations up to 50 microM, fluoxetine, paroxetine, sertraline, norfluoxetine, carbamazepine, clozapine, flurbiprofen, and sulfobromophthalein did not activate the enzyme. These results characterize the role of 3alpha-HSD type III in allopregnanolone formation and suggest that activation of this enzyme by fluoxetine is likely not the mechanism by which fluoxetine increases allopregnanolone concentrations."
],
"offsets": [
[
114,
2434
]
]
}
] | [
{
"id": "12416991_T1",
"type": "CHEMICAL",
"text": [
"Allopregnanolone"
],
"offsets": [
[
114,
130
]
],
"normalized": []
},
{
"id": "12416991_T2",
"type": "CHEMICAL",
"text": [
"5beta-DHP"
],
"offsets": [
[
1214,
1223
]
],
"normalized": []
},
{
"id": "12416991_T3",
"type": "CHEMICAL",
"text": [
"pregnanolone"
],
"offsets": [
[
1259,
1271
]
],
"normalized": []
},
{
"id": "12416991_T4",
"type": "CHEMICAL",
"text": [
"5Beta-DHP"
],
"offsets": [
[
1293,
1302
]
],
"normalized": []
},
{
"id": "12416991_T5",
"type": "CHEMICAL",
"text": [
"5alpha-DHP"
],
"offsets": [
[
1380,
1390
]
],
"normalized": []
},
{
"id": "12416991_T6",
"type": "CHEMICAL",
"text": [
"5alpha-DHP"
],
"offsets": [
[
1469,
1479
]
],
"normalized": []
},
{
"id": "12416991_T7",
"type": "CHEMICAL",
"text": [
"allopregnanolone"
],
"offsets": [
[
1494,
1510
]
],
"normalized": []
},
{
"id": "12416991_T8",
"type": "CHEMICAL",
"text": [
"nicotinamide adenine dinucleotide"
],
"offsets": [
[
1620,
1653
]
],
"normalized": []
},
{
"id": "12416991_T9",
"type": "CHEMICAL",
"text": [
"5alpha-dihydroprogesterone"
],
"offsets": [
[
268,
294
]
],
"normalized": []
},
{
"id": "12416991_T10",
"type": "CHEMICAL",
"text": [
"steroid"
],
"offsets": [
[
1678,
1685
]
],
"normalized": []
},
{
"id": "12416991_T11",
"type": "CHEMICAL",
"text": [
"steroid"
],
"offsets": [
[
1714,
1721
]
],
"normalized": []
},
{
"id": "12416991_T12",
"type": "CHEMICAL",
"text": [
"fluoxetine"
],
"offsets": [
[
1769,
1779
]
],
"normalized": []
},
{
"id": "12416991_T13",
"type": "CHEMICAL",
"text": [
"allopregnanolone"
],
"offsets": [
[
1824,
1840
]
],
"normalized": []
},
{
"id": "12416991_T14",
"type": "CHEMICAL",
"text": [
"5alpha-DHP"
],
"offsets": [
[
296,
306
]
],
"normalized": []
},
{
"id": "12416991_T15",
"type": "CHEMICAL",
"text": [
"fluoxetine"
],
"offsets": [
[
2054,
2064
]
],
"normalized": []
},
{
"id": "12416991_T16",
"type": "CHEMICAL",
"text": [
"paroxetine"
],
"offsets": [
[
2066,
2076
]
],
"normalized": []
},
{
"id": "12416991_T17",
"type": "CHEMICAL",
"text": [
"sertraline"
],
"offsets": [
[
2078,
2088
]
],
"normalized": []
},
{
"id": "12416991_T18",
"type": "CHEMICAL",
"text": [
"norfluoxetine"
],
"offsets": [
[
2090,
2103
]
],
"normalized": []
},
{
"id": "12416991_T19",
"type": "CHEMICAL",
"text": [
"carbamazepine"
],
"offsets": [
[
2105,
2118
]
],
"normalized": []
},
{
"id": "12416991_T20",
"type": "CHEMICAL",
"text": [
"clozapine"
],
"offsets": [
[
2120,
2129
]
],
"normalized": []
},
{
"id": "12416991_T21",
"type": "CHEMICAL",
"text": [
"flurbiprofen"
],
"offsets": [
[
2131,
2143
]
],
"normalized": []
},
{
"id": "12416991_T22",
"type": "CHEMICAL",
"text": [
"sulfobromophthalein"
],
"offsets": [
[
2149,
2168
]
],
"normalized": []
},
{
"id": "12416991_T23",
"type": "CHEMICAL",
"text": [
"allopregnanolone"
],
"offsets": [
[
326,
342
]
],
"normalized": []
},
{
"id": "12416991_T24",
"type": "CHEMICAL",
"text": [
"allopregnanolone"
],
"offsets": [
[
2260,
2276
]
],
"normalized": []
},
{
"id": "12416991_T25",
"type": "CHEMICAL",
"text": [
"fluoxetine"
],
"offsets": [
[
2333,
2343
]
],
"normalized": []
},
{
"id": "12416991_T26",
"type": "CHEMICAL",
"text": [
"fluoxetine"
],
"offsets": [
[
2381,
2391
]
],
"normalized": []
},
{
"id": "12416991_T27",
"type": "CHEMICAL",
"text": [
"allopregnanolone"
],
"offsets": [
[
2402,
2418
]
],
"normalized": []
},
{
"id": "12416991_T28",
"type": "CHEMICAL",
"text": [
"3alpha-hydroxysteroid"
],
"offsets": [
[
373,
394
]
],
"normalized": []
},
{
"id": "12416991_T29",
"type": "CHEMICAL",
"text": [
"allopregnanolone"
],
"offsets": [
[
458,
474
]
],
"normalized": []
},
{
"id": "12416991_T30",
"type": "CHEMICAL",
"text": [
"allopregnanolone"
],
"offsets": [
[
531,
547
]
],
"normalized": []
},
{
"id": "12416991_T31",
"type": "CHEMICAL",
"text": [
"allopregnanolone"
],
"offsets": [
[
687,
703
]
],
"normalized": []
},
{
"id": "12416991_T32",
"type": "CHEMICAL",
"text": [
"5alpha-DHP"
],
"offsets": [
[
773,
783
]
],
"normalized": []
},
{
"id": "12416991_T33",
"type": "CHEMICAL",
"text": [
"fluoxetine"
],
"offsets": [
[
905,
915
]
],
"normalized": []
},
{
"id": "12416991_T34",
"type": "CHEMICAL",
"text": [
"allopregnanolone"
],
"offsets": [
[
992,
1008
]
],
"normalized": []
},
{
"id": "12416991_T35",
"type": "CHEMICAL",
"text": [
"5alpha-DHP"
],
"offsets": [
[
1037,
1047
]
],
"normalized": []
},
{
"id": "12416991_T36",
"type": "CHEMICAL",
"text": [
"allopregnanolone"
],
"offsets": [
[
1080,
1096
]
],
"normalized": []
},
{
"id": "12416991_T37",
"type": "CHEMICAL",
"text": [
"5alpha,20alpha-tetrahydroprogesterone"
],
"offsets": [
[
1101,
1138
]
],
"normalized": []
},
{
"id": "12416991_T38",
"type": "CHEMICAL",
"text": [
"allopregnanolone"
],
"offsets": [
[
12,
28
]
],
"normalized": []
},
{
"id": "12416991_T39",
"type": "CHEMICAL",
"text": [
"3 alpha-hydroxysteroid"
],
"offsets": [
[
58,
80
]
],
"normalized": []
},
{
"id": "12416991_T40",
"type": "GENE-N",
"text": [
"GABA(A) receptor"
],
"offsets": [
[
233,
249
]
],
"normalized": []
},
{
"id": "12416991_T41",
"type": "GENE-Y",
"text": [
"3alpha-HSD type III"
],
"offsets": [
[
1536,
1555
]
],
"normalized": []
},
{
"id": "12416991_T42",
"type": "GENE-Y",
"text": [
"3alpha-HSD type III"
],
"offsets": [
[
1878,
1897
]
],
"normalized": []
},
{
"id": "12416991_T43",
"type": "GENE-Y",
"text": [
"human 3alpha-HSD type III"
],
"offsets": [
[
1967,
1992
]
],
"normalized": []
},
{
"id": "12416991_T44",
"type": "GENE-Y",
"text": [
"3alpha-HSD type III"
],
"offsets": [
[
2237,
2256
]
],
"normalized": []
},
{
"id": "12416991_T45",
"type": "GENE-N",
"text": [
"3alpha-hydroxysteroid dehydrogenases"
],
"offsets": [
[
373,
409
]
],
"normalized": []
},
{
"id": "12416991_T46",
"type": "GENE-N",
"text": [
"3alpha-HSDs"
],
"offsets": [
[
411,
422
]
],
"normalized": []
},
{
"id": "12416991_T47",
"type": "GENE-N",
"text": [
"human 3alpha-HSD"
],
"offsets": [
[
660,
676
]
],
"normalized": []
},
{
"id": "12416991_T48",
"type": "GENE-Y",
"text": [
"human 3alpha-HSD type III"
],
"offsets": [
[
807,
832
]
],
"normalized": []
},
{
"id": "12416991_T49",
"type": "GENE-Y",
"text": [
"3alpha-HSD type III"
],
"offsets": [
[
962,
981
]
],
"normalized": []
},
{
"id": "12416991_T50",
"type": "GENE-Y",
"text": [
"AKR1C2"
],
"offsets": [
[
105,
111
]
],
"normalized": []
},
{
"id": "12416991_T51",
"type": "GENE-Y",
"text": [
"human 3 alpha-hydroxysteroid dehydrogenase type III"
],
"offsets": [
[
52,
103
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12416991_0",
"type": "PRODUCT-OF",
"arg1_id": "12416991_T38",
"arg2_id": "12416991_T51",
"normalized": []
},
{
"id": "12416991_1",
"type": "PRODUCT-OF",
"arg1_id": "12416991_T38",
"arg2_id": "12416991_T50",
"normalized": []
},
{
"id": "12416991_2",
"type": "ACTIVATOR",
"arg1_id": "12416991_T1",
"arg2_id": "12416991_T40",
"normalized": []
},
{
"id": "12416991_3",
"type": "SUBSTRATE",
"arg1_id": "12416991_T9",
"arg2_id": "12416991_T45",
"normalized": []
},
{
"id": "12416991_4",
"type": "SUBSTRATE",
"arg1_id": "12416991_T14",
"arg2_id": "12416991_T45",
"normalized": []
},
{
"id": "12416991_5",
"type": "PRODUCT-OF",
"arg1_id": "12416991_T23",
"arg2_id": "12416991_T45",
"normalized": []
},
{
"id": "12416991_6",
"type": "SUBSTRATE",
"arg1_id": "12416991_T9",
"arg2_id": "12416991_T46",
"normalized": []
},
{
"id": "12416991_7",
"type": "SUBSTRATE",
"arg1_id": "12416991_T14",
"arg2_id": "12416991_T46",
"normalized": []
},
{
"id": "12416991_8",
"type": "PRODUCT-OF",
"arg1_id": "12416991_T23",
"arg2_id": "12416991_T46",
"normalized": []
},
{
"id": "12416991_9",
"type": "PRODUCT-OF",
"arg1_id": "12416991_T31",
"arg2_id": "12416991_T47",
"normalized": []
},
{
"id": "12416991_10",
"type": "SUBSTRATE",
"arg1_id": "12416991_T32",
"arg2_id": "12416991_T48",
"normalized": []
},
{
"id": "12416991_11",
"type": "ACTIVATOR",
"arg1_id": "12416991_T33",
"arg2_id": "12416991_T49",
"normalized": []
},
{
"id": "12416991_12",
"type": "PRODUCT-OF",
"arg1_id": "12416991_T34",
"arg2_id": "12416991_T49",
"normalized": []
},
{
"id": "12416991_13",
"type": "SUBSTRATE",
"arg1_id": "12416991_T6",
"arg2_id": "12416991_T41",
"normalized": []
},
{
"id": "12416991_14",
"type": "PRODUCT-OF",
"arg1_id": "12416991_T7",
"arg2_id": "12416991_T41",
"normalized": []
},
{
"id": "12416991_15",
"type": "SUBSTRATE",
"arg1_id": "12416991_T10",
"arg2_id": "12416991_T41",
"normalized": []
},
{
"id": "12416991_16",
"type": "PRODUCT-OF",
"arg1_id": "12416991_T11",
"arg2_id": "12416991_T41",
"normalized": []
},
{
"id": "12416991_17",
"type": "ACTIVATOR",
"arg1_id": "12416991_T12",
"arg2_id": "12416991_T42",
"normalized": []
},
{
"id": "12416991_18",
"type": "PRODUCT-OF",
"arg1_id": "12416991_T13",
"arg2_id": "12416991_T42",
"normalized": []
},
{
"id": "12416991_19",
"type": "PRODUCT-OF",
"arg1_id": "12416991_T24",
"arg2_id": "12416991_T44",
"normalized": []
},
{
"id": "12416991_20",
"type": "ACTIVATOR",
"arg1_id": "12416991_T25",
"arg2_id": "12416991_T44",
"normalized": []
}
] |
9587031 | 9587031 | [
{
"id": "9587031_title",
"type": "title",
"text": [
"Remethylation defects: guidelines for clinical diagnosis and treatment."
],
"offsets": [
[
0,
71
]
]
},
{
"id": "9587031_abstract",
"type": "abstract",
"text": [
"The main remethylation defects include disorders which all have defective methionine synthesis in common. Methylenetetrahydrofolate reductase deficiency impairs methyltetrahydrofolate synthesis, defects in cytosolic reduction of hydroxocobalamin (CblC/D) impair the synthesis of both methyl- and adenosyl cobalamin and deficiencies of methionine synthase (CblE/G) are associated with defective methyl cobalamin synthesis. The clinical presentation is characterized by acute neurological distress in early infancy. In childhood, patients present with progressive encephalopathy with an end-stage which has many signs in common with the adult onset form. In fact, both have more or less severe signs of subacute degeneration of the cord. Cobalamin defective patients must be treated with parenteral supplementation of hydroxocobalamin (1-2 mg per dose). Some methylenetetrahydrofolate patients could be folate responsive and must have a high-dosage folate trial. In addition, oral betaine supplementation (2-9 g per day depending on age) appears an effective means to prevent further neurological deterioration."
],
"offsets": [
[
72,
1181
]
]
}
] | [
{
"id": "9587031_T1",
"type": "CHEMICAL",
"text": [
"Methylenetetrahydrofolate"
],
"offsets": [
[
178,
203
]
],
"normalized": []
},
{
"id": "9587031_T2",
"type": "CHEMICAL",
"text": [
"methyltetrahydrofolate"
],
"offsets": [
[
233,
255
]
],
"normalized": []
},
{
"id": "9587031_T3",
"type": "CHEMICAL",
"text": [
"hydroxocobalamin"
],
"offsets": [
[
301,
317
]
],
"normalized": []
},
{
"id": "9587031_T4",
"type": "CHEMICAL",
"text": [
"methyl"
],
"offsets": [
[
356,
362
]
],
"normalized": []
},
{
"id": "9587031_T5",
"type": "CHEMICAL",
"text": [
"adenosyl cobalamin"
],
"offsets": [
[
368,
386
]
],
"normalized": []
},
{
"id": "9587031_T6",
"type": "CHEMICAL",
"text": [
"methionine"
],
"offsets": [
[
407,
417
]
],
"normalized": []
},
{
"id": "9587031_T7",
"type": "CHEMICAL",
"text": [
"methyl cobalamin"
],
"offsets": [
[
466,
482
]
],
"normalized": []
},
{
"id": "9587031_T8",
"type": "CHEMICAL",
"text": [
"Cobalamin"
],
"offsets": [
[
808,
817
]
],
"normalized": []
},
{
"id": "9587031_T9",
"type": "CHEMICAL",
"text": [
"methionine"
],
"offsets": [
[
146,
156
]
],
"normalized": []
},
{
"id": "9587031_T10",
"type": "CHEMICAL",
"text": [
"hydroxocobalamin"
],
"offsets": [
[
888,
904
]
],
"normalized": []
},
{
"id": "9587031_T11",
"type": "CHEMICAL",
"text": [
"methylenetetrahydrofolate"
],
"offsets": [
[
929,
954
]
],
"normalized": []
},
{
"id": "9587031_T12",
"type": "CHEMICAL",
"text": [
"folate"
],
"offsets": [
[
973,
979
]
],
"normalized": []
},
{
"id": "9587031_T13",
"type": "CHEMICAL",
"text": [
"betaine"
],
"offsets": [
[
1051,
1058
]
],
"normalized": []
},
{
"id": "9587031_T14",
"type": "GENE-Y",
"text": [
"Methylenetetrahydrofolate reductase"
],
"offsets": [
[
178,
213
]
],
"normalized": []
},
{
"id": "9587031_T15",
"type": "GENE-Y",
"text": [
"methionine synthase"
],
"offsets": [
[
407,
426
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "9587031_0",
"type": "PRODUCT-OF",
"arg1_id": "9587031_T2",
"arg2_id": "9587031_T14",
"normalized": []
},
{
"id": "9587031_1",
"type": "PRODUCT-OF",
"arg1_id": "9587031_T7",
"arg2_id": "9587031_T15",
"normalized": []
}
] |
16325050 | 16325050 | [
{
"id": "16325050_title",
"type": "title",
"text": [
"The Arg389Gly beta1-adrenoceptor polymorphism and catecholamine effects on plasma-renin activity."
],
"offsets": [
[
0,
97
]
]
},
{
"id": "16325050_abstract",
"type": "abstract",
"text": [
"OBJECTIVES: The purpose of this research was to find out whether, in humans, dobutamine-induced hemodynamic effects and increase in plasma-renin activity (PRA) might be beta1-adrenoceptor (beta1AR) genotype-dependent. BACKGROUND: In vitro Arg389Gly-beta1AR polymorphism exhibits decreased receptor signaling. METHODS: We studied 10 male homozygous Arg389-beta1AR subjects and 8 male homozygous Gly389beta1AR subjects; to avoid influences of codon 49 polymorphism, all were homozygous Ser49-beta1AR. Subjects were infused with dobutamine (1 to 6 microg/kg/min) with or without bisoprolol (10 mg orally) pretreatment, and PRA, heart rate, contractility, and blood pressure were assessed. RESULTS: With regard to PRA, dobutamine increased PRA more potently in Arg389-beta1AR versus Gly389-beta1AR subjects. Bisoprolol markedly suppressed the dobutamine-induced PRA increase in Arg389- but only marginally in Gly389-beta1AR subjects. With regard to hemodynamics, dobutamine caused larger heart rate and contractility increases and diastolic blood pressure decreases in Arg389- versus Gly389-beta1AR subjects. Bisoprolol reduced dobutamine-induced heart rate and contractility increases and diastolic blood pressure decreases more potently in Arg389- versus Gly389-beta1AR subjects. CONCLUSIONS: Codon 389 beta1AR polymorphism is a determinant not only of hemodynamic effects but also of PRA. Thus, beta1AR polymorphisms may be useful for predicting therapeutic responses to betaAR-blocker treatment."
],
"offsets": [
[
98,
1593
]
]
}
] | [
{
"id": "16325050_T1",
"type": "CHEMICAL",
"text": [
"Bisoprolol"
],
"offsets": [
[
1203,
1213
]
],
"normalized": []
},
{
"id": "16325050_T2",
"type": "CHEMICAL",
"text": [
"dobutamine"
],
"offsets": [
[
1222,
1232
]
],
"normalized": []
},
{
"id": "16325050_T3",
"type": "CHEMICAL",
"text": [
"dobutamine"
],
"offsets": [
[
624,
634
]
],
"normalized": []
},
{
"id": "16325050_T4",
"type": "CHEMICAL",
"text": [
"bisoprolol"
],
"offsets": [
[
674,
684
]
],
"normalized": []
},
{
"id": "16325050_T5",
"type": "CHEMICAL",
"text": [
"dobutamine"
],
"offsets": [
[
813,
823
]
],
"normalized": []
},
{
"id": "16325050_T6",
"type": "CHEMICAL",
"text": [
"dobutamine"
],
"offsets": [
[
175,
185
]
],
"normalized": []
},
{
"id": "16325050_T7",
"type": "CHEMICAL",
"text": [
"Bisoprolol"
],
"offsets": [
[
902,
912
]
],
"normalized": []
},
{
"id": "16325050_T8",
"type": "CHEMICAL",
"text": [
"dobutamine"
],
"offsets": [
[
937,
947
]
],
"normalized": []
},
{
"id": "16325050_T9",
"type": "CHEMICAL",
"text": [
"dobutamine"
],
"offsets": [
[
1057,
1067
]
],
"normalized": []
},
{
"id": "16325050_T10",
"type": "CHEMICAL",
"text": [
"catecholamine"
],
"offsets": [
[
50,
63
]
],
"normalized": []
},
{
"id": "16325050_T11",
"type": "GENE-Y",
"text": [
"beta1AR"
],
"offsets": [
[
1185,
1192
]
],
"normalized": []
},
{
"id": "16325050_T12",
"type": "GENE-Y",
"text": [
"beta1AR"
],
"offsets": [
[
1358,
1365
]
],
"normalized": []
},
{
"id": "16325050_T13",
"type": "GENE-Y",
"text": [
"beta1AR"
],
"offsets": [
[
1399,
1406
]
],
"normalized": []
},
{
"id": "16325050_T14",
"type": "GENE-Y",
"text": [
"renin"
],
"offsets": [
[
237,
242
]
],
"normalized": []
},
{
"id": "16325050_T15",
"type": "GENE-Y",
"text": [
"beta1AR"
],
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[
1492,
1499
]
],
"normalized": []
},
{
"id": "16325050_T16",
"type": "GENE-N",
"text": [
"betaAR"
],
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[
1568,
1574
]
],
"normalized": []
},
{
"id": "16325050_T17",
"type": "GENE-Y",
"text": [
"beta1-adrenoceptor"
],
"offsets": [
[
267,
285
]
],
"normalized": []
},
{
"id": "16325050_T18",
"type": "GENE-Y",
"text": [
"beta1AR"
],
"offsets": [
[
287,
294
]
],
"normalized": []
},
{
"id": "16325050_T19",
"type": "GENE-N",
"text": [
"Arg389Gly"
],
"offsets": [
[
337,
346
]
],
"normalized": []
},
{
"id": "16325050_T20",
"type": "GENE-Y",
"text": [
"beta1AR"
],
"offsets": [
[
347,
354
]
],
"normalized": []
},
{
"id": "16325050_T21",
"type": "GENE-Y",
"text": [
"beta1AR"
],
"offsets": [
[
453,
460
]
],
"normalized": []
},
{
"id": "16325050_T22",
"type": "GENE-Y",
"text": [
"beta1AR"
],
"offsets": [
[
498,
505
]
],
"normalized": []
},
{
"id": "16325050_T23",
"type": "GENE-Y",
"text": [
"beta1AR"
],
"offsets": [
[
588,
595
]
],
"normalized": []
},
{
"id": "16325050_T24",
"type": "GENE-Y",
"text": [
"beta1AR"
],
"offsets": [
[
862,
869
]
],
"normalized": []
},
{
"id": "16325050_T25",
"type": "GENE-Y",
"text": [
"beta1AR"
],
"offsets": [
[
884,
891
]
],
"normalized": []
},
{
"id": "16325050_T26",
"type": "GENE-Y",
"text": [
"beta1AR"
],
"offsets": [
[
1010,
1017
]
],
"normalized": []
},
{
"id": "16325050_T27",
"type": "GENE-Y",
"text": [
"beta1-adrenoceptor"
],
"offsets": [
[
14,
32
]
],
"normalized": []
},
{
"id": "16325050_T28",
"type": "GENE-N",
"text": [
"Arg389Gly"
],
"offsets": [
[
4,
13
]
],
"normalized": []
},
{
"id": "16325050_T29",
"type": "GENE-Y",
"text": [
"renin"
],
"offsets": [
[
82,
87
]
],
"normalized": []
}
] | [] | [] | [] |
23335106 | 23335106 | [
{
"id": "23335106_title",
"type": "title",
"text": [
"Fast, reversible, and general photomechanical motion in single crystals of various azo compounds using visible light."
],
"offsets": [
[
0,
117
]
]
},
{
"id": "23335106_abstract",
"type": "abstract",
"text": [
"Pseudostilbene-type single crystals exhibit ubiquitous, fast, and reversible photomechanical motion under visible-light irradiation. Push-pull substituents impart extremely rapid switching using just one wavelength of light by shortening the lifetime of the cis-form. This results in a bending motion in the microsecond regime. The influence of crystal density, thickness, and molecular orientation on optimization of the photomechanical effect is investigated."
],
"offsets": [
[
118,
579
]
]
}
] | [
{
"id": "23335106_T1",
"type": "CHEMICAL",
"text": [
"azo"
],
"offsets": [
[
83,
86
]
],
"normalized": []
}
] | [] | [] | [] |
23001627 | 23001627 | [
{
"id": "23001627_title",
"type": "title",
"text": [
"Levothyroxine replacement therapy with vitamin E supplementation prevents oxidative stress and cognitive deficit in experimental hypothyroidism."
],
"offsets": [
[
0,
144
]
]
},
{
"id": "23001627_abstract",
"type": "abstract",
"text": [
"Hypothyroidism has a variety of adverse effects on cognitive function. The treatment of levothyroxine alone cannot restore cognitive defects of hypothyroid patients. Antioxidant vitamin E supplementation could be useful in disturbances which are associated with oxidative stress and could effectively slow the progression of Alzheimer disease. Thus, the purpose of this study was to evaluate oxidative stress status of the serum and hippocampus in hypothyroidism and to examine the effects of levothyroxine replacement therapy with vitamin E supplementation on cognitive deficit. Sprague-Dawley rats were randomly divided into five groups: control group, PTU group, PTU + Vit E group, PTU + L-T4 group, and PTU + L-T4 + Vit E group. Serum and hippocampus malondialdehyde (MDA) levels were determined using the thiobarbituric-acid reactive substances method. Serum and hippocampus superoxide dismutase (SOD) levels were determined by measuring its ability to inhibit the photoreduction of nitroblue tetrazolium. Learning and memory was assessed by Morris water maze test. In the present study, we found that the rats of PTU + Vit E group spent less time to find the platform on days 2, 3, 4, and 5 than the PTU group. Moreover, the rats of PTU + L-T4 + Vit E group spent less time to find the platform on days 4 and 5 than the PTU + L-T4 group. The time spent in the target quadrants was measured in the probe test and no difference was observed in all groups. Oxidative damage has been observed in the serum and hippocampus of hypothyroidism rat. SOD levels of serum and hippocampus tissue were significantly increased and MDA levels were significantly decreased in the PTU + Vit E and PTU + L-T4 + Vit E groups than the PTU and PTU + L-T4 groups. Therefore, these findings indicate that levothyroxine replacement therapy with vitamin E supplementation may ameliorate cognitive deficit in PTU-induced hypothyroidism through the decrease of oxidative stress status."
],
"offsets": [
[
145,
2109
]
]
}
] | [
{
"id": "23001627_T1",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
1264,
1267
]
],
"normalized": []
},
{
"id": "23001627_T2",
"type": "CHEMICAL",
"text": [
"Vit E"
],
"offsets": [
[
1270,
1275
]
],
"normalized": []
},
{
"id": "23001627_T3",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
1351,
1354
]
],
"normalized": []
},
{
"id": "23001627_T4",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
1384,
1387
]
],
"normalized": []
},
{
"id": "23001627_T5",
"type": "CHEMICAL",
"text": [
"L-T4"
],
"offsets": [
[
1390,
1394
]
],
"normalized": []
},
{
"id": "23001627_T6",
"type": "CHEMICAL",
"text": [
"Vit E"
],
"offsets": [
[
1397,
1402
]
],
"normalized": []
},
{
"id": "23001627_T7",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
1471,
1474
]
],
"normalized": []
},
{
"id": "23001627_T8",
"type": "CHEMICAL",
"text": [
"L-T4"
],
"offsets": [
[
1477,
1481
]
],
"normalized": []
},
{
"id": "23001627_T9",
"type": "CHEMICAL",
"text": [
"MDA"
],
"offsets": [
[
1768,
1771
]
],
"normalized": []
},
{
"id": "23001627_T10",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
1815,
1818
]
],
"normalized": []
},
{
"id": "23001627_T11",
"type": "CHEMICAL",
"text": [
"Vit E"
],
"offsets": [
[
1821,
1826
]
],
"normalized": []
},
{
"id": "23001627_T12",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
1831,
1834
]
],
"normalized": []
},
{
"id": "23001627_T13",
"type": "CHEMICAL",
"text": [
"L-T4"
],
"offsets": [
[
1837,
1841
]
],
"normalized": []
},
{
"id": "23001627_T14",
"type": "CHEMICAL",
"text": [
"Vit E"
],
"offsets": [
[
1844,
1849
]
],
"normalized": []
},
{
"id": "23001627_T15",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
1866,
1869
]
],
"normalized": []
},
{
"id": "23001627_T16",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
1874,
1877
]
],
"normalized": []
},
{
"id": "23001627_T17",
"type": "CHEMICAL",
"text": [
"L-T4"
],
"offsets": [
[
1880,
1884
]
],
"normalized": []
},
{
"id": "23001627_T18",
"type": "CHEMICAL",
"text": [
"vitamin E"
],
"offsets": [
[
323,
332
]
],
"normalized": []
},
{
"id": "23001627_T19",
"type": "CHEMICAL",
"text": [
"levothyroxine"
],
"offsets": [
[
1933,
1946
]
],
"normalized": []
},
{
"id": "23001627_T20",
"type": "CHEMICAL",
"text": [
"vitamin E"
],
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[
1972,
1981
]
],
"normalized": []
},
{
"id": "23001627_T21",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
2034,
2037
]
],
"normalized": []
},
{
"id": "23001627_T22",
"type": "CHEMICAL",
"text": [
"levothyroxine"
],
"offsets": [
[
638,
651
]
],
"normalized": []
},
{
"id": "23001627_T23",
"type": "CHEMICAL",
"text": [
"vitamin E"
],
"offsets": [
[
677,
686
]
],
"normalized": []
},
{
"id": "23001627_T24",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
800,
803
]
],
"normalized": []
},
{
"id": "23001627_T25",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
811,
814
]
],
"normalized": []
},
{
"id": "23001627_T26",
"type": "CHEMICAL",
"text": [
"Vit E"
],
"offsets": [
[
817,
822
]
],
"normalized": []
},
{
"id": "23001627_T27",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
830,
833
]
],
"normalized": []
},
{
"id": "23001627_T28",
"type": "CHEMICAL",
"text": [
"L-T4"
],
"offsets": [
[
836,
840
]
],
"normalized": []
},
{
"id": "23001627_T29",
"type": "CHEMICAL",
"text": [
"PTU"
],
"offsets": [
[
852,
855
]
],
"normalized": []
},
{
"id": "23001627_T30",
"type": "CHEMICAL",
"text": [
"L-T4"
],
"offsets": [
[
858,
862
]
],
"normalized": []
},
{
"id": "23001627_T31",
"type": "CHEMICAL",
"text": [
"Vit E"
],
"offsets": [
[
865,
870
]
],
"normalized": []
},
{
"id": "23001627_T32",
"type": "CHEMICAL",
"text": [
"malondialdehyde"
],
"offsets": [
[
900,
915
]
],
"normalized": []
},
{
"id": "23001627_T33",
"type": "CHEMICAL",
"text": [
"MDA"
],
"offsets": [
[
917,
920
]
],
"normalized": []
},
{
"id": "23001627_T34",
"type": "CHEMICAL",
"text": [
"thiobarbituric-acid"
],
"offsets": [
[
955,
974
]
],
"normalized": []
},
{
"id": "23001627_T35",
"type": "CHEMICAL",
"text": [
"superoxide"
],
"offsets": [
[
1025,
1035
]
],
"normalized": []
},
{
"id": "23001627_T36",
"type": "CHEMICAL",
"text": [
"levothyroxine"
],
"offsets": [
[
233,
246
]
],
"normalized": []
},
{
"id": "23001627_T37",
"type": "CHEMICAL",
"text": [
"nitroblue tetrazolium"
],
"offsets": [
[
1133,
1154
]
],
"normalized": []
},
{
"id": "23001627_T38",
"type": "CHEMICAL",
"text": [
"Levothyroxine"
],
"offsets": [
[
0,
13
]
],
"normalized": []
},
{
"id": "23001627_T39",
"type": "CHEMICAL",
"text": [
"vitamin E"
],
"offsets": [
[
39,
48
]
],
"normalized": []
},
{
"id": "23001627_T40",
"type": "GENE-N",
"text": [
"SOD"
],
"offsets": [
[
1692,
1695
]
],
"normalized": []
},
{
"id": "23001627_T41",
"type": "GENE-N",
"text": [
"superoxide dismutase"
],
"offsets": [
[
1025,
1045
]
],
"normalized": []
},
{
"id": "23001627_T42",
"type": "GENE-N",
"text": [
"SOD"
],
"offsets": [
[
1047,
1050
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23001627_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23001627_T10",
"arg2_id": "23001627_T40",
"normalized": []
},
{
"id": "23001627_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23001627_T11",
"arg2_id": "23001627_T40",
"normalized": []
},
{
"id": "23001627_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23001627_T12",
"arg2_id": "23001627_T40",
"normalized": []
},
{
"id": "23001627_3",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23001627_T13",
"arg2_id": "23001627_T40",
"normalized": []
},
{
"id": "23001627_4",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23001627_T14",
"arg2_id": "23001627_T40",
"normalized": []
}
] |
23380477 | 23380477 | [
{
"id": "23380477_title",
"type": "title",
"text": [
"Autophagy takes place in mutated p53 neuroblastoma cells in response to hypoxia mimetic CoCl(2)."
],
"offsets": [
[
0,
96
]
]
},
{
"id": "23380477_abstract",
"type": "abstract",
"text": [
"Solid tumors like neuroblastoma exhibit hypoxic areas, which can lead both to cell death or aggressiveness increase. Hypoxia is a known stress able to induce stabilization of p53, implicated in cell fate regulation. Recently, p53 appeared to be involved in autophagy in an opposite manner, depending on its location: when nuclear, it enhanced transcription of pro-autophagic genes whereas when cytoplasmic, it inhibited the autophagic process. Today, we used cobalt chloride, a hypoxia mimetic that inhibits proteasomal HIF-1 degradation and generates reactive oxygen species (ROS). We focused on CoCl2-induced cell death in a DNA-binding mutated p53 neuroblastoma cell line (SKNBE(2c)). An autophagic signaling was evidenced by an increase of Beclin-1, ATG 5-12, and LC3-II expression whereas the p53(mut) presence decreased with CoCl2 time exposure. Activation of the pathway seemed to protect cells from ROS production and, at least in part, from death. The autophagic inhibitors activated the apoptotic signaling and the death was enhanced. To delineate the eventual implication of the p53(mut) in the autophagic process in response to hypoxia, we monitored signaling in p53(WT)SHSY5Y cells, after either shRNA-p53 down-regulation or transcriptional activity inhibition by pifithrin alpha. We did not detect autophagy neither with p53(wt) nor when p53 was lacking whereas such a response was effective with a mutated or inactivated p53. To conclude, mutated p53 in neuroblastoma cells could be linked with the switch between apoptotic response and cell death by autophagy in response to hypoxic mimetic stress."
],
"offsets": [
[
97,
1711
]
]
}
] | [
{
"id": "23380477_T1",
"type": "CHEMICAL",
"text": [
"cobalt chloride"
],
"offsets": [
[
556,
571
]
],
"normalized": []
},
{
"id": "23380477_T2",
"type": "CHEMICAL",
"text": [
"oxygen"
],
"offsets": [
[
658,
664
]
],
"normalized": []
},
{
"id": "23380477_T3",
"type": "CHEMICAL",
"text": [
"CoCl2"
],
"offsets": [
[
694,
699
]
],
"normalized": []
},
{
"id": "23380477_T4",
"type": "CHEMICAL",
"text": [
"CoCl2"
],
"offsets": [
[
928,
933
]
],
"normalized": []
},
{
"id": "23380477_T5",
"type": "CHEMICAL",
"text": [
"CoCl(2)"
],
"offsets": [
[
88,
95
]
],
"normalized": []
},
{
"id": "23380477_T6",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
1187,
1190
]
],
"normalized": []
},
{
"id": "23380477_T7",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
1272,
1275
]
],
"normalized": []
},
{
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"p53"
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"p53"
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"p53"
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1559,
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"p53"
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"p53"
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"id": "23380477_T15",
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"HIF-1"
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617,
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"id": "23380477_T16",
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"p53"
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"Beclin-1"
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841,
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"ATG 5-12"
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851,
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"id": "23380477_T19",
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"LC3-II"
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865,
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"p53"
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"id": "23380477_T21",
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"p53"
],
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[
33,
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]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23380477_0",
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"arg1_id": "23380477_T1",
"arg2_id": "23380477_T15",
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},
{
"id": "23380477_1",
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"arg2_id": "23380477_T20",
"normalized": []
}
] |
20573261 | 20573261 | [
{
"id": "20573261_title",
"type": "title",
"text": [
"Histamine H4 receptor antagonism diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokines."
],
"offsets": [
[
0,
121
]
]
},
{
"id": "20573261_abstract",
"type": "abstract",
"text": [
"BACKGROUND: Airway remodeling and dysfunction are characteristic features of asthma thought to be caused by aberrant production of Th2 cytokines. Histamine H4 receptor (H4R) perturbation has previously been shown to modify acute inflammation and Th2 cytokine production in a murine model of asthma. We examined the ability of H4R antagonists to therapeutically modify the effects of Th2 cytokine production such as goblet cell hyperplasia (GCH), and collagen deposition in a sub-chronic model of asthma. In addition, effects on Th2 mediated lung dysfunction were also determined. METHODS: Mice were sensitized to ovalbumin (OVA) followed by repeated airway challenge with OVA. After inflammation was established mice were dosed with the H4R antagonist, JNJ 7777120, or anti-IL-13 antibody for comparison. Airway hyperreactivity (AHR) was measured, lungs lavaged and tissues collected for analysis. RESULTS: Therapeutic H4R antagonism inhibited T cell infiltration in to the lung and decreased Th2 cytokines IL-13 and IL-5. IL-13 dependent remodeling parameters such as GCH and lung collagen were reduced. Intervention with H4R antagonist also improved measures of central and peripheral airway dysfunction. CONCLUSIONS: These data demonstrate that therapeutic H4R antagonism can significantly ameliorate allergen induced, Th2 cytokine driven pathologies such as lung remodeling and airway dysfunction. The ability of H4R antagonists to affect these key manifestations of asthma suggests their potential as novel human therapeutics."
],
"offsets": [
[
122,
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]
]
}
] | [
{
"id": "20573261_T1",
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"Histamine"
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268,
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]
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"JNJ 7777120"
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875,
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]
],
"normalized": []
},
{
"id": "20573261_T3",
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"text": [
"Histamine"
],
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[
0,
9
]
],
"normalized": []
},
{
"id": "20573261_T4",
"type": "GENE-Y",
"text": [
"IL-13"
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1129,
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]
],
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},
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"id": "20573261_T5",
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"IL-5"
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1139,
1143
]
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"id": "20573261_T6",
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"IL-13"
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1145,
1150
]
],
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},
{
"id": "20573261_T7",
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"collagen"
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1204,
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]
],
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},
{
"id": "20573261_T8",
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"H4R"
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1245,
1248
]
],
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"id": "20573261_T9",
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"H4R"
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1382,
1385
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],
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},
{
"id": "20573261_T10",
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"Th2 cytokines"
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253,
266
]
],
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},
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"id": "20573261_T11",
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"Th2 cytokine"
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1444,
1456
]
],
"normalized": []
},
{
"id": "20573261_T12",
"type": "GENE-Y",
"text": [
"H4R"
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1539,
1542
]
],
"normalized": []
},
{
"id": "20573261_T13",
"type": "GENE-Y",
"text": [
"Histamine H4 receptor"
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[
268,
289
]
],
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},
{
"id": "20573261_T14",
"type": "GENE-Y",
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"H4R"
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291,
294
]
],
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},
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"id": "20573261_T15",
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"Th2 cytokine"
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368,
380
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],
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},
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"H4R"
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448,
451
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},
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"Th2 cytokine"
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505,
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},
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"collagen"
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572,
580
]
],
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},
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"id": "20573261_T19",
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"text": [
"ovalbumin"
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735,
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],
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},
{
"id": "20573261_T20",
"type": "GENE-Y",
"text": [
"OVA"
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[
746,
749
]
],
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},
{
"id": "20573261_T21",
"type": "GENE-Y",
"text": [
"OVA"
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794,
797
]
],
"normalized": []
},
{
"id": "20573261_T22",
"type": "GENE-Y",
"text": [
"H4R"
],
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[
859,
862
]
],
"normalized": []
},
{
"id": "20573261_T23",
"type": "GENE-Y",
"text": [
"IL-13"
],
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[
896,
901
]
],
"normalized": []
},
{
"id": "20573261_T24",
"type": "GENE-Y",
"text": [
"H4R"
],
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[
1041,
1044
]
],
"normalized": []
},
{
"id": "20573261_T25",
"type": "GENE-N",
"text": [
"Th2 cytokines"
],
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[
1115,
1128
]
],
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},
{
"id": "20573261_T26",
"type": "GENE-Y",
"text": [
"Histamine H4 receptor"
],
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[
0,
21
]
],
"normalized": []
},
{
"id": "20573261_T27",
"type": "GENE-N",
"text": [
"Th2 cytokines"
],
"offsets": [
[
107,
120
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "20573261_0",
"type": "ANTAGONIST",
"arg1_id": "20573261_T2",
"arg2_id": "20573261_T22",
"normalized": []
}
] |
23293094 | 23293094 | [
{
"id": "23293094_title",
"type": "title",
"text": [
"Dietary exposure of mink (Mustela vison) to fish from the upper Hudson River, New York, USA: effects on reproduction and offspring growth and mortality."
],
"offsets": [
[
0,
152
]
]
},
{
"id": "23293094_abstract",
"type": "abstract",
"text": [
"The effects of feeding farm-raised mink (Mustela vison) diets containing polychlorinated biphenyl (PCB)-contaminated fish from the upper Hudson River (New York, USA) on adult reproductive performance and kit growth and mortality were evaluated. Diets contained 2.5 to 20% Hudson River fish, providing 0.72 to 6.1 µg ∑PCBs/g feed (4.8-38 pg toxic equivalents [TEQWHO 2005 ]/g feed). The percentage of stillborn kits per litter was significantly increased by dietary concentrations of 4.5 µg ∑PCBs/g feed (28 pg TEQWHO 2005 /g feed) and greater. All offspring exposed to dietary concentrations of 4.5 and 6.1 µg ∑PCBs/g feed (28 and 38 pg TEQWHO 2005 /g feed) died by 10 weeks of age, and all offspring exposed to 1.5 and 2.8 µg ∑PCBs/g feed (10 and 18 pg TEQWHO 2005 /g feed) died by 31 weeks of age, leaving juveniles in the control and 0.72 µg ∑PCBs/g feed (0.41- and 4.8 pg TEQWHO 2005 /g feed) groups only. The dietary concentration predicted to result in 20% kit mortality (LC20) at six weeks of age was 0.34 µg ∑PCBs/g feed (2.6 pg TEQWHO 2005 /g feed). The corresponding maternal hepatic concentration was 0.80 µg ∑PCBs/g liver, wet weight (13 pg TEQWHO 2005 /g liver, wet wt). Mink residing in the upper Hudson River would be expected to consume species of fish that contain an average of 4.0 µg ∑PCBs/g tissue. Thus, a daily diet composed of less than 10% Hudson River fish could provide a dietary concentration of ∑PCBs that resulted in 20% kit mortality in the present study."
],
"offsets": [
[
153,
1638
]
]
}
] | [
{
"id": "23293094_T1",
"type": "CHEMICAL",
"text": [
"polychlorinated biphenyl"
],
"offsets": [
[
226,
250
]
],
"normalized": []
},
{
"id": "23293094_T2",
"type": "CHEMICAL",
"text": [
"PCB"
],
"offsets": [
[
252,
255
]
],
"normalized": []
}
] | [] | [] | [] |
23556445 | 23556445 | [
{
"id": "23556445_title",
"type": "title",
"text": [
"Genomic variation in the MAP3K5 gene is associated with β-thalassemia disease severity and hydroxyurea treatment efficacy."
],
"offsets": [
[
0,
122
]
]
},
{
"id": "23556445_abstract",
"type": "abstract",
"text": [
"Aim: In this study we explored the association between genetic variations in MAP3K5 and PDE7B genes, residing on chromosome 6q23, and disease severity in β-hemoglobinopathy patients, as well as the association between these variants with response to hydroxyurea (HU) treatment. Furthermore, we examined MAP3K5 expression in the context of high fetal hemoglobin (HbF) and upon HU treatment in erythroid progenitor cells from healthy and KLF1 haploinsufficient individuals. Materials & methods: For this purpose, we genotyped β-thalassemia intermedia and major patients and healthy controls, as well as a cohort of compound heterozygous sickle cell disease/β-thalassemia patients receiving HU as HbF augmentation treatment. Furthermore, we examined MAP3K5 expression in the context of high HbF and upon HU treatment in erythroid progenitor cells from healthy and KLF1 haploinsufficient individuals. Results: A short tandem repeat in the MAP3K5 promoter and two intronic MAP3K5 gene variants, as well as a PDE7B variant, are associated with low HbF levels and a severe disease phenotype. Moreover, MAP3K5 mRNA expression levels are altered in the context of high HbF and are affected by the presence of HU. Lastly, the abovementioned MAP3K5 variants are associated with HU treatment efficacy. Conclusion: Our data suggest that these MAP3K5 variants are indicative of β-thalassemia disease severity and response to HU treatment. Original submitted 24 September 2012; Revision submitted 4 February 2013."
],
"offsets": [
[
123,
1621
]
]
}
] | [
{
"id": "23556445_T1",
"type": "CHEMICAL",
"text": [
"hydroxyurea"
],
"offsets": [
[
373,
384
]
],
"normalized": []
},
{
"id": "23556445_T2",
"type": "CHEMICAL",
"text": [
"hydroxyurea"
],
"offsets": [
[
91,
102
]
],
"normalized": []
},
{
"id": "23556445_T3",
"type": "GENE-Y",
"text": [
"PDE7B"
],
"offsets": [
[
1126,
1131
]
],
"normalized": []
},
{
"id": "23556445_T4",
"type": "GENE-Y",
"text": [
"MAP3K5"
],
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[
1218,
1224
]
],
"normalized": []
},
{
"id": "23556445_T5",
"type": "GENE-Y",
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"MAP3K5"
],
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[
1354,
1360
]
],
"normalized": []
},
{
"id": "23556445_T6",
"type": "GENE-Y",
"text": [
"MAP3K5"
],
"offsets": [
[
1453,
1459
]
],
"normalized": []
},
{
"id": "23556445_T7",
"type": "GENE-Y",
"text": [
"MAP3K5"
],
"offsets": [
[
426,
432
]
],
"normalized": []
},
{
"id": "23556445_T8",
"type": "GENE-Y",
"text": [
"MAP3K5"
],
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[
870,
876
]
],
"normalized": []
},
{
"id": "23556445_T9",
"type": "GENE-Y",
"text": [
"MAP3K5"
],
"offsets": [
[
200,
206
]
],
"normalized": []
},
{
"id": "23556445_T10",
"type": "GENE-Y",
"text": [
"PDE7B"
],
"offsets": [
[
211,
216
]
],
"normalized": []
},
{
"id": "23556445_T11",
"type": "GENE-N",
"text": [
"MAP3K5 promoter"
],
"offsets": [
[
1058,
1073
]
],
"normalized": []
},
{
"id": "23556445_T12",
"type": "GENE-Y",
"text": [
"MAP3K5"
],
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[
1091,
1097
]
],
"normalized": []
},
{
"id": "23556445_T13",
"type": "GENE-Y",
"text": [
"MAP3K5"
],
"offsets": [
[
25,
31
]
],
"normalized": []
}
] | [] | [] | [] |
23618899 | 23618899 | [
{
"id": "23618899_title",
"type": "title",
"text": [
"Expression of WWOX and FHIT is downregulated by exposure to arsenite in human uroepithelial cells."
],
"offsets": [
[
0,
98
]
]
},
{
"id": "23618899_abstract",
"type": "abstract",
"text": [
"Ecological studies in Taiwan, Chile, Argentina, Bangladesh, and Mexico have confirmed significant dose-dependent associations between ingestion of arsenic-contaminated drinking water and the risk of various human malignancies. The FHIT and WWOX genes are active in common fragile sites FRA3B and FRA16D, respectively. Reduced expression of FHIT or WWOX is known to be an early indicator of carcinogen-induced cancers. However, the effect of arsenite on the expressions and molecular mechanisms of these markers is still unclear. The aims of this study were (i) to observe the expression of ATR, WWOX and FHIT proteins in urothelial carcinoma (UC) between endemic and non-endemic areas of blackfoot disease (BFD) by immunohistochemical analyses; (ii) to compare expression of these genes between arsenite-treated SV-HUC-1 human epithelial cells and rat uroepithelial cells; and (iii) to determine the role of DNMT and MEK inhibitors on expressions of WWOX and FHIT in response to arsenite in SV-HUC-1. The experiments revealed that expressions of ATR, WWOX and FHIT in UC significantly differed between BFD areas and non-BFD areas (p=0.003, 0.009 and 0.021, respectively). In fact, the results for the arsenite-treated groups showed that ATR, WWOX and FHIT are downregulated by arsenite in SV-HUC-1. However, the inhibitors suppressed the effects of arsenite on WWOX and FHIT proteins and mRNA expression. In conclusion, arsenite decreased expressions of ATR, WWOX and FHIT via ERK1/2 activation in SV-HUC-1 cells. These findings confirm that dysregulations of these markers may contribute to arsenite-induced carcinogenesis."
],
"offsets": [
[
99,
1723
]
]
}
] | [
{
"id": "23618899_T1",
"type": "CHEMICAL",
"text": [
"arsenite"
],
"offsets": [
[
1300,
1308
]
],
"normalized": []
},
{
"id": "23618899_T2",
"type": "CHEMICAL",
"text": [
"arsenite"
],
"offsets": [
[
1376,
1384
]
],
"normalized": []
},
{
"id": "23618899_T3",
"type": "CHEMICAL",
"text": [
"arsenite"
],
"offsets": [
[
1448,
1456
]
],
"normalized": []
},
{
"id": "23618899_T4",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
246,
253
]
],
"normalized": []
},
{
"id": "23618899_T5",
"type": "CHEMICAL",
"text": [
"arsenite"
],
"offsets": [
[
1691,
1699
]
],
"normalized": []
},
{
"id": "23618899_T6",
"type": "CHEMICAL",
"text": [
"arsenite"
],
"offsets": [
[
540,
548
]
],
"normalized": []
},
{
"id": "23618899_T7",
"type": "CHEMICAL",
"text": [
"arsenite"
],
"offsets": [
[
894,
902
]
],
"normalized": []
},
{
"id": "23618899_T8",
"type": "CHEMICAL",
"text": [
"arsenite"
],
"offsets": [
[
1078,
1086
]
],
"normalized": []
},
{
"id": "23618899_T9",
"type": "CHEMICAL",
"text": [
"arsenite"
],
"offsets": [
[
60,
68
]
],
"normalized": []
},
{
"id": "23618899_T10",
"type": "GENE-Y",
"text": [
"ATR"
],
"offsets": [
[
1145,
1148
]
],
"normalized": []
},
{
"id": "23618899_T11",
"type": "GENE-Y",
"text": [
"WWOX"
],
"offsets": [
[
1150,
1154
]
],
"normalized": []
},
{
"id": "23618899_T12",
"type": "GENE-Y",
"text": [
"FHIT"
],
"offsets": [
[
1159,
1163
]
],
"normalized": []
},
{
"id": "23618899_T13",
"type": "GENE-Y",
"text": [
"ATR"
],
"offsets": [
[
1336,
1339
]
],
"normalized": []
},
{
"id": "23618899_T14",
"type": "GENE-Y",
"text": [
"WWOX"
],
"offsets": [
[
1341,
1345
]
],
"normalized": []
},
{
"id": "23618899_T15",
"type": "GENE-Y",
"text": [
"FHIT"
],
"offsets": [
[
1350,
1354
]
],
"normalized": []
},
{
"id": "23618899_T16",
"type": "GENE-Y",
"text": [
"WWOX"
],
"offsets": [
[
1460,
1464
]
],
"normalized": []
},
{
"id": "23618899_T17",
"type": "GENE-Y",
"text": [
"FHIT"
],
"offsets": [
[
1469,
1473
]
],
"normalized": []
},
{
"id": "23618899_T18",
"type": "GENE-Y",
"text": [
"ATR"
],
"offsets": [
[
1553,
1556
]
],
"normalized": []
},
{
"id": "23618899_T19",
"type": "GENE-Y",
"text": [
"WWOX"
],
"offsets": [
[
1558,
1562
]
],
"normalized": []
},
{
"id": "23618899_T20",
"type": "GENE-Y",
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}
] |
7995016 | 7995016 | [
{
"id": "7995016_title",
"type": "title",
"text": [
"Pharmacokinetic aspects of l-deprenyl (selegiline) and its metabolites."
],
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0,
71
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]
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{
"id": "7995016_abstract",
"type": "abstract",
"text": [
"l-Deprenyl (selegiline), an irreversible and selective inhibitor of monoamine oxidase type B (MAO-B), is rapidly absorbed from the gastrointestinal tract and distributed into tissues. The reaction between MAO and selegiline takes place in two steps. The initial reversible reaction is followed by an irreversible reaction in which selegiline is bound covalently to the flavin part of the enzyme. Studies with positron emission tomography have shown retention of selegiline in brain areas with high MAO-B activity, including striatal structures, hippocampus, thalamus, and substantia nigra. Inhibition of MAO-B in vivo takes place rapidly; for example, platelet MAO is inhibited almost totally within the first 60 minutes after a single 10 mg oral dose of the drug. The recovery of MAO after inhibition depends on the organ and species in question. In rat brain the half-life of recovery in the brain is approximately 8 to 12 days; in rat liver it is shorter, 1 to 3 days. Selegiline is metabolized into l-(-)-desmethylselegiline, l-(-)-methamphetamine, and l-(-)-amphetamine mainly in the liver through the microsomal P-450 system. The stereoselectivity of the metabolites is maintained; no racemic transformation takes place. All three main metabolites are found in human serum, cerebrospinal fluid, and urine, and l-(-)-methamphetamine accounts for most of the metabolite pool. The metabolites are excreted mainly via urine l-(-)-Desmethylselegiline has been shown to be an irreversible inhibitor of MAO-B in the rat and in humans."
],
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72,
1605
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1102,
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285,
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403,
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534,
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140,
149
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27,
37
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39,
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1190,
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277,
280
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570,
575
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676,
681
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140,
164
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"id": "7995016_T22",
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853,
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"MAO-B"
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166,
171
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}
] | [] | [] | [
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"arg2_id": "7995016_T16",
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}
] |
3320565 | 3320565 | [
{
"id": "3320565_title",
"type": "title",
"text": [
"Pharmacological and clinical studies of the antiandrogen Anandron."
],
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0,
66
]
]
},
{
"id": "3320565_abstract",
"type": "abstract",
"text": [
"This paper summarizes the animal and human studies with Anandron available at the time of the meeting. The following was demonstrated in the rat and confirmed in man: interaction of Anandron with the prostatic androgen receptor, antiandrogen activity against testosterone (in particular against the early transient rise induced by LHRH analogs) and adrenal androgens. Thus, as shown in 4 different double blind studies performed in stage D2 prostrate cancer patients, the combination of Anandron with surgical or chemical castration enhanced the beneficial effects of castration alone and thus seems a step forward in the hormonal treatment of prostatic carcinoma."
],
"offsets": [
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67,
731
]
]
}
] | [
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249,
257
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277,
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"id": "3320565_T3",
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326,
338
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"id": "3320565_T4",
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424,
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554,
562
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123,
131
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57,
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"id": "3320565_T8",
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267,
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"id": "3320565_T9",
"type": "GENE-N",
"text": [
"LHRH"
],
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[
398,
402
]
],
"normalized": []
}
] | [] | [] | [] |
9374794 | 9374794 | [
{
"id": "9374794_title",
"type": "title",
"text": [
"Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride."
],
"offsets": [
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0,
97
]
]
},
{
"id": "9374794_abstract",
"type": "abstract",
"text": [
"Cisapride, a gastrointestinal prokinetic agent, is known to cause long Q-T syndrome and ventricular arrhythmias. The cellular mechanism is not known. The human ether-a-go-go-related gene (HERG), which encodes the rapidly activating delayed rectifier K+ current and is important in cardiac repolarization, may serve as a target for the action of cisapride. We tested the hypothesis that cisapride blocks HERG. The whole cell patch-clamp recording technique was used to study HERG channels stably expressed heterologously in HEK293 cells. Under voltage-clamp conditions, cisapride block of HERG is dose dependent with a half-maximal inhibitory concentration of 6.5 nM at 22 degrees C (n = 25 cells). Currents rapidly recovered with drug washout. The onset of block by cisapride required channel activation indicative of open or inactivated state blockage. Block of HERG with cisapride after channel activation was voltage dependent. At -20 mV, 10 nM cisapride reduced HERG tail-current amplitude by 5%, whereas, at + 20 mV, the tail-current amplitude was reduced by 45% (n = 4 cells). At -20 and + 20 mV, 100 nM cisapride reduced tail-current amplitude by 66 and 90%, respectively. We conclude that cisapride is a potent blocker of HERG channels expressed in HEK293 cells. This effect may account for the clinical occurrence of Q-T prolongation and ventricular arrhythmias observed with cisapride."
],
"offsets": [
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98,
1493
]
]
}
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98,
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1208,
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1483,
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348,
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35,
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1328,
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252,
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286,
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572,
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686,
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"HERG"
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1064,
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"id": "9374794_T22",
"type": "GENE-Y",
"text": [
"HERG human cardiac K+ channel"
],
"offsets": [
[
16,
45
]
],
"normalized": []
}
] | [] | [] | [
{
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"arg2_id": "9374794_T22",
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},
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"id": "9374794_1",
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"arg1_id": "9374794_T7",
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},
{
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"arg2_id": "9374794_T19",
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},
{
"id": "9374794_3",
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"arg1_id": "9374794_T10",
"arg2_id": "9374794_T20",
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},
{
"id": "9374794_4",
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"arg1_id": "9374794_T11",
"arg2_id": "9374794_T21",
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},
{
"id": "9374794_5",
"type": "INHIBITOR",
"arg1_id": "9374794_T3",
"arg2_id": "9374794_T14",
"normalized": []
}
] |
23334943 | 23334943 | [
{
"id": "23334943_title",
"type": "title",
"text": [
"High-grade prostate cancer and biochemical recurrence after radical prostatectomy among men using 5α-reductase inhibitors and alpha-blockers."
],
"offsets": [
[
0,
141
]
]
},
{
"id": "23334943_abstract",
"type": "abstract",
"text": [
"BACKGROUND: Two clinical trials have shown that users of 5α-reductase inhibitors finasteride and dutasteride (5-ARIs) have reduced overall prostate cancer risk, while the proportion of high-grade tumors is increased. We studied tumor characteristics, risk of biochemical recurrence and mortality after radical prostatectomy in 5-ARI and alpha-blocker users. METHODS: The study cohort consisted of 1,315 men who underwent radical prostatectomy at the Tampere University Hospital during 1995-2009. Biochemical relapse was defined as serum PSA ≥ 0.2 ng/ml after the operation. Information on mortality and medication purchases was obtained from national registries. Cox proportional regression was used to analyze hazard ratios (HRs) and 95% confidence intervals (95% CI) of biochemical relapse and death. RESULTS: The proportion of high-grade (Gleason 7-10) tumors was significantly elevated among men who had used 5-ARIs for 4 years or longer compared to the non-users (83.3% vs. 53.3%, respectively). Survival curves for biochemical relapse-free survival differed between long-term and short-term 5-ARI users, but the hazard ratio remained statistically non-significant. Risk of biochemical recurrence was elevated among alpha-blocker users (HR 1.68, 95% CI 1.37-2.06), but in sensitivity analyses this was evident only in men using alpha-blockers after prostatectomy. Mortality was not associated with medication usage. CONCLUSIONS: Long-term users of finasteride or dutasteride had more often high-grade prostate cancer. Our results suggest also worse progression-free survival. The association between risk of biochemical recurrence and post-operative alpha-blocker usage suggests that voiding or storage symptoms after prostatectomy may predict biochemical relapse. Prostate © 2013 Wiley Periodicals, Inc."
],
"offsets": [
[
142,
1951
]
]
}
] | [
{
"id": "23334943_T1",
"type": "CHEMICAL",
"text": [
"finasteride"
],
"offsets": [
[
1595,
1606
]
],
"normalized": []
},
{
"id": "23334943_T2",
"type": "CHEMICAL",
"text": [
"dutasteride"
],
"offsets": [
[
1610,
1621
]
],
"normalized": []
},
{
"id": "23334943_T3",
"type": "CHEMICAL",
"text": [
"finasteride"
],
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[
223,
234
]
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"normalized": []
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"id": "23334943_T4",
"type": "CHEMICAL",
"text": [
"dutasteride"
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[
239,
250
]
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"normalized": []
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"id": "23334943_T5",
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"text": [
"PSA"
],
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679,
682
]
],
"normalized": []
},
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"id": "23334943_T6",
"type": "GENE-N",
"text": [
"5α-reductase"
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"offsets": [
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199,
211
]
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"normalized": []
},
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"id": "23334943_T7",
"type": "GENE-N",
"text": [
"5α-reductase"
],
"offsets": [
[
98,
110
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23334943_0",
"type": "INHIBITOR",
"arg1_id": "23334943_T3",
"arg2_id": "23334943_T6",
"normalized": []
},
{
"id": "23334943_1",
"type": "INHIBITOR",
"arg1_id": "23334943_T4",
"arg2_id": "23334943_T6",
"normalized": []
}
] |
23292752 | 23292752 | [
{
"id": "23292752_title",
"type": "title",
"text": [
"New oral anticoagulants: comparative pharmacology with vitamin K antagonists."
],
"offsets": [
[
0,
77
]
]
},
{
"id": "23292752_abstract",
"type": "abstract",
"text": [
"New oral anticoagulants (OACs) that directly inhibit Factor Xa (FXa) or thrombin have been developed for the long-term prevention of thromboembolic disorders. These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences. VKAs are economical and very well characterized, but have important limitations that can outweigh these advantages, such as slow onset of action, narrow therapeutic window and unpredictable anticoagulant effect. VKA-associated dietary precautions, monitoring and dosing adjustments to maintain international normalized ratio (INR) within therapeutic range, and bridging therapy, are inconvenient for patients, expensive, and may result in inappropriate use of VKA therapy. This may lead to increased bleeding risk or reduced anticoagulation and increased risk of thrombotic events. The new OACs have rapid onset of action, low potential for food and drug interactions, and predictable anticoagulant effect that removes the need for routine monitoring. FXa inhibitors, e.g. rivaroxaban and apixaban, are potent, oral direct inhibitors of prothrombinase-bound, clot-associated or free FXa. Both agents have a rapid onset of action, a wide therapeutic window, little or no interaction with food and other drugs, minimal inter-patient variability, and display similar pharmacokinetics in different patient populations. Since both are substrates, co-administration of rivaroxaban and apixaban with strong cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations due to altered clearance rates; consequently, their concomitant use is contraindicated and caution is required when used concomitantly with strong CYP3A4 and P-gp inducers. Although parenteral oral direct thrombin inhibitors (DTIs), such as argatroban and bivalirudin, have been on the market for years, DTIs such as dabigatran are novel synthetic thrombin antagonists. Dabigatran etexilate is a low-molecular-weight non-active pro-drug that is administered orally and converted rapidly to its active form, dabigatran--a potent, competitive and reversible DTI. Dabigatran has an advantage over the indirect thrombin inhibitors, unfractionated heparin and low-molecular-weight heparin, in that it inhibits free and fibrin-bound thrombin. The reversible binding of dabigatran may provide safer and more predictable anticoagulant treatment than seen with irreversible, non-covalent thrombin inhibitors, e.g. hirudin. Dabigatran shows a very low potential for drug-drug interactions. However, co-administration of dabigatran etexilate with other anticoagulants and antiplatelet agents can increase the bleeding risk. Although the new agents are pharmacologically better than VKAs--particularly in terms of fixed dosing, rapid onset of action, no INR monitoring and lower risk of drug interactions--there are some differences between them: the bioavailability of dabigatran is lower than rivaroxaban and apixaban, and so the dabigatran dosage required is higher; lower protein binding of dabigatran reduces the variability related to albuminaemia. The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs > rivaroxaban > apixaban > dabigatran. The convenience of the new OACs has translated into improvements in efficacy and safety as shown in phase III randomized trials. The new anticoagulants so far offer the greatest promise and opportunity for the replacement of VKAs."
],
"offsets": [
[
78,
3609
]
]
}
] | [
{
"id": "23292752_T1",
"type": "CHEMICAL",
"text": [
"rivaroxaban"
],
"offsets": [
[
1137,
1148
]
],
"normalized": []
},
{
"id": "23292752_T2",
"type": "CHEMICAL",
"text": [
"apixaban"
],
"offsets": [
[
1153,
1161
]
],
"normalized": []
},
{
"id": "23292752_T3",
"type": "CHEMICAL",
"text": [
"rivaroxaban"
],
"offsets": [
[
1527,
1538
]
],
"normalized": []
},
{
"id": "23292752_T4",
"type": "CHEMICAL",
"text": [
"apixaban"
],
"offsets": [
[
1543,
1551
]
],
"normalized": []
},
{
"id": "23292752_T5",
"type": "CHEMICAL",
"text": [
"argatroban"
],
"offsets": [
[
1951,
1961
]
],
"normalized": []
},
{
"id": "23292752_T6",
"type": "CHEMICAL",
"text": [
"dabigatran"
],
"offsets": [
[
2027,
2037
]
],
"normalized": []
},
{
"id": "23292752_T7",
"type": "CHEMICAL",
"text": [
"Dabigatran etexilate"
],
"offsets": [
[
2080,
2100
]
],
"normalized": []
},
{
"id": "23292752_T8",
"type": "CHEMICAL",
"text": [
"dabigatran"
],
"offsets": [
[
2217,
2227
]
],
"normalized": []
},
{
"id": "23292752_T9",
"type": "CHEMICAL",
"text": [
"vitamin K"
],
"offsets": [
[
293,
302
]
],
"normalized": []
},
{
"id": "23292752_T10",
"type": "CHEMICAL",
"text": [
"Dabigatran"
],
"offsets": [
[
2271,
2281
]
],
"normalized": []
},
{
"id": "23292752_T11",
"type": "CHEMICAL",
"text": [
"dabigatran"
],
"offsets": [
[
2473,
2483
]
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"normalized": []
},
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"id": "23292752_T12",
"type": "CHEMICAL",
"text": [
"Dabigatran"
],
"offsets": [
[
2624,
2634
]
],
"normalized": []
},
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"id": "23292752_T13",
"type": "CHEMICAL",
"text": [
"dabigatran etexilate"
],
"offsets": [
[
2720,
2740
]
],
"normalized": []
},
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"id": "23292752_T14",
"type": "CHEMICAL",
"text": [
"dabigatran"
],
"offsets": [
[
3068,
3078
]
],
"normalized": []
},
{
"id": "23292752_T15",
"type": "CHEMICAL",
"text": [
"rivaroxaban"
],
"offsets": [
[
3093,
3104
]
],
"normalized": []
},
{
"id": "23292752_T16",
"type": "CHEMICAL",
"text": [
"apixaban"
],
"offsets": [
[
3109,
3117
]
],
"normalized": []
},
{
"id": "23292752_T17",
"type": "CHEMICAL",
"text": [
"dabigatran"
],
"offsets": [
[
3130,
3140
]
],
"normalized": []
},
{
"id": "23292752_T18",
"type": "CHEMICAL",
"text": [
"dabigatran"
],
"offsets": [
[
3193,
3203
]
],
"normalized": []
},
{
"id": "23292752_T19",
"type": "CHEMICAL",
"text": [
"rivaroxaban"
],
"offsets": [
[
3342,
3353
]
],
"normalized": []
},
{
"id": "23292752_T20",
"type": "CHEMICAL",
"text": [
"apixaban"
],
"offsets": [
[
3356,
3364
]
],
"normalized": []
},
{
"id": "23292752_T21",
"type": "CHEMICAL",
"text": [
"dabigatran"
],
"offsets": [
[
3367,
3377
]
],
"normalized": []
},
{
"id": "23292752_T22",
"type": "CHEMICAL",
"text": [
"vitamin K"
],
"offsets": [
[
55,
64
]
],
"normalized": []
},
{
"id": "23292752_T23",
"type": "GENE-Y",
"text": [
"FXa"
],
"offsets": [
[
1116,
1119
]
],
"normalized": []
},
{
"id": "23292752_T24",
"type": "GENE-N",
"text": [
"prothrombinase"
],
"offsets": [
[
1201,
1215
]
],
"normalized": []
},
{
"id": "23292752_T25",
"type": "GENE-Y",
"text": [
"FXa"
],
"offsets": [
[
1247,
1250
]
],
"normalized": []
},
{
"id": "23292752_T26",
"type": "GENE-Y",
"text": [
"cytochrome P450 (CYP) 3A4"
],
"offsets": [
[
1564,
1589
]
],
"normalized": []
},
{
"id": "23292752_T27",
"type": "GENE-Y",
"text": [
"permeability glycoprotein"
],
"offsets": [
[
1594,
1619
]
],
"normalized": []
},
{
"id": "23292752_T28",
"type": "GENE-Y",
"text": [
"P-gp"
],
"offsets": [
[
1621,
1625
]
],
"normalized": []
},
{
"id": "23292752_T29",
"type": "GENE-Y",
"text": [
"CYP3A4"
],
"offsets": [
[
1857,
1863
]
],
"normalized": []
},
{
"id": "23292752_T30",
"type": "GENE-Y",
"text": [
"P-gp"
],
"offsets": [
[
1868,
1872
]
],
"normalized": []
},
{
"id": "23292752_T31",
"type": "GENE-Y",
"text": [
"thrombin"
],
"offsets": [
[
1915,
1923
]
],
"normalized": []
},
{
"id": "23292752_T32",
"type": "GENE-Y",
"text": [
"thrombin"
],
"offsets": [
[
2058,
2066
]
],
"normalized": []
},
{
"id": "23292752_T33",
"type": "GENE-Y",
"text": [
"thrombin"
],
"offsets": [
[
2317,
2325
]
],
"normalized": []
},
{
"id": "23292752_T34",
"type": "GENE-N",
"text": [
"fibrin"
],
"offsets": [
[
2424,
2430
]
],
"normalized": []
},
{
"id": "23292752_T35",
"type": "GENE-Y",
"text": [
"thrombin"
],
"offsets": [
[
2437,
2445
]
],
"normalized": []
},
{
"id": "23292752_T36",
"type": "GENE-Y",
"text": [
"thrombin"
],
"offsets": [
[
2589,
2597
]
],
"normalized": []
},
{
"id": "23292752_T37",
"type": "GENE-Y",
"text": [
"Factor Xa"
],
"offsets": [
[
131,
140
]
],
"normalized": []
},
{
"id": "23292752_T38",
"type": "GENE-Y",
"text": [
"FXa"
],
"offsets": [
[
142,
145
]
],
"normalized": []
},
{
"id": "23292752_T39",
"type": "GENE-Y",
"text": [
"thrombin"
],
"offsets": [
[
150,
158
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23292752_0",
"type": "INHIBITOR",
"arg1_id": "23292752_T1",
"arg2_id": "23292752_T23",
"normalized": []
},
{
"id": "23292752_1",
"type": "INHIBITOR",
"arg1_id": "23292752_T2",
"arg2_id": "23292752_T23",
"normalized": []
},
{
"id": "23292752_2",
"type": "INHIBITOR",
"arg1_id": "23292752_T1",
"arg2_id": "23292752_T24",
"normalized": []
},
{
"id": "23292752_3",
"type": "INHIBITOR",
"arg1_id": "23292752_T2",
"arg2_id": "23292752_T24",
"normalized": []
},
{
"id": "23292752_4",
"type": "INHIBITOR",
"arg1_id": "23292752_T1",
"arg2_id": "23292752_T25",
"normalized": []
},
{
"id": "23292752_5",
"type": "INHIBITOR",
"arg1_id": "23292752_T2",
"arg2_id": "23292752_T25",
"normalized": []
},
{
"id": "23292752_6",
"type": "INHIBITOR",
"arg1_id": "23292752_T5",
"arg2_id": "23292752_T31",
"normalized": []
},
{
"id": "23292752_7",
"type": "ANTAGONIST",
"arg1_id": "23292752_T6",
"arg2_id": "23292752_T32",
"normalized": []
},
{
"id": "23292752_8",
"type": "INHIBITOR",
"arg1_id": "23292752_T10",
"arg2_id": "23292752_T33",
"normalized": []
},
{
"id": "23292752_9",
"type": "INHIBITOR",
"arg1_id": "23292752_T10",
"arg2_id": "23292752_T34",
"normalized": []
},
{
"id": "23292752_10",
"type": "INHIBITOR",
"arg1_id": "23292752_T10",
"arg2_id": "23292752_T35",
"normalized": []
},
{
"id": "23292752_11",
"type": "INHIBITOR",
"arg1_id": "23292752_T11",
"arg2_id": "23292752_T36",
"normalized": []
}
] |
23044992 | 23044992 | [
{
"id": "23044992_title",
"type": "title",
"text": [
"Deletion of CD74, a putative MIF receptor, in mice enhances osteoclastogenesis and decreases bone mass."
],
"offsets": [
[
0,
103
]
]
},
{
"id": "23044992_abstract",
"type": "abstract",
"text": [
"CD74 is a type II transmembrane protein that can act as a receptor for macrophage migration inhibitory factor (MIF) and plays a role in MIF-regulated responses. We reported that MIF inhibited osteoclast formation and MIF knockout (KO) mice had decreased bone mass. We therefore examined if CD74 was involved in the ability of MIF to alter osteoclastogenesis in cultured bone marrow (BM) from wild-type (WT) and CD74-deficient (KO) male mice. We also measured the bone phenotype of CD74 KO male mice. Bone mass in the femur of 8-week-old mice was measured by micro-computed tomography and histomorphometry. Bone marrow cells from CD74 KO mice formed 15% more osteoclast-like cells (OCLs) with macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) (both at 30 ng/mL) compared to WT. Addition of MIF to WT cultures inhibited OCL formation by 16% but had no effect on CD74KO cultures. The number of colony forming unit granulocyte-macrophage (CFU-GM) in the bone marrow of CD74 KO mice was 26% greater than in WT controls. Trabecular bone volume (TBV) in the femurs of CD74 KO male mice was decreased by 26% compared to WT. In addition, cortical area and thickness were decreased by 14% and 11%, respectively. Histomorphometric analysis demonstrated that tartrate-resistant acid phosphatase (TRAP)(+) osteoclast number and area were significantly increased in CD74 KO by 35% and 43%, respectively compared to WT. Finally, we examined the effect of MIF on RANKL-induced-signaling pathways in bone marrow macrophage (BMM) cultures. MIF treatment decreased RANKL-induced nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and c-Fos protein in BMM cultures by 70% and 41%, respectively. Our data demonstrate that CD74 is required for MIF to affect in vitro osteoclastogenesis. Further, the bone phenotype of CD74 KO mice is similar to that of MIF KO mice. MIF treatment of WT cultures suppressed RANKL-induced activator protein 1 (AP-1) expression, which resulted in decreased osteoclast differentiation in vitro. We propose that CD74 plays a critical role in the MIF inhibition of osteoclastogenesis."
],
"offsets": [
[
104,
2244
]
]
}
] | [
{
"id": "23044992_T1",
"type": "CHEMICAL",
"text": [
"tartrate"
],
"offsets": [
[
1393,
1401
]
],
"normalized": []
},
{
"id": "23044992_T2",
"type": "GENE-N",
"text": [
"CD74"
],
"offsets": [
[
104,
108
]
],
"normalized": []
},
{
"id": "23044992_T3",
"type": "GENE-Y",
"text": [
"CD74"
],
"offsets": [
[
1111,
1115
]
],
"normalized": []
},
{
"id": "23044992_T4",
"type": "GENE-Y",
"text": [
"CD74"
],
"offsets": [
[
1207,
1211
]
],
"normalized": []
},
{
"id": "23044992_T5",
"type": "GENE-Y",
"text": [
"MIF"
],
"offsets": [
[
215,
218
]
],
"normalized": []
},
{
"id": "23044992_T6",
"type": "GENE-Y",
"text": [
"tartrate-resistant acid phosphatase"
],
"offsets": [
[
1393,
1428
]
],
"normalized": []
},
{
"id": "23044992_T7",
"type": "GENE-Y",
"text": [
"TRAP"
],
"offsets": [
[
1430,
1434
]
],
"normalized": []
},
{
"id": "23044992_T8",
"type": "GENE-Y",
"text": [
"MIF"
],
"offsets": [
[
240,
243
]
],
"normalized": []
},
{
"id": "23044992_T9",
"type": "GENE-Y",
"text": [
"CD74"
],
"offsets": [
[
1498,
1502
]
],
"normalized": []
},
{
"id": "23044992_T10",
"type": "GENE-Y",
"text": [
"MIF"
],
"offsets": [
[
1586,
1589
]
],
"normalized": []
},
{
"id": "23044992_T11",
"type": "GENE-Y",
"text": [
"RANKL"
],
"offsets": [
[
1593,
1598
]
],
"normalized": []
},
{
"id": "23044992_T12",
"type": "GENE-Y",
"text": [
"MIF"
],
"offsets": [
[
1668,
1671
]
],
"normalized": []
},
{
"id": "23044992_T13",
"type": "GENE-Y",
"text": [
"RANKL"
],
"offsets": [
[
1692,
1697
]
],
"normalized": []
},
{
"id": "23044992_T14",
"type": "GENE-Y",
"text": [
"nuclear factor of activated T cells, cytoplasmic 1"
],
"offsets": [
[
1706,
1756
]
],
"normalized": []
},
{
"id": "23044992_T15",
"type": "GENE-Y",
"text": [
"NFATc1"
],
"offsets": [
[
1758,
1764
]
],
"normalized": []
},
{
"id": "23044992_T16",
"type": "GENE-Y",
"text": [
"c-Fos"
],
"offsets": [
[
1770,
1775
]
],
"normalized": []
},
{
"id": "23044992_T17",
"type": "GENE-Y",
"text": [
"CD74"
],
"offsets": [
[
1856,
1860
]
],
"normalized": []
},
{
"id": "23044992_T18",
"type": "GENE-Y",
"text": [
"MIF"
],
"offsets": [
[
1877,
1880
]
],
"normalized": []
},
{
"id": "23044992_T19",
"type": "GENE-Y",
"text": [
"MIF"
],
"offsets": [
[
282,
285
]
],
"normalized": []
},
{
"id": "23044992_T20",
"type": "GENE-Y",
"text": [
"CD74"
],
"offsets": [
[
1951,
1955
]
],
"normalized": []
},
{
"id": "23044992_T21",
"type": "GENE-Y",
"text": [
"MIF"
],
"offsets": [
[
1986,
1989
]
],
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},
{
"id": "23044992_T22",
"type": "GENE-Y",
"text": [
"MIF"
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[
1999,
2002
]
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{
"id": "23044992_T23",
"type": "GENE-Y",
"text": [
"RANKL"
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2039,
2044
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{
"id": "23044992_T24",
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"text": [
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2053,
2072
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"id": "23044992_T25",
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2074,
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2173,
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2207,
2210
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321,
324
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394,
398
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"MIF"
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430,
433
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515,
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585,
589
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737
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796,
832
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175,
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834,
839
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"NF-κB"
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867,
872
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881,
886
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12,
16
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"MIF"
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29,
32
]
],
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}
] | [] | [] | [] |
23549331 | 23549331 | [
{
"id": "23549331_title",
"type": "title",
"text": [
"A Distal Enhancer Controls Cytokine-dependent Human cPLA2α Gene Expression."
],
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0,
75
]
]
},
{
"id": "23549331_abstract",
"type": "abstract",
"text": [
"Specific control of group IVA cytosolic phospholipase A2 (cPLA2α or PLA2G4A) expression modulates arachidonic acid production, thus tightly regulating the downstream effects of pro- and anti-inflammatory eicosanoids. The significance of this pathway in human disease is apparent in a range of pathologies from inflammation to tumorigenesis. While much of the regulation of cPLA2α has focused on post-translational phosphorylation of the protein, studies on transcriptional regulation of this gene have focused only on proximal promoter regions. We have identified a DNase I hypersensitive site encompassing a 5' distal enhancer element containing a highly conserved consensus AP-1 site involved in transcriptional activation of cPLA2α by IL-1β. ChIP, knockdown, knockout and overexpression analyses have shown that c-Jun acts both in a negative and positive regulatory role. Transcriptional activation of cPLA2α occurs through the phosphorylation of c-Jun in conjunction with increased association of C/EBPβ with the distal novel enhancer. The association of C/EBPβ with the transcriptional activation complex does not require an obvious DNA binding site. These data provide new and important contributions to the understanding of cPLA2α regulation at the transcriptional level with implications to eicosanoid metabolism, cellular signaling and disease pathogenesis."
],
"offsets": [
[
76,
1442
]
]
}
] | [
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"id": "23549331_T1",
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"eicosanoid"
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1375,
1385
]
],
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},
{
"id": "23549331_T2",
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"eicosanoids"
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280,
291
]
],
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{
"id": "23549331_T3",
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"text": [
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174,
190
]
],
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"id": "23549331_T4",
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"text": [
"C/EBPβ"
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1077,
1083
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"id": "23549331_T5",
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"C/EBPβ"
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1135,
1141
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"id": "23549331_T6",
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"cPLA2α"
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1307,
1313
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"group IVA cytosolic phospholipase A2"
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96,
132
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"id": "23549331_T8",
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449,
455
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134,
140
]
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752,
756
]
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},
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"id": "23549331_T11",
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"PLA2G4A"
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144,
151
]
],
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"id": "23549331_T12",
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"cPLA2α"
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804,
810
]
],
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},
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"id": "23549331_T13",
"type": "GENE-Y",
"text": [
"IL-1β"
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814,
819
]
],
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},
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"id": "23549331_T14",
"type": "GENE-Y",
"text": [
"c-Jun"
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891,
896
]
],
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},
{
"id": "23549331_T15",
"type": "GENE-Y",
"text": [
"cPLA2α"
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981,
987
]
],
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},
{
"id": "23549331_T16",
"type": "GENE-Y",
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"c-Jun"
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1026,
1031
]
],
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},
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"id": "23549331_T17",
"type": "GENE-N",
"text": [
"Cytokine"
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27,
35
]
],
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},
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"id": "23549331_T18",
"type": "GENE-Y",
"text": [
"Human cPLA2α"
],
"offsets": [
[
46,
58
]
],
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}
] | [] | [] | [
{
"id": "23549331_0",
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"arg2_id": "23549331_T7",
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},
{
"id": "23549331_1",
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},
{
"id": "23549331_2",
"type": "PRODUCT-OF",
"arg1_id": "23549331_T3",
"arg2_id": "23549331_T11",
"normalized": []
}
] |
7625729 | 7625729 | [
{
"id": "7625729_title",
"type": "title",
"text": [
"Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity."
],
"offsets": [
[
0,
89
]
]
},
{
"id": "7625729_abstract",
"type": "abstract",
"text": [
"Drospirenone (ZK 30595; 6 beta, 7 beta, 15 beta, 16 beta-dimethylen-3-oxo-17 alpha-pregn-4-ene-21, 17-carbolactone) is a novel progestogen under clinical development. Drospirenone is characterized by an innovative pharmacodynamic profile which is very closely related to that of progesterone. Potential applications include oral contraception, hormone replacement therapy and treatment of hormonal disorders. The pharmacological properties of drospirenone were investigated in vitro by receptor binding and transactivation experiments and in vivo in appropriate animal models. In qualitative agreement with progesterone, the compound binds strongly to the progesterone and the mineralocorticoid receptor and with lower affinity to androgen and glucocorticoid receptors. There is no detectable binding to the estrogen receptor. Steroid hormone agonistic and antagonistic activities of progesterone and drospirenone were compared in transactivation experiments. Individual steroid hormone receptors were artificially expressed together with a reporter gene in appropriate cell lines. Both hormones were unable to induce any androgen receptor-mediated agonistic activity. Rather, both progesterone and drospirenone distinctly antagonized androgen-stimulated transcriptional activation. Likewise, both compounds only very weakly activated the mineralocorticoid receptor but showed potent aldosterone antagonistic activity. Drospirenone did not induce glucocorticoid receptor-driven transactivation. Progesterone was a weak agonist in this respect. Drospirenone exerts potent progestogenic and antigonadotropic activity which was studied in various animal species. It efficiently promotes the maintenance of pregnancy in ovariectomized rats, inhibits ovulation in rats and mice and stimulates endometrial transformation in the rabbit. Furthermore, drospirenone shows potent antigonadotropic, i.e., testosterone-lowering activity in male cynomolgus monkeys. The progestogenic potency of drospirenone was found to be in the range of that of norethisterone acetate. The majority of clinically used progestogens are androgenic. Drospirenone, like progesterone, has no androgenic but rather an antiandrogenic effect. This property was demonstrated in castrated, testosterone propionate substituted male rats by a dose-dependent inhibition of accessory sex organ growth (seminal vesicles, prostate). In this model, the potency of drospirenone was about a third that of cyproterone acetate. Drospirenone, like progesterone, shows antimineralocorticoid activity, which causes moderately increased sodium and water excretion. This is an outstanding characteristic which has not been described for any other synthetic progestogen before. Drospirenone is eight to ten times more effective in this respect than spironolactone. The natriuretic effect was demonstrable for at least three weeks upon daily treatment of rats with a dose of 10 mg/animal. Drospirenone is devoid of any estrogenic, glucocorticoid or antiglucocorticoid activity. In summary, drospirenone, like progesterone, combines potent progestogenic with antimineralocorticoid and antiandrogenic activity in a similar dose range.(ABSTRACT TRUNCATED AT 400 WORDS)"
],
"offsets": [
[
90,
3299
]
]
}
] | [
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"id": "7625729_T1",
"type": "CHEMICAL",
"text": [
"Drospirenone"
],
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[
90,
102
]
],
"normalized": []
},
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"id": "7625729_T2",
"type": "CHEMICAL",
"text": [
"androgen"
],
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[
1212,
1220
]
],
"normalized": []
},
{
"id": "7625729_T3",
"type": "CHEMICAL",
"text": [
"progesterone"
],
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[
1272,
1284
]
],
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},
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"id": "7625729_T4",
"type": "CHEMICAL",
"text": [
"drospirenone"
],
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[
1289,
1301
]
],
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},
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"id": "7625729_T5",
"type": "CHEMICAL",
"text": [
"androgen"
],
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[
1325,
1333
]
],
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},
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"id": "7625729_T6",
"type": "CHEMICAL",
"text": [
"progestogen"
],
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[
217,
228
]
],
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},
{
"id": "7625729_T7",
"type": "CHEMICAL",
"text": [
"aldosterone"
],
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[
1474,
1485
]
],
"normalized": []
},
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"id": "7625729_T8",
"type": "CHEMICAL",
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"Drospirenone"
],
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[
1509,
1521
]
],
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},
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"id": "7625729_T9",
"type": "CHEMICAL",
"text": [
"ZK 30595"
],
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[
104,
112
]
],
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},
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"id": "7625729_T10",
"type": "CHEMICAL",
"text": [
"Progesterone"
],
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[
1585,
1597
]
],
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},
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"id": "7625729_T11",
"type": "CHEMICAL",
"text": [
"Drospirenone"
],
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[
1634,
1646
]
],
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},
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"id": "7625729_T12",
"type": "CHEMICAL",
"text": [
"Drospirenone"
],
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[
257,
269
]
],
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},
{
"id": "7625729_T13",
"type": "CHEMICAL",
"text": [
"drospirenone"
],
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[
1933,
1945
]
],
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},
{
"id": "7625729_T14",
"type": "CHEMICAL",
"text": [
"testosterone"
],
"offsets": [
[
1983,
1995
]
],
"normalized": []
},
{
"id": "7625729_T15",
"type": "CHEMICAL",
"text": [
"drospirenone"
],
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[
2071,
2083
]
],
"normalized": []
},
{
"id": "7625729_T16",
"type": "CHEMICAL",
"text": [
"norethisterone acetate"
],
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[
2124,
2146
]
],
"normalized": []
},
{
"id": "7625729_T17",
"type": "CHEMICAL",
"text": [
"progestogens"
],
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[
2180,
2192
]
],
"normalized": []
},
{
"id": "7625729_T18",
"type": "CHEMICAL",
"text": [
"Drospirenone"
],
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[
2209,
2221
]
],
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},
{
"id": "7625729_T19",
"type": "CHEMICAL",
"text": [
"progesterone"
],
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[
2228,
2240
]
],
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},
{
"id": "7625729_T20",
"type": "CHEMICAL",
"text": [
"testosterone propionate"
],
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[
2342,
2365
]
],
"normalized": []
},
{
"id": "7625729_T21",
"type": "CHEMICAL",
"text": [
"6 beta, 7 beta, 15 beta, 16 beta-dimethylen-3-oxo-17 alpha-pregn-4-ene-21, 17-carbolactone"
],
"offsets": [
[
114,
204
]
],
"normalized": []
},
{
"id": "7625729_T22",
"type": "CHEMICAL",
"text": [
"drospirenone"
],
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[
2509,
2521
]
],
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},
{
"id": "7625729_T23",
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"text": [
"cyproterone acetate"
],
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[
2548,
2567
]
],
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},
{
"id": "7625729_T24",
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"Drospirenone"
],
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[
2569,
2581
]
],
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},
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"id": "7625729_T25",
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"text": [
"progesterone"
],
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[
2588,
2600
]
],
"normalized": []
},
{
"id": "7625729_T26",
"type": "CHEMICAL",
"text": [
"sodium"
],
"offsets": [
[
2674,
2680
]
],
"normalized": []
},
{
"id": "7625729_T27",
"type": "CHEMICAL",
"text": [
"progestogen"
],
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[
2793,
2804
]
],
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},
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"id": "7625729_T28",
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"text": [
"Drospirenone"
],
"offsets": [
[
2813,
2825
]
],
"normalized": []
},
{
"id": "7625729_T29",
"type": "CHEMICAL",
"text": [
"progesterone"
],
"offsets": [
[
369,
381
]
],
"normalized": []
},
{
"id": "7625729_T30",
"type": "CHEMICAL",
"text": [
"spironolactone"
],
"offsets": [
[
2884,
2898
]
],
"normalized": []
},
{
"id": "7625729_T31",
"type": "CHEMICAL",
"text": [
"Drospirenone"
],
"offsets": [
[
3023,
3035
]
],
"normalized": []
},
{
"id": "7625729_T32",
"type": "CHEMICAL",
"text": [
"drospirenone"
],
"offsets": [
[
3124,
3136
]
],
"normalized": []
},
{
"id": "7625729_T33",
"type": "CHEMICAL",
"text": [
"progesterone"
],
"offsets": [
[
3143,
3155
]
],
"normalized": []
},
{
"id": "7625729_T34",
"type": "CHEMICAL",
"text": [
"drospirenone"
],
"offsets": [
[
533,
545
]
],
"normalized": []
},
{
"id": "7625729_T35",
"type": "CHEMICAL",
"text": [
"progesterone"
],
"offsets": [
[
697,
709
]
],
"normalized": []
},
{
"id": "7625729_T36",
"type": "CHEMICAL",
"text": [
"progesterone"
],
"offsets": [
[
746,
758
]
],
"normalized": []
},
{
"id": "7625729_T37",
"type": "CHEMICAL",
"text": [
"androgen"
],
"offsets": [
[
821,
829
]
],
"normalized": []
},
{
"id": "7625729_T38",
"type": "CHEMICAL",
"text": [
"estrogen"
],
"offsets": [
[
898,
906
]
],
"normalized": []
},
{
"id": "7625729_T39",
"type": "CHEMICAL",
"text": [
"Steroid hormone"
],
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[
917,
932
]
],
"normalized": []
},
{
"id": "7625729_T40",
"type": "CHEMICAL",
"text": [
"progesterone"
],
"offsets": [
[
974,
986
]
],
"normalized": []
},
{
"id": "7625729_T41",
"type": "CHEMICAL",
"text": [
"drospirenone"
],
"offsets": [
[
991,
1003
]
],
"normalized": []
},
{
"id": "7625729_T42",
"type": "CHEMICAL",
"text": [
"steroid hormone"
],
"offsets": [
[
1061,
1076
]
],
"normalized": []
},
{
"id": "7625729_T43",
"type": "CHEMICAL",
"text": [
"Drospirenone"
],
"offsets": [
[
0,
12
]
],
"normalized": []
},
{
"id": "7625729_T44",
"type": "CHEMICAL",
"text": [
"progestogen"
],
"offsets": [
[
22,
33
]
],
"normalized": []
},
{
"id": "7625729_T45",
"type": "GENE-Y",
"text": [
"androgen receptor"
],
"offsets": [
[
1212,
1229
]
],
"normalized": []
},
{
"id": "7625729_T46",
"type": "GENE-Y",
"text": [
"mineralocorticoid receptor"
],
"offsets": [
[
1429,
1455
]
],
"normalized": []
},
{
"id": "7625729_T47",
"type": "GENE-Y",
"text": [
"glucocorticoid receptor"
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1537,
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{
"id": "7625729_T48",
"type": "GENE-N",
"text": [
"progesterone and the mineralocorticoid receptor"
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746,
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"id": "7625729_T49",
"type": "GENE-N",
"text": [
"androgen and glucocorticoid receptors"
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"id": "7625729_T50",
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"text": [
"estrogen receptor"
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898,
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"id": "7625729_T51",
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"text": [
"steroid hormone receptors"
],
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[
1061,
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]
],
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}
] | [] | [] | [] |
23349485 | 23349485 | [
{
"id": "23349485_title",
"type": "title",
"text": [
"Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high fat diet-induced obesity and insulin resistance in mice."
],
"offsets": [
[
0,
137
]
]
},
{
"id": "23349485_abstract",
"type": "abstract",
"text": [
"A nonsense mutation in cereblon (CRBN) causes a mild type of mental retardation in humans. An earlier study showed that CRBN negatively regulates the functional activity of AMP-activated protein kinase (AMPK) in vitro by binding directly to the α1 subunit of the AMPK complex. However, the in vivo role of CRBN was not studied. To elucidate the physiological functions of Crbn, a mouse strain was generated in which the Crbn gene was deleted throughout the whole body. In Crbn-deficient mice fed a normal diet, AMPK in the liver showed hyper-phosphorylation, which indicated the constitutive activation of AMPK. Since Crbn-deficient mice showed significantly less weight gain when fed a high fat diet and their insulin sensitivity was considerably improved, the functions of Crbn in the liver were primarily investigated. These results provide the first in vivo evidence that Crbn is a negative modulator of AMPK, which suggests that Crbn may be a potential target for metabolic disorders of the liver."
],
"offsets": [
[
138,
1140
]
]
}
] | [
{
"id": "23349485_T1",
"type": "CHEMICAL",
"text": [
"AMP"
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311,
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]
],
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},
{
"id": "23349485_T2",
"type": "GENE-Y",
"text": [
"CRBN"
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258,
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]
],
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},
{
"id": "23349485_T3",
"type": "GENE-N",
"text": [
"AMP-activated protein kinase"
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311,
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]
],
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},
{
"id": "23349485_T4",
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"text": [
"AMPK"
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341,
345
]
],
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},
{
"id": "23349485_T5",
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"text": [
"cereblon"
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161,
169
]
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},
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"id": "23349485_T6",
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"α1 subunit of the AMPK"
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383,
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]
],
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},
{
"id": "23349485_T7",
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"CRBN"
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444,
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]
],
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},
{
"id": "23349485_T8",
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"CRBN"
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171,
175
]
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{
"id": "23349485_T9",
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"Crbn"
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"Crbn"
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558,
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]
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},
{
"id": "23349485_T11",
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"text": [
"Crbn"
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610,
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]
],
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},
{
"id": "23349485_T12",
"type": "GENE-N",
"text": [
"AMPK"
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649,
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]
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},
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"id": "23349485_T13",
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"text": [
"AMPK"
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744,
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]
],
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},
{
"id": "23349485_T14",
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"text": [
"Crbn"
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756,
760
]
],
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},
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"id": "23349485_T15",
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"text": [
"Crbn"
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913,
917
]
],
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},
{
"id": "23349485_T16",
"type": "GENE-Y",
"text": [
"Crbn"
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1014,
1018
]
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},
{
"id": "23349485_T17",
"type": "GENE-N",
"text": [
"AMPK"
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1046,
1050
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},
{
"id": "23349485_T18",
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"Crbn"
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1072,
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]
],
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},
{
"id": "23349485_T19",
"type": "GENE-N",
"text": [
"insulin"
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110,
117
]
],
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},
{
"id": "23349485_T20",
"type": "GENE-Y",
"text": [
"cereblon"
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18,
26
]
],
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},
{
"id": "23349485_T21",
"type": "GENE-N",
"text": [
"AMPK"
],
"offsets": [
[
49,
53
]
],
"normalized": []
}
] | [] | [] | [] |
23363425 | 23363425 | [
{
"id": "23363425_title",
"type": "title",
"text": [
"Silica precipitation by synthetic minicollagens."
],
"offsets": [
[
0,
48
]
]
},
{
"id": "23363425_abstract",
"type": "abstract",
"text": [
"Oligomeric Pro-Hyp-Gly- (POG-) peptides, wherein the collagenous triple helix is supported by C-terminal capping, exhibit silica precipitation properties (O, Hyp = (2S,4R)hydroxyproline). As quantified by a molybdate assay, the length of the covalently tethered triple helix (number of POG units) determines the amount of amorphous silica obtained from silicic acid solution. Although lacking charged side chains, the synthetic collagens precipitate large quantities of silicic acid resulting in micrometer-sized spheres of varying surface morphologies as analyzed by scanning electron microscopy. Similar precipitation efficiencies on a fast time scale of less than 10 min were previously described only for biogenic diatom proteins and sponge collagen, respectively, which have a considerably higher structural complexity and limited accessibility. The minicollagens described here provide an unexpected alternative to the widely used precipitation conditions, which generally depend on (poly-)amines in phosphate buffer. Collagen can form intimate connections with inorganic matter. Hence, silica-enclosed collagens have promising perspectives as composite materials."
],
"offsets": [
[
49,
1219
]
]
}
] | [
{
"id": "23363425_T1",
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"phosphate"
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[
1055,
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]
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},
{
"id": "23363425_T2",
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"text": [
"silica"
],
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[
1142,
1148
]
],
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},
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"id": "23363425_T3",
"type": "CHEMICAL",
"text": [
"Pro-Hyp-Gly"
],
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[
60,
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]
],
"normalized": []
},
{
"id": "23363425_T4",
"type": "CHEMICAL",
"text": [
"silica"
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171,
177
]
],
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},
{
"id": "23363425_T5",
"type": "CHEMICAL",
"text": [
"Hyp"
],
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[
207,
210
]
],
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},
{
"id": "23363425_T6",
"type": "CHEMICAL",
"text": [
"(2S,4R)hydroxyproline"
],
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[
213,
234
]
],
"normalized": []
},
{
"id": "23363425_T7",
"type": "CHEMICAL",
"text": [
"silica"
],
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[
381,
387
]
],
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},
{
"id": "23363425_T8",
"type": "CHEMICAL",
"text": [
"silicic acid"
],
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[
402,
414
]
],
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},
{
"id": "23363425_T9",
"type": "CHEMICAL",
"text": [
"silicic acid"
],
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[
519,
531
]
],
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},
{
"id": "23363425_T10",
"type": "CHEMICAL",
"text": [
"C"
],
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[
143,
144
]
],
"normalized": []
},
{
"id": "23363425_T11",
"type": "CHEMICAL",
"text": [
"(poly-)amines"
],
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[
1038,
1051
]
],
"normalized": []
},
{
"id": "23363425_T12",
"type": "CHEMICAL",
"text": [
"Silica"
],
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[
0,
6
]
],
"normalized": []
},
{
"id": "23363425_T13",
"type": "GENE-N",
"text": [
"Collagen"
],
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[
1073,
1081
]
],
"normalized": []
},
{
"id": "23363425_T14",
"type": "GENE-N",
"text": [
"collagens"
],
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[
1158,
1167
]
],
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},
{
"id": "23363425_T15",
"type": "GENE-N",
"text": [
"triple helix"
],
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311,
323
]
],
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},
{
"id": "23363425_T16",
"type": "GENE-N",
"text": [
"collagens"
],
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[
477,
486
]
],
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},
{
"id": "23363425_T17",
"type": "GENE-N",
"text": [
"collagenous triple helix"
],
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[
102,
126
]
],
"normalized": []
},
{
"id": "23363425_T18",
"type": "GENE-N",
"text": [
"sponge collagen"
],
"offsets": [
[
787,
802
]
],
"normalized": []
}
] | [] | [] | [] |
10430100 | 10430100 | [
{
"id": "10430100_title",
"type": "title",
"text": [
"Antitumor activity of ZD1694 (tomudex) against human head and neck cancer in nude mouse models: role of dosing schedule and plasma thymidine."
],
"offsets": [
[
0,
141
]
]
},
{
"id": "10430100_abstract",
"type": "abstract",
"text": [
"We studied the antitumor activity and toxicity of ZD1694 (tomudex), a specific inhibitor of thymidylate synthase (TS), in nude mice bearing human head and neck squamous cell carcinoma A253 and FaDu xenografts. Mice were treated by single i.v. push (i.v. x 1), i.v. push once a week for 3 weeks (weekly x 3), and i.v. push once a day for 5 days (daily x 5), and the maximum tolerated doses (MTDs) of ZD1694 were 300 mg/kg, 60 mg/kg/week, and 30 mg/kg/day, respectively. ZD1694 was moderately active against both A253 and FaDu xenografts. Antitumor activity was schedule-dependent in both tumors: weekly x 3 > or = i.v. x 1 >> daily x 5. In contrast, the rank order of toxicity was daily x 5 >> weekly x 3 > or = i.v. x 1. ZD1694 at the MTD produced 20% complete tumor regression and 20% partial tumor regression (PR) with i.v. x 1 and weekly x 3 schedules and 12-day tumor growth delay with daily x 5 schedule against FaDu xenografts. No complete tumor regression was achieved with ZD1694 with any schedule against A253; a 20% PR, 40% PR, and 10-day tumor growth delay were observed with i.v. x 1, weekly x 3, and daily x 5 schedules, respectively. The data indicate that ZD1694 was slightly more effective against FaDu than against A253. Of interest and potential clinical importance was the observation that ZD1694 was still active at doses lower than the MTD (> or =1/3 MTD), which showed a high therapeutic index and wide safety margin. Study of ZD1694 compared with 5-fluorouracil and 5-fluoro-2'-deoxyuridine at the MTD revealed that the antitumor activity of ZD1694 was comparable with or superior to 5-fluorouracil and 5-fluoro-2'-deoxyuridine against both A253 and FaDu xenografts, with less toxicity. High plasma thymidine in mouse relative to human (approximately 1.3 microM and <0.1 microM, respectively) may complicate the study of antitumor activity and toxicity of TS inhibitors with human tumor xenografts grown in the mouse. To test this hypothesis, we preadministered methoxypolyethyleneglycol-conjugated thymidine phosphorylase (MPEG-TPase; 2500 units/kg/dose) to reduce mouse plasma thymidine, then treated with various doses of ZD1694 using the daily x 5 or i.v. x 1 schedules in the A253 tumor model. MPEG-TPase significantly increased the toxicity of ZD1694; the MTD of ZD1694 plus MPEG-TPase was reduced 3- and 10-fold compared with ZD1694 alone for i.v x 1 and daily x 5 schedules, respectively. However, preadministration of MPEG-TPase did not potentiate the antitumor activity of ZD1694 with either schedule. The data indicate that the study of TS inhibitors in rodent models may not be suitable for predicting a safe dose for clinical study. However, rodent models, particularly human tumor xenografts, are still useful models for evaluation of antitumor activity and schedule selection for TS inhibitors."
],
"offsets": [
[
142,
2974
]
]
}
] | [
{
"id": "10430100_T1",
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"ZD1694"
],
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[
1313,
1319
]
],
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},
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"id": "10430100_T2",
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"ZD1694"
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1451,
1457
]
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"ZD1694"
],
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1591,
1597
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],
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"id": "10430100_T4",
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"5-fluorouracil"
],
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[
1612,
1626
]
],
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},
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"id": "10430100_T5",
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"5-fluoro-2'-deoxyuridine"
],
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1631,
1655
]
],
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},
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"id": "10430100_T6",
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"ZD1694"
],
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1707,
1713
]
],
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"id": "10430100_T7",
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"5-fluorouracil"
],
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[
1749,
1763
]
],
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},
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"id": "10430100_T8",
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"5-fluoro-2'-deoxyuridine"
],
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1768,
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]
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"id": "10430100_T9",
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"thymidine"
],
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1864,
1873
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],
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]
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2164,
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2244,
2253
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"MPEG"
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2446,
2450
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"ZD1694"
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"ZD1694"
],
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611,
617
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"ZD1694"
],
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192,
198
]
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{
"id": "10430100_T23",
"type": "CHEMICAL",
"text": [
"tomudex"
],
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[
200,
207
]
],
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},
{
"id": "10430100_T24",
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"ZD1694"
],
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[
863,
869
]
],
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},
{
"id": "10430100_T25",
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"text": [
"thymidylate"
],
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[
234,
245
]
],
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},
{
"id": "10430100_T26",
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"ZD1694"
],
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[
1123,
1129
]
],
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},
{
"id": "10430100_T27",
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"text": [
"thymidine"
],
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[
131,
140
]
],
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},
{
"id": "10430100_T28",
"type": "CHEMICAL",
"text": [
"ZD1694"
],
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[
22,
28
]
],
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},
{
"id": "10430100_T29",
"type": "CHEMICAL",
"text": [
"tomudex"
],
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[
30,
37
]
],
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},
{
"id": "10430100_T30",
"type": "GENE-Y",
"text": [
"TS"
],
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[
256,
258
]
],
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},
{
"id": "10430100_T31",
"type": "GENE-Y",
"text": [
"TS"
],
"offsets": [
[
2021,
2023
]
],
"normalized": []
},
{
"id": "10430100_T32",
"type": "GENE-Y",
"text": [
"methoxypolyethyleneglycol-conjugated thymidine phosphorylase"
],
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[
2127,
2187
]
],
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},
{
"id": "10430100_T33",
"type": "GENE-Y",
"text": [
"MPEG-TPase"
],
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[
2189,
2199
]
],
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},
{
"id": "10430100_T34",
"type": "GENE-Y",
"text": [
"MPEG-TPase"
],
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[
2364,
2374
]
],
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},
{
"id": "10430100_T35",
"type": "GENE-Y",
"text": [
"MPEG-TPase"
],
"offsets": [
[
2446,
2456
]
],
"normalized": []
},
{
"id": "10430100_T36",
"type": "GENE-Y",
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"MPEG-TPase"
],
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[
2592,
2602
]
],
"normalized": []
},
{
"id": "10430100_T37",
"type": "GENE-Y",
"text": [
"TS"
],
"offsets": [
[
2713,
2715
]
],
"normalized": []
},
{
"id": "10430100_T38",
"type": "GENE-Y",
"text": [
"TS"
],
"offsets": [
[
2960,
2962
]
],
"normalized": []
},
{
"id": "10430100_T39",
"type": "GENE-Y",
"text": [
"thymidylate synthase"
],
"offsets": [
[
234,
254
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "10430100_0",
"type": "INHIBITOR",
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}
] |
23360412 | 23360412 | [
{
"id": "23360412_title",
"type": "title",
"text": [
"Bioactivation of the nasal toxicant 2,6-dichlorobenzonitrile: an assessment of metabolic activity in human nasal mucosa and identification of indicators of exposure and potential toxicity."
],
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0,
188
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"type": "abstract",
"text": [
"The herbicide 2,6-dichlorobenzonitrile (DCBN) is a potent nasal toxicant in rodents; however, it is not known whether DCBN causes similar nasal toxicity in humans. The tissue-selective toxicity of DCBN in mouse nasal mucosa is largely dependent on target tissue bioactivation by CYP2A5. The human orthologues of CYP2A5, CYP2A6 and CYP2A13, are both expressed in nasal mucosa and are capable of activating DCBN. In this study, we directly determined the ability of human nasal mucosa to bioactivate DCBN. We also tested the suitability of a glutathione conjugate of DCBN (GS-DCBN) or its derivatives as biomarkers of DCBN exposure and nasal toxicity in mouse models. We found that human fetal nasal mucosa microsomes catalyze the formation of GS-DCBN, with a Km value comparable to that of adult mouse nasal mucosa microsomes. The activity of the human nasal mucosa microsomes was inhibited by 8-methoxypsoralen, a known CYP2A inhibitor. GS-DCBN and its metabolites were detected in the nasal mucosa and nasal-wash fluid obtained from DCBN-treated mice, in amounts that increased with escalations in DCBN dose, and they were all still detectable at 24 h after a DCBN treatment (at 10 mg/kg). Further studies in Cyp2a5-null mice indicated that GS-DCBN and its metabolites in nasal-wash fluid were generated in the nasal mucosa, rather than in other organs. Thus, our data indicate for the first time that the human nasal mucosa is capable of bioactivating DCBN and that GS-DCBN and its metabolites in nasal-wash fluid may collectively serve as indicators of DCBN exposure and potential nasal toxicity in humans."
],
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1109,
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}
] | [] | [] | [
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}
] |
23569204 | 23569204 | [
{
"id": "23569204_title",
"type": "title",
"text": [
"Structural and functional characterization of a phosphatase domain within yeast general transcription factor TFIIIC."
],
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0,
116
]
]
},
{
"id": "23569204_abstract",
"type": "abstract",
"text": [
"Saccharomyces cerevisiae τ55, a subunit of the RNA polymerase III-specific general transcription factor TFIIIC, comprises an N-terminal histidine phosphatase domain (τ55-HPD) whose catalytic activity and cellular function is poorly understood. We solved the crystal structures of τ55-HPD and its closely related paralogue Huf and used in silico docking methods to identify phospho-serine and phospho-tyrosine containing peptides as possible substrates that were subsequently validated using in vitro phosphatase assays. A comparative phospho-proteomic study identified additional phosphopeptides as possible targets, which show the involvement of these two phosphatases in the regulation of a variety of cellular functions. Our results identify τ55-HPD and Huf as bona fide protein phosphatases, characterize their substrate specificities and provide a small set of regulated phosphosite targets in vivo."
],
"offsets": [
[
117,
1021
]
]
}
] | [
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"id": "23569204_T1",
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"N"
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242,
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]
],
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},
{
"id": "23569204_T2",
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"text": [
"histidine"
],
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253,
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]
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{
"id": "23569204_T3",
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],
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],
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},
{
"id": "23569204_T4",
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]
],
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{
"id": "23569204_T5",
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"phospho"
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651,
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]
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"id": "23569204_T6",
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"Saccharomyces cerevisiae τ55"
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117,
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"id": "23569204_T7",
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242,
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]
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"id": "23569204_T9",
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"τ55"
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283,
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"id": "23569204_T10",
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397,
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401,
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439,
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164,
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617,
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"id": "23569204_T16",
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774,
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},
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"id": "23569204_T17",
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862,
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866,
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"id": "23569204_T19",
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891,
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"id": "23569204_T20",
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109,
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"id": "23569204_T21",
"type": "GENE-N",
"text": [
"phosphatase domain"
],
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48,
66
]
],
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}
] | [] | [] | [
{
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"type": "PART-OF",
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"arg2_id": "23569204_T6",
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}
] |
23470287 | 23470287 | [
{
"id": "23470287_title",
"type": "title",
"text": [
"A newly synthesized sinapic Acid derivative inhibits endothelial activation in vitro and in vivo."
],
"offsets": [
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0,
97
]
]
},
{
"id": "23470287_abstract",
"type": "abstract",
"text": [
"Inhibition of oxidative stress and inflammation in vascular endothelial cells (ECs) may represent a new therapeutic strategy against endothelial activation. Sinapic acid (SA), a phenylpropanoid compound, is found in natural herbs and high-bran cereals and has moderate antioxidant activity. We aimed to develop new SA agents with the properties of antioxidation and blocking EC activation for possible therapy of cardiovascular disease. We designed and synthesized 10 SA derivatives according to their chemical structures. Preliminary screening of the compounds involved scavenging hydroxyl radicals and 2,2-diphenyl-1-picrylhydrazyl (DPPH(⋅)), croton oil-induced ear edema in mice, and analysis of the mRNA expression of adhesion molecules in ECs. 1-Acetyl-sinapic acyl-4-(3'-chlorine-)benzylpiperazine (SA9) had the strongest antioxidant and anti-inflammatory activities both in vitro and in vivo. Thus, the effect of SA9 was further studied. SA9 inhibited tumor necrosis factor α-induced upregulation of adhesion molecules in ECs at both mRNA and protein levels, as well as the consequent monocyte adhesion to ECs. In vivo, result of face-to-face immunostaining showed that SA9 reduced lipopolysaccharide-induced expression of intercellular adhesion molecule-1 in mouse aortic intima. To study the molecular mechanism, results from luciferase assay, nuclear translocation of NF-κB, and Western blot indicated that the mechanism of the anti-inflammatory effects of SA9 might be suppression of intracellular generation of ROS and inhibition of NF-κB activation in ECs. SA9 is a prototype of a novel class of antioxidant with anti-inflammatory effects in ECs. It may represent a new therapeutic approach for preventing endothelial activation in cardiovascular disorders."
],
"offsets": [
[
98,
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]
]
}
] | [
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"id": "23470287_T1",
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"SA9"
],
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1565,
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"id": "23470287_T2",
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"SA9"
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1668,
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"id": "23470287_T3",
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255,
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"id": "23470287_T4",
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276,
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"id": "23470287_T5",
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"hydroxyl"
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680,
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]
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"id": "23470287_T6",
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],
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]
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},
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"id": "23470287_T7",
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"DPPH(⋅)"
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740
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"id": "23470287_T8",
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"1-Acetyl-sinapic acyl-4-(3'-chlorine-)benzylpiperazine"
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847,
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"id": "23470287_T9",
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"id": "23470287_T10",
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"SA9"
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1018,
1021
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"id": "23470287_T11",
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"SA9"
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1043,
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"sinapic Acid"
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20,
32
]
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},
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"id": "23470287_T13",
"type": "GENE-Y",
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"intercellular adhesion molecule-1"
],
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[
1328,
1361
]
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},
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"id": "23470287_T14",
"type": "GENE-N",
"text": [
"NF-κB"
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1476,
1481
]
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},
{
"id": "23470287_T15",
"type": "GENE-N",
"text": [
"NF-κB"
],
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1643,
1648
]
],
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},
{
"id": "23470287_T16",
"type": "GENE-Y",
"text": [
"tumor necrosis factor α"
],
"offsets": [
[
1057,
1080
]
],
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}
] | [] | [] | [
{
"id": "23470287_0",
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},
{
"id": "23470287_1",
"type": "INHIBITOR",
"arg1_id": "23470287_T1",
"arg2_id": "23470287_T15",
"normalized": []
}
] |
17089011 | 17089011 | [
{
"id": "17089011_title",
"type": "title",
"text": [
"DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes."
],
"offsets": [
[
0,
211
]
]
},
{
"id": "17089011_abstract",
"type": "abstract",
"text": [
"Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of topoisomerase IIalpha (TOP2A) inhibitors doxorubicin and etopoxide (VP-16) demonstrated a 2- to 3-fold increase in FAS promoter activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of FAS promoter following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the FAS promoter was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, FAS promoter activity and FAS protein expression were significantly reduced. Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinoma cells."
],
"offsets": [
[
212,
3015
]
]
}
] | [
{
"id": "17089011_T1",
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"Fatty acid"
],
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212,
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]
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},
{
"id": "17089011_T2",
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"text": [
"doxorubicin"
],
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1459,
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{
"id": "17089011_T3",
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"etopoxide"
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1475,
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]
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"id": "17089011_T4",
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"VP-16"
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1486,
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"id": "17089011_T5",
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],
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1735,
1749
]
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1771,
1780
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1820,
1830
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1846
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57,
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1284
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1441,
1446
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1941,
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2003,
2015
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2035,
2076
]
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2078,
2083
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2116,
2119
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2271
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2276,
2279
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2296,
2301
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2302,
2305
]
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233,
236
]
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2337,
2342
]
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2404,
2409
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2410,
2413
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2457,
2469
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"FAS"
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2483,
2486
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2573,
2578
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2691,
2694
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"TOP2A"
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2740,
2745
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"FAS"
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2780,
2783
]
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},
{
"id": "17089011_T37",
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"Her-2"
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2822,
2827
]
],
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},
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"neu"
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2828,
2831
]
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},
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"id": "17089011_T39",
"type": "GENE-Y",
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"TOP2A"
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2832,
2837
]
],
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},
{
"id": "17089011_T40",
"type": "GENE-Y",
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"FAS"
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2930,
2933
]
],
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},
{
"id": "17089011_T41",
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"Her-2"
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2935,
2940
]
],
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},
{
"id": "17089011_T42",
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"neu"
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2941,
2944
]
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},
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"TOP2A"
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2949,
2954
]
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},
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"id": "17089011_T44",
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"FAS"
],
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566,
569
]
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},
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"Her-2"
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578,
583
]
],
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},
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"neu"
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584,
587
]
],
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},
{
"id": "17089011_T47",
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"erbB-2"
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589,
595
]
],
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},
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"id": "17089011_T48",
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711,
716
]
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"id": "17089011_T49",
"type": "GENE-Y",
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717,
720
]
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"id": "17089011_T50",
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"FAS"
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801,
804
]
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"id": "17089011_T51",
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919,
924
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925,
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1093,
1096
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1151,
1154
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1165
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1166,
1169
]
],
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0,
25
]
],
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},
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"id": "17089011_T58",
"type": "GENE-Y",
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"FAS"
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180,
183
]
],
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},
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"id": "17089011_T59",
"type": "GENE-Y",
"text": [
"Her-2"
],
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185,
190
]
],
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},
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"id": "17089011_T60",
"type": "GENE-Y",
"text": [
"neu"
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191,
194
]
],
"normalized": []
},
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"id": "17089011_T61",
"type": "GENE-Y",
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"TOP2A"
],
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199,
204
]
],
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},
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"id": "17089011_T62",
"type": "GENE-Y",
"text": [
"TOP2A"
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27,
32
]
],
"normalized": []
},
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"id": "17089011_T63",
"type": "GENE-Y",
"text": [
"fatty acid synthase"
],
"offsets": [
[
57,
76
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17089011_0",
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"arg2_id": "17089011_T13",
"normalized": []
},
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},
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},
{
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"arg2_id": "17089011_T14",
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},
{
"id": "17089011_4",
"type": "INHIBITOR",
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},
{
"id": "17089011_5",
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"arg2_id": "17089011_T14",
"normalized": []
},
{
"id": "17089011_6",
"type": "ACTIVATOR",
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"arg2_id": "17089011_T15",
"normalized": []
},
{
"id": "17089011_7",
"type": "ACTIVATOR",
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"arg2_id": "17089011_T15",
"normalized": []
},
{
"id": "17089011_8",
"type": "ACTIVATOR",
"arg1_id": "17089011_T4",
"arg2_id": "17089011_T15",
"normalized": []
}
] |
17408310 | 17408310 | [
{
"id": "17408310_title",
"type": "title",
"text": [
"Application of the bradford hill criteria to assess the causality of cisapride-induced arrhythmia: a model for assessing causal association in pharmacovigilance."
],
"offsets": [
[
0,
161
]
]
},
{
"id": "17408310_abstract",
"type": "abstract",
"text": [
"INTRODUCTION: The Bradford Hill criteria are a widely used, useful tool for the assessment of biomedical causation. We have examined their application to pharmacovigilance using the example of cisapride-induced QTc interval prolongation/arrhythmia. METHODS: A literature search was conducted using MEDLINE, EMBASE, Reactions Weekly and regulatory websites to identify evidence for the association between cisapride and QTc interval prolongation/arrhythmia that had been published in the English language. Two hundred and five publications were identified as being potentially suitable for the study. After excluding irrelevant articles, studies on high-risk populations and review articles, 70 publications were assessed using the Bradford Hill criteria. These included 24 case reports, case series or spontaneous report summaries; eight epidemiological studies; 22 clinical studies; and 16 experimental (in vivo and in vitro) publications. RESULTS: The most compelling evidence for an association between cisapride use and QTc interval prolongation/arrhythmia came from case/spontaneous reports and biological plausibility. Considering the rare incidence of serious cardiac events, these criteria formed the basis for the strength of the association. The number of reports from different populations showed consistency. Specificity was supported by clinical and cardiographic characterisation of the events. There were temporal relationships between the events and the initiation of cisapride treatment, increases in the dosage and the receipt of interacting medications. The relationships between the adverse events and the latter two factors exhibited biological gradients. Experimental evidence could be found from biological models, as well as reports of positive dechallenge and/or rechallenge found in individual patients. Cisapride was found to bind the human ether-a-go-go-related gene (HERG) potassium channel, which provides a plausible mechanism for QTc interval prolongation/arrhythmia. Other QTc interval-prolonging/arrhythmic drugs that also bind to HERG provided an analogy for cisapride causing QTc interval prolongation/arrhythmia via this mechanism. The evidence provided by clinical studies was inconsistent, and epidemiological studies failed to demonstrate an association. Nevertheless, this did not prevent the assessment of causation. DISCUSSION: This study showed how different types of evidence found in pharmacovigilance can be evaluated using the Bradford Hill criteria. Further work is required to examine how the criteria can be applied to different types of adverse events and how they may be applied to pharmacovigilance."
],
"offsets": [
[
162,
2815
]
]
}
] | [
{
"id": "17408310_T1",
"type": "CHEMICAL",
"text": [
"cisapride"
],
"offsets": [
[
1168,
1177
]
],
"normalized": []
},
{
"id": "17408310_T2",
"type": "CHEMICAL",
"text": [
"cisapride"
],
"offsets": [
[
1646,
1655
]
],
"normalized": []
},
{
"id": "17408310_T3",
"type": "CHEMICAL",
"text": [
"Cisapride"
],
"offsets": [
[
1992,
2001
]
],
"normalized": []
},
{
"id": "17408310_T4",
"type": "CHEMICAL",
"text": [
"potassium"
],
"offsets": [
[
2064,
2073
]
],
"normalized": []
},
{
"id": "17408310_T5",
"type": "CHEMICAL",
"text": [
"cisapride"
],
"offsets": [
[
355,
364
]
],
"normalized": []
},
{
"id": "17408310_T6",
"type": "CHEMICAL",
"text": [
"cisapride"
],
"offsets": [
[
2256,
2265
]
],
"normalized": []
},
{
"id": "17408310_T7",
"type": "CHEMICAL",
"text": [
"cisapride"
],
"offsets": [
[
567,
576
]
],
"normalized": []
},
{
"id": "17408310_T8",
"type": "CHEMICAL",
"text": [
"cisapride"
],
"offsets": [
[
69,
78
]
],
"normalized": []
},
{
"id": "17408310_T9",
"type": "GENE-Y",
"text": [
"human ether-a-go-go-related gene (HERG) potassium channel"
],
"offsets": [
[
2024,
2081
]
],
"normalized": []
},
{
"id": "17408310_T10",
"type": "GENE-Y",
"text": [
"HERG"
],
"offsets": [
[
2227,
2231
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17408310_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "17408310_T3",
"arg2_id": "17408310_T9",
"normalized": []
},
{
"id": "17408310_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "17408310_T6",
"arg2_id": "17408310_T10",
"normalized": []
}
] |
16876126 | 16876126 | [
{
"id": "16876126_title",
"type": "title",
"text": [
"RNA interference-triggered reversal of ABCC2-dependent cisplatin resistance in human cancer cells."
],
"offsets": [
[
0,
98
]
]
},
{
"id": "16876126_abstract",
"type": "abstract",
"text": [
"The adenosine triphosphate binding cassette (ABC)-transporter ABCC2 (MRP2/cMOAT) can mediate resistance against the commonly used anticancer drugs cisplatin and paclitaxel. To overcome the ABCC2-depending drug resistance, two specific anti-ABCC2 small interfering RNAs (siRNAs) were designed for transient triggering of the gene-silencing RNA interference (RNAi) pathway in the cisplatin-resistant human ovarian carcinoma cell line A2780RCIS. Since both siRNAs showed biological activity, for stable inhibition of ABCC2 a corresponding short hairpin RNA (shRNA)-encoding expression vector was designed. By treatment of A2780RCIS cells with this construct, the expressions of the targeted ABCC2 encoding mRNA and transport protein were inhibited. These effects were accompanied by reversal of resistance against cisplatin and paclitaxel. Thus, the data demonstrate the utility of the analyzed RNAs as powerful laboratory tools and indicate that siRNA- and shRNA-mediated RNAi-based gene therapeutic approaches may be applicable in preventing and reversing ABCC2-depending drug resistance."
],
"offsets": [
[
99,
1186
]
]
}
] | [
{
"id": "16876126_T1",
"type": "CHEMICAL",
"text": [
"cisplatin"
],
"offsets": [
[
246,
255
]
],
"normalized": []
},
{
"id": "16876126_T2",
"type": "CHEMICAL",
"text": [
"paclitaxel"
],
"offsets": [
[
260,
270
]
],
"normalized": []
},
{
"id": "16876126_T3",
"type": "CHEMICAL",
"text": [
"cisplatin"
],
"offsets": [
[
477,
486
]
],
"normalized": []
},
{
"id": "16876126_T4",
"type": "CHEMICAL",
"text": [
"adenosine triphosphate"
],
"offsets": [
[
103,
125
]
],
"normalized": []
},
{
"id": "16876126_T5",
"type": "CHEMICAL",
"text": [
"cisplatin"
],
"offsets": [
[
910,
919
]
],
"normalized": []
},
{
"id": "16876126_T6",
"type": "CHEMICAL",
"text": [
"paclitaxel"
],
"offsets": [
[
924,
934
]
],
"normalized": []
},
{
"id": "16876126_T7",
"type": "CHEMICAL",
"text": [
"cisplatin"
],
"offsets": [
[
55,
64
]
],
"normalized": []
},
{
"id": "16876126_T8",
"type": "GENE-Y",
"text": [
"ABCC2"
],
"offsets": [
[
1154,
1159
]
],
"normalized": []
},
{
"id": "16876126_T9",
"type": "GENE-Y",
"text": [
"ABCC2"
],
"offsets": [
[
288,
293
]
],
"normalized": []
},
{
"id": "16876126_T10",
"type": "GENE-Y",
"text": [
"ABCC2"
],
"offsets": [
[
339,
344
]
],
"normalized": []
},
{
"id": "16876126_T11",
"type": "GENE-N",
"text": [
"adenosine triphosphate binding cassette (ABC)-transporter"
],
"offsets": [
[
103,
160
]
],
"normalized": []
},
{
"id": "16876126_T12",
"type": "GENE-Y",
"text": [
"ABCC2"
],
"offsets": [
[
613,
618
]
],
"normalized": []
},
{
"id": "16876126_T13",
"type": "GENE-Y",
"text": [
"ABCC2"
],
"offsets": [
[
161,
166
]
],
"normalized": []
},
{
"id": "16876126_T14",
"type": "GENE-Y",
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"ABCC2"
],
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"id": "16876126_T15",
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"text": [
"MRP2"
],
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[
168,
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]
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"id": "16876126_T16",
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"text": [
"cMOAT"
],
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173,
178
]
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"id": "16876126_T17",
"type": "GENE-Y",
"text": [
"ABCC2"
],
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[
39,
44
]
],
"normalized": []
}
] | [] | [] | [] |
6433001 | 6433001 | [
{
"id": "6433001_title",
"type": "title",
"text": [
"Effects of metal cations and calmodulin antagonists on [3H] nitrendipine binding in smooth and cardiac muscle."
],
"offsets": [
[
0,
110
]
]
},
{
"id": "6433001_abstract",
"type": "abstract",
"text": [
"It was previously reported that [3H]nitrendipine binding to a microsomal fraction from intestinal smooth muscle was dependent upon the presence of divalent metal cations (Bolger et al., J. Pharmacol. Exp. Ther. 225: 291-309, 1983). The effects of cations and calmodulin antagonists on [3H]nitrendipine binding in smooth and cardiac muscle have been studied further. Treatment of ileal and aortic smooth muscle and cardiac muscle with EDTA reduced specific [3H]nitrendipine binding by 70 to 95%. Microsomes from rabbit ventricle were more resistant to EDTA treatment than were those from ileal smooth muscle, but low concentrations of Ca++ (less than 10(-5) M) produced half-maximal restoration of binding in both tissues. The ability of cations at a concentration of 10(-3) M to restore binding to membranes from guinea-pig ileum was in the sequence, Ca++ = Sr++ greater than Mg++ = Mn++ = Co++ greater than Ba++ = Ni++ greater than Zn++ = Cd++ greater than La = Sm = Tm . In contrast to the activation of calmodulin-dependent processes, the ability of these cations to restore [3H]nitrendipine binding did not correlate linearly with ionic radius. However, calmodulin antagonists were found to inhibit [3H]nitrendipine binding with the order of potency: pimozide greater than less than calmidazolium (R 24571) greater than trifluoperazine greater than chlorpromazine greater than promethazine greater than chlorpromazine sulfoxide, that correlates quite well with the potency of these drugs as inhibitors of calmodulin-dependent processes. The results suggest that calmodulin antagonists bind to a protein associated with the [3H]nitrendipine binding site that has a hydrophobic domain similar to that exposed on calmodulin by Ca++, but that this protein is not calmodulin itself."
],
"offsets": [
[
111,
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]
]
}
] | [
{
"id": "6433001_T1",
"type": "CHEMICAL",
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"[3H]nitrendipine"
],
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]
],
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},
{
"id": "6433001_T2",
"type": "CHEMICAL",
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"[3H]nitrendipine"
],
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1314,
1330
]
],
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},
{
"id": "6433001_T3",
"type": "CHEMICAL",
"text": [
"pimozide"
],
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1366,
1374
]
],
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},
{
"id": "6433001_T4",
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"text": [
"calmidazolium"
],
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1398,
1411
]
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"id": "6433001_T5",
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"R 24571"
],
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1413,
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]
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"id": "6433001_T6",
"type": "CHEMICAL",
"text": [
"trifluoperazine"
],
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1435,
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]
],
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},
{
"id": "6433001_T7",
"type": "CHEMICAL",
"text": [
"chlorpromazine"
],
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[
1464,
1478
]
],
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},
{
"id": "6433001_T8",
"type": "CHEMICAL",
"text": [
"promethazine"
],
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[
1492,
1504
]
],
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},
{
"id": "6433001_T9",
"type": "CHEMICAL",
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"chlorpromazine sulfoxide"
],
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1518,
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]
],
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},
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"id": "6433001_T10",
"type": "CHEMICAL",
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"[3H]nitrendipine"
],
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[
1738,
1754
]
],
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},
{
"id": "6433001_T11",
"type": "CHEMICAL",
"text": [
"Ca++"
],
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1839,
1843
]
],
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},
{
"id": "6433001_T12",
"type": "CHEMICAL",
"text": [
"[3H]nitrendipine"
],
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396,
412
]
],
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},
{
"id": "6433001_T13",
"type": "CHEMICAL",
"text": [
"[3H]nitrendipine"
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143,
159
]
],
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},
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"id": "6433001_T14",
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"text": [
"EDTA"
],
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545,
549
]
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"[3H]nitrendipine"
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{
"id": "6433001_T16",
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"text": [
"EDTA"
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662,
666
]
],
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},
{
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"text": [
"Ca++"
],
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745,
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]
],
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"id": "6433001_T18",
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"text": [
"Ca++"
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{
"id": "6433001_T19",
"type": "CHEMICAL",
"text": [
"Sr++"
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969,
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]
],
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},
{
"id": "6433001_T20",
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"text": [
"Mg++"
],
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987,
991
]
],
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},
{
"id": "6433001_T21",
"type": "CHEMICAL",
"text": [
"Mn++"
],
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[
994,
998
]
],
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},
{
"id": "6433001_T22",
"type": "CHEMICAL",
"text": [
"Co++"
],
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[
1001,
1005
]
],
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},
{
"id": "6433001_T23",
"type": "CHEMICAL",
"text": [
"Ba++"
],
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[
1019,
1023
]
],
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},
{
"id": "6433001_T24",
"type": "CHEMICAL",
"text": [
"Ni++"
],
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[
1026,
1030
]
],
"normalized": []
},
{
"id": "6433001_T25",
"type": "CHEMICAL",
"text": [
"Zn++"
],
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[
1044,
1048
]
],
"normalized": []
},
{
"id": "6433001_T26",
"type": "CHEMICAL",
"text": [
"Cd++"
],
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[
1051,
1055
]
],
"normalized": []
},
{
"id": "6433001_T27",
"type": "CHEMICAL",
"text": [
"La"
],
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[
1069,
1071
]
],
"normalized": []
},
{
"id": "6433001_T28",
"type": "CHEMICAL",
"text": [
"Sm"
],
"offsets": [
[
1074,
1076
]
],
"normalized": []
},
{
"id": "6433001_T29",
"type": "CHEMICAL",
"text": [
"Tm"
],
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[
1079,
1081
]
],
"normalized": []
},
{
"id": "6433001_T30",
"type": "CHEMICAL",
"text": [
"[3H] nitrendipine"
],
"offsets": [
[
55,
72
]
],
"normalized": []
},
{
"id": "6433001_T31",
"type": "GENE-N",
"text": [
"calmodulin"
],
"offsets": [
[
1117,
1127
]
],
"normalized": []
},
{
"id": "6433001_T32",
"type": "GENE-N",
"text": [
"calmodulin"
],
"offsets": [
[
1269,
1279
]
],
"normalized": []
},
{
"id": "6433001_T33",
"type": "GENE-N",
"text": [
"calmodulin"
],
"offsets": [
[
1620,
1630
]
],
"normalized": []
},
{
"id": "6433001_T34",
"type": "GENE-N",
"text": [
"calmodulin"
],
"offsets": [
[
1677,
1687
]
],
"normalized": []
},
{
"id": "6433001_T35",
"type": "GENE-N",
"text": [
"calmodulin"
],
"offsets": [
[
1825,
1835
]
],
"normalized": []
},
{
"id": "6433001_T36",
"type": "GENE-N",
"text": [
"calmodulin"
],
"offsets": [
[
1874,
1884
]
],
"normalized": []
},
{
"id": "6433001_T37",
"type": "GENE-N",
"text": [
"calmodulin"
],
"offsets": [
[
370,
380
]
],
"normalized": []
},
{
"id": "6433001_T38",
"type": "GENE-N",
"text": [
"calmodulin"
],
"offsets": [
[
29,
39
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "6433001_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "6433001_T2",
"arg2_id": "6433001_T32",
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},
{
"id": "6433001_1",
"type": "DIRECT-REGULATOR",
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},
{
"id": "6433001_2",
"type": "DIRECT-REGULATOR",
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},
{
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"type": "DIRECT-REGULATOR",
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"arg2_id": "6433001_T32",
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},
{
"id": "6433001_4",
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},
{
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},
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},
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},
{
"id": "6433001_8",
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},
{
"id": "6433001_9",
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},
{
"id": "6433001_10",
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},
{
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"type": "ANTAGONIST",
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},
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"id": "6433001_12",
"type": "ANTAGONIST",
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},
{
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},
{
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"type": "ANTAGONIST",
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},
{
"id": "6433001_15",
"type": "INHIBITOR",
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"arg2_id": "6433001_T33",
"normalized": []
},
{
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"type": "INHIBITOR",
"arg1_id": "6433001_T4",
"arg2_id": "6433001_T33",
"normalized": []
},
{
"id": "6433001_17",
"type": "INHIBITOR",
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"arg2_id": "6433001_T33",
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},
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"type": "INHIBITOR",
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"normalized": []
},
{
"id": "6433001_19",
"type": "INHIBITOR",
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"arg2_id": "6433001_T33",
"normalized": []
},
{
"id": "6433001_20",
"type": "INHIBITOR",
"arg1_id": "6433001_T8",
"arg2_id": "6433001_T33",
"normalized": []
},
{
"id": "6433001_21",
"type": "INHIBITOR",
"arg1_id": "6433001_T9",
"arg2_id": "6433001_T33",
"normalized": []
},
{
"id": "6433001_22",
"type": "DIRECT-REGULATOR",
"arg1_id": "6433001_T10",
"arg2_id": "6433001_T34",
"normalized": []
}
] |
16981227 | 16981227 | [
{
"id": "16981227_title",
"type": "title",
"text": [
"Effects of DRD2 and CYP2D6 genotypes on delta EEG power response to aripiprazole in healthy male volunteers: a preliminary study."
],
"offsets": [
[
0,
129
]
]
},
{
"id": "16981227_abstract",
"type": "abstract",
"text": [
"The aim of the present study was to evaluate the effects of polymorphisms in dopamine D2 receptor (DRD2) and cytochrome P450 (CYP) 2D6 genes on delta EEG power response to aripiprazole in healthy male volunteers. Seventeen volunteers were recruited according to the DRD2 Taq1A genotype, and separated into the following groups: homozygous wild-type (A2/A2, n = 7), heterozygous (A2/A1, n = 5) and homozygous variant-type (A1/A1, n = 5) groups. After enrollment in this study, they were genotyped for CYP2D6. The volunteers received single 10 mg oral doses of aripiprazole, in accordance with an open-label parallel group study design. Plasma levels of aripiprazole and its metabolite were determined and EEGs were obtained simultaneously. The pharmacodynamic parameter was absolute delta power in the Cz channel. The changes of delta power were not different according to DRD2 Taq1A genotypes. As to the CYP2D6 allele, the subjects had the following CYP2D6 genotypes: *10/*10 (n = 4), *1/*10 (n = 5), *1/*5 (n = 2), *1/*1 (n = 3), *2/*41 (n = 1), *2/*2 (n = 1), *2N/*10 (n = 1). Subjects exhibiting the *1/*5 and *1/*10 genotypes showed a trend toward high area under the plasma aripiprazole concentration-time curve (AUC), which was linearly related to area under the EEG response-time curve (AUEC). Our results demonstrate a need for further evaluation of the CYP2D6 genotypic effect on the pharmacodynamics of aripiprazole."
],
"offsets": [
[
130,
1556
]
]
}
] | [
{
"id": "16981227_T1",
"type": "CHEMICAL",
"text": [
"aripiprazole"
],
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[
1309,
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]
],
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{
"id": "16981227_T2",
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"aripiprazole"
],
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1543,
1555
]
],
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"id": "16981227_T3",
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"aripiprazole"
],
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302,
314
]
],
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"id": "16981227_T4",
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"text": [
"aripiprazole"
],
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[
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]
],
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},
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"id": "16981227_T5",
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"aripiprazole"
],
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[
782,
794
]
],
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},
{
"id": "16981227_T6",
"type": "CHEMICAL",
"text": [
"dopamine"
],
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[
207,
215
]
],
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},
{
"id": "16981227_T7",
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"aripiprazole"
],
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[
68,
80
]
],
"normalized": []
},
{
"id": "16981227_T8",
"type": "GENE-Y",
"text": [
"cytochrome P450 (CYP) 2D6"
],
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[
239,
264
]
],
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},
{
"id": "16981227_T9",
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"CYP2D6"
],
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[
1492,
1498
]
],
"normalized": []
},
{
"id": "16981227_T10",
"type": "GENE-Y",
"text": [
"DRD2"
],
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[
396,
400
]
],
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},
{
"id": "16981227_T11",
"type": "GENE-Y",
"text": [
"CYP2D6"
],
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[
630,
636
]
],
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},
{
"id": "16981227_T12",
"type": "GENE-Y",
"text": [
"dopamine D2 receptor"
],
"offsets": [
[
207,
227
]
],
"normalized": []
},
{
"id": "16981227_T13",
"type": "GENE-Y",
"text": [
"DRD2"
],
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1002,
1006
]
],
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},
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"id": "16981227_T14",
"type": "GENE-Y",
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"CYP2D6"
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1034,
1040
]
],
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},
{
"id": "16981227_T15",
"type": "GENE-Y",
"text": [
"CYP2D6"
],
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[
1080,
1086
]
],
"normalized": []
},
{
"id": "16981227_T16",
"type": "GENE-Y",
"text": [
"DRD2"
],
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[
229,
233
]
],
"normalized": []
},
{
"id": "16981227_T17",
"type": "GENE-Y",
"text": [
"DRD2"
],
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11,
15
]
],
"normalized": []
},
{
"id": "16981227_T18",
"type": "GENE-Y",
"text": [
"CYP2D6"
],
"offsets": [
[
20,
26
]
],
"normalized": []
}
] | [] | [] | [] |
23192350 | 23192350 | [
{
"id": "23192350_title",
"type": "title",
"text": [
"Silencing α1,3-fucosyltransferases in human leukocytes reveals a role for FUT9 enzyme during E-selectin-mediated cell adhesion."
],
"offsets": [
[
0,
127
]
]
},
{
"id": "23192350_abstract",
"type": "abstract",
"text": [
"Leukocyte adhesion during inflammation is initiated by the binding of sialofucosylated carbohydrates expressed on leukocytes to endothelial E/P-selectin. Although the glycosyltransferases (glycoTs) constructing selectin-ligands have largely been identified using knock-out mice, important differences may exist between humans and mice. To address this, we developed a systematic lentivirus-based shRNA delivery workflow to create human leukocytic HL-60 cell lines that lack up to three glycoTs. Using this, the contributions of all three myeloid α1,3-fucosyltransferases (FUT4, FUT7, and FUT9) to selectin-ligand biosynthesis were evaluated. The cell adhesion properties of these modified cells to L-, E-, and P-selectin under hydrodynamic shear were compared with bone marrow-derived neutrophils from Fut4(-/-)Fut7(-/-) dual knock-out mice. Results demonstrate that predominantly FUT7, and to a lesser extent FUT4, forms the selectin-ligand at the N terminus of leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) in humans and mice. Here, 85% reduction in leukocyte interaction was observed in human FUT4(-)7(-) dual knockdowns on P/L-selectin substrates. Unlike Fut4(-/-)Fut7(-/-) mouse neutrophils, however, human knockdowns lacking FUT4 and FUT7 only exhibited partial reduction in rolling interaction on E-selectin. In this case, the third α1,3-fucosyltransferase FUT9 played an important role because leukocyte adhesion was reduced by 50-60% in FUT9-HL-60, 70-80% in dual knockdown FUT7(-)9(-) cells, and ∼85% in FUT4(-)7(-)9(-) triple knockdowns. Gene silencing results are in agreement with gain-of-function experiments where all three fucosyltransferases conferred E-selectin-mediated rolling in HEK293T cells. This study advances new tools to study human glycoT function. It suggests a species-specific role for FUT9 during the biosynthesis of human E-selectin ligands."
],
"offsets": [
[
128,
2008
]
]
}
] | [
{
"id": "23192350_T1",
"type": "CHEMICAL",
"text": [
"carbohydrates"
],
"offsets": [
[
215,
228
]
],
"normalized": []
},
{
"id": "23192350_T2",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
1077,
1078
]
],
"normalized": []
},
{
"id": "23192350_T3",
"type": "GENE-N",
"text": [
"PSGL-1"
],
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1135,
1141
]
],
"normalized": []
},
{
"id": "23192350_T4",
"type": "GENE-N",
"text": [
"human FUT4(-)7"
],
"offsets": [
[
1224,
1238
]
],
"normalized": []
},
{
"id": "23192350_T5",
"type": "GENE-N",
"text": [
"P/L-selectin"
],
"offsets": [
[
1261,
1273
]
],
"normalized": []
},
{
"id": "23192350_T6",
"type": "GENE-Y",
"text": [
"Fut4"
],
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1293,
1297
]
],
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},
{
"id": "23192350_T7",
"type": "GENE-Y",
"text": [
"Fut7"
],
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[
1302,
1306
]
],
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},
{
"id": "23192350_T8",
"type": "GENE-Y",
"text": [
"FUT4"
],
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[
1365,
1369
]
],
"normalized": []
},
{
"id": "23192350_T9",
"type": "GENE-Y",
"text": [
"FUT7"
],
"offsets": [
[
1374,
1378
]
],
"normalized": []
},
{
"id": "23192350_T10",
"type": "GENE-Y",
"text": [
"E-selectin"
],
"offsets": [
[
1438,
1448
]
],
"normalized": []
},
{
"id": "23192350_T11",
"type": "GENE-N",
"text": [
"α1,3-fucosyltransferase"
],
"offsets": [
[
1474,
1497
]
],
"normalized": []
},
{
"id": "23192350_T12",
"type": "GENE-Y",
"text": [
"FUT9"
],
"offsets": [
[
1498,
1502
]
],
"normalized": []
},
{
"id": "23192350_T13",
"type": "GENE-N",
"text": [
"E/P-selectin"
],
"offsets": [
[
268,
280
]
],
"normalized": []
},
{
"id": "23192350_T14",
"type": "GENE-Y",
"text": [
"FUT9"
],
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[
1580,
1584
]
],
"normalized": []
},
{
"id": "23192350_T15",
"type": "GENE-N",
"text": [
"FUT7(-)9"
],
"offsets": [
[
1617,
1625
]
],
"normalized": []
},
{
"id": "23192350_T16",
"type": "GENE-N",
"text": [
"FUT4(-)7(-)9"
],
"offsets": [
[
1648,
1660
]
],
"normalized": []
},
{
"id": "23192350_T17",
"type": "GENE-N",
"text": [
"fucosyltransferases"
],
"offsets": [
[
1773,
1792
]
],
"normalized": []
},
{
"id": "23192350_T18",
"type": "GENE-N",
"text": [
"glycosyltransferases"
],
"offsets": [
[
295,
315
]
],
"normalized": []
},
{
"id": "23192350_T19",
"type": "GENE-Y",
"text": [
"E-selectin"
],
"offsets": [
[
1803,
1813
]
],
"normalized": []
},
{
"id": "23192350_T20",
"type": "GENE-N",
"text": [
"human glycoT"
],
"offsets": [
[
1888,
1900
]
],
"normalized": []
},
{
"id": "23192350_T21",
"type": "GENE-Y",
"text": [
"FUT9"
],
"offsets": [
[
1951,
1955
]
],
"normalized": []
},
{
"id": "23192350_T22",
"type": "GENE-Y",
"text": [
"human E-selectin"
],
"offsets": [
[
1983,
1999
]
],
"normalized": []
},
{
"id": "23192350_T23",
"type": "GENE-N",
"text": [
"glycoTs"
],
"offsets": [
[
317,
324
]
],
"normalized": []
},
{
"id": "23192350_T24",
"type": "GENE-N",
"text": [
"selectin"
],
"offsets": [
[
339,
347
]
],
"normalized": []
},
{
"id": "23192350_T25",
"type": "GENE-N",
"text": [
"glycoTs"
],
"offsets": [
[
614,
621
]
],
"normalized": []
},
{
"id": "23192350_T26",
"type": "GENE-N",
"text": [
"α1,3-fucosyltransferases"
],
"offsets": [
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674,
698
]
],
"normalized": []
},
{
"id": "23192350_T27",
"type": "GENE-Y",
"text": [
"FUT4"
],
"offsets": [
[
700,
704
]
],
"normalized": []
},
{
"id": "23192350_T28",
"type": "GENE-Y",
"text": [
"FUT7"
],
"offsets": [
[
706,
710
]
],
"normalized": []
},
{
"id": "23192350_T29",
"type": "GENE-Y",
"text": [
"FUT9"
],
"offsets": [
[
716,
720
]
],
"normalized": []
},
{
"id": "23192350_T30",
"type": "GENE-N",
"text": [
"selectin"
],
"offsets": [
[
725,
733
]
],
"normalized": []
},
{
"id": "23192350_T31",
"type": "GENE-N",
"text": [
"L-, E-, and P-selectin"
],
"offsets": [
[
826,
848
]
],
"normalized": []
},
{
"id": "23192350_T32",
"type": "GENE-Y",
"text": [
"Fut4"
],
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930,
934
]
],
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},
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"type": "GENE-Y",
"text": [
"Fut7"
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939,
943
]
],
"normalized": []
},
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"id": "23192350_T34",
"type": "GENE-Y",
"text": [
"FUT7"
],
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[
1009,
1013
]
],
"normalized": []
},
{
"id": "23192350_T35",
"type": "GENE-Y",
"text": [
"FUT4"
],
"offsets": [
[
1038,
1042
]
],
"normalized": []
},
{
"id": "23192350_T36",
"type": "GENE-N",
"text": [
"selectin"
],
"offsets": [
[
1054,
1062
]
],
"normalized": []
},
{
"id": "23192350_T37",
"type": "GENE-N",
"text": [
"P-selectin glycoprotein ligand-1"
],
"offsets": [
[
1101,
1133
]
],
"normalized": []
},
{
"id": "23192350_T38",
"type": "GENE-N",
"text": [
"α1,3-fucosyltransferases"
],
"offsets": [
[
10,
34
]
],
"normalized": []
},
{
"id": "23192350_T39",
"type": "GENE-Y",
"text": [
"FUT9"
],
"offsets": [
[
74,
78
]
],
"normalized": []
},
{
"id": "23192350_T40",
"type": "GENE-Y",
"text": [
"E-selectin"
],
"offsets": [
[
93,
103
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23192350_0",
"type": "PART-OF",
"arg1_id": "23192350_T2",
"arg2_id": "23192350_T37",
"normalized": []
}
] |
23117207 | 23117207 | [
{
"id": "23117207_title",
"type": "title",
"text": [
"The S349T mutation of SQSTM1 links Keap1/Nrf2 signalling to Paget's disease of bone."
],
"offsets": [
[
0,
84
]
]
},
{
"id": "23117207_abstract",
"type": "abstract",
"text": [
"Mutations affecting the Sequestosome 1 (SQSTM1) gene commonly occur in patients with the skeletal disorder Paget's disease of bone (PDB), a condition characterised by defective osteoclast differentiation and function. Whilst most mutations cluster within the ubiquitin-associated (UBA) domain of the SQSTM1 protein, and are associated with dysregulated NFκB signalling, several non-UBA domain mutations have also been identified. Keap1 is a SQSTM1-interacting protein that regulates the levels and activity of the Nrf2 transcription factor. This in turn controls the expression of numerous cytoprotective genes that contribute to the cell's capacity to defend itself against chemical and oxidative stress, through binding to the antioxidant response element (ARE). The PDB-associated S349T mutation maps to the Keap1-interacting region (KIR) of SQSTM1, however the effects of PDB mutant SQSTM1 on Keap1 function have not been investigated. Here we show that unlike other SQSTM1 mutations, the S349T mutation results in neither impaired ubiquitin-binding function in pull-down assays, nor dysregulated NFκB signalling in luciferase reporter assays. Keap1 is expressed in differentiating osteoclast-like cells and the S349T mutation selectively impairs the SQSTM1-Keap1 interaction in co-immunoprecipitations, which molecular modelling indicates results from effects on critical hydrogen bonds required to stabilise the KIR-Keap1 complex. Further, S349T mutant SQSTM1, but not other PDB-associated mutants, showed reduced ability to activate Nrf2 signalling as assessed by ARE-luciferase reporter assays. Thus, SQSTM1-mediated dysregulation of the Keap1-Nrf2 axis, which could potentially lead to aberrant production of oxidative response genes, may contribute to disease aetiology in a subset of PDB patients."
],
"offsets": [
[
85,
1893
]
]
}
] | [
{
"id": "23117207_T1",
"type": "CHEMICAL",
"text": [
"hydrogen"
],
"offsets": [
[
1462,
1470
]
],
"normalized": []
},
{
"id": "23117207_T2",
"type": "GENE-N",
"text": [
"ubiquitin"
],
"offsets": [
[
1121,
1130
]
],
"normalized": []
},
{
"id": "23117207_T3",
"type": "GENE-N",
"text": [
"NFκB"
],
"offsets": [
[
1186,
1190
]
],
"normalized": []
},
{
"id": "23117207_T4",
"type": "GENE-Y",
"text": [
"Keap1"
],
"offsets": [
[
1233,
1238
]
],
"normalized": []
},
{
"id": "23117207_T5",
"type": "GENE-N",
"text": [
"S349T"
],
"offsets": [
[
1301,
1306
]
],
"normalized": []
},
{
"id": "23117207_T6",
"type": "GENE-Y",
"text": [
"SQSTM1"
],
"offsets": [
[
1340,
1346
]
],
"normalized": []
},
{
"id": "23117207_T7",
"type": "GENE-Y",
"text": [
"Keap1"
],
"offsets": [
[
1347,
1352
]
],
"normalized": []
},
{
"id": "23117207_T8",
"type": "GENE-N",
"text": [
"KIR"
],
"offsets": [
[
1503,
1506
]
],
"normalized": []
},
{
"id": "23117207_T9",
"type": "GENE-Y",
"text": [
"Keap1"
],
"offsets": [
[
1507,
1512
]
],
"normalized": []
},
{
"id": "23117207_T10",
"type": "GENE-N",
"text": [
"S349T"
],
"offsets": [
[
1531,
1536
]
],
"normalized": []
},
{
"id": "23117207_T11",
"type": "GENE-Y",
"text": [
"SQSTM1"
],
"offsets": [
[
1544,
1550
]
],
"normalized": []
},
{
"id": "23117207_T12",
"type": "GENE-Y",
"text": [
"Nrf2"
],
"offsets": [
[
1625,
1629
]
],
"normalized": []
},
{
"id": "23117207_T13",
"type": "GENE-N",
"text": [
"ARE"
],
"offsets": [
[
1656,
1659
]
],
"normalized": []
},
{
"id": "23117207_T14",
"type": "GENE-Y",
"text": [
"SQSTM1"
],
"offsets": [
[
1694,
1700
]
],
"normalized": []
},
{
"id": "23117207_T15",
"type": "GENE-Y",
"text": [
"Keap1"
],
"offsets": [
[
1731,
1736
]
],
"normalized": []
},
{
"id": "23117207_T16",
"type": "GENE-Y",
"text": [
"Nrf2"
],
"offsets": [
[
1737,
1741
]
],
"normalized": []
},
{
"id": "23117207_T17",
"type": "GENE-Y",
"text": [
"Sequestosome 1"
],
"offsets": [
[
109,
123
]
],
"normalized": []
},
{
"id": "23117207_T18",
"type": "GENE-N",
"text": [
"ubiquitin-associated (UBA) domain"
],
"offsets": [
[
344,
377
]
],
"normalized": []
},
{
"id": "23117207_T19",
"type": "GENE-Y",
"text": [
"SQSTM1"
],
"offsets": [
[
385,
391
]
],
"normalized": []
},
{
"id": "23117207_T20",
"type": "GENE-N",
"text": [
"NFκB"
],
"offsets": [
[
438,
442
]
],
"normalized": []
},
{
"id": "23117207_T21",
"type": "GENE-N",
"text": [
"UBA domain"
],
"offsets": [
[
467,
477
]
],
"normalized": []
},
{
"id": "23117207_T22",
"type": "GENE-Y",
"text": [
"SQSTM1"
],
"offsets": [
[
125,
131
]
],
"normalized": []
},
{
"id": "23117207_T23",
"type": "GENE-Y",
"text": [
"Keap1"
],
"offsets": [
[
515,
520
]
],
"normalized": []
},
{
"id": "23117207_T24",
"type": "GENE-Y",
"text": [
"SQSTM1"
],
"offsets": [
[
526,
532
]
],
"normalized": []
},
{
"id": "23117207_T25",
"type": "GENE-Y",
"text": [
"Nrf2"
],
"offsets": [
[
599,
603
]
],
"normalized": []
},
{
"id": "23117207_T26",
"type": "GENE-N",
"text": [
"antioxidant response element"
],
"offsets": [
[
814,
842
]
],
"normalized": []
},
{
"id": "23117207_T27",
"type": "GENE-N",
"text": [
"ARE"
],
"offsets": [
[
844,
847
]
],
"normalized": []
},
{
"id": "23117207_T28",
"type": "GENE-N",
"text": [
"S349T"
],
"offsets": [
[
869,
874
]
],
"normalized": []
},
{
"id": "23117207_T29",
"type": "GENE-N",
"text": [
"Keap1-interacting region"
],
"offsets": [
[
896,
920
]
],
"normalized": []
},
{
"id": "23117207_T30",
"type": "GENE-N",
"text": [
"KIR"
],
"offsets": [
[
922,
925
]
],
"normalized": []
},
{
"id": "23117207_T31",
"type": "GENE-Y",
"text": [
"SQSTM1"
],
"offsets": [
[
930,
936
]
],
"normalized": []
},
{
"id": "23117207_T32",
"type": "GENE-Y",
"text": [
"SQSTM1"
],
"offsets": [
[
972,
978
]
],
"normalized": []
},
{
"id": "23117207_T33",
"type": "GENE-Y",
"text": [
"Keap1"
],
"offsets": [
[
982,
987
]
],
"normalized": []
},
{
"id": "23117207_T34",
"type": "GENE-Y",
"text": [
"SQSTM1"
],
"offsets": [
[
1056,
1062
]
],
"normalized": []
},
{
"id": "23117207_T35",
"type": "GENE-N",
"text": [
"S349T"
],
"offsets": [
[
1078,
1083
]
],
"normalized": []
},
{
"id": "23117207_T36",
"type": "GENE-Y",
"text": [
"SQSTM1"
],
"offsets": [
[
22,
28
]
],
"normalized": []
},
{
"id": "23117207_T37",
"type": "GENE-Y",
"text": [
"Keap1"
],
"offsets": [
[
35,
40
]
],
"normalized": []
},
{
"id": "23117207_T38",
"type": "GENE-Y",
"text": [
"Nrf2"
],
"offsets": [
[
41,
45
]
],
"normalized": []
},
{
"id": "23117207_T39",
"type": "GENE-N",
"text": [
"S349T"
],
"offsets": [
[
4,
9
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23117207_0",
"type": "PART-OF",
"arg1_id": "23117207_T1",
"arg2_id": "23117207_T8",
"normalized": []
},
{
"id": "23117207_1",
"type": "PART-OF",
"arg1_id": "23117207_T1",
"arg2_id": "23117207_T9",
"normalized": []
}
] |
23526814 | 23526814 | [
{
"id": "23526814_title",
"type": "title",
"text": [
"tert-Butylcarbamate-Containing Histone Deacetylase Inhibitors: Apoptosis Induction, Cytodifferentiation, and Antiproliferative Activities in Cancer Cells."
],
"offsets": [
[
0,
154
]
]
},
{
"id": "23526814_abstract",
"type": "abstract",
"text": [
"Herein we report novel pyrrole- and benzene-based hydroxamates (8, 10) and 2'-aminoanilides (9, 11) bearing the tert-butylcarbamate group at the CAP moiety as histone deacetylase (HDAC) inhibitors. Compounds 8 b and 10 c selectively inhibited HDAC6 at the nanomolar level, whereas the other hydroxamates effected an increase in acetyl-α-tubulin levels in human acute myeloid leukemia U937 cells. In the same cell line, compounds 8 b and 10 c elicited 18.4 and 21.4 % apoptosis, respectively (SAHA: 16.9 %), and the pyrrole anilide 9 c displayed the highest cytodifferentiating effect (90.9 %). In tests against a wide range of various cancer cell lines to determine its antiproliferative effects, compound 10 c exhibited growth inhibition from sub-micromolar (neuroblastoma LAN-5 and SH-SY5Y cells, chronic myeloid leukemia K562 cells) to low-micromolar (lung H1299 and A549, colon HCT116 and HT29 cancer cells) concentrations. In HT29 cells, 10 c increased histone H3 acetylation, and decreased the colony-forming potential of the cancer cells by up to 60 %."
],
"offsets": [
[
155,
1214
]
]
}
] | [
{
"id": "23526814_T1",
"type": "CHEMICAL",
"text": [
"tert-butylcarbamate"
],
"offsets": [
[
267,
286
]
],
"normalized": []
},
{
"id": "23526814_T2",
"type": "CHEMICAL",
"text": [
"pyrrole"
],
"offsets": [
[
178,
185
]
],
"normalized": []
},
{
"id": "23526814_T3",
"type": "CHEMICAL",
"text": [
"hydroxamates"
],
"offsets": [
[
446,
458
]
],
"normalized": []
},
{
"id": "23526814_T4",
"type": "CHEMICAL",
"text": [
"benzene"
],
"offsets": [
[
191,
198
]
],
"normalized": []
},
{
"id": "23526814_T5",
"type": "CHEMICAL",
"text": [
"SAHA"
],
"offsets": [
[
647,
651
]
],
"normalized": []
},
{
"id": "23526814_T6",
"type": "CHEMICAL",
"text": [
"hydroxamates"
],
"offsets": [
[
205,
217
]
],
"normalized": []
},
{
"id": "23526814_T7",
"type": "CHEMICAL",
"text": [
"pyrrole anilide"
],
"offsets": [
[
670,
685
]
],
"normalized": []
},
{
"id": "23526814_T8",
"type": "CHEMICAL",
"text": [
"2'-aminoanilides"
],
"offsets": [
[
230,
246
]
],
"normalized": []
},
{
"id": "23526814_T9",
"type": "CHEMICAL",
"text": [
"tert-Butylcarbamate"
],
"offsets": [
[
0,
19
]
],
"normalized": []
},
{
"id": "23526814_T10",
"type": "GENE-N",
"text": [
"histone deacetylase"
],
"offsets": [
[
314,
333
]
],
"normalized": []
},
{
"id": "23526814_T11",
"type": "GENE-N",
"text": [
"HDAC"
],
"offsets": [
[
335,
339
]
],
"normalized": []
},
{
"id": "23526814_T12",
"type": "GENE-Y",
"text": [
"HDAC6"
],
"offsets": [
[
398,
403
]
],
"normalized": []
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15240758 | 15240758 | [
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"GABA-induced currents have been characterized in isolated horizontal cells from lower vertebrates but not in mammalian horizontal cells. Therefore horizontal cells were isolated after enzymatical and mechanical dissociation of the adult mouse retina and visually identified. We recorded from horizontal cell bodies using the whole cell and outside-out configuration of the patch-clamp technique. Extracellular application of GABA induced inward currents carried by chloride ions. GABA-evoked currents were completely and reversibly blocked by the competitive GABAA receptor antagonist bicuculline (IC50 = 1.7 microM), indicating expression of GABAA but not GABAC receptors. Their affinity for GABA was moderate (EC50 = 30 microM), and the Hill coefficient was 1.3, corresponding to two GABA binding sites. GABA responses were partially reduced by picrotoxin with differential effects on peak and steady-state current values. Zinc blocked the GABA response with an IC50 value of 7.3 microM in a noncompetitive manner. Furthermore, GABA receptors of horizontal cells were modulated by extracellular application of diazepam, zolpidem, methyl 6,7-dimethoxy-4-ethyl-beta-carboxylate, pentobarbital, and alphaxalone, thus showing typical pharmacological properties of CNS GABAA receptors. GABA-evoked single-channel currents were characterized by a main conductance state of 29.8 pS and two subconductance states (20.2 and 10.8 pS, respectively). Kinetic analysis of single-channel events within bursts revealed similar mean open and closed times for the main conductance and the 20.2-pS subconductance state, resulting in open probabilities of 44.6 and 42.7%, respectively. The ratio of open to closed times, however, was significantly different for the 10.8-pS subconductance state with an open probability of 57.2%."
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"GABA"
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