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11986668 | 11986668 | [
{
"id": "11986668_title",
"type": "title",
"text": [
"Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice."
],
"offsets": [
[
0,
106
]
]
},
{
"id": "11986668_abstract",
"type": "abstract",
"text": [
"Minocycline mediates neuroprotection in experimental models of neurodegeneration. It inhibits the activity of caspase-1, caspase-3, inducible form of nitric oxide synthetase (iNOS) and p38 mitogen-activated protein kinase (MAPK). Although minocycline does not directly inhibit these enzymes, the effects may result from interference with upstream mechanisms resulting in their secondary activation. Because the above-mentioned factors are important in amyotrophic lateral sclerosis (ALS), we tested minocycline in mice with ALS. Here we report that minocycline delays disease onset and extends survival in ALS mice. Given the broad efficacy of minocycline, understanding its mechanisms of action is of great importance. We find that minocycline inhibits mitochondrial permeability-transition-mediated cytochrome c release. Minocycline-mediated inhibition of cytochrome c release is demonstrated in vivo, in cells, and in isolated mitochondria. Understanding the mechanism of action of minocycline will assist in the development and testing of more powerful and effective analogues. Because of the safety record of minocycline, and its ability to penetrate the blood-brain barrier, this drug may be a novel therapy for ALS."
],
"offsets": [
[
107,
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]
]
}
] | [
{
"id": "11986668_T1",
"type": "CHEMICAL",
"text": [
"Minocycline"
],
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[
107,
118
]
],
"normalized": []
},
{
"id": "11986668_T2",
"type": "CHEMICAL",
"text": [
"minocycline"
],
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[
1221,
1232
]
],
"normalized": []
},
{
"id": "11986668_T3",
"type": "CHEMICAL",
"text": [
"nitric oxide"
],
"offsets": [
[
257,
269
]
],
"normalized": []
},
{
"id": "11986668_T4",
"type": "CHEMICAL",
"text": [
"minocycline"
],
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[
346,
357
]
],
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},
{
"id": "11986668_T5",
"type": "CHEMICAL",
"text": [
"minocycline"
],
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[
606,
617
]
],
"normalized": []
},
{
"id": "11986668_T6",
"type": "CHEMICAL",
"text": [
"minocycline"
],
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[
656,
667
]
],
"normalized": []
},
{
"id": "11986668_T7",
"type": "CHEMICAL",
"text": [
"minocycline"
],
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[
751,
762
]
],
"normalized": []
},
{
"id": "11986668_T8",
"type": "CHEMICAL",
"text": [
"minocycline"
],
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[
840,
851
]
],
"normalized": []
},
{
"id": "11986668_T9",
"type": "CHEMICAL",
"text": [
"Minocycline"
],
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[
930,
941
]
],
"normalized": []
},
{
"id": "11986668_T10",
"type": "CHEMICAL",
"text": [
"minocycline"
],
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[
1092,
1103
]
],
"normalized": []
},
{
"id": "11986668_T11",
"type": "CHEMICAL",
"text": [
"Minocycline"
],
"offsets": [
[
0,
11
]
],
"normalized": []
},
{
"id": "11986668_T12",
"type": "GENE-Y",
"text": [
"caspase-1"
],
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[
217,
226
]
],
"normalized": []
},
{
"id": "11986668_T13",
"type": "GENE-Y",
"text": [
"caspase-3"
],
"offsets": [
[
228,
237
]
],
"normalized": []
},
{
"id": "11986668_T14",
"type": "GENE-Y",
"text": [
"inducible form of nitric oxide synthetase"
],
"offsets": [
[
239,
280
]
],
"normalized": []
},
{
"id": "11986668_T15",
"type": "GENE-Y",
"text": [
"iNOS"
],
"offsets": [
[
282,
286
]
],
"normalized": []
},
{
"id": "11986668_T16",
"type": "GENE-N",
"text": [
"p38"
],
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[
292,
295
]
],
"normalized": []
},
{
"id": "11986668_T17",
"type": "GENE-N",
"text": [
"mitogen-activated protein kinase"
],
"offsets": [
[
296,
328
]
],
"normalized": []
},
{
"id": "11986668_T18",
"type": "GENE-N",
"text": [
"MAPK"
],
"offsets": [
[
330,
334
]
],
"normalized": []
},
{
"id": "11986668_T19",
"type": "GENE-Y",
"text": [
"cytochrome c"
],
"offsets": [
[
908,
920
]
],
"normalized": []
},
{
"id": "11986668_T20",
"type": "GENE-Y",
"text": [
"cytochrome c"
],
"offsets": [
[
965,
977
]
],
"normalized": []
},
{
"id": "11986668_T21",
"type": "GENE-Y",
"text": [
"cytochrome c"
],
"offsets": [
[
21,
33
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "11986668_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "11986668_T11",
"arg2_id": "11986668_T21",
"normalized": []
},
{
"id": "11986668_1",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "11986668_T8",
"arg2_id": "11986668_T19",
"normalized": []
},
{
"id": "11986668_2",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "11986668_T9",
"arg2_id": "11986668_T20",
"normalized": []
}
] |
23353698 | 23353698 | [
{
"id": "23353698_title",
"type": "title",
"text": [
"ABT-737 resistance in B-cells isolated from chronic lymphocytic leukemia patients and leukemia cell lines is overcome by the pleiotropic kinase inhibitor quercetin through Mcl-1 down-regulation."
],
"offsets": [
[
0,
194
]
]
},
{
"id": "23353698_abstract",
"type": "abstract",
"text": [
"Chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in adult population and despite numerous studies, it is considered an incurable disease. Since CLL is characterized by overexpression of pro-survival Bcl-2 family members, treatments with their antagonists, such as ABT-737, represent a promising new therapeutic strategy. ABT-737 is a BH3 mimetic agent which binds Bcl-2, Bcl-XL and Bcl-w with high affinity, while weakly interacts with Mcl-1 and Bfl-1. Previous studies demonstrated that quercetin, a flavonoid naturally present in food and beverages, was able to sensitize B-cells isolated from CLL patients to apoptosis when associated with death ligands or fludarabine, through a mechanism involving Mcl-1 down-regulation. Here, we report that the association between ABT-737 and quercetin synergistically induces apoptosis in B-cells and in five leukemic cell lines (Combination Index <1). Peripheral blood mononuclear cell from healthy donors were not affected by quercetin treatment. The molecular pathways triggered by quercetin have been investigated in HPB-ALL cells, characterized by the highest resistance to both ABT-737 and quercetin when applied as single molecules, but highly sensitivity to the co-treatment. In this cell line, quercetin down-regulated Mcl-1 through the inhibition of PI3K/Akt signaling pathway, leading to Mcl-1 instability. The same mechanism was confirmed in B-cells. These results may open new clinical perspectives based on a translational approach in CLL therapy."
],
"offsets": [
[
195,
1721
]
]
}
] | [
{
"id": "23353698_T1",
"type": "CHEMICAL",
"text": [
"quercetin"
],
"offsets": [
[
1245,
1254
]
],
"normalized": []
},
{
"id": "23353698_T2",
"type": "CHEMICAL",
"text": [
"ABT-737"
],
"offsets": [
[
1344,
1351
]
],
"normalized": []
},
{
"id": "23353698_T3",
"type": "CHEMICAL",
"text": [
"quercetin"
],
"offsets": [
[
1356,
1365
]
],
"normalized": []
},
{
"id": "23353698_T4",
"type": "CHEMICAL",
"text": [
"quercetin"
],
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[
1463,
1472
]
],
"normalized": []
},
{
"id": "23353698_T5",
"type": "CHEMICAL",
"text": [
"ABT-737"
],
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[
483,
490
]
],
"normalized": []
},
{
"id": "23353698_T6",
"type": "CHEMICAL",
"text": [
"ABT-737"
],
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[
540,
547
]
],
"normalized": []
},
{
"id": "23353698_T7",
"type": "CHEMICAL",
"text": [
"quercetin"
],
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[
707,
716
]
],
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},
{
"id": "23353698_T8",
"type": "CHEMICAL",
"text": [
"flavonoid"
],
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[
720,
729
]
],
"normalized": []
},
{
"id": "23353698_T9",
"type": "CHEMICAL",
"text": [
"ABT-737"
],
"offsets": [
[
990,
997
]
],
"normalized": []
},
{
"id": "23353698_T10",
"type": "CHEMICAL",
"text": [
"quercetin"
],
"offsets": [
[
1002,
1011
]
],
"normalized": []
},
{
"id": "23353698_T11",
"type": "CHEMICAL",
"text": [
"quercetin"
],
"offsets": [
[
1188,
1197
]
],
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},
{
"id": "23353698_T12",
"type": "CHEMICAL",
"text": [
"ABT-737"
],
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[
0,
7
]
],
"normalized": []
},
{
"id": "23353698_T13",
"type": "CHEMICAL",
"text": [
"quercetin"
],
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[
154,
163
]
],
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},
{
"id": "23353698_T14",
"type": "GENE-Y",
"text": [
"Mcl-1"
],
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[
1488,
1493
]
],
"normalized": []
},
{
"id": "23353698_T15",
"type": "GENE-N",
"text": [
"PI3K"
],
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[
1520,
1524
]
],
"normalized": []
},
{
"id": "23353698_T16",
"type": "GENE-N",
"text": [
"Akt"
],
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[
1525,
1528
]
],
"normalized": []
},
{
"id": "23353698_T17",
"type": "GENE-Y",
"text": [
"Mcl-1"
],
"offsets": [
[
1559,
1564
]
],
"normalized": []
},
{
"id": "23353698_T18",
"type": "GENE-Y",
"text": [
"Bcl-2"
],
"offsets": [
[
418,
423
]
],
"normalized": []
},
{
"id": "23353698_T19",
"type": "GENE-Y",
"text": [
"Bcl-2"
],
"offsets": [
[
583,
588
]
],
"normalized": []
},
{
"id": "23353698_T20",
"type": "GENE-Y",
"text": [
"Bcl-XL"
],
"offsets": [
[
590,
596
]
],
"normalized": []
},
{
"id": "23353698_T21",
"type": "GENE-Y",
"text": [
"Bcl-w"
],
"offsets": [
[
601,
606
]
],
"normalized": []
},
{
"id": "23353698_T22",
"type": "GENE-Y",
"text": [
"Mcl-1"
],
"offsets": [
[
655,
660
]
],
"normalized": []
},
{
"id": "23353698_T23",
"type": "GENE-Y",
"text": [
"Bfl-1"
],
"offsets": [
[
665,
670
]
],
"normalized": []
},
{
"id": "23353698_T24",
"type": "GENE-Y",
"text": [
"Mcl-1"
],
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[
922,
927
]
],
"normalized": []
},
{
"id": "23353698_T25",
"type": "GENE-N",
"text": [
"pleiotropic kinase"
],
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[
125,
143
]
],
"normalized": []
},
{
"id": "23353698_T26",
"type": "GENE-Y",
"text": [
"Mcl-1"
],
"offsets": [
[
172,
177
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23353698_0",
"type": "INHIBITOR",
"arg1_id": "23353698_T13",
"arg2_id": "23353698_T25",
"normalized": []
},
{
"id": "23353698_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "23353698_T6",
"arg2_id": "23353698_T19",
"normalized": []
},
{
"id": "23353698_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "23353698_T6",
"arg2_id": "23353698_T20",
"normalized": []
},
{
"id": "23353698_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "23353698_T6",
"arg2_id": "23353698_T21",
"normalized": []
},
{
"id": "23353698_4",
"type": "INHIBITOR",
"arg1_id": "23353698_T4",
"arg2_id": "23353698_T15",
"normalized": []
},
{
"id": "23353698_5",
"type": "INHIBITOR",
"arg1_id": "23353698_T4",
"arg2_id": "23353698_T16",
"normalized": []
},
{
"id": "23353698_6",
"type": "ANTAGONIST",
"arg1_id": "23353698_T5",
"arg2_id": "23353698_T18",
"normalized": []
}
] |
17537059 | 17537059 | [
{
"id": "17537059_title",
"type": "title",
"text": [
"Plasma protein binding properties to immobilized heparin and heparin-albumin conjugate."
],
"offsets": [
[
0,
87
]
]
},
{
"id": "17537059_abstract",
"type": "abstract",
"text": [
"Selective adhesion of plasma proteins to immobilized heparin is considered to be beneficial regarding hemocompatibility of foreign materials in contact with blood. Prothrombin, thrombin, antithrombin III (AT3), and fibrinogen were selected for analysis in an experimental model. Biomolecular interaction analysis employing surface plasmon resonance was utilized to record and analyze their binding properties in real time. Biotinylated heparin, heparin-albumin conjugate, and albumin, respectively, were immobilized onto streptavidin-coated sensors as ligands. Prothrombin did not bind to any of the ligand surfaces and no specific binding of any of the plasma proteins to albumin was observed. Binding kinetics of thrombin to heparin and to heparin-albumin conjugate were calculated using two different methods. For heparin, identical K(D)(equilibrium dissociation constant) values of 61 x 10(-9) M were obtained with both methods. For the conjugate, only slightly different K(D) values of 111 x 10(-9) and 104 x 10(-9) M, respectively, were calculated. The affinity of thrombin toward the heparin-coated surface proved to be higher than its affinity toward the heparin conjugate. The binding pattern of AT3 to both heparin and heparin-albumin conjugate, although specific, was biphasic, possibly due to a conformational change during the binding process. Steady-state kinetic analysis revealed a K(D) value of 281 +/- 24 x 10(-9) M for the heparin surface. For the conjugate surface, a K(D) of 53 +/- 5 x 10(-9) M was calculated, indicating a higher affinity toward heparin-albumin conjugate. A high-affinity binding of fibrinogen to high-density surfaces of both heparin and the conjugate was observed. However, as binding to low-density surfaces was considerably reduced, specificity remained uncertain."
],
"offsets": [
[
88,
1895
]
]
}
] | [
{
"id": "17537059_T1",
"type": "GENE-Y",
"text": [
"thrombin"
],
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[
1159,
1167
]
],
"normalized": []
},
{
"id": "17537059_T2",
"type": "GENE-Y",
"text": [
"AT3"
],
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[
1293,
1296
]
],
"normalized": []
},
{
"id": "17537059_T3",
"type": "GENE-Y",
"text": [
"albumin"
],
"offsets": [
[
1325,
1332
]
],
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},
{
"id": "17537059_T4",
"type": "GENE-Y",
"text": [
"albumin"
],
"offsets": [
[
1664,
1671
]
],
"normalized": []
},
{
"id": "17537059_T5",
"type": "GENE-N",
"text": [
"fibrinogen"
],
"offsets": [
[
1710,
1720
]
],
"normalized": []
},
{
"id": "17537059_T6",
"type": "GENE-Y",
"text": [
"Prothrombin"
],
"offsets": [
[
252,
263
]
],
"normalized": []
},
{
"id": "17537059_T7",
"type": "GENE-Y",
"text": [
"thrombin"
],
"offsets": [
[
265,
273
]
],
"normalized": []
},
{
"id": "17537059_T8",
"type": "GENE-Y",
"text": [
"antithrombin III"
],
"offsets": [
[
275,
291
]
],
"normalized": []
},
{
"id": "17537059_T9",
"type": "GENE-Y",
"text": [
"AT3"
],
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[
293,
296
]
],
"normalized": []
},
{
"id": "17537059_T10",
"type": "GENE-N",
"text": [
"fibrinogen"
],
"offsets": [
[
303,
313
]
],
"normalized": []
},
{
"id": "17537059_T11",
"type": "GENE-Y",
"text": [
"albumin"
],
"offsets": [
[
541,
548
]
],
"normalized": []
},
{
"id": "17537059_T12",
"type": "GENE-Y",
"text": [
"albumin"
],
"offsets": [
[
564,
571
]
],
"normalized": []
},
{
"id": "17537059_T13",
"type": "GENE-Y",
"text": [
"Prothrombin"
],
"offsets": [
[
649,
660
]
],
"normalized": []
},
{
"id": "17537059_T14",
"type": "GENE-Y",
"text": [
"albumin"
],
"offsets": [
[
761,
768
]
],
"normalized": []
},
{
"id": "17537059_T15",
"type": "GENE-Y",
"text": [
"thrombin"
],
"offsets": [
[
803,
811
]
],
"normalized": []
},
{
"id": "17537059_T16",
"type": "GENE-Y",
"text": [
"albumin"
],
"offsets": [
[
838,
845
]
],
"normalized": []
},
{
"id": "17537059_T17",
"type": "GENE-Y",
"text": [
"albumin"
],
"offsets": [
[
69,
76
]
],
"normalized": []
}
] | [] | [] | [] |
23017408 | 23017408 | [
{
"id": "23017408_title",
"type": "title",
"text": [
"Phenylalanine ammonia lyase (PAL) enzyme activity and antioxidant properties of some cyanobacteria isolates."
],
"offsets": [
[
0,
108
]
]
},
{
"id": "23017408_abstract",
"type": "abstract",
"text": [
"In the present study, six cyanobacteria isolates were evaluated for the PAL enzyme activity, and their methanol extracts were assessed for the total phenolic amount and other antioxidant parameters. Synechocystis sp. BASO444 and Synechocystis sp. BASO673 isolates with high levels of total phenols (66.0±1.2μg/mg, 78.1±1.8μg/mg, respectively) also showed high levels of PAL activities (20.5±3.1U/mg protein, 17.2±2.3U/mg protein, respectively) and strong antioxidant activities. To understand the effect of l-phenylalanine (l-phe) on the PAL activity, total phenolic amount, and phenolic constituents, isolates were evaluated with 100mg/l l-phe. While PAL activities exhibited no significant change with l-phe addition, total phenolic amount of the isolates significantly increased. HPLC analysis revealed gallic acid, trans-cinnamic acid, p-coumaric acid, and ferulic acid as the main compounds. Results suggested that the two isolate mights be an important source for the l-phe inducible phenolic compounds."
],
"offsets": [
[
109,
1118
]
]
}
] | [
{
"id": "23017408_T1",
"type": "CHEMICAL",
"text": [
"methanol"
],
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[
212,
220
]
],
"normalized": []
},
{
"id": "23017408_T2",
"type": "CHEMICAL",
"text": [
"phenolic"
],
"offsets": [
[
258,
266
]
],
"normalized": []
},
{
"id": "23017408_T3",
"type": "CHEMICAL",
"text": [
"phenols"
],
"offsets": [
[
399,
406
]
],
"normalized": []
},
{
"id": "23017408_T4",
"type": "CHEMICAL",
"text": [
"l-phenylalanine"
],
"offsets": [
[
616,
631
]
],
"normalized": []
},
{
"id": "23017408_T5",
"type": "CHEMICAL",
"text": [
"l-phe"
],
"offsets": [
[
633,
638
]
],
"normalized": []
},
{
"id": "23017408_T6",
"type": "CHEMICAL",
"text": [
"phenolic"
],
"offsets": [
[
667,
675
]
],
"normalized": []
},
{
"id": "23017408_T7",
"type": "CHEMICAL",
"text": [
"phenolic"
],
"offsets": [
[
688,
696
]
],
"normalized": []
},
{
"id": "23017408_T8",
"type": "CHEMICAL",
"text": [
"l-phe"
],
"offsets": [
[
748,
753
]
],
"normalized": []
},
{
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"PAL"
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}
] | [] | [] | [
{
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},
{
"id": "23017408_1",
"type": "INDIRECT-UPREGULATOR",
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"arg2_id": "23017408_T20",
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}
] |
1346768 | 1346768 | [
{
"id": "1346768_title",
"type": "title",
"text": [
"Subtypes of alpha 1- and alpha 2-adrenergic receptors."
],
"offsets": [
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0,
54
]
]
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{
"id": "1346768_abstract",
"type": "abstract",
"text": [
"The adrenergic receptors are members of the superfamily of G protein-coupled receptors. There are three major types of adrenergic receptors: alpha 1, alpha 2, and beta. Each of these three major types can be divided into three subtypes. Within the alpha 1-adrenergic receptors, alpha 1A and alpha 1B subtypes have been defined pharmacologically on the basis of reversible antagonists, such as WB4101 and phentolamine, and the irreversible antagonist chloroethylclonidine. In at least some tissues the mechanism of action of the alpha 1A subtype is related to activation of a calcium channel, whereas the alpha 1B receptor exerts its effect through the second messenger inositol trisphosphate. Both of these receptor subtypes as well as a third, the alpha 1C, have been identified by molecular cloning. Three pharmacological subtypes of the alpha 2-adrenergic receptor have also been identified. Prototypic tissues and cell lines in continuous culture have been developed for each of these subtypes, which facilitated their study. The definition of the alpha 2 subtypes has been based on radioligand binding data and more limited functional data. All three subtypes have been shown to inhibit the activation of adenylate cyclase and thus reduce the levels of cAMP. Three alpha 2-adrenergic receptor subtypes have been identified by molecular cloning in both the human and rat species. There is reasonable agreement between the pharmacological identified subtypes and those identified by molecular cloning."
],
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55,
1559
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]
}
] | [
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"id": "1346768_T1",
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1265,
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]
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"id": "1346768_T2",
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"cAMP"
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1313,
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]
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"id": "1346768_T3",
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"WB4101"
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448,
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]
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"id": "1346768_T4",
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"text": [
"phentolamine"
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459,
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]
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"id": "1346768_T5",
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"chloroethylclonidine"
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505,
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]
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"id": "1346768_T6",
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"calcium"
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630,
637
]
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"id": "1346768_T7",
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"inositol trisphosphate"
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724,
746
]
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"id": "1346768_T8",
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"adrenergic receptors: alpha 1, alpha 2, and beta"
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174,
222
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"id": "1346768_T9",
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1265,
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"id": "1346768_T11",
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]
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"id": "1346768_T12",
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"id": "1346768_T13",
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"calcium channel"
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630,
645
]
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"id": "1346768_T14",
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114,
141
]
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"alpha 1- and alpha 2-adrenergic receptors"
],
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12,
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]
],
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}
] | [] | [] | [
{
"id": "1346768_0",
"type": "PRODUCT-OF",
"arg1_id": "1346768_T2",
"arg2_id": "1346768_T9",
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}
] |
11299519 | 11299519 | [
{
"id": "11299519_title",
"type": "title",
"text": [
"Mutations in the follicle-stimulating hormone-beta (FSH beta) and FSH receptor genes in mice and humans."
],
"offsets": [
[
0,
104
]
]
},
{
"id": "11299519_abstract",
"type": "abstract",
"text": [
"Follicle-stimulating hormone (FSH), a dimeric glycoprotein synthesized in the anterior pituitary gland, is important for the production of sex steroids and gametes. FSH-beta (FSH beta) and FSH receptor (FSHR) knockout mice display impaired ovarian follicular development and infertility in females and small testes, oligospermia, and fertility in males. Humans with FSH beta gene mutations tend to have a more severe phenotype than those with FSHR gene mutations, although infertility and varying degrees of impaired sex steroid production occur in both types of mutations. Data from human and mouse mutations in the FSH beta and FSHR genes suggest that FSH is necessary for normal pubertal development and fertility in males and females."
],
"offsets": [
[
105,
843
]
]
}
] | [
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"id": "11299519_T1",
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"steroids"
],
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248,
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]
],
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"id": "11299519_T2",
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"steroid"
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626,
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]
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},
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"id": "11299519_T3",
"type": "GENE-N",
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105,
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]
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},
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"id": "11299519_T4",
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270,
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"id": "11299519_T5",
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280,
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]
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},
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"id": "11299519_T6",
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"FSH receptor"
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294,
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]
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},
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"id": "11299519_T7",
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"FSHR"
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308,
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]
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"id": "11299519_T8",
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"FSH"
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135,
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]
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"id": "11299519_T9",
"type": "GENE-Y",
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"FSH beta"
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471,
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]
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"id": "11299519_T10",
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"FSHR"
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548,
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]
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"id": "11299519_T11",
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"FSH beta"
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722,
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]
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},
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"id": "11299519_T12",
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"FSHR"
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735,
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]
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},
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"id": "11299519_T13",
"type": "GENE-N",
"text": [
"FSH"
],
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759,
762
]
],
"normalized": []
},
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"id": "11299519_T14",
"type": "GENE-N",
"text": [
"follicle-stimulating hormone-beta"
],
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17,
50
]
],
"normalized": []
},
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"id": "11299519_T15",
"type": "GENE-N",
"text": [
"FSH beta"
],
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[
52,
60
]
],
"normalized": []
},
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"id": "11299519_T16",
"type": "GENE-N",
"text": [
"FSH receptor"
],
"offsets": [
[
66,
78
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "11299519_0",
"type": "PRODUCT-OF",
"arg1_id": "11299519_T1",
"arg2_id": "11299519_T8",
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},
{
"id": "11299519_1",
"type": "PRODUCT-OF",
"arg1_id": "11299519_T1",
"arg2_id": "11299519_T3",
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},
{
"id": "11299519_2",
"type": "PRODUCT-OF",
"arg1_id": "11299519_T2",
"arg2_id": "11299519_T9",
"normalized": []
}
] |
23468082 | 23468082 | [
{
"id": "23468082_title",
"type": "title",
"text": [
"Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models."
],
"offsets": [
[
0,
152
]
]
},
{
"id": "23468082_abstract",
"type": "abstract",
"text": [
"PURPOSE: Activating mutations in FGFR2 have been identified as potential therapeutic targets in endometrial cancer, typically occurring alongside genetic alterations that disrupt the mTOR pathway, such as PTEN loss. These observations suggest that the mTOR pathway may act in concert with oncogenic FGFR2 to drive endometrial cancer growth in a subset of patients. The aim of this study was to examine the therapeutic potential of a rational drug combination based on the simultaneous targeting of mutant-FGFR2 and mTOR-driven signaling pathways in endometrial cancer cells. METHODS: Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. Ridaforolimus is a selective inhibitor of mTOR that has demonstrated positive clinical activity in endometrial cancer. The combinatorial effects of ponatinib and ridaforolimus on growth of endometrial cancer models, and their modes of action, were evaluated in vitro and in vivo. RESULTS: The combination of ponatinib and ridaforolimus had a synergistic effect on the in vitro growth of endometrial lines bearing an activating FGFR2 mutation, irrespective of PTEN status. Concomitant inhibition of both FGFR2 and mTOR signaling pathways was observed, with simultaneous blockade resulting in enhanced cell cycle arrest. Ponatinib and ridaforolimus each demonstrated inhibition of tumor growth in vivo, but dual inhibition by the combination of agents resulted in superior efficacy and induced tumor regression in an endometrial xenograft. CONCLUSIONS: These encouraging preclinical findings suggest the inhibition of both FGFR2 and mTOR by the ponatinib-ridaforolimus combination may provide a new therapeutic strategy to treat advanced endometrial cancers with dual pathway dysregulation."
],
"offsets": [
[
153,
1934
]
]
}
] | [
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"id": "23468082_T1",
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"ponatinib"
],
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[
1154,
1163
]
],
"normalized": []
},
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"id": "23468082_T2",
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"ridaforolimus"
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]
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"id": "23468082_T3",
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1465,
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]
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"id": "23468082_T4",
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]
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"id": "23468082_T5",
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"ponatinib"
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1789,
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]
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"id": "23468082_T6",
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]
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737,
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"id": "23468082_T8",
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"id": "23468082_T10",
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"ridaforolimus"
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1008,
1021
]
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"id": "23468082_T11",
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"ponatinib"
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40,
49
]
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},
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"id": "23468082_T12",
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54,
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]
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},
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"id": "23468082_T13",
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"FGFR2"
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1273,
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]
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},
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1305,
1309
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"id": "23468082_T15",
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1349,
1354
]
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},
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1359,
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"id": "23468082_T17",
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1767,
1772
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"mTOR"
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336,
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]
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},
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"id": "23468082_T20",
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"PTEN"
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358,
362
]
],
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},
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"id": "23468082_T21",
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"mTOR"
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405,
409
]
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},
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"id": "23468082_T22",
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"FGFR2"
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452,
457
]
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"id": "23468082_T23",
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"FGFR2"
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186,
191
]
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},
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"id": "23468082_T24",
"type": "GENE-Y",
"text": [
"FGFR2"
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[
658,
663
]
],
"normalized": []
},
{
"id": "23468082_T25",
"type": "GENE-Y",
"text": [
"mTOR-"
],
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[
668,
673
]
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"normalized": []
},
{
"id": "23468082_T26",
"type": "GENE-N",
"text": [
"kinase"
],
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[
772,
778
]
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},
{
"id": "23468082_T27",
"type": "GENE-N",
"text": [
"FGFR"
],
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[
833,
837
]
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},
{
"id": "23468082_T28",
"type": "GENE-Y",
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"mTOR"
],
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[
888,
892
]
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},
{
"id": "23468082_T29",
"type": "GENE-Y",
"text": [
"FGFR2"
],
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[
113,
118
]
],
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},
{
"id": "23468082_T30",
"type": "GENE-Y",
"text": [
"FGFR2"
],
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[
22,
27
]
],
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},
{
"id": "23468082_T31",
"type": "GENE-Y",
"text": [
"mTOR"
],
"offsets": [
[
32,
36
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23468082_0",
"type": "INHIBITOR",
"arg1_id": "23468082_T7",
"arg2_id": "23468082_T26",
"normalized": []
},
{
"id": "23468082_1",
"type": "INHIBITOR",
"arg1_id": "23468082_T7",
"arg2_id": "23468082_T27",
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},
{
"id": "23468082_2",
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},
{
"id": "23468082_3",
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"arg2_id": "23468082_T17",
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},
{
"id": "23468082_4",
"type": "INHIBITOR",
"arg1_id": "23468082_T5",
"arg2_id": "23468082_T18",
"normalized": []
},
{
"id": "23468082_5",
"type": "INHIBITOR",
"arg1_id": "23468082_T6",
"arg2_id": "23468082_T17",
"normalized": []
},
{
"id": "23468082_6",
"type": "INHIBITOR",
"arg1_id": "23468082_T6",
"arg2_id": "23468082_T18",
"normalized": []
}
] |
23248200 | 23248200 | [
{
"id": "23248200_title",
"type": "title",
"text": [
"Drug-drug interactions between rosuvastatin and oral antidiabetic drugs occurring at the level of OATP1B1."
],
"offsets": [
[
0,
106
]
]
},
{
"id": "23248200_abstract",
"type": "abstract",
"text": [
"Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1*15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity. Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with oral antidiabetics in the clinic. The aim of this study was to investigate possible drug-drug interactions between these drugs at the level of OATP1B1 and OATP1B1*15. We generated human embryonic kidney (HEK)293 cells stably overexpressing OATP1B1 or OATP1B1*15 that showed similar protein expression levels of OATP1B1 and OATP1B1*15 at the cell membrane as measured by liquid chromatography-tandem mass spectrometry. In HEK-OATP1B1*15 cells, the V(max) for OATP1B1-mediated transport of E(2)17β-G (estradiol 17β-d-glucuronide) was decreased >60%, whereas K(m) values (Michaelis constant) were comparable. Uptake of rosuvastatin in HEK-OATP1B1 cells (K(m) 13.1 ± 0.43 μM) was nearly absent in HEK-OATP1B1*15 cells. Interestingly, several oral antidiabetics (glyburide, glimepiride, troglitazone, pioglitazone, glipizide, gliclazide, and tolbutamide), but not metformin, were identified as significant inhibitors of the OATP1B1-mediated transport of rosuvastatin. The IC(50) values for inhibition of E(2)17β-G uptake were similar between OATP1B1 and OATP1B1*15. In conclusion, these studies indicate that several oral antidiabetic drugs affect the OATP1B1-mediated uptake of rosuvastatin in vitro. The next step will be to translate these data to the clinical situation, as it remains to be established whether the studied oral antidiabetics indeed affect the clinical pharmacokinetic profile of rosuvastatin in patients."
],
"offsets": [
[
107,
1826
]
]
}
] | [
{
"id": "23248200_T1",
"type": "CHEMICAL",
"text": [
"glyburide"
],
"offsets": [
[
1164,
1173
]
],
"normalized": []
},
{
"id": "23248200_T2",
"type": "CHEMICAL",
"text": [
"glimepiride"
],
"offsets": [
[
1175,
1186
]
],
"normalized": []
},
{
"id": "23248200_T3",
"type": "CHEMICAL",
"text": [
"troglitazone"
],
"offsets": [
[
1188,
1200
]
],
"normalized": []
},
{
"id": "23248200_T4",
"type": "CHEMICAL",
"text": [
"pioglitazone"
],
"offsets": [
[
1202,
1214
]
],
"normalized": []
},
{
"id": "23248200_T5",
"type": "CHEMICAL",
"text": [
"glipizide"
],
"offsets": [
[
1216,
1225
]
],
"normalized": []
},
{
"id": "23248200_T6",
"type": "CHEMICAL",
"text": [
"gliclazide"
],
"offsets": [
[
1227,
1237
]
],
"normalized": []
},
{
"id": "23248200_T7",
"type": "CHEMICAL",
"text": [
"tolbutamide"
],
"offsets": [
[
1243,
1254
]
],
"normalized": []
},
{
"id": "23248200_T8",
"type": "CHEMICAL",
"text": [
"metformin"
],
"offsets": [
[
1265,
1274
]
],
"normalized": []
},
{
"id": "23248200_T9",
"type": "CHEMICAL",
"text": [
"rosuvastatin"
],
"offsets": [
[
1355,
1367
]
],
"normalized": []
},
{
"id": "23248200_T10",
"type": "CHEMICAL",
"text": [
"E(2)17β-G"
],
"offsets": [
[
1405,
1414
]
],
"normalized": []
},
{
"id": "23248200_T11",
"type": "CHEMICAL",
"text": [
"rosuvastatin"
],
"offsets": [
[
1580,
1592
]
],
"normalized": []
},
{
"id": "23248200_T12",
"type": "CHEMICAL",
"text": [
"rosuvastatin"
],
"offsets": [
[
1801,
1813
]
],
"normalized": []
},
{
"id": "23248200_T13",
"type": "CHEMICAL",
"text": [
"Rosuvastatin"
],
"offsets": [
[
329,
341
]
],
"normalized": []
},
{
"id": "23248200_T14",
"type": "CHEMICAL",
"text": [
"estradiol 17β-d-glucuronide"
],
"offsets": [
[
905,
932
]
],
"normalized": []
},
{
"id": "23248200_T15",
"type": "CHEMICAL",
"text": [
"rosuvastatin"
],
"offsets": [
[
1022,
1034
]
],
"normalized": []
},
{
"id": "23248200_T16",
"type": "CHEMICAL",
"text": [
"rosuvastatin"
],
"offsets": [
[
31,
43
]
],
"normalized": []
},
{
"id": "23248200_T17",
"type": "GENE-Y",
"text": [
"Organic anion-transporting polypeptide 1B1"
],
"offsets": [
[
107,
149
]
],
"normalized": []
},
{
"id": "23248200_T18",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
1325,
1332
]
],
"normalized": []
},
{
"id": "23248200_T19",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
237,
244
]
],
"normalized": []
},
{
"id": "23248200_T20",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
1443,
1450
]
],
"normalized": []
},
{
"id": "23248200_T21",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
1455,
1462
]
],
"normalized": []
},
{
"id": "23248200_T22",
"type": "GENE-N",
"text": [
"Asn130Asp"
],
"offsets": [
[
249,
258
]
],
"normalized": []
},
{
"id": "23248200_T23",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
1553,
1560
]
],
"normalized": []
},
{
"id": "23248200_T24",
"type": "GENE-N",
"text": [
"Val174Ala"
],
"offsets": [
[
263,
272
]
],
"normalized": []
},
{
"id": "23248200_T25",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
348,
355
]
],
"normalized": []
},
{
"id": "23248200_T26",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
549,
556
]
],
"normalized": []
},
{
"id": "23248200_T27",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
151,
158
]
],
"normalized": []
},
{
"id": "23248200_T28",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
561,
568
]
],
"normalized": []
},
{
"id": "23248200_T29",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
646,
653
]
],
"normalized": []
},
{
"id": "23248200_T30",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
657,
664
]
],
"normalized": []
},
{
"id": "23248200_T31",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
717,
724
]
],
"normalized": []
},
{
"id": "23248200_T32",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
729,
736
]
],
"normalized": []
},
{
"id": "23248200_T33",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
831,
838
]
],
"normalized": []
},
{
"id": "23248200_T34",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
864,
871
]
],
"normalized": []
},
{
"id": "23248200_T35",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
1042,
1049
]
],
"normalized": []
},
{
"id": "23248200_T36",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
1103,
1110
]
],
"normalized": []
},
{
"id": "23248200_T37",
"type": "GENE-Y",
"text": [
"OATP1B1"
],
"offsets": [
[
98,
105
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23248200_0",
"type": "SUBSTRATE",
"arg1_id": "23248200_T13",
"arg2_id": "23248200_T25",
"normalized": []
},
{
"id": "23248200_1",
"type": "SUBSTRATE",
"arg1_id": "23248200_T11",
"arg2_id": "23248200_T23",
"normalized": []
},
{
"id": "23248200_2",
"type": "SUBSTRATE",
"arg1_id": "23248200_T14",
"arg2_id": "23248200_T34",
"normalized": []
},
{
"id": "23248200_3",
"type": "SUBSTRATE",
"arg1_id": "23248200_T15",
"arg2_id": "23248200_T35",
"normalized": []
},
{
"id": "23248200_4",
"type": "INHIBITOR",
"arg1_id": "23248200_T1",
"arg2_id": "23248200_T18",
"normalized": []
},
{
"id": "23248200_5",
"type": "INHIBITOR",
"arg1_id": "23248200_T2",
"arg2_id": "23248200_T18",
"normalized": []
},
{
"id": "23248200_6",
"type": "INHIBITOR",
"arg1_id": "23248200_T3",
"arg2_id": "23248200_T18",
"normalized": []
},
{
"id": "23248200_7",
"type": "INHIBITOR",
"arg1_id": "23248200_T4",
"arg2_id": "23248200_T18",
"normalized": []
},
{
"id": "23248200_8",
"type": "INHIBITOR",
"arg1_id": "23248200_T5",
"arg2_id": "23248200_T18",
"normalized": []
},
{
"id": "23248200_9",
"type": "INHIBITOR",
"arg1_id": "23248200_T6",
"arg2_id": "23248200_T18",
"normalized": []
},
{
"id": "23248200_10",
"type": "INHIBITOR",
"arg1_id": "23248200_T7",
"arg2_id": "23248200_T18",
"normalized": []
},
{
"id": "23248200_11",
"type": "SUBSTRATE",
"arg1_id": "23248200_T9",
"arg2_id": "23248200_T18",
"normalized": []
},
{
"id": "23248200_12",
"type": "SUBSTRATE",
"arg1_id": "23248200_T10",
"arg2_id": "23248200_T20",
"normalized": []
},
{
"id": "23248200_13",
"type": "SUBSTRATE",
"arg1_id": "23248200_T10",
"arg2_id": "23248200_T21",
"normalized": []
}
] |
21262851 | 21262851 | [
{
"id": "21262851_title",
"type": "title",
"text": [
"Inhibition of recombinant L-type voltage-gated calcium channels by positive allosteric modulators of GABAA receptors."
],
"offsets": [
[
0,
117
]
]
},
{
"id": "21262851_abstract",
"type": "abstract",
"text": [
"Benzodiazepines (BDZs) depress neuronal excitability via positive allosteric modulation of inhibitory GABA(A) receptors (GABA(A)R). BDZs and other positive GABA(A)R modulators, including barbiturates, ethanol, and neurosteroids, can also inhibit L-type voltage-gated calcium channels (L-VGCCs), which could contribute to reduced neuronal excitability. Because neuronal L-VGCC function is up-regulated after long-term GABA(A)R modulator exposure, an interaction with L-VGCCs may also play a role in physical dependence. The current studies assessed the effects of BDZs (diazepam, flurazepam, and desalkylflurazepam), allopregnanolone, pentobarbital, and ethanol on whole-cell Ba(2+) currents through recombinant neuronal Ca(v)1.2 and Ca(v)1.3 L-VGCCs expressed with beta(3) and alpha(2)delta-1 in HEK293T cells. Allopregnanolone was the most potent inhibitor (IC(50), approximately 10 muM), followed by BDZs (IC(50), approximately 50 muM), pentobarbital (IC(50), 0.3-1 mM), and ethanol (IC(50), approximately 300 mM). Ca(v)1.3 channels were less sensitive to pentobarbital inhibition than Ca(v)1.2 channels, similar to dihydropyridine (DHP) L-VGCC antagonists. All GABA(A)R modulators induced a negative shift in the steady-state inactivation curve of Ca(v)1.3 channels, but only BDZs and pentobarbital induced a negative shift in Ca(v)1.2 channel inactivation. Mutation of the high-affinity DHP binding site (T1039Y and Q1043M) in Ca(v)1.2 channels reduced pentobarbital potency. Despite the structural similarity between benzothiazepines and BDZs, mutation of an amino acid important for diltiazem potency (I1150A) did not affect diazepam potency. Although L-VGCC inhibition by BDZs occurred at concentrations that are possibly too high to be clinically relevant and is not likely to play a role in the up-regulation of L-VGCCs during long-term treatment, pentobarbital and ethanol inhibited L-VGCCs at clinically relevant concentrations."
],
"offsets": [
[
118,
2057
]
]
}
] | [
{
"id": "21262851_T1",
"type": "CHEMICAL",
"text": [
"Benzodiazepines"
],
"offsets": [
[
118,
133
]
],
"normalized": []
},
{
"id": "21262851_T2",
"type": "CHEMICAL",
"text": [
"pentobarbital"
],
"offsets": [
[
1176,
1189
]
],
"normalized": []
},
{
"id": "21262851_T3",
"type": "CHEMICAL",
"text": [
"dihydropyridine"
],
"offsets": [
[
1236,
1251
]
],
"normalized": []
},
{
"id": "21262851_T4",
"type": "CHEMICAL",
"text": [
"DHP"
],
"offsets": [
[
1253,
1256
]
],
"normalized": []
},
{
"id": "21262851_T5",
"type": "CHEMICAL",
"text": [
"BDZs"
],
"offsets": [
[
1397,
1401
]
],
"normalized": []
},
{
"id": "21262851_T6",
"type": "CHEMICAL",
"text": [
"pentobarbital"
],
"offsets": [
[
1406,
1419
]
],
"normalized": []
},
{
"id": "21262851_T7",
"type": "CHEMICAL",
"text": [
"BDZs"
],
"offsets": [
[
250,
254
]
],
"normalized": []
},
{
"id": "21262851_T8",
"type": "CHEMICAL",
"text": [
"DHP"
],
"offsets": [
[
1509,
1512
]
],
"normalized": []
},
{
"id": "21262851_T9",
"type": "CHEMICAL",
"text": [
"pentobarbital"
],
"offsets": [
[
1575,
1588
]
],
"normalized": []
},
{
"id": "21262851_T10",
"type": "CHEMICAL",
"text": [
"benzothiazepines"
],
"offsets": [
[
1640,
1656
]
],
"normalized": []
},
{
"id": "21262851_T11",
"type": "CHEMICAL",
"text": [
"BDZs"
],
"offsets": [
[
1661,
1665
]
],
"normalized": []
},
{
"id": "21262851_T12",
"type": "CHEMICAL",
"text": [
"amino acid"
],
"offsets": [
[
1682,
1692
]
],
"normalized": []
},
{
"id": "21262851_T13",
"type": "CHEMICAL",
"text": [
"diltiazem"
],
"offsets": [
[
1707,
1716
]
],
"normalized": []
},
{
"id": "21262851_T14",
"type": "CHEMICAL",
"text": [
"diazepam"
],
"offsets": [
[
1749,
1757
]
],
"normalized": []
},
{
"id": "21262851_T15",
"type": "CHEMICAL",
"text": [
"BDZs"
],
"offsets": [
[
1797,
1801
]
],
"normalized": []
},
{
"id": "21262851_T16",
"type": "CHEMICAL",
"text": [
"BDZs"
],
"offsets": [
[
135,
139
]
],
"normalized": []
},
{
"id": "21262851_T17",
"type": "CHEMICAL",
"text": [
"pentobarbital"
],
"offsets": [
[
1975,
1988
]
],
"normalized": []
},
{
"id": "21262851_T18",
"type": "CHEMICAL",
"text": [
"barbiturates"
],
"offsets": [
[
305,
317
]
],
"normalized": []
},
{
"id": "21262851_T19",
"type": "CHEMICAL",
"text": [
"ethanol"
],
"offsets": [
[
319,
326
]
],
"normalized": []
},
{
"id": "21262851_T20",
"type": "CHEMICAL",
"text": [
"neurosteroids"
],
"offsets": [
[
332,
345
]
],
"normalized": []
},
{
"id": "21262851_T21",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
385,
392
]
],
"normalized": []
},
{
"id": "21262851_T22",
"type": "CHEMICAL",
"text": [
"BDZs"
],
"offsets": [
[
681,
685
]
],
"normalized": []
},
{
"id": "21262851_T23",
"type": "CHEMICAL",
"text": [
"diazepam"
],
"offsets": [
[
687,
695
]
],
"normalized": []
},
{
"id": "21262851_T24",
"type": "CHEMICAL",
"text": [
"flurazepam"
],
"offsets": [
[
697,
707
]
],
"normalized": []
},
{
"id": "21262851_T25",
"type": "CHEMICAL",
"text": [
"desalkylflurazepam"
],
"offsets": [
[
713,
731
]
],
"normalized": []
},
{
"id": "21262851_T26",
"type": "CHEMICAL",
"text": [
"allopregnanolone"
],
"offsets": [
[
734,
750
]
],
"normalized": []
},
{
"id": "21262851_T27",
"type": "CHEMICAL",
"text": [
"pentobarbital"
],
"offsets": [
[
752,
765
]
],
"normalized": []
},
{
"id": "21262851_T28",
"type": "CHEMICAL",
"text": [
"ethanol"
],
"offsets": [
[
771,
778
]
],
"normalized": []
},
{
"id": "21262851_T29",
"type": "CHEMICAL",
"text": [
"Ba(2+)"
],
"offsets": [
[
793,
799
]
],
"normalized": []
},
{
"id": "21262851_T30",
"type": "CHEMICAL",
"text": [
"Allopregnanolone"
],
"offsets": [
[
929,
945
]
],
"normalized": []
},
{
"id": "21262851_T31",
"type": "CHEMICAL",
"text": [
"BDZs"
],
"offsets": [
[
1020,
1024
]
],
"normalized": []
},
{
"id": "21262851_T32",
"type": "CHEMICAL",
"text": [
"pentobarbital"
],
"offsets": [
[
1057,
1070
]
],
"normalized": []
},
{
"id": "21262851_T33",
"type": "CHEMICAL",
"text": [
"ethanol"
],
"offsets": [
[
1095,
1102
]
],
"normalized": []
},
{
"id": "21262851_T34",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
47,
54
]
],
"normalized": []
},
{
"id": "21262851_T35",
"type": "GENE-Y",
"text": [
"Ca(v)1.3"
],
"offsets": [
[
1135,
1143
]
],
"normalized": []
},
{
"id": "21262851_T36",
"type": "GENE-N",
"text": [
"GABA(A) receptors"
],
"offsets": [
[
220,
237
]
],
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1726,
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1776,
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364,
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535,
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26,
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] |
23411259 | 23411259 | [
{
"id": "23411259_title",
"type": "title",
"text": [
"A water-alcohol extract of Citrus grandis whole fruits has beneficial metabolic effects in the obese Zucker rats fed with high fat/high cholesterol diet."
],
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0,
153
]
]
},
{
"id": "23411259_abstract",
"type": "abstract",
"text": [
"Epidemiological studies suggest that citrus fruits and compounds such as flavonoids, limonoids and pectins have health promoting effects. Our aim was to study the effects of Citrus grandis (L.) Osbeck var. tomentosa hort. fruit extract on the energy metabolism. A whole fruit powder from dry water and alcohol extracts of C. grandis containing 19% naringin flavonoid was prepared. The effects of the citrus extract were followed in the obese Zucker rats fed with the HFD. The circulatory levels of GLP-1 decreased significantly by the extract in comparison to the HFD group, whereas the decreased ghrelin levels were reversed. The levels of PYY were decreased in all HFD groups. The leptin amounts decreased but not significantly whereas insulin and amylin were unchanged. The cholesterol and glucose levels were somewhat but not systematically improved in the HFD fed rats. Further studies are needed to identify the active compounds and their mechanisms."
],
"offsets": [
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154,
1110
]
]
}
] | [
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456,
463
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},
{
"id": "23411259_T2",
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502,
510
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],
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"id": "23411259_T3",
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227,
237
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],
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931,
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947,
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"id": "23411259_T6",
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"text": [
"cholesterol"
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136,
147
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"id": "23411259_T7",
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8,
15
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652,
657
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751,
758
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"amylin"
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904,
910
]
],
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}
] | [] | [] | [] |
23639187 | 23639187 | [
{
"id": "23639187_title",
"type": "title",
"text": [
"Amelioration of palmitate-induced insulin resistance in C2C12 muscle cells by rooibos (Aspalathus linearis)."
],
"offsets": [
[
0,
108
]
]
},
{
"id": "23639187_abstract",
"type": "abstract",
"text": [
"Increased levels of free fatty acids (FFAs), specifically saturated free fatty acids such as palmitate are associated with insulin resistance of muscle, fat and liver. Skeletal muscle, responsible for up to 80% of the glucose disposal from the peripheral circulation, is particularly vulnerable to increased levels of saturated FFAs. Rooibos (Aspalathus linearis) and its unique dihydrochalcone C-glucoside, aspalathin, shown to reduce hyperglycemia in diabetic rats, could play a role in preventing or ameliorating the development of insulin resistance. This study aims to establish whether rooibos can ameliorate experimentally-induced insulin-resistance in C2C12 skeletal muscle cells. Palmitate-induced insulin resistant C2C12 cells were treated with an aspalathin-enriched green (unfermented) rooibos extract (GRE), previously shown for its blood glucose lowering effect in vitro and in vivo or an aqueous extract of fermented rooibos (FRE). Glucose uptake and mitochondrial activity were measured using 2-deoxy-[(3)H]-d-glucose, MTT and ATP assays, respectively. Expression of proteins relevant to glucose metabolism was analysed by Western blot. GRE contained higher levels of all compounds, except the enolic phenylpyruvic acid-2-O-glucoside and luteolin-7-O-glucoside. Both rooibos extracts increased glucose uptake, mitochondrial activity and ATP production. Compared to FRE, GRE was more effective at increasing glucose uptake and ATP production. At a mechanistic level both extracts down-regulated PKC θ activation, which is associated with palmitate-induced insulin resistance. Furthermore, the extracts increased activation of key regulatory proteins (AKT and AMPK) involved in insulin-dependent and non-insulin regulated signalling pathways. Protein levels of the glucose transporter (GLUT4) involved in glucose transport via these two pathways were also increased. This in vitro study therefore confirms that rooibos can ameliorate palmitate-induced insulin resistance in C2C12 skeletal muscle cells. Inhibition of PKC θ activation and increased activation of AMPK and AKT offer a plausible mechanistic explanation for this ameliorative effect."
],
"offsets": [
[
109,
2269
]
]
}
] | [
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"id": "23639187_T1",
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],
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1118,
1142
]
],
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},
{
"id": "23639187_T2",
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"MTT"
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1144,
1147
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],
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{
"id": "23639187_T3",
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"ATP"
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1152,
1155
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"id": "23639187_T4",
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"glucose"
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1213,
1220
]
],
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},
{
"id": "23639187_T5",
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"phenylpyruvic acid-2-O-glucoside"
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1326,
1358
]
],
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},
{
"id": "23639187_T6",
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"luteolin-7-O-glucoside"
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1363,
1385
]
],
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"glucose"
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1419,
1426
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],
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"ATP"
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1462,
1465
]
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"glucose"
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1532,
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]
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"ATP"
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1551,
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"palmitate"
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1662,
1671
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"glucose"
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1888,
1895
]
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"glucose"
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1928,
1935
]
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"palmitate"
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2057,
2066
]
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"text": [
"free fatty acids"
],
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129,
145
]
],
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{
"id": "23639187_T16",
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"glucose"
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327,
334
]
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},
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"id": "23639187_T17",
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"FFAs"
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437,
441
]
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488,
515
]
],
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"FFAs"
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147,
151
]
],
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{
"id": "23639187_T20",
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"aspalathin"
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[
517,
527
]
],
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},
{
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"saturated free fatty acids"
],
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[
167,
193
]
],
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},
{
"id": "23639187_T22",
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"Palmitate"
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798,
807
]
],
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},
{
"id": "23639187_T23",
"type": "CHEMICAL",
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"aspalathin"
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[
867,
877
]
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},
{
"id": "23639187_T24",
"type": "CHEMICAL",
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"glucose"
],
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[
961,
968
]
],
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},
{
"id": "23639187_T25",
"type": "CHEMICAL",
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"palmitate"
],
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[
202,
211
]
],
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},
{
"id": "23639187_T26",
"type": "CHEMICAL",
"text": [
"Glucose"
],
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[
1056,
1063
]
],
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},
{
"id": "23639187_T27",
"type": "CHEMICAL",
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"palmitate"
],
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[
16,
25
]
],
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},
{
"id": "23639187_T28",
"type": "GENE-Y",
"text": [
"insulin"
],
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[
232,
239
]
],
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},
{
"id": "23639187_T29",
"type": "GENE-Y",
"text": [
"PKC θ"
],
"offsets": [
[
1619,
1624
]
],
"normalized": []
},
{
"id": "23639187_T30",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1680,
1687
]
],
"normalized": []
},
{
"id": "23639187_T31",
"type": "GENE-Y",
"text": [
"AKT"
],
"offsets": [
[
1775,
1778
]
],
"normalized": []
},
{
"id": "23639187_T32",
"type": "GENE-Y",
"text": [
"AMPK"
],
"offsets": [
[
1783,
1787
]
],
"normalized": []
},
{
"id": "23639187_T33",
"type": "GENE-N",
"text": [
"insulin"
],
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[
1801,
1808
]
],
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},
{
"id": "23639187_T34",
"type": "GENE-N",
"text": [
"insulin"
],
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[
1827,
1834
]
],
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},
{
"id": "23639187_T35",
"type": "GENE-N",
"text": [
"glucose transporter"
],
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[
1888,
1907
]
],
"normalized": []
},
{
"id": "23639187_T36",
"type": "GENE-Y",
"text": [
"GLUT4"
],
"offsets": [
[
1909,
1914
]
],
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},
{
"id": "23639187_T37",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
2075,
2082
]
],
"normalized": []
},
{
"id": "23639187_T38",
"type": "GENE-Y",
"text": [
"PKC θ"
],
"offsets": [
[
2140,
2145
]
],
"normalized": []
},
{
"id": "23639187_T39",
"type": "GENE-Y",
"text": [
"AMPK"
],
"offsets": [
[
2185,
2189
]
],
"normalized": []
},
{
"id": "23639187_T40",
"type": "GENE-Y",
"text": [
"AKT"
],
"offsets": [
[
2194,
2197
]
],
"normalized": []
},
{
"id": "23639187_T41",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
644,
651
]
],
"normalized": []
},
{
"id": "23639187_T42",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
747,
754
]
],
"normalized": []
},
{
"id": "23639187_T43",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
34,
41
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23639187_0",
"type": "SUBSTRATE",
"arg1_id": "23639187_T13",
"arg2_id": "23639187_T35",
"normalized": []
},
{
"id": "23639187_1",
"type": "SUBSTRATE",
"arg1_id": "23639187_T13",
"arg2_id": "23639187_T36",
"normalized": []
}
] |
23019138 | 23019138 | [
{
"id": "23019138_title",
"type": "title",
"text": [
"Diuretic effects of cannabinoids."
],
"offsets": [
[
0,
33
]
]
},
{
"id": "23019138_abstract",
"type": "abstract",
"text": [
"In vivo effects of cannabinoid (CB) agonists are often assessed using four well-established measures: locomotor activity, hypothermia, cataleptic-like effects, and analgesia. The present studies demonstrate that doses of CB agonists that produce these effects also reliably increase diuresis. Diuretic effects of several CB agonists were measured in female rats over 2 hours immediately after drug injection, and results were compared with hypothermic effects. Direct-acting CB1 agonists, including Δ(9)-tetrahydrocannabinol, WIN 55,212 [R-(1)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate], AM2389 [9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol], and AM4054 [9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol], produced dose-dependent increases in diuresis and decreases in colonic temperature, with slightly lower ED(50) values for diuresis than for hypothermia. The highest doses of cannabinoid drugs yielded, on average, 26-32 g/kg urine; comparable effects were obtained with 10 mg/kg furosemide and 3.0 mg/kg trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50-488). Methanandamide (10.0 mg/kg) had lesser effect than other CB agonists, and the CB2 agonist AM1241 [1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole], the anandamide transport inhibitor AM404, and the CB antagonist rimonabant did not have diuretic effects. In further studies, the diuretic effects of the CB1 agonist AM4054 were similar in male and female rats, displayed a relatively rapid onset to action, and were dose-dependently antagonized by 30 minutes pretreatment with rimonabant, but not by the vanilloid receptor type I antagonist capsazepine, nor were the effects of WIN 55,212 antagonized by the CB2 antagonist AM630 [(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)]. These data indicate that cannabinoids have robust diuretic effects in rats that are mediated via CB1 receptor mechanisms."
],
"offsets": [
[
34,
2080
]
]
}
] | [
{
"id": "23019138_T1",
"type": "CHEMICAL",
"text": [
"furosemide"
],
"offsets": [
[
1110,
1120
]
],
"normalized": []
},
{
"id": "23019138_T2",
"type": "CHEMICAL",
"text": [
"trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide"
],
"offsets": [
[
1135,
1215
]
],
"normalized": []
},
{
"id": "23019138_T3",
"type": "CHEMICAL",
"text": [
"U50-488"
],
"offsets": [
[
1217,
1224
]
],
"normalized": []
},
{
"id": "23019138_T4",
"type": "CHEMICAL",
"text": [
"Methanandamide"
],
"offsets": [
[
1227,
1241
]
],
"normalized": []
},
{
"id": "23019138_T5",
"type": "CHEMICAL",
"text": [
"AM1241"
],
"offsets": [
[
1317,
1323
]
],
"normalized": []
},
{
"id": "23019138_T6",
"type": "CHEMICAL",
"text": [
"1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole"
],
"offsets": [
[
1325,
1387
]
],
"normalized": []
},
{
"id": "23019138_T7",
"type": "CHEMICAL",
"text": [
"anandamide"
],
"offsets": [
[
1394,
1404
]
],
"normalized": []
},
{
"id": "23019138_T8",
"type": "CHEMICAL",
"text": [
"AM404"
],
"offsets": [
[
1425,
1430
]
],
"normalized": []
},
{
"id": "23019138_T9",
"type": "CHEMICAL",
"text": [
"rimonabant"
],
"offsets": [
[
1454,
1464
]
],
"normalized": []
},
{
"id": "23019138_T10",
"type": "CHEMICAL",
"text": [
"AM4054"
],
"offsets": [
[
1556,
1562
]
],
"normalized": []
},
{
"id": "23019138_T11",
"type": "CHEMICAL",
"text": [
"rimonabant"
],
"offsets": [
[
1717,
1727
]
],
"normalized": []
},
{
"id": "23019138_T12",
"type": "CHEMICAL",
"text": [
"vanilloid"
],
"offsets": [
[
1744,
1753
]
],
"normalized": []
},
{
"id": "23019138_T13",
"type": "CHEMICAL",
"text": [
"capsazepine"
],
"offsets": [
[
1781,
1792
]
],
"normalized": []
},
{
"id": "23019138_T14",
"type": "CHEMICAL",
"text": [
"WIN 55,212"
],
"offsets": [
[
1818,
1828
]
],
"normalized": []
},
{
"id": "23019138_T15",
"type": "CHEMICAL",
"text": [
"AM630"
],
"offsets": [
[
1863,
1868
]
],
"normalized": []
},
{
"id": "23019138_T16",
"type": "CHEMICAL",
"text": [
"(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)"
],
"offsets": [
[
1870,
1956
]
],
"normalized": []
},
{
"id": "23019138_T17",
"type": "CHEMICAL",
"text": [
"Δ(9)-tetrahydrocannabinol"
],
"offsets": [
[
533,
558
]
],
"normalized": []
},
{
"id": "23019138_T18",
"type": "CHEMICAL",
"text": [
"WIN 55,212"
],
"offsets": [
[
560,
570
]
],
"normalized": []
},
{
"id": "23019138_T19",
"type": "CHEMICAL",
"text": [
"R-(1)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate"
],
"offsets": [
[
572,
693
]
],
"normalized": []
},
{
"id": "23019138_T20",
"type": "CHEMICAL",
"text": [
"AM2389"
],
"offsets": [
[
696,
702
]
],
"normalized": []
},
{
"id": "23019138_T21",
"type": "CHEMICAL",
"text": [
"9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol"
],
"offsets": [
[
704,
760
]
],
"normalized": []
},
{
"id": "23019138_T22",
"type": "CHEMICAL",
"text": [
"AM4054"
],
"offsets": [
[
767,
773
]
],
"normalized": []
},
{
"id": "23019138_T23",
"type": "CHEMICAL",
"text": [
"9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol"
],
"offsets": [
[
775,
829
]
],
"normalized": []
},
{
"id": "23019138_T24",
"type": "GENE-Y",
"text": [
"CB2"
],
"offsets": [
[
1305,
1308
]
],
"normalized": []
},
{
"id": "23019138_T25",
"type": "GENE-Y",
"text": [
"CB1"
],
"offsets": [
[
1544,
1547
]
],
"normalized": []
},
{
"id": "23019138_T26",
"type": "GENE-Y",
"text": [
"vanilloid receptor type I"
],
"offsets": [
[
1744,
1769
]
],
"normalized": []
},
{
"id": "23019138_T27",
"type": "GENE-Y",
"text": [
"CB2"
],
"offsets": [
[
1848,
1851
]
],
"normalized": []
},
{
"id": "23019138_T28",
"type": "GENE-Y",
"text": [
"CB1"
],
"offsets": [
[
2056,
2059
]
],
"normalized": []
},
{
"id": "23019138_T29",
"type": "GENE-Y",
"text": [
"CB1"
],
"offsets": [
[
509,
512
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23019138_0",
"type": "AGONIST",
"arg1_id": "23019138_T17",
"arg2_id": "23019138_T29",
"normalized": []
},
{
"id": "23019138_1",
"type": "AGONIST",
"arg1_id": "23019138_T18",
"arg2_id": "23019138_T29",
"normalized": []
},
{
"id": "23019138_2",
"type": "AGONIST",
"arg1_id": "23019138_T19",
"arg2_id": "23019138_T29",
"normalized": []
},
{
"id": "23019138_3",
"type": "AGONIST",
"arg1_id": "23019138_T20",
"arg2_id": "23019138_T29",
"normalized": []
},
{
"id": "23019138_4",
"type": "AGONIST",
"arg1_id": "23019138_T21",
"arg2_id": "23019138_T29",
"normalized": []
},
{
"id": "23019138_5",
"type": "AGONIST",
"arg1_id": "23019138_T22",
"arg2_id": "23019138_T29",
"normalized": []
},
{
"id": "23019138_6",
"type": "AGONIST",
"arg1_id": "23019138_T23",
"arg2_id": "23019138_T29",
"normalized": []
},
{
"id": "23019138_7",
"type": "AGONIST",
"arg1_id": "23019138_T5",
"arg2_id": "23019138_T24",
"normalized": []
},
{
"id": "23019138_8",
"type": "AGONIST",
"arg1_id": "23019138_T6",
"arg2_id": "23019138_T24",
"normalized": []
},
{
"id": "23019138_9",
"type": "AGONIST",
"arg1_id": "23019138_T8",
"arg2_id": "23019138_T24",
"normalized": []
},
{
"id": "23019138_10",
"type": "AGONIST",
"arg1_id": "23019138_T10",
"arg2_id": "23019138_T25",
"normalized": []
},
{
"id": "23019138_11",
"type": "ANTAGONIST",
"arg1_id": "23019138_T11",
"arg2_id": "23019138_T25",
"normalized": []
},
{
"id": "23019138_12",
"type": "ANTAGONIST",
"arg1_id": "23019138_T13",
"arg2_id": "23019138_T26",
"normalized": []
},
{
"id": "23019138_13",
"type": "ANTAGONIST",
"arg1_id": "23019138_T15",
"arg2_id": "23019138_T27",
"normalized": []
},
{
"id": "23019138_14",
"type": "ANTAGONIST",
"arg1_id": "23019138_T16",
"arg2_id": "23019138_T27",
"normalized": []
},
{
"id": "23019138_15",
"type": "AGONIST",
"arg1_id": "23019138_T14",
"arg2_id": "23019138_T27",
"normalized": []
}
] |
10768298 | 10768298 | [
{
"id": "10768298_title",
"type": "title",
"text": [
"Topiramate as an inhibitor of carbonic anhydrase isoenzymes."
],
"offsets": [
[
0,
60
]
]
},
{
"id": "10768298_abstract",
"type": "abstract",
"text": [
"PURPOSE: This study investigated the effectiveness of topiramate (TPM) as an inhibitor of six isozymes of carbonic anhydrase (CA). METHODS: The inhibition constants (Ki) of TPM and acetazolamide (AZM) for CA I, CA II, CA III, CA IV, CA V, and CA VI were determined for human (HCA), rat (RCA), or mouse (MCA). The activity of CA was studied by using purified isozymes, erythrocytes, subcellular fractions of kidney or brain, and saliva, and was assayed at 37 degrees C or 25 degrees C by 18O mass spectrometry and/or by measuring the pH shift at 0 degrees C. RESULTS: Topiramate Ki values for HCA I, HCA II, HCA IV, and HCA VI were approximately 100, 7, 10, and >100 microM, respectively. TPM Ki values for RCA I, RCA II, RCA III, RCA IV, and RCA V were approximately 180, 0.1 to 1, >100, 0.2 to 10 and 18 microM, respectively. For RCA II and RCA IV, the Ki values were temperature dependent. TPM Ki values for MCA II and MCA IV ranged between 1 and 20 microM. CONCLUSIONS: These results indicate that TPM is more potent as an inhibitor of CA II and CA IV than of CA I, CA III, and CA VI. In all three species, AZM was usually 10 to 100 times more potent than TPM as an inhibitor of CA isozymes."
],
"offsets": [
[
61,
1255
]
]
}
] | [
{
"id": "10768298_T1",
"type": "CHEMICAL",
"text": [
"TPM"
],
"offsets": [
[
1062,
1065
]
],
"normalized": []
},
{
"id": "10768298_T2",
"type": "CHEMICAL",
"text": [
"carbonic"
],
"offsets": [
[
167,
175
]
],
"normalized": []
},
{
"id": "10768298_T3",
"type": "CHEMICAL",
"text": [
"AZM"
],
"offsets": [
[
1171,
1174
]
],
"normalized": []
},
{
"id": "10768298_T4",
"type": "CHEMICAL",
"text": [
"TPM"
],
"offsets": [
[
1220,
1223
]
],
"normalized": []
},
{
"id": "10768298_T5",
"type": "CHEMICAL",
"text": [
"TPM"
],
"offsets": [
[
234,
237
]
],
"normalized": []
},
{
"id": "10768298_T6",
"type": "CHEMICAL",
"text": [
"acetazolamide"
],
"offsets": [
[
242,
255
]
],
"normalized": []
},
{
"id": "10768298_T7",
"type": "CHEMICAL",
"text": [
"AZM"
],
"offsets": [
[
257,
260
]
],
"normalized": []
},
{
"id": "10768298_T8",
"type": "CHEMICAL",
"text": [
"topiramate"
],
"offsets": [
[
115,
125
]
],
"normalized": []
},
{
"id": "10768298_T9",
"type": "CHEMICAL",
"text": [
"Topiramate"
],
"offsets": [
[
628,
638
]
],
"normalized": []
},
{
"id": "10768298_T10",
"type": "CHEMICAL",
"text": [
"TPM"
],
"offsets": [
[
127,
130
]
],
"normalized": []
},
{
"id": "10768298_T11",
"type": "CHEMICAL",
"text": [
"TPM"
],
"offsets": [
[
749,
752
]
],
"normalized": []
},
{
"id": "10768298_T12",
"type": "CHEMICAL",
"text": [
"TPM"
],
"offsets": [
[
953,
956
]
],
"normalized": []
},
{
"id": "10768298_T13",
"type": "CHEMICAL",
"text": [
"Topiramate"
],
"offsets": [
[
0,
10
]
],
"normalized": []
},
{
"id": "10768298_T14",
"type": "CHEMICAL",
"text": [
"carbonic"
],
"offsets": [
[
30,
38
]
],
"normalized": []
},
{
"id": "10768298_T15",
"type": "GENE-N",
"text": [
"CA II"
],
"offsets": [
[
1100,
1105
]
],
"normalized": []
},
{
"id": "10768298_T16",
"type": "GENE-N",
"text": [
"CA IV"
],
"offsets": [
[
1110,
1115
]
],
"normalized": []
},
{
"id": "10768298_T17",
"type": "GENE-N",
"text": [
"carbonic anhydrase"
],
"offsets": [
[
167,
185
]
],
"normalized": []
},
{
"id": "10768298_T18",
"type": "GENE-N",
"text": [
"CA I"
],
"offsets": [
[
1124,
1128
]
],
"normalized": []
},
{
"id": "10768298_T19",
"type": "GENE-N",
"text": [
"CA III"
],
"offsets": [
[
1130,
1136
]
],
"normalized": []
},
{
"id": "10768298_T20",
"type": "GENE-N",
"text": [
"CA VI"
],
"offsets": [
[
1142,
1147
]
],
"normalized": []
},
{
"id": "10768298_T21",
"type": "GENE-N",
"text": [
"CA"
],
"offsets": [
[
1243,
1245
]
],
"normalized": []
},
{
"id": "10768298_T22",
"type": "GENE-N",
"text": [
"CA"
],
"offsets": [
[
187,
189
]
],
"normalized": []
},
{
"id": "10768298_T23",
"type": "GENE-N",
"text": [
"CA I"
],
"offsets": [
[
266,
270
]
],
"normalized": []
},
{
"id": "10768298_T24",
"type": "GENE-N",
"text": [
"CA II"
],
"offsets": [
[
272,
277
]
],
"normalized": []
},
{
"id": "10768298_T25",
"type": "GENE-N",
"text": [
"CA III"
],
"offsets": [
[
279,
285
]
],
"normalized": []
},
{
"id": "10768298_T26",
"type": "GENE-N",
"text": [
"CA IV"
],
"offsets": [
[
287,
292
]
],
"normalized": []
},
{
"id": "10768298_T27",
"type": "GENE-N",
"text": [
"CA V"
],
"offsets": [
[
294,
298
]
],
"normalized": []
},
{
"id": "10768298_T28",
"type": "GENE-N",
"text": [
"CA VI"
],
"offsets": [
[
304,
309
]
],
"normalized": []
},
{
"id": "10768298_T29",
"type": "GENE-N",
"text": [
"HCA"
],
"offsets": [
[
337,
340
]
],
"normalized": []
},
{
"id": "10768298_T30",
"type": "GENE-N",
"text": [
"RCA"
],
"offsets": [
[
348,
351
]
],
"normalized": []
},
{
"id": "10768298_T31",
"type": "GENE-N",
"text": [
"MCA"
],
"offsets": [
[
364,
367
]
],
"normalized": []
},
{
"id": "10768298_T32",
"type": "GENE-N",
"text": [
"CA"
],
"offsets": [
[
386,
388
]
],
"normalized": []
},
{
"id": "10768298_T33",
"type": "GENE-Y",
"text": [
"HCA I"
],
"offsets": [
[
653,
658
]
],
"normalized": []
},
{
"id": "10768298_T34",
"type": "GENE-Y",
"text": [
"HCA II"
],
"offsets": [
[
660,
666
]
],
"normalized": []
},
{
"id": "10768298_T35",
"type": "GENE-Y",
"text": [
"HCA IV"
],
"offsets": [
[
668,
674
]
],
"normalized": []
},
{
"id": "10768298_T36",
"type": "GENE-Y",
"text": [
"HCA VI"
],
"offsets": [
[
680,
686
]
],
"normalized": []
},
{
"id": "10768298_T37",
"type": "GENE-Y",
"text": [
"RCA I"
],
"offsets": [
[
767,
772
]
],
"normalized": []
},
{
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23319584 | 23319584 | [
{
"id": "23319584_title",
"type": "title",
"text": [
"Comparison of orientation and rotational motion of skeletal muscle cross-bridges containing phosphorylated and dephosphorylated myosin regulatory light chain."
],
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"id": "23319584_abstract",
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"text": [
"Calcium binding to thin filaments is a major element controlling active force generation in striated muscles. Recent evidence suggests that processes other than Ca(2+) binding, such as phosphorylation of myosin regulatory light chain (RLC) also controls contraction of vertebrate striated muscle (Cooke, R. (2011) Biophys. Rev. 3, 33-45). Electron paramagnetic resonance (EPR) studies using nucleotide analog spin label probes showed that dephosphorylated myosin heads are highly ordered in the relaxed fibers and have very low ATPase activity. This ordered structure of myosin cross-bridges disappears with the phosphorylation of RLC (Stewart, M. (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 430-435). The slower ATPase activity in the dephosporylated moiety has been defined as a new super-relaxed state (SRX). It can be observed in both skeletal and cardiac muscle fibers (Hooijman, P., Stewart, M. A., and Cooke, R. (2011) Biophys. J. 100, 1969-1976). Given the importance of the finding that suggests a novel pathway of regulation of skeletal muscle, we aim to examine the effects of phosphorylation on cross-bridge orientation and rotational motion. We find that: (i) relaxed cross-bridges, but not active ones, are statistically better ordered in muscle where the RLC is dephosporylated compared with phosphorylated RLC; (ii) relaxed phosphorylated and dephosphorylated cross-bridges rotate equally slowly; and (iii) active phosphorylated cross-bridges rotate considerably faster than dephosphorylated ones during isometric contraction but the duty cycle remained the same, suggesting that both phosphorylated and dephosphorylated muscles develop the same isometric tension at full Ca(2+) saturation. A simple theory was developed to account for this fact."
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] | [] | [] | [] |
15494548 | 15494548 | [
{
"id": "15494548_title",
"type": "title",
"text": [
"Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity."
],
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"text": [
"The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit COX-2 in humans while sparing prostaglandin formation from COX-1. Celecoxib and rofecoxib were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective COX-2 inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed COX-2 inhibitors that we have studied. Recombinant human COX-1 and COX-2 were used to screen for new highly potent and in vitro selective COX-2 inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. Valdecoxib potently inhibits recombinant COX-2, with an IC(50) of 0.005 microM; this compares with IC values of 0.05 microM for celecoxib, 0.5 microM for rofecoxib, and 5 microM for etoricoxib. Unique binding interactions of valdecoxib with COX-2 translate into a fast rate of inactivation of COX-2 (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib). The overall saturation binding affinity for COX-2 of valdecoxib is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for rofecoxib, and 260 nM for etoricoxib), with a slow off-rate (t(1/2) approximately 98 min). Valdecoxib inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 microM). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for COX-2. Valdecoxib showed similar activity in the human whole-blood COX assay (COX-2 IC(50) = 0.24 microM; COX-1 IC(50) = 21.9 microM). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg). In these same animals, COX-1 was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans."
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] |
23403085 | 23403085 | [
{
"id": "23403085_title",
"type": "title",
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"Neuroprotective effects of mercaptoethylleonurine and mercaptoethylguanidine analogs on hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells."
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0,
156
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]
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{
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"type": "abstract",
"text": [
"A series of mercaptoethylleonurine and mercaptoethylguanidine derivatives were designed and synthesized. Their neuroprotective effects toward H2O2-induced apoptosis were investigated in human SH-SY5Y cells. The results from these studies identified several potent compounds, with compound 8k emerging as the most effective. Further investigation demonstrated that 8k reduced H2O2-induced activation of mitochondrial apoptosis by inhibiting the expression of Bax and elevating the expression of Bcl-2. Moreover, the molecular mechanism underlying the observed neuroprotective effects of 8k was exerted via the Akt and JNK pathways. Compound 8k can be a lead compound for further discovery of neuroprotective medicine."
],
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157,
873
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]
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] |
9587066 | 9587066 | [
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"type": "title",
"text": [
"The molecular genetic approach to \"Bartter's syndrome\"."
],
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0,
55
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]
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"type": "abstract",
"text": [
"The term \"Bartter's syndrome\" comprises a set of autosomal recessively inherited renal tubular disorders characterized by hypokalemia, metabolic alkalosis, hyperreninism, and hyperaldosteronism but normal blood pressure. Additional clinical and biochemical features led to a classification into phenotypically different tubulopathies: Gitelman's syndrome, hyperprostaglandin E syndrome (antenatal Bartter's syndrome), and classic Bartter's syndrome. Gitelman's syndrome results from mutations in the SLC12A3 gene encoding the human thiazide-sensitive sodium chloride cotransporter, leading to impaired reabsorption of sodium chloride in the distal convoluted tubule. Genetic heterogeneity of hyperprostaglandin E syndrome has been demonstrated by identification of mutations in the SLC12A1 gene as well as in the KCNJ1 gene. Mutations in SLC12A1 coding for the bumetanide-sensitive sodium potassium 2 chloride cotransporter (NKCC2) cause defective reabsorption of sodium chloride in the thick ascending limb of Henle's loop. Mutations in KCNJ1 leading to loss of function of the potassium channel ROMK disrupt potassium recycling back to the tubule lumen and inhibit thereby the NKCC2 activity. A third gene for hyperprostaglandin E syndrome has been mapped to the short arm of chromosome 1, and it remains to be evaluated whether other genes are involved in the pathogenesis of this disease. Classic Bartter's syndrome has been demonstrated to result from defective chloride transport across the basolateral membrane in the distal nephron due to mutations in the chloride channel gene CLCNKB. This article reviews the molecular genetic approach that has led to identification of genetic defects underlying the different hypokalemic tubulopathies."
],
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56,
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981,
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}
] | [] | [] | [
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"arg2_id": "9587066_T15",
"normalized": []
}
] |
23472952 | 23472952 | [
{
"id": "23472952_title",
"type": "title",
"text": [
"Discovery of (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid and congeners as highly potent inhibitors of human arginases I and II for treatment of myocardial reperfusion injury."
],
"offsets": [
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0,
192
]
]
},
{
"id": "23472952_abstract",
"type": "abstract",
"text": [
"Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II."
],
"offsets": [
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193,
1077
]
]
}
] | [
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340,
368
]
],
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},
{
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416,
477
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375,
383
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120,
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}
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"arg1_id": "23472952_T2",
"arg2_id": "23472952_T6",
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}
] |
23270282 | 23270282 | [
{
"id": "23270282_title",
"type": "title",
"text": [
"Differential Effects of Crambescins and Crambescidin 816 in Voltage-Gated Sodium, Potassium and Calcium Channels in Neurons."
],
"offsets": [
[
0,
124
]
]
},
{
"id": "23270282_abstract",
"type": "abstract",
"text": [
"Crambescins and crambescidins are two families of guanidine alkaloids from the marine sponge Crambe crambe. Although very little information about their biological effect has been reported, it is known that crambescidin 816 (Cramb816) blocks calcium channels in a neuroblastoma X glioma cell line. Taking this into account, and the fact that ion channels are frequent targets for natural toxins, we examined the effect of Cramb816 and three compounds from the crambescin family, norcrambescin A2 (NcrambA2), crambescin A2 (CrambA2), and crambescin C1 (CrambC1), in the main voltage-dependent ion channels in neurons: sodium, potassium, and calcium channels. Electrophysiological recordings of voltage gated sodium, potassium, and calcium currents, in the presence of these guanidine alkaloids, were performed in cortical neurons from embryonic mice. Different effects were discovered: crambescins inhibited K(+) currents with the following potency: NcrambA2 > CrambC1 > CrambA2, while Cramb816 lacked an effect. Only CrambC1 and Cramb816 partially blocked Na(+) total current. However, Cramb816 partially blocked Ca(2+) , while NcrambA2 did not. Since the blocking effect of Cramb816 on calcium currents has not been previously reported in detail, we further pharmacologically isolated the two main fractions of HVA Ca(2+) channels in neurons and investigated the Cramb816 effect on them. Here, we revealed that Cav1 or L-type calcium channels are the main target for Cramb816. These two families of guanidine alkaloids clearly showed a structure-activity relationship with the crambescins acting on voltage-gated potassium channels, while Cramb816 blocks the voltage-gated calcium channel Cav1 with higher potency than nifedipine. The novel evidence that Cramb816 partially blocked Ca(V) and Na(V) channels in neurons suggests that this compound might be involved in decreasing the neurotransmitter release and synaptic transmission in the central nervous system. The findings presented here provide the first detailed approach on the different effects of crambescin and crambescidin compounds in voltage-gated sodium, potassium, and calcium channels in neurons and thus provide a basis for future studies."
],
"offsets": [
[
125,
2332
]
]
}
] | [
{
"id": "23270282_T1",
"type": "CHEMICAL",
"text": [
"Crambescins"
],
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[
125,
136
]
],
"normalized": []
},
{
"id": "23270282_T2",
"type": "CHEMICAL",
"text": [
"CrambC1"
],
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1142,
1149
]
],
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},
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"id": "23270282_T3",
"type": "CHEMICAL",
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"Cramb816"
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1154,
1162
]
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"id": "23270282_T4",
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"Na(+)"
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1181,
1186
]
],
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"id": "23270282_T5",
"type": "CHEMICAL",
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"Cramb816"
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1211,
1219
]
],
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"id": "23270282_T6",
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"Ca(2+)"
],
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[
1238,
1244
]
],
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},
{
"id": "23270282_T7",
"type": "CHEMICAL",
"text": [
"NcrambA2"
],
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[
1253,
1261
]
],
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},
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"id": "23270282_T8",
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"Cramb816"
],
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1300,
1308
]
],
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"id": "23270282_T9",
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"calcium"
],
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1312,
1319
]
],
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"id": "23270282_T10",
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"Ca(2+)"
],
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[
1441,
1447
]
],
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},
{
"id": "23270282_T11",
"type": "CHEMICAL",
"text": [
"Cramb816"
],
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1489,
1497
]
],
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"id": "23270282_T12",
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"calcium"
],
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1552,
1559
]
],
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"id": "23270282_T13",
"type": "CHEMICAL",
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"Cramb816"
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1593,
1601
]
],
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"id": "23270282_T14",
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"guanidine alkaloids"
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1625,
1644
]
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"id": "23270282_T15",
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"crambescins"
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1703,
1714
]
],
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"potassium"
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1739,
1748
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"crambescidins"
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141,
154
]
],
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"Cramb816"
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1765,
1773
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"calcium"
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1799,
1806
]
],
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},
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"id": "23270282_T20",
"type": "CHEMICAL",
"text": [
"nifedipine"
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[
1845,
1855
]
],
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},
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"id": "23270282_T21",
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"Cramb816"
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[
1881,
1889
]
],
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},
{
"id": "23270282_T22",
"type": "CHEMICAL",
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"Ca"
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[
1908,
1910
]
],
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},
{
"id": "23270282_T23",
"type": "CHEMICAL",
"text": [
"Na"
],
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[
1918,
1920
]
],
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},
{
"id": "23270282_T24",
"type": "CHEMICAL",
"text": [
"crambescin"
],
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[
2182,
2192
]
],
"normalized": []
},
{
"id": "23270282_T25",
"type": "CHEMICAL",
"text": [
"crambescidin"
],
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[
2197,
2209
]
],
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},
{
"id": "23270282_T26",
"type": "CHEMICAL",
"text": [
"crambescidin 816"
],
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[
332,
348
]
],
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},
{
"id": "23270282_T27",
"type": "CHEMICAL",
"text": [
"sodium"
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[
2237,
2243
]
],
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},
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"id": "23270282_T28",
"type": "CHEMICAL",
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"potassium"
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[
2245,
2254
]
],
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},
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"calcium"
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2260,
2267
]
],
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},
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"id": "23270282_T30",
"type": "CHEMICAL",
"text": [
"Cramb816"
],
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350,
358
]
],
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},
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"id": "23270282_T31",
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"calcium"
],
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[
367,
374
]
],
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},
{
"id": "23270282_T32",
"type": "CHEMICAL",
"text": [
"Cramb816"
],
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[
547,
555
]
],
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},
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"id": "23270282_T33",
"type": "CHEMICAL",
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"crambescin"
],
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[
585,
595
]
],
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},
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"id": "23270282_T34",
"type": "CHEMICAL",
"text": [
"norcrambescin A2"
],
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[
604,
620
]
],
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},
{
"id": "23270282_T35",
"type": "CHEMICAL",
"text": [
"NcrambA2"
],
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[
622,
630
]
],
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},
{
"id": "23270282_T36",
"type": "CHEMICAL",
"text": [
"guanidine alkaloids"
],
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[
175,
194
]
],
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},
{
"id": "23270282_T37",
"type": "CHEMICAL",
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"crambescin A2"
],
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[
633,
646
]
],
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},
{
"id": "23270282_T38",
"type": "CHEMICAL",
"text": [
"CrambA2"
],
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[
648,
655
]
],
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},
{
"id": "23270282_T39",
"type": "CHEMICAL",
"text": [
"crambescin C1"
],
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[
662,
675
]
],
"normalized": []
},
{
"id": "23270282_T40",
"type": "CHEMICAL",
"text": [
"CrambC1"
],
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[
677,
684
]
],
"normalized": []
},
{
"id": "23270282_T41",
"type": "CHEMICAL",
"text": [
"sodium"
],
"offsets": [
[
742,
748
]
],
"normalized": []
},
{
"id": "23270282_T42",
"type": "CHEMICAL",
"text": [
"potassium"
],
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[
750,
759
]
],
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},
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"id": "23270282_T43",
"type": "CHEMICAL",
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"calcium"
],
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[
765,
772
]
],
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},
{
"id": "23270282_T44",
"type": "CHEMICAL",
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"sodium"
],
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[
832,
838
]
],
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},
{
"id": "23270282_T45",
"type": "CHEMICAL",
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"potassium"
],
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[
840,
849
]
],
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},
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"id": "23270282_T46",
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"calcium"
],
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855,
862
]
],
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},
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"id": "23270282_T47",
"type": "CHEMICAL",
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"guanidine alkaloids"
],
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[
898,
917
]
],
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},
{
"id": "23270282_T48",
"type": "CHEMICAL",
"text": [
"crambescins"
],
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[
1010,
1021
]
],
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},
{
"id": "23270282_T49",
"type": "CHEMICAL",
"text": [
"K(+)"
],
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[
1032,
1036
]
],
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},
{
"id": "23270282_T50",
"type": "CHEMICAL",
"text": [
"NcrambA2"
],
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[
1074,
1082
]
],
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},
{
"id": "23270282_T51",
"type": "CHEMICAL",
"text": [
"CrambC1"
],
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[
1085,
1092
]
],
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},
{
"id": "23270282_T52",
"type": "CHEMICAL",
"text": [
"CrambA2"
],
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[
1095,
1102
]
],
"normalized": []
},
{
"id": "23270282_T53",
"type": "CHEMICAL",
"text": [
"Cramb816"
],
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[
1110,
1118
]
],
"normalized": []
},
{
"id": "23270282_T54",
"type": "CHEMICAL",
"text": [
"Crambescidin 816"
],
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[
40,
56
]
],
"normalized": []
},
{
"id": "23270282_T55",
"type": "CHEMICAL",
"text": [
"Sodium"
],
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[
74,
80
]
],
"normalized": []
},
{
"id": "23270282_T56",
"type": "CHEMICAL",
"text": [
"Potassium"
],
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[
82,
91
]
],
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},
{
"id": "23270282_T57",
"type": "CHEMICAL",
"text": [
"Calcium"
],
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[
96,
103
]
],
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},
{
"id": "23270282_T58",
"type": "GENE-N",
"text": [
"Ca(2+) channels"
],
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[
1441,
1456
]
],
"normalized": []
},
{
"id": "23270282_T59",
"type": "GENE-N",
"text": [
"Cav1"
],
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[
1537,
1541
]
],
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},
{
"id": "23270282_T60",
"type": "GENE-N",
"text": [
"L-type calcium channels"
],
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[
1545,
1568
]
],
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},
{
"id": "23270282_T61",
"type": "GENE-N",
"text": [
"voltage-gated potassium channels"
],
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[
1725,
1757
]
],
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},
{
"id": "23270282_T62",
"type": "GENE-N",
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"voltage-gated calcium channel"
],
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[
1785,
1814
]
],
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},
{
"id": "23270282_T63",
"type": "GENE-N",
"text": [
"Cav1"
],
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[
1815,
1819
]
],
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},
{
"id": "23270282_T64",
"type": "GENE-N",
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"Ca(V)"
],
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[
1908,
1913
]
],
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},
{
"id": "23270282_T65",
"type": "GENE-N",
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"Na(V) channels"
],
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[
1918,
1932
]
],
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},
{
"id": "23270282_T66",
"type": "GENE-N",
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"voltage-gated sodium, potassium, and calcium channels"
],
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[
2223,
2276
]
],
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},
{
"id": "23270282_T67",
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"calcium channels"
],
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[
367,
383
]
],
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},
{
"id": "23270282_T68",
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"ion channels"
],
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[
467,
479
]
],
"normalized": []
},
{
"id": "23270282_T69",
"type": "GENE-N",
"text": [
"voltage-dependent ion channels"
],
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[
699,
729
]
],
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},
{
"id": "23270282_T70",
"type": "GENE-N",
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"sodium, potassium, and calcium channels"
],
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[
742,
781
]
],
"normalized": []
},
{
"id": "23270282_T71",
"type": "GENE-N",
"text": [
"Voltage-Gated Sodium, Potassium and Calcium Channels"
],
"offsets": [
[
60,
112
]
],
"normalized": []
}
] | [] | [] | [
{
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"type": "INHIBITOR",
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"arg2_id": "23270282_T67",
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},
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},
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},
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},
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},
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},
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},
{
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"type": "INHIBITOR",
"arg1_id": "23270282_T21",
"arg2_id": "23270282_T65",
"normalized": []
}
] |
12016548 | 12016548 | [
{
"id": "12016548_title",
"type": "title",
"text": [
"Hepatotoxicity of commonly used drugs: nonsteroidal anti-inflammatory drugs, antihypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents, psychotropic drugs."
],
"offsets": [
[
0,
176
]
]
},
{
"id": "12016548_abstract",
"type": "abstract",
"text": [
"Hepatotoxic adverse drug reactions have contributed to the decline of many promising therapies, even among mainstream medication classes (bromfenac and troglitazone are recent examples). The spectrum of nonsteroidal anti-inflammatory drug-related liver toxicity continues to expand, with reports in children, interactive toxicity in persons with hepatitis C, and recognition of the toxicity of both the preferential and selective cyclooxygenase-2 inhibitors. Of the antihypertensive agents, methyldopa is now rarely prescribed and adverse effects are reported infrequently, whereas cases of liver injury associated with the angiotensin receptor and converting enzyme inhibitors are increasingly reported. Of the antidiabetic agents, acarbose, gliclazide, metformin, and human insulin have been implicated in causing liver injury. To date, the newer thiazolidinediones do not appear to share the hepatotoxic potential of troglitazone, although a few reports of acute hepatitis have accrued. Although liver injury has been associated with the \"statins,\" the frequency of such toxicity is lower than that of the background population and the value of biochemical monitoring remains unproved. Newer concepts in anticonvulsant hepatotoxicity have been the recognition of the reactive metabolite syndrome, delineation of the risk factors for valproic acid toxicity, the potential role of carnitine in preventing valproic acid hepatotoxicity, and the toxicity of second-line antiepileptic drugs. Liver injury associated with newer psychotropic agents, particularly the selective serotonin reuptake inhibitors, is also discussed. The focus of the review is the hepatotoxicity of commonly used drugs with particular reference to recent and novel reports of toxicity. Well-known causes of liver injury such as chlorpromazine, phenytoin, and methyldopa are not discussed."
],
"offsets": [
[
177,
2037
]
]
}
] | [
{
"id": "12016548_T1",
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"valproic acid"
],
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[
1513,
1526
]
],
"normalized": []
},
{
"id": "12016548_T2",
"type": "CHEMICAL",
"text": [
"bromfenac"
],
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[
315,
324
]
],
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},
{
"id": "12016548_T3",
"type": "CHEMICAL",
"text": [
"carnitine"
],
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[
1559,
1568
]
],
"normalized": []
},
{
"id": "12016548_T4",
"type": "CHEMICAL",
"text": [
"valproic acid"
],
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[
1583,
1596
]
],
"normalized": []
},
{
"id": "12016548_T5",
"type": "CHEMICAL",
"text": [
"troglitazone"
],
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[
329,
341
]
],
"normalized": []
},
{
"id": "12016548_T6",
"type": "CHEMICAL",
"text": [
"serotonin"
],
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[
1749,
1758
]
],
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},
{
"id": "12016548_T7",
"type": "CHEMICAL",
"text": [
"chlorpromazine"
],
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[
1977,
1991
]
],
"normalized": []
},
{
"id": "12016548_T8",
"type": "CHEMICAL",
"text": [
"phenytoin"
],
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[
1993,
2002
]
],
"normalized": []
},
{
"id": "12016548_T9",
"type": "CHEMICAL",
"text": [
"methyldopa"
],
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[
2008,
2018
]
],
"normalized": []
},
{
"id": "12016548_T10",
"type": "CHEMICAL",
"text": [
"angiotensin"
],
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[
801,
812
]
],
"normalized": []
},
{
"id": "12016548_T11",
"type": "CHEMICAL",
"text": [
"acarbose"
],
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[
910,
918
]
],
"normalized": []
},
{
"id": "12016548_T12",
"type": "CHEMICAL",
"text": [
"gliclazide"
],
"offsets": [
[
920,
930
]
],
"normalized": []
},
{
"id": "12016548_T13",
"type": "CHEMICAL",
"text": [
"metformin"
],
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[
932,
941
]
],
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},
{
"id": "12016548_T14",
"type": "CHEMICAL",
"text": [
"thiazolidinediones"
],
"offsets": [
[
1026,
1044
]
],
"normalized": []
},
{
"id": "12016548_T15",
"type": "CHEMICAL",
"text": [
"troglitazone"
],
"offsets": [
[
1097,
1109
]
],
"normalized": []
},
{
"id": "12016548_T16",
"type": "GENE-Y",
"text": [
"cyclooxygenase-2"
],
"offsets": [
[
607,
623
]
],
"normalized": []
},
{
"id": "12016548_T17",
"type": "GENE-N",
"text": [
"angiotensin receptor"
],
"offsets": [
[
801,
821
]
],
"normalized": []
},
{
"id": "12016548_T18",
"type": "GENE-Y",
"text": [
"converting enzyme"
],
"offsets": [
[
826,
843
]
],
"normalized": []
},
{
"id": "12016548_T19",
"type": "GENE-Y",
"text": [
"human insulin"
],
"offsets": [
[
947,
960
]
],
"normalized": []
}
] | [] | [] | [] |
8398139 | 8398139 | [
{
"id": "8398139_title",
"type": "title",
"text": [
"A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms."
],
"offsets": [
[
0,
123
]
]
},
{
"id": "8398139_abstract",
"type": "abstract",
"text": [
"We report the cloning and characterization of a novel serotonin receptor, designated as 5-HT7, which is coupled to the stimulation of adenylyl cyclase. 5-HT7 mRNA is expressed discretely throughout the CNS, predominantly in the thalamus and hypothalamus. 5-HT7 has a unique pharmacological profile that redefines agonist and antagonist classification of ligands previously thought to be \"selective.\" The circadian phase of spontaneous neuronal activity of the rat suprachiasmatic nucleus of the hypothalamus advances in response to serotonin ligands with a pharmacological profile consistent exclusively with that of 5-HT7. These findings suggest a physiological role in the regulation of circadian rhythms for one subtype of serotonin receptor, 5-HT7, and provide a pharmacological test to evaluate its role in other neuronal systems."
],
"offsets": [
[
124,
959
]
]
}
] | [
{
"id": "8398139_T1",
"type": "CHEMICAL",
"text": [
"adenylyl"
],
"offsets": [
[
258,
266
]
],
"normalized": []
},
{
"id": "8398139_T2",
"type": "CHEMICAL",
"text": [
"serotonin"
],
"offsets": [
[
656,
665
]
],
"normalized": []
},
{
"id": "8398139_T3",
"type": "CHEMICAL",
"text": [
"serotonin"
],
"offsets": [
[
178,
187
]
],
"normalized": []
},
{
"id": "8398139_T4",
"type": "CHEMICAL",
"text": [
"serotonin"
],
"offsets": [
[
36,
45
]
],
"normalized": []
},
{
"id": "8398139_T5",
"type": "CHEMICAL",
"text": [
"adenylyl"
],
"offsets": [
[
8,
16
]
],
"normalized": []
},
{
"id": "8398139_T6",
"type": "GENE-N",
"text": [
"adenylyl cyclase"
],
"offsets": [
[
258,
274
]
],
"normalized": []
},
{
"id": "8398139_T7",
"type": "GENE-Y",
"text": [
"5-HT7"
],
"offsets": [
[
276,
281
]
],
"normalized": []
},
{
"id": "8398139_T8",
"type": "GENE-Y",
"text": [
"5-HT7"
],
"offsets": [
[
379,
384
]
],
"normalized": []
},
{
"id": "8398139_T9",
"type": "GENE-N",
"text": [
"serotonin receptor"
],
"offsets": [
[
178,
196
]
],
"normalized": []
},
{
"id": "8398139_T10",
"type": "GENE-Y",
"text": [
"5-HT7"
],
"offsets": [
[
741,
746
]
],
"normalized": []
},
{
"id": "8398139_T11",
"type": "GENE-N",
"text": [
"serotonin receptor"
],
"offsets": [
[
850,
868
]
],
"normalized": []
},
{
"id": "8398139_T12",
"type": "GENE-Y",
"text": [
"5-HT7"
],
"offsets": [
[
870,
875
]
],
"normalized": []
},
{
"id": "8398139_T13",
"type": "GENE-Y",
"text": [
"5-HT7"
],
"offsets": [
[
212,
217
]
],
"normalized": []
},
{
"id": "8398139_T14",
"type": "GENE-N",
"text": [
"serotonin receptor"
],
"offsets": [
[
36,
54
]
],
"normalized": []
},
{
"id": "8398139_T15",
"type": "GENE-Y",
"text": [
"5-HT7"
],
"offsets": [
[
56,
61
]
],
"normalized": []
},
{
"id": "8398139_T16",
"type": "GENE-N",
"text": [
"adenylyl cyclase"
],
"offsets": [
[
8,
24
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "8398139_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "8398139_T2",
"arg2_id": "8398139_T10",
"normalized": []
}
] |
20618322 | 20618322 | [
{
"id": "20618322_title",
"type": "title",
"text": [
"Copy number variations of the human histamine H4 receptor gene are associated with systemic lupus erythematosus."
],
"offsets": [
[
0,
112
]
]
},
{
"id": "20618322_abstract",
"type": "abstract",
"text": [
"BACKGROUND: Systemic lupus erythematosus (SLE) is a complex genetic disease; the histamine H4 receptor (HRH4) has been shown to be related to different kinds of autoimmune disorders; and copy number variations (CNVs) have been found to be associated with various types of diseases. OBJECTIVES: To explore a possible association between HRH4 (formerly H4R) CNVs and the risk of SLE. METHODS: Genomic DNA and RNA from 340 patients with SLE and 392 healthy controls were extracted, and CNVs and mRNA levels of HRH4 were examined. RESULTS: The expression of HRH4 mRNA was significantly increased in patients with SLE compared with controls. Amplification of HRH4 copy numbers significantly increased the risk of SLE [P < 0.001, odds ratio (OR) 2.26, 95% confidence interval (CI) 1.50-3.40]. HRH4 amplifications also positively correlated with the incidence of arthritis (P = 0.019, OR 1.96, 95% CI 1.11-3.47), and proteinuria (P < 0.001, OR 2.95, 95% CI 1.73-5.00) and antinuclear antibody abnormalities (P < 0.001, OR 2.97, 95% CI 1.66-5.33). Deletions of HRH4 copy numbers were protective against proteinuria (P = 0.03, OR 0.50, 95% CI 0.26-0.94). CONCLUSION: CNVs of the HRH4 gene are associated with SLE."
],
"offsets": [
[
113,
1317
]
]
}
] | [
{
"id": "20618322_T1",
"type": "CHEMICAL",
"text": [
"histamine"
],
"offsets": [
[
194,
203
]
],
"normalized": []
},
{
"id": "20618322_T2",
"type": "CHEMICAL",
"text": [
"histamine"
],
"offsets": [
[
36,
45
]
],
"normalized": []
},
{
"id": "20618322_T3",
"type": "GENE-Y",
"text": [
"HRH4"
],
"offsets": [
[
217,
221
]
],
"normalized": []
},
{
"id": "20618322_T4",
"type": "GENE-Y",
"text": [
"HRH4"
],
"offsets": [
[
1166,
1170
]
],
"normalized": []
},
{
"id": "20618322_T5",
"type": "GENE-Y",
"text": [
"HRH4"
],
"offsets": [
[
1283,
1287
]
],
"normalized": []
},
{
"id": "20618322_T6",
"type": "GENE-Y",
"text": [
"HRH4"
],
"offsets": [
[
449,
453
]
],
"normalized": []
},
{
"id": "20618322_T7",
"type": "GENE-Y",
"text": [
"H4R"
],
"offsets": [
[
464,
467
]
],
"normalized": []
},
{
"id": "20618322_T8",
"type": "GENE-Y",
"text": [
"HRH4"
],
"offsets": [
[
620,
624
]
],
"normalized": []
},
{
"id": "20618322_T9",
"type": "GENE-Y",
"text": [
"HRH4"
],
"offsets": [
[
667,
671
]
],
"normalized": []
},
{
"id": "20618322_T10",
"type": "GENE-Y",
"text": [
"HRH4"
],
"offsets": [
[
767,
771
]
],
"normalized": []
},
{
"id": "20618322_T11",
"type": "GENE-Y",
"text": [
"HRH4"
],
"offsets": [
[
900,
904
]
],
"normalized": []
},
{
"id": "20618322_T12",
"type": "GENE-Y",
"text": [
"histamine H4 receptor"
],
"offsets": [
[
194,
215
]
],
"normalized": []
},
{
"id": "20618322_T13",
"type": "GENE-Y",
"text": [
"human histamine H4 receptor"
],
"offsets": [
[
30,
57
]
],
"normalized": []
}
] | [] | [] | [] |
19057128 | 19057128 | [
{
"id": "19057128_title",
"type": "title",
"text": [
"Captopril attenuates matrix metalloproteinase-2 and -9 in monocrotaline-induced right ventricular hypertrophy in rats."
],
"offsets": [
[
0,
118
]
]
},
{
"id": "19057128_abstract",
"type": "abstract",
"text": [
"Little is known about the influence of angiotensin converting enzyme (ACE) inhibitors on matrix metalloproteinase (MMP) in right ventricular remodeling. We investigated the effect of captopril, an ACE inhibitor, on MMP-2 and MMP-9 in monocrotaline-induced right ventricular hypertrophy. Six-week-old male Wistar rats were injected intraperitoneally with monocrotaline (60 mg/kg) or saline. The rats were administrated captopril (30 mg/kg per day) or a vehicle orally for 24 days from the day of monocrotaline injection. At day 25, echocardiography was performed and hearts were excised. Expressions and activities of MMP-2 and MMP-9 were measured by Western blotting and by gelatin zymography, respectively. In monocrotaline-injected rats, right ventricular weight/tail length ratio increased significantly. Histological analysis revealed cardiomyocyte hypertrophy and fibrosis in right ventricular sections. Echocardiography showed right ventricular dysfunction compared with saline-injected rats. The right ventricular hypertrophy, fibrosis, and dysfunction were inhibited by captopril. However, captopril did not attenuate an increase in pulmonary artery pressure. MMP-2 and MMP-9 expressions and activities in right ventricles increased significantly in monocrotaline-injected rats and captopril inhibited them. These findings indicate that captopril attenuates the development of monocrotaline-induced right ventricular hypertrophy in association with inhibition of MMP-2 and MMP-9 in rats."
],
"offsets": [
[
119,
1614
]
]
}
] | [
{
"id": "19057128_T1",
"type": "CHEMICAL",
"text": [
"captopril"
],
"offsets": [
[
1197,
1206
]
],
"normalized": []
},
{
"id": "19057128_T2",
"type": "CHEMICAL",
"text": [
"captopril"
],
"offsets": [
[
1217,
1226
]
],
"normalized": []
},
{
"id": "19057128_T3",
"type": "CHEMICAL",
"text": [
"monocrotaline"
],
"offsets": [
[
1377,
1390
]
],
"normalized": []
},
{
"id": "19057128_T4",
"type": "CHEMICAL",
"text": [
"captopril"
],
"offsets": [
[
1409,
1418
]
],
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},
{
"id": "19057128_T5",
"type": "CHEMICAL",
"text": [
"captopril"
],
"offsets": [
[
1464,
1473
]
],
"normalized": []
},
{
"id": "19057128_T6",
"type": "CHEMICAL",
"text": [
"monocrotaline"
],
"offsets": [
[
1504,
1517
]
],
"normalized": []
},
{
"id": "19057128_T7",
"type": "CHEMICAL",
"text": [
"captopril"
],
"offsets": [
[
302,
311
]
],
"normalized": []
},
{
"id": "19057128_T8",
"type": "CHEMICAL",
"text": [
"monocrotaline"
],
"offsets": [
[
353,
366
]
],
"normalized": []
},
{
"id": "19057128_T9",
"type": "CHEMICAL",
"text": [
"monocrotaline"
],
"offsets": [
[
473,
486
]
],
"normalized": []
},
{
"id": "19057128_T10",
"type": "CHEMICAL",
"text": [
"angiotensin"
],
"offsets": [
[
158,
169
]
],
"normalized": []
},
{
"id": "19057128_T11",
"type": "CHEMICAL",
"text": [
"captopril"
],
"offsets": [
[
537,
546
]
],
"normalized": []
},
{
"id": "19057128_T12",
"type": "CHEMICAL",
"text": [
"monocrotaline"
],
"offsets": [
[
614,
627
]
],
"normalized": []
},
{
"id": "19057128_T13",
"type": "CHEMICAL",
"text": [
"monocrotaline"
],
"offsets": [
[
830,
843
]
],
"normalized": []
},
{
"id": "19057128_T14",
"type": "CHEMICAL",
"text": [
"Captopril"
],
"offsets": [
[
0,
9
]
],
"normalized": []
},
{
"id": "19057128_T15",
"type": "CHEMICAL",
"text": [
"monocrotaline"
],
"offsets": [
[
58,
71
]
],
"normalized": []
},
{
"id": "19057128_T16",
"type": "GENE-N",
"text": [
"MMP"
],
"offsets": [
[
234,
237
]
],
"normalized": []
},
{
"id": "19057128_T17",
"type": "GENE-Y",
"text": [
"MMP-2"
],
"offsets": [
[
1287,
1292
]
],
"normalized": []
},
{
"id": "19057128_T18",
"type": "GENE-Y",
"text": [
"MMP-9"
],
"offsets": [
[
1297,
1302
]
],
"normalized": []
},
{
"id": "19057128_T19",
"type": "GENE-Y",
"text": [
"MMP-2"
],
"offsets": [
[
1590,
1595
]
],
"normalized": []
},
{
"id": "19057128_T20",
"type": "GENE-Y",
"text": [
"MMP-9"
],
"offsets": [
[
1600,
1605
]
],
"normalized": []
},
{
"id": "19057128_T21",
"type": "GENE-Y",
"text": [
"ACE"
],
"offsets": [
[
316,
319
]
],
"normalized": []
},
{
"id": "19057128_T22",
"type": "GENE-Y",
"text": [
"MMP-2"
],
"offsets": [
[
334,
339
]
],
"normalized": []
},
{
"id": "19057128_T23",
"type": "GENE-Y",
"text": [
"MMP-9"
],
"offsets": [
[
344,
349
]
],
"normalized": []
},
{
"id": "19057128_T24",
"type": "GENE-Y",
"text": [
"angiotensin converting enzyme"
],
"offsets": [
[
158,
187
]
],
"normalized": []
},
{
"id": "19057128_T25",
"type": "GENE-Y",
"text": [
"MMP-2"
],
"offsets": [
[
736,
741
]
],
"normalized": []
},
{
"id": "19057128_T26",
"type": "GENE-Y",
"text": [
"MMP-9"
],
"offsets": [
[
746,
751
]
],
"normalized": []
},
{
"id": "19057128_T27",
"type": "GENE-Y",
"text": [
"ACE"
],
"offsets": [
[
189,
192
]
],
"normalized": []
},
{
"id": "19057128_T28",
"type": "GENE-N",
"text": [
"matrix metalloproteinase"
],
"offsets": [
[
208,
232
]
],
"normalized": []
},
{
"id": "19057128_T29",
"type": "GENE-N",
"text": [
"matrix metalloproteinase-2 and -9"
],
"offsets": [
[
21,
54
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "19057128_0",
"type": "INHIBITOR",
"arg1_id": "19057128_T7",
"arg2_id": "19057128_T21",
"normalized": []
},
{
"id": "19057128_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "19057128_T3",
"arg2_id": "19057128_T17",
"normalized": []
},
{
"id": "19057128_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "19057128_T3",
"arg2_id": "19057128_T18",
"normalized": []
},
{
"id": "19057128_3",
"type": "ACTIVATOR",
"arg1_id": "19057128_T3",
"arg2_id": "19057128_T17",
"normalized": []
},
{
"id": "19057128_4",
"type": "ACTIVATOR",
"arg1_id": "19057128_T3",
"arg2_id": "19057128_T18",
"normalized": []
},
{
"id": "19057128_5",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "19057128_T4",
"arg2_id": "19057128_T17",
"normalized": []
},
{
"id": "19057128_6",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "19057128_T4",
"arg2_id": "19057128_T18",
"normalized": []
},
{
"id": "19057128_7",
"type": "INHIBITOR",
"arg1_id": "19057128_T4",
"arg2_id": "19057128_T17",
"normalized": []
},
{
"id": "19057128_8",
"type": "INHIBITOR",
"arg1_id": "19057128_T4",
"arg2_id": "19057128_T18",
"normalized": []
},
{
"id": "19057128_9",
"type": "ACTIVATOR",
"arg1_id": "19057128_T6",
"arg2_id": "19057128_T19",
"normalized": []
},
{
"id": "19057128_10",
"type": "ACTIVATOR",
"arg1_id": "19057128_T6",
"arg2_id": "19057128_T20",
"normalized": []
},
{
"id": "19057128_11",
"type": "INHIBITOR",
"arg1_id": "19057128_T5",
"arg2_id": "19057128_T19",
"normalized": []
},
{
"id": "19057128_12",
"type": "INHIBITOR",
"arg1_id": "19057128_T5",
"arg2_id": "19057128_T20",
"normalized": []
}
] |
23393216 | 23393216 | [
{
"id": "23393216_title",
"type": "title",
"text": [
"Decreased serum concentrations of 25-hydroxycholecalciferol are associated with increased risk of progression to impaired fasting glucose and diabetes."
],
"offsets": [
[
0,
151
]
]
},
{
"id": "23393216_abstract",
"type": "abstract",
"text": [
"OBJECTIVE To study the association between vitamin D status and the risk of incident impaired fasting glucose (IFG) and diabetes in a population-based cohort of diabetes-free subjects. RESEARCH DESIGN AND METHODS In a historical prospective cohort study of subjects from the Clalit Health Services database, which includes information on nearly 4 million people, diabetes-free subjects aged 40-70 years with serum 25-hydroxycholecalciferol (25-OHD) measurements available were followed for 2 years to assess the development of IFG and diabetes in five 25-OHD subgroups: ≥25, 25.1-37.5, 37.6-50, 50.1-75, and >75 nmol/L. RESULTS The baseline cohort included 117,960 adults: 83,526 normoglycemic subjects and 34,434 subjects with IFG. During follow-up, 8,629 subjects (10.3% of the normoglycemic group) developed IFG, and 2,162 subjects (1.8% of the total cohort) progressed to diabetes. A multivariable model adjusted for age, sex, population group, immigrant status, BMI, season of vitamin D measurement, LDL and HDL cholesterol, triglycerides, estimated glomerular filtration rate, history of hypertension or cardiovascular disease, Charlson comorbidity index, smoking, and socioeconomic status revealed an inverse association between 25-OHD and the risk of progression to IFG and diabetes. The odds of transitioning from normoglycemia to IFG, from normoglycemia to diabetes, and from IFG to diabetes in subjects with a 25-OHD level ≤25 nmol/L were greater than those of subjects with a 25-OHD level >75 nmol/L [odds ratio 1.13 (95% CI 1.03-1.24), 1.77 (1.11-2.83), and 1.43 (1.16-1.76), respectively]. CONCLUSIONS Vitamin D deficiency appears to be an independent risk factor for the development of IFG and diabetes."
],
"offsets": [
[
152,
1870
]
]
}
] | [
{
"id": "23393216_T1",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
1169,
1180
]
],
"normalized": []
},
{
"id": "23393216_T2",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
254,
261
]
],
"normalized": []
},
{
"id": "23393216_T3",
"type": "CHEMICAL",
"text": [
"triglycerides"
],
"offsets": [
[
1182,
1195
]
],
"normalized": []
},
{
"id": "23393216_T4",
"type": "CHEMICAL",
"text": [
"25-OHD"
],
"offsets": [
[
1388,
1394
]
],
"normalized": []
},
{
"id": "23393216_T5",
"type": "CHEMICAL",
"text": [
"25-OHD"
],
"offsets": [
[
1573,
1579
]
],
"normalized": []
},
{
"id": "23393216_T6",
"type": "CHEMICAL",
"text": [
"25-OHD"
],
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1640,
1646
]
],
"normalized": []
},
{
"id": "23393216_T7",
"type": "CHEMICAL",
"text": [
"Vitamin D"
],
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1768,
1777
]
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"normalized": []
},
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"id": "23393216_T8",
"type": "CHEMICAL",
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"25-hydroxycholecalciferol"
],
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566,
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]
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"id": "23393216_T9",
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"vitamin D"
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195,
204
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"25-OHD"
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704,
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"vitamin D"
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"id": "23393216_T13",
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"glucose"
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130,
137
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"id": "23393216_T15",
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"LDL"
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"id": "23393216_T16",
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"HDL"
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1165,
1168
]
],
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}
] | [] | [] | [] |
23362262 | 23362262 | [
{
"id": "23362262_title",
"type": "title",
"text": [
"Transforming growth factor β integrates Smad 3 to mechanistic target of rapamycin complexes to arrest deptor abundance for glomerular mesangial cell hypertrophy."
],
"offsets": [
[
0,
161
]
]
},
{
"id": "23362262_abstract",
"type": "abstract",
"text": [
"In many renal diseases, transforming growth factor β (TGFβ)-stimulated canonical Smad 3 and noncanonical mechanistic target of rapamycin (mTOR) promote increased protein synthesis and mesangial cell hypertrophy. The cellular underpinnings involving these signaling molecules to regulate mesangial cell hypertrophy are not fully understood. Deptor has recently been identified as an mTOR interacting protein and functions as an endogenous inhibitor of the kinase activity for both TORC1 and TORC2. Prolonged incubation of mesangial cells with TGFβ reduced the levels of deptor concomitant with an increase in TORC1 and TORC2 activity. Sustained TGFβ activation was required to inhibit association of deptor with mTOR, whereas rapid activation had no effect. Using the mTOR inhibitor PP242, we found that TGFβ-induced both early and sustained activation of TORC1 and TORC2 was necessary for deptor suppression. PP242-induced reversal of deptor suppression by TGFβ was associated with a significant inhibition of TGFβ-stimulated protein synthesis and hypertrophy. Interestingly, expression of siRNA against Smad 3 or Smad 7, which blocks TGFβ receptor-specific Smad 3 signaling, prevented TGFβ-induced suppression of deptor abundance and TORC1/2 activities. Furthermore, overexpression of Smad 3 decreased deptor expression similar to TGFβ stimulation concomitant with increased TORC1 and TORC2 activities. Finally, knockdown of deptor reversed Smad 7-mediated inhibition of protein synthesis and mesangial cell hypertrophy induced by TGFβ. These data reveal the requirement of both early and late activation of mTOR for TGFβ-induced protein synthesis. Our results support that TGFβ-stimulated Smad 3 acts as a key node to instill a feedback loop between deptor down-regulation and TORC1/2 activation in driving mesangial cell hypertrophy."
],
"offsets": [
[
162,
1998
]
]
}
] | [
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"id": "23362262_T1",
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"text": [
"rapamycin"
],
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289,
298
]
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},
{
"id": "23362262_T2",
"type": "CHEMICAL",
"text": [
"PP242,"
],
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[
944,
950
]
],
"normalized": []
},
{
"id": "23362262_T3",
"type": "CHEMICAL",
"text": [
"PP242"
],
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[
1071,
1076
]
],
"normalized": []
},
{
"id": "23362262_T4",
"type": "CHEMICAL",
"text": [
"rapamycin"
],
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[
72,
81
]
],
"normalized": []
},
{
"id": "23362262_T5",
"type": "GENE-Y",
"text": [
"TGFβ"
],
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[
1172,
1176
]
],
"normalized": []
},
{
"id": "23362262_T6",
"type": "GENE-Y",
"text": [
"mechanistic target of rapamycin"
],
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[
267,
298
]
],
"normalized": []
},
{
"id": "23362262_T7",
"type": "GENE-Y",
"text": [
"Smad 3"
],
"offsets": [
[
1266,
1272
]
],
"normalized": []
},
{
"id": "23362262_T8",
"type": "GENE-Y",
"text": [
"Smad 7"
],
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[
1276,
1282
]
],
"normalized": []
},
{
"id": "23362262_T9",
"type": "GENE-N",
"text": [
"TGFβ receptor"
],
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[
1297,
1310
]
],
"normalized": []
},
{
"id": "23362262_T10",
"type": "GENE-Y",
"text": [
"Smad 3"
],
"offsets": [
[
1320,
1326
]
],
"normalized": []
},
{
"id": "23362262_T11",
"type": "GENE-Y",
"text": [
"TGFβ"
],
"offsets": [
[
1348,
1352
]
],
"normalized": []
},
{
"id": "23362262_T12",
"type": "GENE-Y",
"text": [
"deptor"
],
"offsets": [
[
1376,
1382
]
],
"normalized": []
},
{
"id": "23362262_T13",
"type": "GENE-N",
"text": [
"TORC1/2"
],
"offsets": [
[
1397,
1404
]
],
"normalized": []
},
{
"id": "23362262_T14",
"type": "GENE-Y",
"text": [
"Smad 3"
],
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[
1448,
1454
]
],
"normalized": []
},
{
"id": "23362262_T15",
"type": "GENE-Y",
"text": [
"deptor"
],
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[
1465,
1471
]
],
"normalized": []
},
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"id": "23362262_T16",
"type": "GENE-Y",
"text": [
"TGFβ"
],
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[
1494,
1498
]
],
"normalized": []
},
{
"id": "23362262_T17",
"type": "GENE-Y",
"text": [
"TORC1"
],
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[
1538,
1543
]
],
"normalized": []
},
{
"id": "23362262_T18",
"type": "GENE-Y",
"text": [
"mTOR"
],
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[
300,
304
]
],
"normalized": []
},
{
"id": "23362262_T19",
"type": "GENE-Y",
"text": [
"TORC2"
],
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[
1548,
1553
]
],
"normalized": []
},
{
"id": "23362262_T20",
"type": "GENE-Y",
"text": [
"deptor"
],
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[
1588,
1594
]
],
"normalized": []
},
{
"id": "23362262_T21",
"type": "GENE-Y",
"text": [
"Smad 7"
],
"offsets": [
[
1604,
1610
]
],
"normalized": []
},
{
"id": "23362262_T22",
"type": "GENE-Y",
"text": [
"TGFβ"
],
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[
1694,
1698
]
],
"normalized": []
},
{
"id": "23362262_T23",
"type": "GENE-Y",
"text": [
"mTOR"
],
"offsets": [
[
1771,
1775
]
],
"normalized": []
},
{
"id": "23362262_T24",
"type": "GENE-Y",
"text": [
"TGFβ"
],
"offsets": [
[
1780,
1784
]
],
"normalized": []
},
{
"id": "23362262_T25",
"type": "GENE-Y",
"text": [
"TGFβ"
],
"offsets": [
[
1837,
1841
]
],
"normalized": []
},
{
"id": "23362262_T26",
"type": "GENE-Y",
"text": [
"Smad 3"
],
"offsets": [
[
1853,
1859
]
],
"normalized": []
},
{
"id": "23362262_T27",
"type": "GENE-Y",
"text": [
"deptor"
],
"offsets": [
[
1914,
1920
]
],
"normalized": []
},
{
"id": "23362262_T28",
"type": "GENE-N",
"text": [
"TORC1/2"
],
"offsets": [
[
1941,
1948
]
],
"normalized": []
},
{
"id": "23362262_T29",
"type": "GENE-Y",
"text": [
"transforming growth factor β"
],
"offsets": [
[
186,
214
]
],
"normalized": []
},
{
"id": "23362262_T30",
"type": "GENE-Y",
"text": [
"Deptor"
],
"offsets": [
[
502,
508
]
],
"normalized": []
},
{
"id": "23362262_T31",
"type": "GENE-Y",
"text": [
"mTOR"
],
"offsets": [
[
544,
548
]
],
"normalized": []
},
{
"id": "23362262_T32",
"type": "GENE-N",
"text": [
"kinase"
],
"offsets": [
[
617,
623
]
],
"normalized": []
},
{
"id": "23362262_T33",
"type": "GENE-Y",
"text": [
"TORC1"
],
"offsets": [
[
642,
647
]
],
"normalized": []
},
{
"id": "23362262_T34",
"type": "GENE-Y",
"text": [
"TORC2"
],
"offsets": [
[
652,
657
]
],
"normalized": []
},
{
"id": "23362262_T35",
"type": "GENE-Y",
"text": [
"TGFβ"
],
"offsets": [
[
704,
708
]
],
"normalized": []
},
{
"id": "23362262_T36",
"type": "GENE-Y",
"text": [
"TGFβ"
],
"offsets": [
[
216,
220
]
],
"normalized": []
},
{
"id": "23362262_T37",
"type": "GENE-Y",
"text": [
"deptor"
],
"offsets": [
[
731,
737
]
],
"normalized": []
},
{
"id": "23362262_T38",
"type": "GENE-Y",
"text": [
"TORC1"
],
"offsets": [
[
770,
775
]
],
"normalized": []
},
{
"id": "23362262_T39",
"type": "GENE-Y",
"text": [
"TORC2"
],
"offsets": [
[
780,
785
]
],
"normalized": []
},
{
"id": "23362262_T40",
"type": "GENE-Y",
"text": [
"TGFβ"
],
"offsets": [
[
806,
810
]
],
"normalized": []
},
{
"id": "23362262_T41",
"type": "GENE-Y",
"text": [
"deptor"
],
"offsets": [
[
861,
867
]
],
"normalized": []
},
{
"id": "23362262_T42",
"type": "GENE-N",
"text": [
"mTOR"
],
"offsets": [
[
873,
877
]
],
"normalized": []
},
{
"id": "23362262_T43",
"type": "GENE-Y",
"text": [
"mTOR"
],
"offsets": [
[
929,
933
]
],
"normalized": []
},
{
"id": "23362262_T44",
"type": "GENE-Y",
"text": [
"TGFβ"
],
"offsets": [
[
965,
969
]
],
"normalized": []
},
{
"id": "23362262_T45",
"type": "GENE-Y",
"text": [
"Smad 3"
],
"offsets": [
[
243,
249
]
],
"normalized": []
},
{
"id": "23362262_T46",
"type": "GENE-Y",
"text": [
"TORC1"
],
"offsets": [
[
1017,
1022
]
],
"normalized": []
},
{
"id": "23362262_T47",
"type": "GENE-Y",
"text": [
"TORC2"
],
"offsets": [
[
1027,
1032
]
],
"normalized": []
},
{
"id": "23362262_T48",
"type": "GENE-Y",
"text": [
"deptor"
],
"offsets": [
[
1051,
1057
]
],
"normalized": []
},
{
"id": "23362262_T49",
"type": "GENE-Y",
"text": [
"deptor"
],
"offsets": [
[
1097,
1103
]
],
"normalized": []
},
{
"id": "23362262_T50",
"type": "GENE-Y",
"text": [
"TGFβ"
],
"offsets": [
[
1119,
1123
]
],
"normalized": []
},
{
"id": "23362262_T51",
"type": "GENE-Y",
"text": [
"Transforming growth factor β"
],
"offsets": [
[
0,
28
]
],
"normalized": []
},
{
"id": "23362262_T52",
"type": "GENE-Y",
"text": [
"deptor"
],
"offsets": [
[
102,
108
]
],
"normalized": []
},
{
"id": "23362262_T53",
"type": "GENE-Y",
"text": [
"Smad 3"
],
"offsets": [
[
40,
46
]
],
"normalized": []
},
{
"id": "23362262_T54",
"type": "GENE-Y",
"text": [
"mechanistic target of rapamycin"
],
"offsets": [
[
50,
81
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23362262_0",
"type": "INHIBITOR",
"arg1_id": "23362262_T2",
"arg2_id": "23362262_T43",
"normalized": []
},
{
"id": "23362262_1",
"type": "ACTIVATOR",
"arg1_id": "23362262_T3",
"arg2_id": "23362262_T49",
"normalized": []
}
] |
23256441 | 23256441 | [
{
"id": "23256441_title",
"type": "title",
"text": [
"Bamboo salt has in vitro anticancer activity in HCT-116 cells and exerts anti-metastatic effects in vivo."
],
"offsets": [
[
0,
105
]
]
},
{
"id": "23256441_abstract",
"type": "abstract",
"text": [
"Bamboo salt is a traditional food widely used in Korea. The in vitro anticancer effects of this salt were evaluated in HCT-116 human colon cancer cells using a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. A 1% salt concentration of bamboo salt baked nine times (9×) inhibited the growth of HCT-116 cells by 53%, which was higher than salt baked three times (3×) or once (1×; 44% and 41%, respectively) and much higher than solar sea salt (Korean sea salt) and purified salt (22% and 18%, respectively). To elucidate the inhibitory mechanisms underlying the anticancer effect of the salt samples in cancer cells, expression of genes associated with apoptosis, inflammation, and metastasis was measured with reverse transcription-polymerase chain reaction and Western blotting. Bamboo salt (9×) significantly induced apoptosis in cancer cells (P<.05) by upregulating Bax, caspase-9, and caspase-3, and downregulating Bcl-2. The expression of genes associated with inflammation (NF-κB, iNOS, and COX-2) was significantly downregulated (P<.05) by 9× bamboo salt, demonstrating its anti-inflammatory properties. The 9× bamboo salt also exerted a greater anti-metastatic effect on cancer cells than the other salts as demonstrated by decreased mRNA expression of MMP genes and increased expression of tissue inhibitors of metalloproteinases, which was confirmed by the inhibition of tumor metastasis induced in colon 26-M3.1 cells in BALB/c mice. In contrast, purified and solar salts increased metastasis in the mice. Our results demonstrated that 9× bamboo salt had the most potent in vitro anticancer effect, induced apoptosis, had anti-inflammatory activities, and exerted in vivo anti-metastatic effects. Additionally, the anticancer, anti-inflammatory, and anti-metastatic effects of the 1× and 3× bamboo salts were stronger than those of the purified and solar salts."
],
"offsets": [
[
106,
2003
]
]
}
] | [
{
"id": "23256441_T1",
"type": "CHEMICAL",
"text": [
"solar salts"
],
"offsets": [
[
1602,
1613
]
],
"normalized": []
},
{
"id": "23256441_T2",
"type": "CHEMICAL",
"text": [
"3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide"
],
"offsets": [
[
266,
326
]
],
"normalized": []
},
{
"id": "23256441_T3",
"type": "CHEMICAL",
"text": [
"solar salts"
],
"offsets": [
[
1991,
2002
]
],
"normalized": []
},
{
"id": "23256441_T4",
"type": "CHEMICAL",
"text": [
"MTT"
],
"offsets": [
[
328,
331
]
],
"normalized": []
},
{
"id": "23256441_T5",
"type": "GENE-N",
"text": [
"NF-κB"
],
"offsets": [
[
1111,
1116
]
],
"normalized": []
},
{
"id": "23256441_T6",
"type": "GENE-Y",
"text": [
"iNOS"
],
"offsets": [
[
1118,
1122
]
],
"normalized": []
},
{
"id": "23256441_T7",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
1128,
1133
]
],
"normalized": []
},
{
"id": "23256441_T8",
"type": "GENE-N",
"text": [
"MMP"
],
"offsets": [
[
1392,
1395
]
],
"normalized": []
},
{
"id": "23256441_T9",
"type": "GENE-N",
"text": [
"tissue inhibitors of metalloproteinases"
],
"offsets": [
[
1430,
1469
]
],
"normalized": []
},
{
"id": "23256441_T10",
"type": "GENE-Y",
"text": [
"Bax"
],
"offsets": [
[
1000,
1003
]
],
"normalized": []
},
{
"id": "23256441_T11",
"type": "GENE-Y",
"text": [
"caspase-9"
],
"offsets": [
[
1005,
1014
]
],
"normalized": []
},
{
"id": "23256441_T12",
"type": "GENE-Y",
"text": [
"caspase-3"
],
"offsets": [
[
1020,
1029
]
],
"normalized": []
},
{
"id": "23256441_T13",
"type": "GENE-Y",
"text": [
"Bcl-2"
],
"offsets": [
[
1050,
1055
]
],
"normalized": []
}
] | [] | [] | [] |
16985933 | 16985933 | [
{
"id": "16985933_title",
"type": "title",
"text": [
"Gonadotropin-releasing hormone antagonist in the management of prostate cancer."
],
"offsets": [
[
0,
79
]
]
},
{
"id": "16985933_abstract",
"type": "abstract",
"text": [
"Luteinizing hormone-releasing hormone (LHRH) agonist therapy to induce medical castration has become the most common form of hormonal therapy for advanced and metastatic prostate cancer. When treatment is started, LHRH agonists initially stimulate the release of LH, causing a surge in serum testosterone that can precipitate a \"flare\" phenomenon or worsening of disease, particularly in patients with bone metastatic disease. Gonadotropin-releasing hormone (GnRH) receptor antagonism represents a newer approach to medical castration. Abarelix is a pure GnRH receptor antagonist that is devoid of any LHRH agonist activity. Results from 1 phase II and 3 phase III clinical trials demonstrate that abarelix produces medical castration more quickly and without causing testosterone surge, as compared with LHRH agonists with or without a nonsteroidal antagonist. The safety profile in terms of adverse events is comparable between the 2 types of treatment, but the lack of testosterone surge with abarelix might confer a safety advantage by abolishing the risk of a disease flare."
],
"offsets": [
[
80,
1159
]
]
}
] | [
{
"id": "16985933_T1",
"type": "CHEMICAL",
"text": [
"testosterone"
],
"offsets": [
[
372,
384
]
],
"normalized": []
},
{
"id": "16985933_T2",
"type": "CHEMICAL",
"text": [
"testosterone"
],
"offsets": [
[
848,
860
]
],
"normalized": []
},
{
"id": "16985933_T3",
"type": "CHEMICAL",
"text": [
"testosterone"
],
"offsets": [
[
1052,
1064
]
],
"normalized": []
},
{
"id": "16985933_T4",
"type": "GENE-Y",
"text": [
"Luteinizing hormone-releasing hormone"
],
"offsets": [
[
80,
117
]
],
"normalized": []
},
{
"id": "16985933_T5",
"type": "GENE-Y",
"text": [
"LHRH"
],
"offsets": [
[
294,
298
]
],
"normalized": []
},
{
"id": "16985933_T6",
"type": "GENE-N",
"text": [
"LH"
],
"offsets": [
[
343,
345
]
],
"normalized": []
},
{
"id": "16985933_T7",
"type": "GENE-Y",
"text": [
"LHRH"
],
"offsets": [
[
119,
123
]
],
"normalized": []
},
{
"id": "16985933_T8",
"type": "GENE-Y",
"text": [
"Gonadotropin-releasing hormone (GnRH) receptor"
],
"offsets": [
[
507,
553
]
],
"normalized": []
},
{
"id": "16985933_T9",
"type": "GENE-Y",
"text": [
"GnRH receptor"
],
"offsets": [
[
635,
648
]
],
"normalized": []
},
{
"id": "16985933_T10",
"type": "GENE-Y",
"text": [
"LHRH"
],
"offsets": [
[
682,
686
]
],
"normalized": []
},
{
"id": "16985933_T11",
"type": "GENE-Y",
"text": [
"LHRH"
],
"offsets": [
[
885,
889
]
],
"normalized": []
},
{
"id": "16985933_T12",
"type": "GENE-Y",
"text": [
"Gonadotropin-releasing hormone"
],
"offsets": [
[
0,
30
]
],
"normalized": []
}
] | [] | [] | [] |
19302827 | 19302827 | [
{
"id": "19302827_title",
"type": "title",
"text": [
"Novel signaling pathways promote a paracrine wave of prostacyclin-induced vascular smooth muscle differentiation."
],
"offsets": [
[
0,
113
]
]
},
{
"id": "19302827_abstract",
"type": "abstract",
"text": [
"The important athero-protective role of prostacyclin is becoming increasingly evident as recent studies have revealed adverse cardiovascular effects in mice lacking the prostacyclin receptor, in patients taking selective COX-2 inhibitors, and in patients in the presence of a dysfunctional prostacyclin receptor genetic variant. We have recently reported that this protective mechanism includes the promotion of a quiescent differentiated phenotype in human vascular smooth muscle cells (VSMC). Herein, we address the intriguing question of how localized endothelial release of the very unstable eicosanoid, prostacyclin, exerts a profound effect on the vascular media, often 30 cell layers thick. We report a novel PKA-, Akt-1- and ERK1/2-dependent prostacyclin-induced prostacyclin release that appears to play an important role in propagation of the quiescent, differentiated phenotype through adjacent arterial smooth muscle cells in the vascular media. Treating VSMC with the prostacyclin analog iloprost induced differentiation (contractile protein expression and contractile morphology), and also up-regulated COX-2 expression, leading to prostacyclin release by VSMC. This paracrine prostacyclin release, in turn, promoted differentiation and COX-2 induction in neighboring VSMC that were not exposed to iloprost. Using siRNA and pharmacologic inhibitors, we report that this positive feedback mechanism, prostacyclin-induced prostacyclin release, is mediated by cAMP/PKA signaling, ERK1/2 activation, and a novel prostacyclin receptor signaling pathway, inhibition of Akt-1. Furthermore, these pathways appear to be regulated by the prostacyclin receptor independently of one another. We conclude that prevention of de-differentiation and proliferation through a paracrine positive feedback mechanism is a major cardioprotective function of prostacyclin."
],
"offsets": [
[
114,
1977
]
]
}
] | [
{
"id": "19302827_T1",
"type": "CHEMICAL",
"text": [
"iloprost"
],
"offsets": [
[
1115,
1123
]
],
"normalized": []
},
{
"id": "19302827_T2",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
1260,
1272
]
],
"normalized": []
},
{
"id": "19302827_T3",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
1305,
1317
]
],
"normalized": []
},
{
"id": "19302827_T4",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
1527,
1539
]
],
"normalized": []
},
{
"id": "19302827_T5",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
1548,
1560
]
],
"normalized": []
},
{
"id": "19302827_T6",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
1636,
1648
]
],
"normalized": []
},
{
"id": "19302827_T7",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
1756,
1768
]
],
"normalized": []
},
{
"id": "19302827_T8",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
283,
295
]
],
"normalized": []
},
{
"id": "19302827_T9",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
1964,
1976
]
],
"normalized": []
},
{
"id": "19302827_T10",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
404,
416
]
],
"normalized": []
},
{
"id": "19302827_T11",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
154,
166
]
],
"normalized": []
},
{
"id": "19302827_T12",
"type": "CHEMICAL",
"text": [
"eicosanoid"
],
"offsets": [
[
710,
720
]
],
"normalized": []
},
{
"id": "19302827_T13",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
722,
734
]
],
"normalized": []
},
{
"id": "19302827_T14",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
864,
876
]
],
"normalized": []
},
{
"id": "19302827_T15",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
885,
897
]
],
"normalized": []
},
{
"id": "19302827_T16",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
1095,
1107
]
],
"normalized": []
},
{
"id": "19302827_T17",
"type": "CHEMICAL",
"text": [
"prostacyclin"
],
"offsets": [
[
53,
65
]
],
"normalized": []
},
{
"id": "19302827_T18",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
1231,
1236
]
],
"normalized": []
},
{
"id": "19302827_T19",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
1365,
1370
]
],
"normalized": []
},
{
"id": "19302827_T20",
"type": "GENE-N",
"text": [
"PKA"
],
"offsets": [
[
1590,
1593
]
],
"normalized": []
},
{
"id": "19302827_T21",
"type": "GENE-N",
"text": [
"ERK1/2"
],
"offsets": [
[
1605,
1611
]
],
"normalized": []
},
{
"id": "19302827_T22",
"type": "GENE-Y",
"text": [
"prostacyclin receptor"
],
"offsets": [
[
1636,
1657
]
],
"normalized": []
},
{
"id": "19302827_T23",
"type": "GENE-Y",
"text": [
"Akt-1"
],
"offsets": [
[
1691,
1696
]
],
"normalized": []
},
{
"id": "19302827_T24",
"type": "GENE-Y",
"text": [
"prostacyclin receptor"
],
"offsets": [
[
1756,
1777
]
],
"normalized": []
},
{
"id": "19302827_T25",
"type": "GENE-Y",
"text": [
"prostacyclin receptor"
],
"offsets": [
[
283,
304
]
],
"normalized": []
},
{
"id": "19302827_T26",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
335,
340
]
],
"normalized": []
},
{
"id": "19302827_T27",
"type": "GENE-Y",
"text": [
"prostacyclin receptor"
],
"offsets": [
[
404,
425
]
],
"normalized": []
},
{
"id": "19302827_T28",
"type": "GENE-N",
"text": [
"PKA"
],
"offsets": [
[
830,
833
]
],
"normalized": []
},
{
"id": "19302827_T29",
"type": "GENE-Y",
"text": [
"Akt-1"
],
"offsets": [
[
836,
841
]
],
"normalized": []
},
{
"id": "19302827_T30",
"type": "GENE-N",
"text": [
"ERK1/2"
],
"offsets": [
[
847,
853
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "19302827_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "19302827_T1",
"arg2_id": "19302827_T18",
"normalized": []
},
{
"id": "19302827_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "19302827_T16",
"arg2_id": "19302827_T18",
"normalized": []
},
{
"id": "19302827_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "19302827_T3",
"arg2_id": "19302827_T19",
"normalized": []
},
{
"id": "19302827_3",
"type": "PRODUCT-OF",
"arg1_id": "19302827_T2",
"arg2_id": "19302827_T18",
"normalized": []
}
] |
23274909 | 23274909 | [
{
"id": "23274909_title",
"type": "title",
"text": [
"Nogo-a downregulation improves insulin secretion in mice."
],
"offsets": [
[
0,
57
]
]
},
{
"id": "23274909_abstract",
"type": "abstract",
"text": [
"Type 2 diabetes (T2D) is characterized by β-cell dysfunction and the subsequent depletion of insulin production, usually in a context of increased peripheral insulin resistance. T2D patients are routinely treated with oral antidiabetic agents such as sulfonylureas or dipeptidyl peptidase-4 antagonists, which promote glucose- and incretin-dependent insulin secretion, respectively. Interestingly, insulin secretion may also be induced by neural stimulation. Here we report the expression of Nogo-A in β-cells. Nogo-A is a membrane protein that inhibits neurite outgrowth and cell migration in the central nervous system. We observed that Nogo-A-deficient mice display improved insulin secretion and glucose clearance. This was associated with a stronger parasympathetic input and higher sensitivity of β-cells to the cholinergic analog carbachol. Insulin secretion was also improved in diabetic db/db mice treated with neutralizing antibody against Nogo-A. Together, these findings suggest that promoting the vagal stimulation of insulin secretion through the selective inhibition of Nogo-A could be a novel therapeutic approach in T2D."
],
"offsets": [
[
58,
1195
]
]
}
] | [
{
"id": "23274909_T1",
"type": "CHEMICAL",
"text": [
"sulfonylureas"
],
"offsets": [
[
309,
322
]
],
"normalized": []
},
{
"id": "23274909_T2",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
376,
383
]
],
"normalized": []
},
{
"id": "23274909_T3",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
758,
765
]
],
"normalized": []
},
{
"id": "23274909_T4",
"type": "CHEMICAL",
"text": [
"carbachol"
],
"offsets": [
[
895,
904
]
],
"normalized": []
},
{
"id": "23274909_T5",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1089,
1096
]
],
"normalized": []
},
{
"id": "23274909_T6",
"type": "GENE-Y",
"text": [
"Nogo-A"
],
"offsets": [
[
1143,
1149
]
],
"normalized": []
},
{
"id": "23274909_T7",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
216,
223
]
],
"normalized": []
},
{
"id": "23274909_T8",
"type": "GENE-Y",
"text": [
"dipeptidyl peptidase-4"
],
"offsets": [
[
326,
348
]
],
"normalized": []
},
{
"id": "23274909_T9",
"type": "GENE-N",
"text": [
"incretin"
],
"offsets": [
[
389,
397
]
],
"normalized": []
},
{
"id": "23274909_T10",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
408,
415
]
],
"normalized": []
},
{
"id": "23274909_T11",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
456,
463
]
],
"normalized": []
},
{
"id": "23274909_T12",
"type": "GENE-Y",
"text": [
"Nogo-A"
],
"offsets": [
[
550,
556
]
],
"normalized": []
},
{
"id": "23274909_T13",
"type": "GENE-Y",
"text": [
"Nogo-A"
],
"offsets": [
[
569,
575
]
],
"normalized": []
},
{
"id": "23274909_T14",
"type": "GENE-Y",
"text": [
"Nogo-A"
],
"offsets": [
[
697,
703
]
],
"normalized": []
},
{
"id": "23274909_T15",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
736,
743
]
],
"normalized": []
},
{
"id": "23274909_T16",
"type": "GENE-N",
"text": [
"Insulin"
],
"offsets": [
[
906,
913
]
],
"normalized": []
},
{
"id": "23274909_T17",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
151,
158
]
],
"normalized": []
},
{
"id": "23274909_T18",
"type": "GENE-Y",
"text": [
"Nogo-A"
],
"offsets": [
[
1008,
1014
]
],
"normalized": []
},
{
"id": "23274909_T19",
"type": "GENE-Y",
"text": [
"Nogo-a"
],
"offsets": [
[
0,
6
]
],
"normalized": []
},
{
"id": "23274909_T20",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
31,
38
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23274909_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23274909_T1",
"arg2_id": "23274909_T10",
"normalized": []
}
] |
12185406 | 12185406 | [
{
"id": "12185406_title",
"type": "title",
"text": [
"Bupropion occupancy of the dopamine transporter is low during clinical treatment."
],
"offsets": [
[
0,
81
]
]
},
{
"id": "12185406_abstract",
"type": "abstract",
"text": [
"RATIONALE: Bupropion is thought to treat major depression by blocking the dopamine transporter (DAT) because bupropion appears to have a selective affinity for the DAT. The validity of this mechanism has been questioned because the affinity of bupropion for the DAT is quite low. OBJECTIVE: To determine the occupancy of bupropion for the DAT during clinical treatment of patients with depression. METHODS: Positron emission tomography with [(11)C]-RTI32 was used to determine the striatal DAT binding potential (BP) of eight depressed patients before and during treatment with bupropion. BP is proportional to available receptor density (receptors not blocked by drug). Occupancy is the percent change in BP. Eight healthy subjects were similarly studied in a test-retest design. RESULTS: No significant difference in DAT BP was found after bupropion treatment in comparison to the test-retest data. The occupancy after bupropion treatment was 14% (confidence interval 6-22%) as compared to 7% in the test-retest condition. CONCLUSIONS: Bupropion treatment occupies less than 22% of DAT sites. This raises the question as to whether a DAT occupancy of less than 22% is therapeutic or whether there is another mechanism involved during treatment with bupropion."
],
"offsets": [
[
82,
1343
]
]
}
] | [
{
"id": "12185406_T1",
"type": "CHEMICAL",
"text": [
"Bupropion"
],
"offsets": [
[
1120,
1129
]
],
"normalized": []
},
{
"id": "12185406_T2",
"type": "CHEMICAL",
"text": [
"bupropion"
],
"offsets": [
[
191,
200
]
],
"normalized": []
},
{
"id": "12185406_T3",
"type": "CHEMICAL",
"text": [
"Bupropion"
],
"offsets": [
[
93,
102
]
],
"normalized": []
},
{
"id": "12185406_T4",
"type": "CHEMICAL",
"text": [
"bupropion"
],
"offsets": [
[
1333,
1342
]
],
"normalized": []
},
{
"id": "12185406_T5",
"type": "CHEMICAL",
"text": [
"bupropion"
],
"offsets": [
[
326,
335
]
],
"normalized": []
},
{
"id": "12185406_T6",
"type": "CHEMICAL",
"text": [
"bupropion"
],
"offsets": [
[
403,
412
]
],
"normalized": []
},
{
"id": "12185406_T7",
"type": "CHEMICAL",
"text": [
"[(11)C]-RTI32"
],
"offsets": [
[
523,
536
]
],
"normalized": []
},
{
"id": "12185406_T8",
"type": "CHEMICAL",
"text": [
"bupropion"
],
"offsets": [
[
660,
669
]
],
"normalized": []
},
{
"id": "12185406_T9",
"type": "CHEMICAL",
"text": [
"dopamine"
],
"offsets": [
[
156,
164
]
],
"normalized": []
},
{
"id": "12185406_T10",
"type": "CHEMICAL",
"text": [
"bupropion"
],
"offsets": [
[
924,
933
]
],
"normalized": []
},
{
"id": "12185406_T11",
"type": "CHEMICAL",
"text": [
"bupropion"
],
"offsets": [
[
1003,
1012
]
],
"normalized": []
},
{
"id": "12185406_T12",
"type": "CHEMICAL",
"text": [
"Bupropion"
],
"offsets": [
[
0,
9
]
],
"normalized": []
},
{
"id": "12185406_T13",
"type": "CHEMICAL",
"text": [
"dopamine"
],
"offsets": [
[
27,
35
]
],
"normalized": []
},
{
"id": "12185406_T14",
"type": "GENE-Y",
"text": [
"DAT"
],
"offsets": [
[
1166,
1169
]
],
"normalized": []
},
{
"id": "12185406_T15",
"type": "GENE-Y",
"text": [
"DAT"
],
"offsets": [
[
1218,
1221
]
],
"normalized": []
},
{
"id": "12185406_T16",
"type": "GENE-Y",
"text": [
"DAT"
],
"offsets": [
[
246,
249
]
],
"normalized": []
},
{
"id": "12185406_T17",
"type": "GENE-Y",
"text": [
"DAT"
],
"offsets": [
[
344,
347
]
],
"normalized": []
},
{
"id": "12185406_T18",
"type": "GENE-Y",
"text": [
"DAT"
],
"offsets": [
[
421,
424
]
],
"normalized": []
},
{
"id": "12185406_T19",
"type": "GENE-Y",
"text": [
"DAT"
],
"offsets": [
[
572,
575
]
],
"normalized": []
},
{
"id": "12185406_T20",
"type": "GENE-Y",
"text": [
"dopamine transporter"
],
"offsets": [
[
156,
176
]
],
"normalized": []
},
{
"id": "12185406_T21",
"type": "GENE-Y",
"text": [
"DAT"
],
"offsets": [
[
901,
904
]
],
"normalized": []
},
{
"id": "12185406_T22",
"type": "GENE-Y",
"text": [
"DAT"
],
"offsets": [
[
178,
181
]
],
"normalized": []
},
{
"id": "12185406_T23",
"type": "GENE-Y",
"text": [
"dopamine transporter"
],
"offsets": [
[
27,
47
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12185406_0",
"type": "INHIBITOR",
"arg1_id": "12185406_T3",
"arg2_id": "12185406_T20",
"normalized": []
},
{
"id": "12185406_1",
"type": "INHIBITOR",
"arg1_id": "12185406_T3",
"arg2_id": "12185406_T22",
"normalized": []
},
{
"id": "12185406_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "12185406_T2",
"arg2_id": "12185406_T16",
"normalized": []
},
{
"id": "12185406_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "12185406_T5",
"arg2_id": "12185406_T17",
"normalized": []
},
{
"id": "12185406_4",
"type": "DIRECT-REGULATOR",
"arg1_id": "12185406_T7",
"arg2_id": "12185406_T19",
"normalized": []
},
{
"id": "12185406_5",
"type": "DIRECT-REGULATOR",
"arg1_id": "12185406_T12",
"arg2_id": "12185406_T23",
"normalized": []
},
{
"id": "12185406_6",
"type": "DIRECT-REGULATOR",
"arg1_id": "12185406_T1",
"arg2_id": "12185406_T14",
"normalized": []
},
{
"id": "12185406_7",
"type": "DIRECT-REGULATOR",
"arg1_id": "12185406_T4",
"arg2_id": "12185406_T15",
"normalized": []
}
] |
23395003 | 23395003 | [
{
"id": "23395003_title",
"type": "title",
"text": [
"Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation."
],
"offsets": [
[
0,
100
]
]
},
{
"id": "23395003_abstract",
"type": "abstract",
"text": [
"Polycomb repressive complex 1 (PRC1) catalyzes lysine 119 monoubiquitylation on H2A (H2AK119ub1) and regulates pluripotency in embryonic stem cells (ESCs). However, the mechanisms controlling the binding of PRC1 to genomic sites and its catalytic activity are poorly understood. Here, we show that Fbxl10 interacts with Ring1B and Nspc1, forming a noncanonical PRC1 that is required for H2AK119ub1 in mouse ESCs. Genome-wide analyses reveal that Fbxl10 preferentially binds to CpG islands and colocalizes with Ring1B on Polycomb target genes. Notably, Fbxl10 depletion causes a decrease in Ring1B binding to target genes and a major loss of H2AK119ub1. Furthermore, genetic analyses demonstrate that Fbxl10 DNA binding capability and integration into PRC1 are required for H2AK119 ubiquitylation. ESCs lacking Fbxl10, like previously characterized Polycomb mutants, cannot differentiate properly. These results demonstrate that Fbxl10 has a key role in regulating Ring1B recruitment to its target genes and H2AK119 ubiquitylation in ESCs."
],
"offsets": [
[
101,
1139
]
]
}
] | [
{
"id": "23395003_T1",
"type": "CHEMICAL",
"text": [
"lysine"
],
"offsets": [
[
148,
154
]
],
"normalized": []
},
{
"id": "23395003_T2",
"type": "CHEMICAL",
"text": [
"CpG"
],
"offsets": [
[
578,
581
]
],
"normalized": []
},
{
"id": "23395003_T3",
"type": "CHEMICAL",
"text": [
"CpG"
],
"offsets": [
[
55,
58
]
],
"normalized": []
},
{
"id": "23395003_T4",
"type": "GENE-N",
"text": [
"Polycomb repressive complex 1"
],
"offsets": [
[
101,
130
]
],
"normalized": []
},
{
"id": "23395003_T5",
"type": "GENE-N",
"text": [
"H2A"
],
"offsets": [
[
1108,
1111
]
],
"normalized": []
},
{
"id": "23395003_T6",
"type": "GENE-N",
"text": [
"PRC1"
],
"offsets": [
[
308,
312
]
],
"normalized": []
},
{
"id": "23395003_T7",
"type": "GENE-Y",
"text": [
"Fbxl10"
],
"offsets": [
[
399,
405
]
],
"normalized": []
},
{
"id": "23395003_T8",
"type": "GENE-N",
"text": [
"PRC1"
],
"offsets": [
[
132,
136
]
],
"normalized": []
},
{
"id": "23395003_T9",
"type": "GENE-Y",
"text": [
"Ring1B"
],
"offsets": [
[
421,
427
]
],
"normalized": []
},
{
"id": "23395003_T10",
"type": "GENE-Y",
"text": [
"Nspc1"
],
"offsets": [
[
432,
437
]
],
"normalized": []
},
{
"id": "23395003_T11",
"type": "GENE-N",
"text": [
"PRC1"
],
"offsets": [
[
462,
466
]
],
"normalized": []
},
{
"id": "23395003_T12",
"type": "GENE-N",
"text": [
"H2A"
],
"offsets": [
[
488,
491
]
],
"normalized": []
},
{
"id": "23395003_T13",
"type": "GENE-Y",
"text": [
"Fbxl10"
],
"offsets": [
[
547,
553
]
],
"normalized": []
},
{
"id": "23395003_T14",
"type": "GENE-Y",
"text": [
"Ring1B"
],
"offsets": [
[
611,
617
]
],
"normalized": []
},
{
"id": "23395003_T15",
"type": "GENE-N",
"text": [
"Polycomb"
],
"offsets": [
[
621,
629
]
],
"normalized": []
},
{
"id": "23395003_T16",
"type": "GENE-Y",
"text": [
"Fbxl10"
],
"offsets": [
[
653,
659
]
],
"normalized": []
},
{
"id": "23395003_T17",
"type": "GENE-Y",
"text": [
"Ring1B"
],
"offsets": [
[
691,
697
]
],
"normalized": []
},
{
"id": "23395003_T18",
"type": "GENE-N",
"text": [
"H2A"
],
"offsets": [
[
742,
745
]
],
"normalized": []
},
{
"id": "23395003_T19",
"type": "GENE-Y",
"text": [
"Fbxl10"
],
"offsets": [
[
801,
807
]
],
"normalized": []
},
{
"id": "23395003_T20",
"type": "GENE-N",
"text": [
"PRC1"
],
"offsets": [
[
852,
856
]
],
"normalized": []
},
{
"id": "23395003_T21",
"type": "GENE-N",
"text": [
"H2A"
],
"offsets": [
[
874,
877
]
],
"normalized": []
},
{
"id": "23395003_T22",
"type": "GENE-N",
"text": [
"H2A"
],
"offsets": [
[
181,
184
]
],
"normalized": []
},
{
"id": "23395003_T23",
"type": "GENE-Y",
"text": [
"Fbxl10"
],
"offsets": [
[
911,
917
]
],
"normalized": []
},
{
"id": "23395003_T24",
"type": "GENE-N",
"text": [
"Polycomb"
],
"offsets": [
[
949,
957
]
],
"normalized": []
},
{
"id": "23395003_T25",
"type": "GENE-N",
"text": [
"H2A"
],
"offsets": [
[
186,
189
]
],
"normalized": []
},
{
"id": "23395003_T26",
"type": "GENE-Y",
"text": [
"Fbxl10"
],
"offsets": [
[
1029,
1035
]
],
"normalized": []
},
{
"id": "23395003_T27",
"type": "GENE-Y",
"text": [
"Ring1B"
],
"offsets": [
[
1065,
1071
]
],
"normalized": []
},
{
"id": "23395003_T28",
"type": "GENE-Y",
"text": [
"Fbxl10"
],
"offsets": [
[
0,
6
]
],
"normalized": []
},
{
"id": "23395003_T29",
"type": "GENE-N",
"text": [
"polycomb repressive complex 1"
],
"offsets": [
[
22,
51
]
],
"normalized": []
},
{
"id": "23395003_T30",
"type": "GENE-Y",
"text": [
"Kdm2b"
],
"offsets": [
[
7,
12
]
],
"normalized": []
},
{
"id": "23395003_T31",
"type": "GENE-N",
"text": [
"H2A"
],
"offsets": [
[
81,
84
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23395003_0",
"type": "PART-OF",
"arg1_id": "23395003_T1",
"arg2_id": "23395003_T22",
"normalized": []
},
{
"id": "23395003_1",
"type": "PART-OF",
"arg1_id": "23395003_T1",
"arg2_id": "23395003_T25",
"normalized": []
},
{
"id": "23395003_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "23395003_T2",
"arg2_id": "23395003_T13",
"normalized": []
},
{
"id": "23395003_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "23395003_T3",
"arg2_id": "23395003_T29",
"normalized": []
}
] |
23386248 | 23386248 | [
{
"id": "23386248_title",
"type": "title",
"text": [
"Refining the UGT1A haplotype associated with irinotecan-induced hematological toxicity in metastatic colorectal cancer patients treated with 5-fluorouracil/irinotecan-based regimens."
],
"offsets": [
[
0,
182
]
]
},
{
"id": "23386248_abstract",
"type": "abstract",
"text": [
"Despite the importance of UDP-glucuronosyltransferase (UGT) 1A1*28 in irinotecan pharmacogenetics, our capability to predict drug-induced severe toxicity remains limited. We aimed at identifying novel genetic markers that would improve prediction of irinotecan toxicity and response in advanced colorectal cancer patients treated with folic acid (leucovorin), fluorouracil (5-FU), and irinotecan (camptosar)-based regimens. The relationships between UGT1A candidate markers across the gene (n = 21) and toxicity were prospectively evaluated in 167 patients. We included variants in the 3'untranscribed region (3'UTR) of the UGT1A locus, not studied in this context yet. These genetic markers were further investigated in 250 Italian FOLFIRI-treated patients. Several functional UGT1A variants, including UGT1A1*28, significantly influenced risk of severe hematologic toxicity. As previously reported in the Italian cohort, a 5-marker risk haplotype [haplotype II (HII); UGTs 1A9/1A7/1A1] was associated with severe neutropenia in our cohort [odds ratio (OR) = 2.43; P = 0.004]. The inclusion of a 3'UTR single-nucleotide polymorphism (SNP) permitted refinement of the previously defined HI, in which HIa was associated with the absence of severe neutropenia in combined cohorts (OR = 0.55; P = 0.038). Among all tested UGT1A variations and upon multivariate analyses, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to neutropenia grade 3-4. Haplotype analyses of these markers with the 3'UTR SNP allowed the identification of a protective HI (OR = 0.50; P = 0.048) and two risk haplotypes, HII and HIII, characterized by 2 and 3 unfavorable alleles, respectively, revealing a dosage effect (ORs of 2.15 and 5.28; P ≤ 0.030). Our results suggest that specific SNPs in UGT1A, other than UGT1A1*28, may influence irinotecan toxicity and should be considered to refine pharmacogenetic testing."
],
"offsets": [
[
183,
2132
]
]
}
] | [
{
"id": "23386248_T1",
"type": "CHEMICAL",
"text": [
"irinotecan"
],
"offsets": [
[
2053,
2063
]
],
"normalized": []
},
{
"id": "23386248_T2",
"type": "CHEMICAL",
"text": [
"irinotecan"
],
"offsets": [
[
433,
443
]
],
"normalized": []
},
{
"id": "23386248_T3",
"type": "CHEMICAL",
"text": [
"UDP"
],
"offsets": [
[
209,
212
]
],
"normalized": []
},
{
"id": "23386248_T4",
"type": "CHEMICAL",
"text": [
"folic acid"
],
"offsets": [
[
518,
528
]
],
"normalized": []
},
{
"id": "23386248_T5",
"type": "CHEMICAL",
"text": [
"leucovorin"
],
"offsets": [
[
530,
540
]
],
"normalized": []
},
{
"id": "23386248_T6",
"type": "CHEMICAL",
"text": [
"fluorouracil"
],
"offsets": [
[
543,
555
]
],
"normalized": []
},
{
"id": "23386248_T7",
"type": "CHEMICAL",
"text": [
"5-FU"
],
"offsets": [
[
557,
561
]
],
"normalized": []
},
{
"id": "23386248_T8",
"type": "CHEMICAL",
"text": [
"irinotecan"
],
"offsets": [
[
568,
578
]
],
"normalized": []
},
{
"id": "23386248_T9",
"type": "CHEMICAL",
"text": [
"camptosar"
],
"offsets": [
[
580,
589
]
],
"normalized": []
},
{
"id": "23386248_T10",
"type": "CHEMICAL",
"text": [
"irinotecan"
],
"offsets": [
[
253,
263
]
],
"normalized": []
},
{
"id": "23386248_T11",
"type": "CHEMICAL",
"text": [
"FOLFIRI"
],
"offsets": [
[
916,
923
]
],
"normalized": []
},
{
"id": "23386248_T12",
"type": "CHEMICAL",
"text": [
"5-fluorouracil"
],
"offsets": [
[
141,
155
]
],
"normalized": []
},
{
"id": "23386248_T13",
"type": "CHEMICAL",
"text": [
"irinotecan"
],
"offsets": [
[
156,
166
]
],
"normalized": []
},
{
"id": "23386248_T14",
"type": "CHEMICAL",
"text": [
"irinotecan"
],
"offsets": [
[
45,
55
]
],
"normalized": []
},
{
"id": "23386248_T15",
"type": "GENE-N",
"text": [
"UGT1A"
],
"offsets": [
[
1502,
1507
]
],
"normalized": []
},
{
"id": "23386248_T16",
"type": "GENE-Y",
"text": [
"UGT1A1"
],
"offsets": [
[
1554,
1560
]
],
"normalized": []
},
{
"id": "23386248_T17",
"type": "GENE-N",
"text": [
"UGT1A"
],
"offsets": [
[
1640,
1645
]
],
"normalized": []
},
{
"id": "23386248_T18",
"type": "GENE-N",
"text": [
"UGT1A"
],
"offsets": [
[
2010,
2015
]
],
"normalized": []
},
{
"id": "23386248_T19",
"type": "GENE-Y",
"text": [
"UGT1A1"
],
"offsets": [
[
2028,
2034
]
],
"normalized": []
},
{
"id": "23386248_T20",
"type": "GENE-Y",
"text": [
"UDP-glucuronosyltransferase (UGT) 1A1"
],
"offsets": [
[
209,
246
]
],
"normalized": []
},
{
"id": "23386248_T21",
"type": "GENE-N",
"text": [
"UGT1A"
],
"offsets": [
[
633,
638
]
],
"normalized": []
},
{
"id": "23386248_T22",
"type": "GENE-N",
"text": [
"UGT1A"
],
"offsets": [
[
807,
812
]
],
"normalized": []
},
{
"id": "23386248_T23",
"type": "GENE-N",
"text": [
"UGT1A"
],
"offsets": [
[
961,
966
]
],
"normalized": []
},
{
"id": "23386248_T24",
"type": "GENE-Y",
"text": [
"UGT1A1"
],
"offsets": [
[
987,
993
]
],
"normalized": []
},
{
"id": "23386248_T25",
"type": "GENE-N",
"text": [
"UGTs"
],
"offsets": [
[
1153,
1157
]
],
"normalized": []
},
{
"id": "23386248_T26",
"type": "GENE-N",
"text": [
"UGT1A"
],
"offsets": [
[
13,
18
]
],
"normalized": []
}
] | [] | [] | [] |
17353078 | 17353078 | [
{
"id": "17353078_title",
"type": "title",
"text": [
"Fluvastatin ameliorates endotoxin induced multiple organ failure in conscious rats."
],
"offsets": [
[
0,
83
]
]
},
{
"id": "17353078_abstract",
"type": "abstract",
"text": [
"OBJECTIVES: Sepsis is a severe inflammatory disorder that may lead to multiple organ failure. Lipopolysaccharide (LPS) is associated with Gram-negative sepsis and can activate monocytes and macrophages to release pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and anti-inflammatory mediator such as interleukin-10 (IL-10). In this present study, we used fluvastatin, a HMG-CoA reductase inhibitor, to study its effects upon LPS-induced endotoxic shock in conscious rats. METHODS: The experiments were designed that rats received an intravenous injection of 1mg/kg fluvastatin followed 10min later, by an intravenous injection of 10mg/kg Klebsiella pneumoniae LPS, the latter inducing endotoxic shock amongst conscious rats. Subsequently, the levels of certain biochemical variables and cytokines in serum were then measured during the ensuing 48-h period following sepsis. These included total cholesterol (TCH), triglyceride (TG), blood urea nitrogen (BUN), creatinine (Cre), creatine phosphokinase (CPK), lactic dehydrogenase (LDH), aspartate transferase (GOT), alanine transferase (GPT), tumor necrosis factor-alpha, interleukin-10 and nitric oxide. RESULTS: LPS significantly increased blood TG, BUN, Cre, LDH, CPK, GOT, GPT, TNF-alpha, IL-10 and NO levels but decreased the blood TCH level. Pretreatment of test rats with fluvastatin decreased blood levels of certain markers of organ injury, suppressed the release of TNF-alpha and increased IL-10, and NO levels following LPS treatment. Fluvastatin did not affect the blood TCH and TG level subsequent to the development of sepsis. CONCLUSIONS: Pre-treatment with fluvastatin suppresses the release of plasma TNF-alpha, increases plasma IL-10, and NO production, and decreases the levels of markers of organ injury associated with endotoxic shock, so ameliorating LPS-induced organ damage amongst conscious rats."
],
"offsets": [
[
84,
2000
]
]
}
] | [
{
"id": "17353078_T1",
"type": "CHEMICAL",
"text": [
"creatinine"
],
"offsets": [
[
1090,
1100
]
],
"normalized": []
},
{
"id": "17353078_T2",
"type": "CHEMICAL",
"text": [
"Cre"
],
"offsets": [
[
1102,
1105
]
],
"normalized": []
},
{
"id": "17353078_T3",
"type": "CHEMICAL",
"text": [
"creatine"
],
"offsets": [
[
1108,
1116
]
],
"normalized": []
},
{
"id": "17353078_T4",
"type": "CHEMICAL",
"text": [
"lactic"
],
"offsets": [
[
1138,
1144
]
],
"normalized": []
},
{
"id": "17353078_T5",
"type": "CHEMICAL",
"text": [
"aspartate"
],
"offsets": [
[
1166,
1175
]
],
"normalized": []
},
{
"id": "17353078_T6",
"type": "CHEMICAL",
"text": [
"alanine"
],
"offsets": [
[
1195,
1202
]
],
"normalized": []
},
{
"id": "17353078_T7",
"type": "CHEMICAL",
"text": [
"nitric oxide"
],
"offsets": [
[
1270,
1282
]
],
"normalized": []
},
{
"id": "17353078_T8",
"type": "CHEMICAL",
"text": [
"TG"
],
"offsets": [
[
1327,
1329
]
],
"normalized": []
},
{
"id": "17353078_T9",
"type": "CHEMICAL",
"text": [
"Cre"
],
"offsets": [
[
1336,
1339
]
],
"normalized": []
},
{
"id": "17353078_T10",
"type": "CHEMICAL",
"text": [
"NO"
],
"offsets": [
[
1382,
1384
]
],
"normalized": []
},
{
"id": "17353078_T11",
"type": "CHEMICAL",
"text": [
"fluvastatin"
],
"offsets": [
[
1458,
1469
]
],
"normalized": []
},
{
"id": "17353078_T12",
"type": "CHEMICAL",
"text": [
"NO"
],
"offsets": [
[
1590,
1592
]
],
"normalized": []
},
{
"id": "17353078_T13",
"type": "CHEMICAL",
"text": [
"Fluvastatin"
],
"offsets": [
[
1625,
1636
]
],
"normalized": []
},
{
"id": "17353078_T14",
"type": "CHEMICAL",
"text": [
"TG"
],
"offsets": [
[
1670,
1672
]
],
"normalized": []
},
{
"id": "17353078_T15",
"type": "CHEMICAL",
"text": [
"fluvastatin"
],
"offsets": [
[
1752,
1763
]
],
"normalized": []
},
{
"id": "17353078_T16",
"type": "CHEMICAL",
"text": [
"NO"
],
"offsets": [
[
1836,
1838
]
],
"normalized": []
},
{
"id": "17353078_T17",
"type": "CHEMICAL",
"text": [
"nitric oxide"
],
"offsets": [
[
373,
385
]
],
"normalized": []
},
{
"id": "17353078_T18",
"type": "CHEMICAL",
"text": [
"NO"
],
"offsets": [
[
387,
389
]
],
"normalized": []
},
{
"id": "17353078_T19",
"type": "CHEMICAL",
"text": [
"fluvastatin"
],
"offsets": [
[
485,
496
]
],
"normalized": []
},
{
"id": "17353078_T20",
"type": "CHEMICAL",
"text": [
"HMG-CoA"
],
"offsets": [
[
500,
507
]
],
"normalized": []
},
{
"id": "17353078_T21",
"type": "CHEMICAL",
"text": [
"fluvastatin"
],
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695,
706
]
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{
"id": "17353078_T22",
"type": "CHEMICAL",
"text": [
"cholesterol"
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[
1025,
1036
]
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"normalized": []
},
{
"id": "17353078_T23",
"type": "CHEMICAL",
"text": [
"triglyceride"
],
"offsets": [
[
1044,
1056
]
],
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},
{
"id": "17353078_T24",
"type": "CHEMICAL",
"text": [
"TG"
],
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1058,
1060
]
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},
{
"id": "17353078_T25",
"type": "CHEMICAL",
"text": [
"urea nitrogen"
],
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[
1069,
1082
]
],
"normalized": []
},
{
"id": "17353078_T26",
"type": "CHEMICAL",
"text": [
"Fluvastatin"
],
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[
0,
11
]
],
"normalized": []
},
{
"id": "17353078_T27",
"type": "GENE-N",
"text": [
"creatine phosphokinase"
],
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[
1108,
1130
]
],
"normalized": []
},
{
"id": "17353078_T28",
"type": "GENE-N",
"text": [
"CPK"
],
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[
1132,
1135
]
],
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},
{
"id": "17353078_T29",
"type": "GENE-N",
"text": [
"lactic dehydrogenase"
],
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[
1138,
1158
]
],
"normalized": []
},
{
"id": "17353078_T30",
"type": "GENE-N",
"text": [
"LDH"
],
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[
1160,
1163
]
],
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},
{
"id": "17353078_T31",
"type": "GENE-N",
"text": [
"aspartate transferase"
],
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[
1166,
1187
]
],
"normalized": []
},
{
"id": "17353078_T32",
"type": "GENE-N",
"text": [
"GOT"
],
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[
1189,
1192
]
],
"normalized": []
},
{
"id": "17353078_T33",
"type": "GENE-N",
"text": [
"alanine transferase"
],
"offsets": [
[
1195,
1214
]
],
"normalized": []
},
{
"id": "17353078_T34",
"type": "GENE-Y",
"text": [
"GPT"
],
"offsets": [
[
1216,
1219
]
],
"normalized": []
},
{
"id": "17353078_T35",
"type": "GENE-Y",
"text": [
"tumor necrosis factor-alpha"
],
"offsets": [
[
1222,
1249
]
],
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},
{
"id": "17353078_T36",
"type": "GENE-Y",
"text": [
"interleukin-10"
],
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[
1251,
1265
]
],
"normalized": []
},
{
"id": "17353078_T37",
"type": "GENE-N",
"text": [
"LDH"
],
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[
1341,
1344
]
],
"normalized": []
},
{
"id": "17353078_T38",
"type": "GENE-N",
"text": [
"CPK"
],
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1346,
1349
]
],
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},
{
"id": "17353078_T39",
"type": "GENE-N",
"text": [
"GOT"
],
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1351,
1354
]
],
"normalized": []
},
{
"id": "17353078_T40",
"type": "GENE-Y",
"text": [
"GPT"
],
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[
1356,
1359
]
],
"normalized": []
},
{
"id": "17353078_T41",
"type": "GENE-Y",
"text": [
"TNF-alpha"
],
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[
1361,
1370
]
],
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},
{
"id": "17353078_T42",
"type": "GENE-Y",
"text": [
"IL-10"
],
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[
1372,
1377
]
],
"normalized": []
},
{
"id": "17353078_T43",
"type": "GENE-Y",
"text": [
"TNF-alpha"
],
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[
1555,
1564
]
],
"normalized": []
},
{
"id": "17353078_T44",
"type": "GENE-Y",
"text": [
"IL-10"
],
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[
1579,
1584
]
],
"normalized": []
},
{
"id": "17353078_T45",
"type": "GENE-Y",
"text": [
"TNF-alpha"
],
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[
1797,
1806
]
],
"normalized": []
},
{
"id": "17353078_T46",
"type": "GENE-Y",
"text": [
"IL-10"
],
"offsets": [
[
1825,
1830
]
],
"normalized": []
},
{
"id": "17353078_T47",
"type": "GENE-Y",
"text": [
"tumor necrosis factor-alpha"
],
"offsets": [
[
332,
359
]
],
"normalized": []
},
{
"id": "17353078_T48",
"type": "GENE-Y",
"text": [
"TNF-alpha"
],
"offsets": [
[
361,
370
]
],
"normalized": []
},
{
"id": "17353078_T49",
"type": "GENE-Y",
"text": [
"interleukin-10"
],
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[
430,
444
]
],
"normalized": []
},
{
"id": "17353078_T50",
"type": "GENE-Y",
"text": [
"IL-10"
],
"offsets": [
[
446,
451
]
],
"normalized": []
},
{
"id": "17353078_T51",
"type": "GENE-Y",
"text": [
"HMG-CoA reductase"
],
"offsets": [
[
500,
517
]
],
"normalized": []
},
{
"id": "17353078_T52",
"type": "GENE-N",
"text": [
"cytokines"
],
"offsets": [
[
917,
926
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17353078_0",
"type": "INHIBITOR",
"arg1_id": "17353078_T19",
"arg2_id": "17353078_T51",
"normalized": []
},
{
"id": "17353078_1",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "17353078_T11",
"arg2_id": "17353078_T43",
"normalized": []
},
{
"id": "17353078_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "17353078_T11",
"arg2_id": "17353078_T44",
"normalized": []
},
{
"id": "17353078_3",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "17353078_T15",
"arg2_id": "17353078_T45",
"normalized": []
},
{
"id": "17353078_4",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "17353078_T15",
"arg2_id": "17353078_T46",
"normalized": []
}
] |
17277115 | 17277115 | [
{
"id": "17277115_title",
"type": "title",
"text": [
"Regulation of CD8+ T lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor gamma."
],
"offsets": [
[
0,
130
]
]
},
{
"id": "17277115_abstract",
"type": "abstract",
"text": [
"Vitamin A and its derivatives regulate a broad array of immune functions. The effects of these retinoids are mediated through members of retinoic acid receptors (RARs) and retinoid X receptors. However, the role of individual retinoid receptors in the pleiotropic effects of retinoids remains unclear. To dissect the role of these receptors in the immune system, we analyzed immune cell development and function in mice conditionally lacking RARgamma, the third member of the RAR family. We show that RARgamma is dispensable for T and B lymphocyte development, the humoral immune response to a T-dependent Ag and in vitro Th cell differentiation. However, RARgamma-deficient mice had a defective primary and memory CD8(+) T cell response to Listeria monocytogenes infection. Unexpectedly, RARgamma-deficient macrophages exhibited impaired inflammatory cytokine production upon TLR stimulation. These results suggest that under physiological condition, RARgamma is a positive regulator of inflammatory cytokine production."
],
"offsets": [
[
131,
1152
]
]
}
] | [
{
"id": "17277115_T1",
"type": "CHEMICAL",
"text": [
"Vitamin A"
],
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[
131,
140
]
],
"normalized": []
},
{
"id": "17277115_T2",
"type": "CHEMICAL",
"text": [
"retinoic acid"
],
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[
268,
281
]
],
"normalized": []
},
{
"id": "17277115_T3",
"type": "CHEMICAL",
"text": [
"retinoid"
],
"offsets": [
[
303,
311
]
],
"normalized": []
},
{
"id": "17277115_T4",
"type": "CHEMICAL",
"text": [
"retinoid"
],
"offsets": [
[
357,
365
]
],
"normalized": []
},
{
"id": "17277115_T5",
"type": "CHEMICAL",
"text": [
"retinoids"
],
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[
406,
415
]
],
"normalized": []
},
{
"id": "17277115_T6",
"type": "CHEMICAL",
"text": [
"Ag"
],
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[
737,
739
]
],
"normalized": []
},
{
"id": "17277115_T7",
"type": "CHEMICAL",
"text": [
"retinoids"
],
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[
226,
235
]
],
"normalized": []
},
{
"id": "17277115_T8",
"type": "CHEMICAL",
"text": [
"retinoic acid"
],
"offsets": [
[
101,
114
]
],
"normalized": []
},
{
"id": "17277115_T9",
"type": "GENE-N",
"text": [
"cytokin"
],
"offsets": [
[
1132,
1139
]
],
"normalized": []
},
{
"id": "17277115_T10",
"type": "GENE-N",
"text": [
"retinoic acid receptors"
],
"offsets": [
[
268,
291
]
],
"normalized": []
},
{
"id": "17277115_T11",
"type": "GENE-N",
"text": [
"RARs"
],
"offsets": [
[
293,
297
]
],
"normalized": []
},
{
"id": "17277115_T12",
"type": "GENE-N",
"text": [
"retinoid X receptors"
],
"offsets": [
[
303,
323
]
],
"normalized": []
},
{
"id": "17277115_T13",
"type": "GENE-N",
"text": [
"retinoid receptors"
],
"offsets": [
[
357,
375
]
],
"normalized": []
},
{
"id": "17277115_T14",
"type": "GENE-Y",
"text": [
"RARgamma"
],
"offsets": [
[
573,
581
]
],
"normalized": []
},
{
"id": "17277115_T15",
"type": "GENE-N",
"text": [
"RAR"
],
"offsets": [
[
607,
610
]
],
"normalized": []
},
{
"id": "17277115_T16",
"type": "GENE-Y",
"text": [
"RARgamma"
],
"offsets": [
[
632,
640
]
],
"normalized": []
},
{
"id": "17277115_T17",
"type": "GENE-Y",
"text": [
"RARgamma"
],
"offsets": [
[
787,
795
]
],
"normalized": []
},
{
"id": "17277115_T18",
"type": "GENE-Y",
"text": [
"RARgamma"
],
"offsets": [
[
920,
928
]
],
"normalized": []
},
{
"id": "17277115_T19",
"type": "GENE-N",
"text": [
"cytokine"
],
"offsets": [
[
983,
991
]
],
"normalized": []
},
{
"id": "17277115_T20",
"type": "GENE-N",
"text": [
"TLR"
],
"offsets": [
[
1008,
1011
]
],
"normalized": []
},
{
"id": "17277115_T21",
"type": "GENE-Y",
"text": [
"RARgamma"
],
"offsets": [
[
1083,
1091
]
],
"normalized": []
},
{
"id": "17277115_T22",
"type": "GENE-Y",
"text": [
"retinoic acid receptor gamma"
],
"offsets": [
[
101,
129
]
],
"normalized": []
},
{
"id": "17277115_T23",
"type": "GENE-N",
"text": [
"cytokine"
],
"offsets": [
[
78,
86
]
],
"normalized": []
}
] | [] | [] | [] |
23230281 | 23230281 | [
{
"id": "23230281_title",
"type": "title",
"text": [
"Increased oxidized low-density lipoprotein causes blood-brain barrier disruption in early-onset preeclampsia through LOX-1."
],
"offsets": [
[
0,
123
]
]
},
{
"id": "23230281_abstract",
"type": "abstract",
"text": [
"Early-onset preeclampsia (EPE) is a severe form of preeclampsia that involves life-threatening neurological complications. However, the underlying mechanism by which EPE affects the maternal brain is not known. We hypothesized that plasma from women with EPE increases blood-brain barrier (BBB) permeability vs. plasma from women with late-onset preeclampsia (LPE) or normal pregnancy (NP) and investigated its underlying mechanism by perfusing cerebral veins from nonpregnant rats (n=6-7/group) with human plasma from women with EPE, LPE, or NP and measuring permeability. We show that plasma from women with EPE significantly increased BBB permeability vs. plasma from women with LPE or NP (P<0.001). BBB disruption in response to EPE plasma was due to a 260% increase of circulating oxidized LDL (oxLDL) binding to its receptor, LOX-1, and subsequent generation of peroxynitrite (P<0.001). A rat model with pathologically high lipid levels in pregnancy showed symptoms of preeclampsia, including elevated blood pressure, growth-restricted fetuses, and LOX-1-dependent BBB disruption, similar to EPE (P<0.05). Thus, we have identified LOX-1 activation by oxLDL and subsequent peroxynitrite generation as a novel mechanism by which disruption of the BBB occurs in EPE. As increased BBB permeability is a primary means by which seizure and other neurological symptoms ensue, our findings highlight oxLDL, LOX-1, and peroxynitrite as important therapeutic targets in EPE."
],
"offsets": [
[
124,
1594
]
]
}
] | [
{
"id": "23230281_T1",
"type": "CHEMICAL",
"text": [
"peroxynitrite"
],
"offsets": [
[
1302,
1315
]
],
"normalized": []
},
{
"id": "23230281_T2",
"type": "CHEMICAL",
"text": [
"peroxynitrite"
],
"offsets": [
[
1540,
1553
]
],
"normalized": []
},
{
"id": "23230281_T3",
"type": "CHEMICAL",
"text": [
"peroxynitrite"
],
"offsets": [
[
992,
1005
]
],
"normalized": []
},
{
"id": "23230281_T4",
"type": "GENE-Y",
"text": [
"LOX-1"
],
"offsets": [
[
1179,
1184
]
],
"normalized": []
},
{
"id": "23230281_T5",
"type": "GENE-Y",
"text": [
"LOX-1"
],
"offsets": [
[
1261,
1266
]
],
"normalized": []
},
{
"id": "23230281_T6",
"type": "GENE-N",
"text": [
"oxLDL"
],
"offsets": [
[
1281,
1286
]
],
"normalized": []
},
{
"id": "23230281_T7",
"type": "GENE-N",
"text": [
"oxLDL"
],
"offsets": [
[
1522,
1527
]
],
"normalized": []
},
{
"id": "23230281_T8",
"type": "GENE-Y",
"text": [
"LOX-1"
],
"offsets": [
[
1529,
1534
]
],
"normalized": []
},
{
"id": "23230281_T9",
"type": "GENE-N",
"text": [
"oxidized LDL"
],
"offsets": [
[
910,
922
]
],
"normalized": []
},
{
"id": "23230281_T10",
"type": "GENE-N",
"text": [
"oxLDL"
],
"offsets": [
[
924,
929
]
],
"normalized": []
},
{
"id": "23230281_T11",
"type": "GENE-Y",
"text": [
"LOX-1"
],
"offsets": [
[
956,
961
]
],
"normalized": []
},
{
"id": "23230281_T12",
"type": "GENE-N",
"text": [
"oxidized low-density lipoprotein"
],
"offsets": [
[
10,
42
]
],
"normalized": []
},
{
"id": "23230281_T13",
"type": "GENE-Y",
"text": [
"LOX-1"
],
"offsets": [
[
117,
122
]
],
"normalized": []
}
] | [] | [] | [] |
17197042 | 17197042 | [
{
"id": "17197042_title",
"type": "title",
"text": [
"Development and validation of a non-radioactive DNA polymerase assay for studying cytomegalovirus resistance to foscarnet."
],
"offsets": [
[
0,
122
]
]
},
{
"id": "17197042_abstract",
"type": "abstract",
"text": [
"Phenotypic characterisation of the human cytomegalovirus (HCMV) pUL54 DNA polymerase is a useful tool for testing for mutations in the UL54 gene thought to render HCMV resistant to foscarnet. In this study, an in-house non-isotopic method for assessing polymerase enzymatic activity in the presence and absence of foscarnet was developed and its utility for HCMV polymerase phenotyping evaluated. Polymerase activity was assessed by monitoring the incorporation of digoxigenin-labelled nucleotides into the growing DNA chain and foscarnet concentrations inhibiting enzymatic activity by 50% were determined. HCMV DNA polymerases were synthesised in vitro by expression of UL54 under the control of the T7 promoter. Mutations of interest were introduced into the wild-type UL54 gene by site-directed mutagenesis. Mutated polymerases and polymerases from HCMV reference strains were studied. The activity of polymerases containing mutations known to confer resistance to foscarnet (V715M, T700A and N495K) was inhibited by concentrations of foscarnet eight to 14 times higher than those required to inhibit wild-type polymerases. Our in-house non-radioactive phenotypic assay was sensitive and reproducible. It is also easy to perform and could provide a convenient method for characterising mutations conferring resistance to foscarnet in HCMV."
],
"offsets": [
[
123,
1466
]
]
}
] | [
{
"id": "17197042_T1",
"type": "CHEMICAL",
"text": [
"foscarnet"
],
"offsets": [
[
1162,
1171
]
],
"normalized": []
},
{
"id": "17197042_T2",
"type": "CHEMICAL",
"text": [
"foscarnet"
],
"offsets": [
[
1448,
1457
]
],
"normalized": []
},
{
"id": "17197042_T3",
"type": "CHEMICAL",
"text": [
"foscarnet"
],
"offsets": [
[
304,
313
]
],
"normalized": []
},
{
"id": "17197042_T4",
"type": "CHEMICAL",
"text": [
"foscarnet"
],
"offsets": [
[
437,
446
]
],
"normalized": []
},
{
"id": "17197042_T5",
"type": "CHEMICAL",
"text": [
"digoxigenin"
],
"offsets": [
[
588,
599
]
],
"normalized": []
},
{
"id": "17197042_T6",
"type": "CHEMICAL",
"text": [
"foscarnet"
],
"offsets": [
[
652,
661
]
],
"normalized": []
},
{
"id": "17197042_T7",
"type": "CHEMICAL",
"text": [
"foscarnet"
],
"offsets": [
[
1092,
1101
]
],
"normalized": []
},
{
"id": "17197042_T8",
"type": "CHEMICAL",
"text": [
"foscarnet"
],
"offsets": [
[
112,
121
]
],
"normalized": []
},
{
"id": "17197042_T9",
"type": "GENE-N",
"text": [
"polymerases"
],
"offsets": [
[
1238,
1249
]
],
"normalized": []
},
{
"id": "17197042_T10",
"type": "GENE-Y",
"text": [
"UL54"
],
"offsets": [
[
258,
262
]
],
"normalized": []
},
{
"id": "17197042_T11",
"type": "GENE-Y",
"text": [
"human cytomegalovirus (HCMV) pUL54"
],
"offsets": [
[
158,
192
]
],
"normalized": []
},
{
"id": "17197042_T12",
"type": "GENE-N",
"text": [
"HCMV polymerase"
],
"offsets": [
[
481,
496
]
],
"normalized": []
},
{
"id": "17197042_T13",
"type": "GENE-N",
"text": [
"Polymerase"
],
"offsets": [
[
520,
530
]
],
"normalized": []
},
{
"id": "17197042_T14",
"type": "GENE-N",
"text": [
"HCMV DNA polymerases"
],
"offsets": [
[
731,
751
]
],
"normalized": []
},
{
"id": "17197042_T15",
"type": "GENE-Y",
"text": [
"UL54"
],
"offsets": [
[
795,
799
]
],
"normalized": []
},
{
"id": "17197042_T16",
"type": "GENE-N",
"text": [
"T7 promoter"
],
"offsets": [
[
825,
836
]
],
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{
"id": "17197042_T17",
"type": "GENE-N",
"text": [
"DNA polymerase"
],
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193,
207
]
],
"normalized": []
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{
"id": "17197042_T18",
"type": "GENE-Y",
"text": [
"UL54"
],
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895,
899
]
],
"normalized": []
},
{
"id": "17197042_T19",
"type": "GENE-N",
"text": [
"polymerases"
],
"offsets": [
[
943,
954
]
],
"normalized": []
},
{
"id": "17197042_T20",
"type": "GENE-N",
"text": [
"polymerases"
],
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959,
970
]
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},
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"id": "17197042_T21",
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"polymerases"
],
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1029,
1040
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"V715M"
],
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1103,
1108
]
],
"normalized": []
},
{
"id": "17197042_T23",
"type": "GENE-N",
"text": [
"T700A"
],
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1110,
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]
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},
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"id": "17197042_T24",
"type": "GENE-N",
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"N495K"
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1120,
1125
]
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"normalized": []
},
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"id": "17197042_T25",
"type": "GENE-N",
"text": [
"DNA polymerase"
],
"offsets": [
[
48,
62
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17197042_0",
"type": "INHIBITOR",
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"arg2_id": "17197042_T21",
"normalized": []
},
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"type": "INHIBITOR",
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},
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"id": "17197042_4",
"type": "INHIBITOR",
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},
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"type": "INHIBITOR",
"arg1_id": "17197042_T8",
"arg2_id": "17197042_T25",
"normalized": []
}
] |
16014042 | 16014042 | [
{
"id": "16014042_title",
"type": "title",
"text": [
"Cystine and glutamate transport in renal epithelial cells transfected with human system x(-) (c)."
],
"offsets": [
[
0,
97
]
]
},
{
"id": "16014042_abstract",
"type": "abstract",
"text": [
"BACKGROUND: System x(-) (c) is a heterodimeric transporter, comprised of a light chain, xCT, and heavy chain, 4F2hc, which mediates the sodium-independent exchange of cystine and glutamate at the plasma membrane. In the current study we tested the hypothesis that stable transfection of Madin-Darby canine kidney (MDCK) cells with human xCT and 4F2hc results in the expression of functional system x(-) (c). METHODS: MDCK cells were transfected stably with human clones for xCT and 4F2hc. Analyses of time- and temperature-dependence, saturation kinetics, and substrate specificity of l-cystine and l-glutamate transport were carried out in control and xCT-4F2hc-transfected MDCK cells. We also measured the uptake of l-cystine in Xenopus oocytes expressing human xCT and/or 4F2hc or xCT and/or rBAT (a heavy chain homologous to 4F2hc). RESULTS: All of the different sets of data revealed that transport of l-cystine and l-glutamate increased significantly (twofold to threefold) in the MDCK cells subsequent to transfection with xCT-4F2hc. Moreover, uptake of l-cystine also increased (about tenfold) in Xenopus oocytes expressing hxCT and h4F2hc. Biochemical analyses of l-cystine uptake in oocytes verified our findings in the transfected MDCK cells. Interestingly, in oocytes injected with rBAT with or without xCT, uptake of l-cystine was significantly greater than that in water-injected oocytes. CONCLUSION: Our findings indicate that stable transfection of MDCK cells with xCT and 4F2hc results in a cell-line expressing a functional system x(-) (c) transporter that can utilize l-cystine and l-glutamate as substrates. This study apparently represents the first stable transfection of a mammalian cell line with system x(-) (c)."
],
"offsets": [
[
98,
1835
]
]
}
] | [
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"id": "16014042_T1",
"type": "CHEMICAL",
"text": [
"l-cystine"
],
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1159,
1168
]
],
"normalized": []
},
{
"id": "16014042_T2",
"type": "CHEMICAL",
"text": [
"l-cystine"
],
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1271,
1280
]
],
"normalized": []
},
{
"id": "16014042_T3",
"type": "CHEMICAL",
"text": [
"l-cystine"
],
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]
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"id": "16014042_T4",
"type": "CHEMICAL",
"text": [
"sodium"
],
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234,
240
]
],
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},
{
"id": "16014042_T5",
"type": "CHEMICAL",
"text": [
"l-cystine"
],
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[
1685,
1694
]
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"normalized": []
},
{
"id": "16014042_T6",
"type": "CHEMICAL",
"text": [
"l-glutamate"
],
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1699,
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]
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"normalized": []
},
{
"id": "16014042_T7",
"type": "CHEMICAL",
"text": [
"cystine"
],
"offsets": [
[
265,
272
]
],
"normalized": []
},
{
"id": "16014042_T8",
"type": "CHEMICAL",
"text": [
"glutamate"
],
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277,
286
]
],
"normalized": []
},
{
"id": "16014042_T9",
"type": "CHEMICAL",
"text": [
"l-cystine"
],
"offsets": [
[
683,
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]
],
"normalized": []
},
{
"id": "16014042_T10",
"type": "CHEMICAL",
"text": [
"l-glutamate"
],
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[
697,
708
]
],
"normalized": []
},
{
"id": "16014042_T11",
"type": "CHEMICAL",
"text": [
"l-cystine"
],
"offsets": [
[
816,
825
]
],
"normalized": []
},
{
"id": "16014042_T12",
"type": "CHEMICAL",
"text": [
"l-cystine"
],
"offsets": [
[
1005,
1014
]
],
"normalized": []
},
{
"id": "16014042_T13",
"type": "CHEMICAL",
"text": [
"l-glutamate"
],
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[
1019,
1030
]
],
"normalized": []
},
{
"id": "16014042_T14",
"type": "CHEMICAL",
"text": [
"Cystine"
],
"offsets": [
[
0,
7
]
],
"normalized": []
},
{
"id": "16014042_T15",
"type": "CHEMICAL",
"text": [
"glutamate"
],
"offsets": [
[
12,
21
]
],
"normalized": []
},
{
"id": "16014042_T16",
"type": "GENE-Y",
"text": [
"xCT"
],
"offsets": [
[
1128,
1131
]
],
"normalized": []
},
{
"id": "16014042_T17",
"type": "GENE-Y",
"text": [
"4F2hc"
],
"offsets": [
[
1132,
1137
]
],
"normalized": []
},
{
"id": "16014042_T18",
"type": "GENE-Y",
"text": [
"4F2hc"
],
"offsets": [
[
208,
213
]
],
"normalized": []
},
{
"id": "16014042_T19",
"type": "GENE-Y",
"text": [
"hxCT"
],
"offsets": [
[
1230,
1234
]
],
"normalized": []
},
{
"id": "16014042_T20",
"type": "GENE-Y",
"text": [
"h4F2hc"
],
"offsets": [
[
1239,
1245
]
],
"normalized": []
},
{
"id": "16014042_T21",
"type": "GENE-Y",
"text": [
"System x(-) (c)"
],
"offsets": [
[
110,
125
]
],
"normalized": []
},
{
"id": "16014042_T22",
"type": "GENE-Y",
"text": [
"rBAT"
],
"offsets": [
[
1392,
1396
]
],
"normalized": []
},
{
"id": "16014042_T23",
"type": "GENE-Y",
"text": [
"xCT"
],
"offsets": [
[
1413,
1416
]
],
"normalized": []
},
{
"id": "16014042_T24",
"type": "GENE-Y",
"text": [
"xCT"
],
"offsets": [
[
1579,
1582
]
],
"normalized": []
},
{
"id": "16014042_T25",
"type": "GENE-Y",
"text": [
"4F2hc"
],
"offsets": [
[
1587,
1592
]
],
"normalized": []
},
{
"id": "16014042_T26",
"type": "GENE-Y",
"text": [
"x(-) (c) transporter"
],
"offsets": [
[
1647,
1667
]
],
"normalized": []
},
{
"id": "16014042_T27",
"type": "GENE-Y",
"text": [
"system x(-) (c)"
],
"offsets": [
[
1819,
1834
]
],
"normalized": []
},
{
"id": "16014042_T28",
"type": "GENE-Y",
"text": [
"human xCT"
],
"offsets": [
[
429,
438
]
],
"normalized": []
},
{
"id": "16014042_T29",
"type": "GENE-Y",
"text": [
"4F2hc"
],
"offsets": [
[
443,
448
]
],
"normalized": []
},
{
"id": "16014042_T30",
"type": "GENE-Y",
"text": [
"xCT"
],
"offsets": [
[
572,
575
]
],
"normalized": []
},
{
"id": "16014042_T31",
"type": "GENE-Y",
"text": [
"4F2hc"
],
"offsets": [
[
580,
585
]
],
"normalized": []
},
{
"id": "16014042_T32",
"type": "GENE-Y",
"text": [
"xCT"
],
"offsets": [
[
751,
754
]
],
"normalized": []
},
{
"id": "16014042_T33",
"type": "GENE-Y",
"text": [
"4F2hc"
],
"offsets": [
[
755,
760
]
],
"normalized": []
},
{
"id": "16014042_T34",
"type": "GENE-Y",
"text": [
"human xCT"
],
"offsets": [
[
856,
865
]
],
"normalized": []
},
{
"id": "16014042_T35",
"type": "GENE-Y",
"text": [
"4F2hc"
],
"offsets": [
[
873,
878
]
],
"normalized": []
},
{
"id": "16014042_T36",
"type": "GENE-Y",
"text": [
"xCT"
],
"offsets": [
[
882,
885
]
],
"normalized": []
},
{
"id": "16014042_T37",
"type": "GENE-Y",
"text": [
"rBAT"
],
"offsets": [
[
893,
897
]
],
"normalized": []
},
{
"id": "16014042_T38",
"type": "GENE-Y",
"text": [
"4F2hc"
],
"offsets": [
[
927,
932
]
],
"normalized": []
},
{
"id": "16014042_T39",
"type": "GENE-Y",
"text": [
"xCT"
],
"offsets": [
[
186,
189
]
],
"normalized": []
},
{
"id": "16014042_T40",
"type": "GENE-Y",
"text": [
"human system x(-) (c)"
],
"offsets": [
[
75,
96
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16014042_0",
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"arg2_id": "16014042_T40",
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},
{
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"arg1_id": "16014042_T15",
"arg2_id": "16014042_T40",
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{
"id": "16014042_2",
"type": "SUBSTRATE",
"arg1_id": "16014042_T7",
"arg2_id": "16014042_T21",
"normalized": []
},
{
"id": "16014042_3",
"type": "SUBSTRATE",
"arg1_id": "16014042_T7",
"arg2_id": "16014042_T39",
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{
"id": "16014042_4",
"type": "SUBSTRATE",
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{
"id": "16014042_5",
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"id": "16014042_11",
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"arg2_id": "16014042_T19",
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"type": "SUBSTRATE",
"arg1_id": "16014042_T3",
"arg2_id": "16014042_T22",
"normalized": []
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"type": "SUBSTRATE",
"arg1_id": "16014042_T5",
"arg2_id": "16014042_T26",
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"type": "SUBSTRATE",
"arg1_id": "16014042_T5",
"arg2_id": "16014042_T24",
"normalized": []
},
{
"id": "16014042_28",
"type": "SUBSTRATE",
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"arg2_id": "16014042_T24",
"normalized": []
},
{
"id": "16014042_29",
"type": "SUBSTRATE",
"arg1_id": "16014042_T5",
"arg2_id": "16014042_T25",
"normalized": []
},
{
"id": "16014042_30",
"type": "SUBSTRATE",
"arg1_id": "16014042_T6",
"arg2_id": "16014042_T25",
"normalized": []
}
] |
16897043 | 16897043 | [
{
"id": "16897043_title",
"type": "title",
"text": [
"ABCC8 and ABCC9: ABC transporters that regulate K+ channels."
],
"offsets": [
[
0,
60
]
]
},
{
"id": "16897043_abstract",
"type": "abstract",
"text": [
"The sulfonylurea receptors (SURs) ABCC8/SUR1 and ABCC9/SUR2 are members of the C-branch of the transport adenosine triphosphatase superfamily. Unlike their brethren, the SURs have no identified transport function; instead, evolution has matched these molecules with K(+) selective pores, either K(IR)6.1/KCNJ8 or K(IR)6.2/KCNJ11, to assemble adenosine triphosphate (ATP)-sensitive K(+) channels found in endocrine cells, neurons, and both smooth and striated muscle. Adenine nucleotides, the major regulators of ATP-sensitive K(+) (K(ATP)) channel activity, exert a dual action. Nucleotide binding to the pore reduces the activity or channel open probability, whereas Mg-nucleotide binding and/or hydrolysis in the nucleotide-binding domains of SUR antagonize this inhibitory action to stimulate channel openings. Mutations in either subunit can alter this balance and, in the case of the SUR1/KIR6.2 channels found in neurons and insulin-secreting pancreatic beta cells, are the cause of monogenic forms of hyperinsulinemic hypoglycemia and neonatal diabetes. Additionally, the subtle dysregulation of K(ATP) channel activity by a K(IR)6.2 polymorphism has been suggested as a predisposing factor in type 2 diabetes mellitus. Studies on K(ATP) channel null mice are clarifying the roles of these metabolically sensitive channels in a variety of tissues."
],
"offsets": [
[
61,
1415
]
]
}
] | [
{
"id": "16897043_T1",
"type": "CHEMICAL",
"text": [
"adenosine"
],
"offsets": [
[
166,
175
]
],
"normalized": []
},
{
"id": "16897043_T2",
"type": "CHEMICAL",
"text": [
"K"
],
"offsets": [
[
1164,
1165
]
],
"normalized": []
},
{
"id": "16897043_T3",
"type": "CHEMICAL",
"text": [
"ATP"
],
"offsets": [
[
1166,
1169
]
],
"normalized": []
},
{
"id": "16897043_T4",
"type": "CHEMICAL",
"text": [
"K"
],
"offsets": [
[
1299,
1300
]
],
"normalized": []
},
{
"id": "16897043_T5",
"type": "CHEMICAL",
"text": [
"ATP"
],
"offsets": [
[
1301,
1304
]
],
"normalized": []
},
{
"id": "16897043_T6",
"type": "CHEMICAL",
"text": [
"K(+)"
],
"offsets": [
[
327,
331
]
],
"normalized": []
},
{
"id": "16897043_T7",
"type": "CHEMICAL",
"text": [
"adenosine triphosphate"
],
"offsets": [
[
403,
425
]
],
"normalized": []
},
{
"id": "16897043_T8",
"type": "CHEMICAL",
"text": [
"ATP"
],
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[
427,
430
]
],
"normalized": []
},
{
"id": "16897043_T9",
"type": "CHEMICAL",
"text": [
"K(+)"
],
"offsets": [
[
442,
446
]
],
"normalized": []
},
{
"id": "16897043_T10",
"type": "CHEMICAL",
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65,
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528,
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"Nucleotide"
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"nucleotide"
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"K+"
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50
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"adenosine triphosphate (ATP)-sensitive K(+) channels"
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403,
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100
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"SUR1"
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101,
105
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"sulfonylurea receptors"
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65,
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"ABCC9"
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110,
115
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116,
120
]
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"nucleotide-binding domains"
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"SUR1"
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"KIR6.2"
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"insulin"
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]
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190
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0,
5
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10,
15
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"ABC transporters"
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]
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"type": "GENE-N",
"text": [
"K+ channels"
],
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48,
59
]
],
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}
] | [] | [] | [
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"type": "DIRECT-REGULATOR",
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"arg2_id": "16897043_T37",
"normalized": []
}
] |
12927226 | 12927226 | [
{
"id": "12927226_title",
"type": "title",
"text": [
"AT1 antagonism by eprosartan lowers heart rate variability and baroreflex gain."
],
"offsets": [
[
0,
79
]
]
},
{
"id": "12927226_abstract",
"type": "abstract",
"text": [
"INTRODUCTION: Blockade of the renin-angiotensin system (RAS) by ACE inhibitors has been demonstrated to reduce total mortality in cardiovascular diseases. This advantage was attributed in part to changes of autonomic cardiovascular control, exemplified by an increase of heart rate variability (HRV) and baroreflex gain (BRG). We sought to assess the effects of the angiotensin type 1 (AT1) receptor blocker eprosartan on HRV and BRG. MATERIALS AND METHODS: In a double-blind randomized cross-over design 25 young males took eprosartan (600 mg/day) and placebo each for a period of 7 days with a wash-out period of at least 4 weeks in between. At the end of the intake phases simultaneous recordings of arterial blood pressure (AP; Finapres) and electrocardiogram (ECG) were taken. Power spectra of HRV and arterial blood pressure variability (APV) were calculated by fast Fourier transform (FFT) and served to calculate BRG. Ang-II levels were measured by radioimmunoassay. RESULTS: Eprosartan tended to lower mean AP, it slightly increased heart rate (HR) (p<0.05), and markedly increased circulating Ang-II levels (p<0.01). Eprosartan diminished the total power of HRV (p<0.05) and the BRG (p<0.01). The low/high frequency (LF/HF) ratio of HRV and the APV were not altered. CONCLUSIONS: AT1 antagonism by eprosartan lowers heart rate variability and baroreflex gain. We speculate that these findings are due to the marked increase in circulating angiotensin II (Ang II). Further studies are needed to clarify whether angiotensin type 1 (AT1) blockers with potential actions inside the blood-brain barrier (BBB) may have different effects on HRV and BRG."
],
"offsets": [
[
80,
1736
]
]
}
] | [
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"id": "12927226_T2",
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"Eprosartan"
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1207,
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]
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"id": "12927226_T3",
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"eprosartan"
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]
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"id": "12927226_T4",
"type": "CHEMICAL",
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"angiotensin II"
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"id": "12927226_T5",
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"Ang II"
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"angiotensin"
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]
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"angiotensin"
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116,
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]
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"Eprosartan"
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"eprosartan"
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18,
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]
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"Ang-II"
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1183,
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"AT1"
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1373
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"angiotensin II"
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1529,
1543
]
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"Ang II"
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1545,
1551
]
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"angiotensin type 1"
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1600,
1618
]
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"AT1"
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1623
]
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"renin"
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110,
115
]
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"angiotensin"
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116,
127
]
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"type": "GENE-Y",
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"angiotensin type 1 (AT1) receptor"
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446,
479
]
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},
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"id": "12927226_T22",
"type": "GENE-Y",
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"ACE"
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144,
147
]
],
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"Ang-II"
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1006,
1012
]
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},
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"id": "12927226_T24",
"type": "GENE-Y",
"text": [
"AT1"
],
"offsets": [
[
0,
3
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12927226_0",
"type": "ANTAGONIST",
"arg1_id": "12927226_T12",
"arg2_id": "12927226_T24",
"normalized": []
},
{
"id": "12927226_1",
"type": "INHIBITOR",
"arg1_id": "12927226_T9",
"arg2_id": "12927226_T21",
"normalized": []
},
{
"id": "12927226_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "12927226_T11",
"arg2_id": "12927226_T13",
"normalized": []
},
{
"id": "12927226_3",
"type": "ANTAGONIST",
"arg1_id": "12927226_T3",
"arg2_id": "12927226_T14",
"normalized": []
}
] |
8836655 | 8836655 | [
{
"id": "8836655_title",
"type": "title",
"text": [
"Epinastine (WAL 801CL) modulates the noncholinergic contraction in guinea-pig airways in vitro by a prejunctional 5-HT1-like receptor."
],
"offsets": [
[
0,
134
]
]
},
{
"id": "8836655_abstract",
"type": "abstract",
"text": [
"Electrical field stimulation (EFS) of guinea-pig airways, in vitro, evokes an excitatory nonadrenergic noncholinergic (eNANC) contraction mediated by release of tachykinins from sensory nerve endings. Epinastine (WAL 801CL) is an antihistaminic drug with binding affinity at certain other receptors, including alpha-adrenergic receptors and various serotonin (5-HT) receptor subtypes. It is used in asthma treatment; however, its mechanism of action remains to be fully defined. We have investigated whether epinastine could modulate the eNANC contraction in guinea-pig airways in vitro, and have tried to elucidate its receptor mechanism. Epinastine (0.1-100 microM) produced a concentration-dependent inhibition of the noncholinergic contraction, with a maximum inhibition of 91 +/- 7% at 100 microM. Pretreatment of the tissues with combined 5-HT1/5-HT2 antagonists, methysergide (1 microM) or methiothepin (0.1 microM), significantly attenuated the inhibitory effect of epinastine on the noncholinergic contraction. Pretreatment with tropisetron (1 microM), a 5-HT3 antagonist, ketanserin (10 microM), a 5-HT2 antagonist, thioperamide (10 microM), a histamine H3 antagonist, or phentolamine (10 microM), an alpha-adrenergic antagonist, however, had no effect. Chlorpheniramine (10 microM), another histamine H1 receptor antagonist without significant 5-HT receptor binding affinity, did not produce any inhibition of the eNANC contraction. Epinastine (100 microM) did not displace the dose-response curve to exogenously applied substance P (0.01-10 microM). These results suggest that epinastine, although identified as a 5-HT antagonist, acts as a 5-HT1 agonist and that it inhibits the noncholinergic contraction in guinea-pig airways through stimulation of a prejunctional 5-HT1-like receptor, located to sensory nerves."
],
"offsets": [
[
135,
1962
]
]
}
] | [
{
"id": "8836655_T1",
"type": "CHEMICAL",
"text": [
"tropisetron"
],
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[
1173,
1184
]
],
"normalized": []
},
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"id": "8836655_T2",
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"ketanserin"
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[
1217,
1227
]
],
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"id": "8836655_T3",
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"thioperamide"
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[
1261,
1273
]
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"id": "8836655_T4",
"type": "CHEMICAL",
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"histamine"
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[
1289,
1298
]
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"id": "8836655_T5",
"type": "CHEMICAL",
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"phentolamine"
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[
1317,
1329
]
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"id": "8836655_T6",
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"Chlorpheniramine"
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1399,
1415
]
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"histamine"
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[
1437,
1446
]
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"id": "8836655_T8",
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"5-HT"
],
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[
1490,
1494
]
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"Epinastine"
],
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1579,
1589
]
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"id": "8836655_T10",
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"epinastine"
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[
1724,
1734
]
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"id": "8836655_T11",
"type": "CHEMICAL",
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"5-HT"
],
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[
1761,
1765
]
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"id": "8836655_T12",
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"Epinastine"
],
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[
336,
346
]
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"id": "8836655_T13",
"type": "CHEMICAL",
"text": [
"WAL 801CL"
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[
348,
357
]
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{
"id": "8836655_T14",
"type": "CHEMICAL",
"text": [
"serotonin"
],
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[
484,
493
]
],
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"id": "8836655_T15",
"type": "CHEMICAL",
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"5-HT"
],
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[
495,
499
]
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"id": "8836655_T16",
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"epinastine"
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643,
653
]
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"Epinastine"
],
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[
775,
785
]
],
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{
"id": "8836655_T18",
"type": "CHEMICAL",
"text": [
"methysergide"
],
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[
1005,
1017
]
],
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{
"id": "8836655_T19",
"type": "CHEMICAL",
"text": [
"methiothepin"
],
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[
1032,
1044
]
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"id": "8836655_T20",
"type": "CHEMICAL",
"text": [
"epinastine"
],
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[
1109,
1119
]
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{
"id": "8836655_T21",
"type": "CHEMICAL",
"text": [
"Epinastine"
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[
0,
10
]
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{
"id": "8836655_T22",
"type": "CHEMICAL",
"text": [
"WAL 801CL"
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[
12,
21
]
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{
"id": "8836655_T23",
"type": "GENE-N",
"text": [
"5-HT3"
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1243,
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"text": [
"histamine H3"
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1289,
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1437,
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"text": [
"5-HT1-like receptor"
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"offsets": [
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114,
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]
],
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}
] | [] | [] | [
{
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"arg2_id": "8836655_T34",
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},
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},
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},
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},
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},
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},
{
"id": "8836655_12",
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},
{
"id": "8836655_13",
"type": "ACTIVATOR",
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"arg2_id": "8836655_T30",
"normalized": []
}
] |
14654525 | 14654525 | [
{
"id": "14654525_title",
"type": "title",
"text": [
"An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients."
],
"offsets": [
[
0,
131
]
]
},
{
"id": "14654525_abstract",
"type": "abstract",
"text": [
"PURPOSE: Obtaining direct and rapid proof of molecular activity in early clinical trials is critical for optimal clinical development of novel targeted therapies. SU11248 is an oral multitargeted kinase inhibitor with selectivity for fms-related tyrosine kinase 3/Flk2 (FLT3), platelet-derived growth factor receptor alpha/beta, vascular endothelial growth factor receptor 1/2, and KIT receptor tyrosine kinases. FLT3 is a promising candidate for targeted therapy in acute myeloid leukemia (AML), because activating mutations occur in up to 30% of patients. We conducted an innovative single-dose clinical study with a primary objective to demonstrate inhibition of FLT3 phosphorylation by SU11248 in AML. EXPERIMENTAL DESIGN: Twenty-nine AML patients each received a single dose of SU11248, escalated from 50 to 350 mg, in increments of 50 mg and cohorts of three to six patients. FLT3 phosphorylation and plasma pharmacokinetics were evaluated at seven time points over 48 h after SU11248 administration, and FLT3 genotype was determined. Study drug-related adverse events occurred in 31% of patients, mainly grade 1 or 2 diarrhea and nausea, at higher dose levels. RESULTS: Inhibition of FLT3 phosphorylation was apparent in 50% of FLT3-wild-type (WT) patients and in 100% of FLT3-mutant patients. FLT3 internal tandem duplication (ITD) mutants showed increased sensitivity relative to FLT3-WT, consistent with preclinical predictions. The primary end point, strong inhibition of FLT3 phosphorylation in >50% patients, was reached in 200 mg and higher dose cohorts. Downstream signaling pathways were also inhibited; signal transducer and activator of transcription 5 (STAT5) was reduced primarily in internal tandem duplication patients and at late time points in FLT3-WT patients, whereas extracellular signal-regulated kinase (ERK) activity was reduced in the majority of patients, independent of FLT3 inhibition. CONCLUSIONS: This novel translational study bridges preclinical models to the patient setting and provides the first evidence of anti-FLT3 activity in patients. Proof of target inhibition accomplishes a crucial milestone in the development of novel oncology therapeutics."
],
"offsets": [
[
132,
2323
]
]
}
] | [
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"id": "14654525_T1",
"type": "CHEMICAL",
"text": [
"SU11248"
],
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295,
302
]
],
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},
{
"id": "14654525_T2",
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"text": [
"tyrosine"
],
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378,
386
]
],
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},
{
"id": "14654525_T3",
"type": "CHEMICAL",
"text": [
"tyrosine"
],
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527,
535
]
],
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},
{
"id": "14654525_T4",
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822,
829
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"id": "14654525_T5",
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"SU11248"
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915,
922
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"id": "14654525_T6",
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"SU11248"
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1115,
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"id": "14654525_T7",
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"text": [
"SU11248"
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88,
95
]
],
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},
{
"id": "14654525_T8",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
1143,
1147
]
],
"normalized": []
},
{
"id": "14654525_T9",
"type": "GENE-Y",
"text": [
"FLT3"
],
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[
1323,
1327
]
],
"normalized": []
},
{
"id": "14654525_T10",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
1367,
1371
]
],
"normalized": []
},
{
"id": "14654525_T11",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
1411,
1415
]
],
"normalized": []
},
{
"id": "14654525_T12",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
1433,
1437
]
],
"normalized": []
},
{
"id": "14654525_T13",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
1521,
1525
]
],
"normalized": []
},
{
"id": "14654525_T14",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
1615,
1619
]
],
"normalized": []
},
{
"id": "14654525_T15",
"type": "GENE-Y",
"text": [
"signal transducer and activator of transcription 5"
],
"offsets": [
[
1752,
1802
]
],
"normalized": []
},
{
"id": "14654525_T16",
"type": "GENE-Y",
"text": [
"STAT5"
],
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[
1804,
1809
]
],
"normalized": []
},
{
"id": "14654525_T17",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
1900,
1904
]
],
"normalized": []
},
{
"id": "14654525_T18",
"type": "GENE-N",
"text": [
"extracellular signal-regulated kinase"
],
"offsets": [
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1926,
1963
]
],
"normalized": []
},
{
"id": "14654525_T19",
"type": "GENE-N",
"text": [
"ERK"
],
"offsets": [
[
1965,
1968
]
],
"normalized": []
},
{
"id": "14654525_T20",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
2035,
2039
]
],
"normalized": []
},
{
"id": "14654525_T21",
"type": "GENE-N",
"text": [
"kinase"
],
"offsets": [
[
328,
334
]
],
"normalized": []
},
{
"id": "14654525_T22",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
2186,
2190
]
],
"normalized": []
},
{
"id": "14654525_T23",
"type": "GENE-Y",
"text": [
"fms-related tyrosine kinase 3"
],
"offsets": [
[
366,
395
]
],
"normalized": []
},
{
"id": "14654525_T24",
"type": "GENE-Y",
"text": [
"Flk2"
],
"offsets": [
[
396,
400
]
],
"normalized": []
},
{
"id": "14654525_T25",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
402,
406
]
],
"normalized": []
},
{
"id": "14654525_T26",
"type": "GENE-N",
"text": [
"platelet-derived growth factor receptor alpha/beta"
],
"offsets": [
[
409,
459
]
],
"normalized": []
},
{
"id": "14654525_T27",
"type": "GENE-N",
"text": [
"vascular endothelial growth factor receptor 1/2"
],
"offsets": [
[
461,
508
]
],
"normalized": []
},
{
"id": "14654525_T28",
"type": "GENE-N",
"text": [
"KIT"
],
"offsets": [
[
514,
517
]
],
"normalized": []
},
{
"id": "14654525_T29",
"type": "GENE-N",
"text": [
"tyrosine kinases"
],
"offsets": [
[
527,
543
]
],
"normalized": []
},
{
"id": "14654525_T30",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
545,
549
]
],
"normalized": []
},
{
"id": "14654525_T31",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
798,
802
]
],
"normalized": []
},
{
"id": "14654525_T32",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
1014,
1018
]
],
"normalized": []
},
{
"id": "14654525_T33",
"type": "GENE-Y",
"text": [
"FLT3"
],
"offsets": [
[
64,
68
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "14654525_0",
"type": "INHIBITOR",
"arg1_id": "14654525_T7",
"arg2_id": "14654525_T33",
"normalized": []
},
{
"id": "14654525_1",
"type": "INHIBITOR",
"arg1_id": "14654525_T1",
"arg2_id": "14654525_T21",
"normalized": []
},
{
"id": "14654525_2",
"type": "INHIBITOR",
"arg1_id": "14654525_T1",
"arg2_id": "14654525_T23",
"normalized": []
},
{
"id": "14654525_3",
"type": "INHIBITOR",
"arg1_id": "14654525_T1",
"arg2_id": "14654525_T24",
"normalized": []
},
{
"id": "14654525_4",
"type": "INHIBITOR",
"arg1_id": "14654525_T1",
"arg2_id": "14654525_T25",
"normalized": []
},
{
"id": "14654525_5",
"type": "INHIBITOR",
"arg1_id": "14654525_T1",
"arg2_id": "14654525_T28",
"normalized": []
},
{
"id": "14654525_6",
"type": "INHIBITOR",
"arg1_id": "14654525_T1",
"arg2_id": "14654525_T29",
"normalized": []
},
{
"id": "14654525_7",
"type": "INHIBITOR",
"arg1_id": "14654525_T4",
"arg2_id": "14654525_T31",
"normalized": []
}
] |
23376407 | 23376407 | [
{
"id": "23376407_title",
"type": "title",
"text": [
"Excessive ethanol consumption under exposure to lead intensifies disorders in bone metabolism: A study in a rat model."
],
"offsets": [
[
0,
118
]
]
},
{
"id": "23376407_abstract",
"type": "abstract",
"text": [
"It was investigated whether ethanol (Et) modifies the damaging impact of lead (Pb) on bone metabolism in a rat model reflecting excessive alcohol consumption by humans exposed to relatively high levels of this metal. For this purpose, markers of bone formation (osteocalcin, procollagen I, osteoprotegerin, alkaline phosphatase) and resorption (telopeptides of collagen I, soluble receptor activator of nuclear factor-κB ligand), calciotropic hormones (parathormone, calcitonin, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) in the serum, and the femur content of mineral (including calcium - Ca and inorganic phosphorus - Pi) and organic components were estimated in the rats exposed to 500mg Pb/l (in drinking water) or/and Et (5g/kg b.wt./24h, by oral gavage) for 12weeks. Moreover, Ca and Pi in the serum and urine, alkaline phosphatase in the bone tissue and Pb in the blood and femur were determined. The exposure to Pb or/and Et decreased bone formation and increased its resorption resulting in the bone demineralization. These effects were accompanied by destroying the hormonal regulation of mineral metabolism, and Ca and Pi imbalance. The co-exposure to Pb and Et-induced disorders in bone metabolism were more advanced than those caused by Pb alone. Et co-administration increased Pb concentration in the blood and decreased its accumulation in the bone. This paper is the first report providing evidence that consumption of Et under exposure to Pb intensifies disorders in bone metabolism and that destroying of the receptor activator nuclear factor-κB (RANK)/RANK ligand/osteoprotegerin system is involved in the mechanisms of interactive action of these xenobiotics on the skeleton. The modifying impact of Et may be an effect of its independent osteotropic action and interaction with Pb. Based on the results it can be concluded that alcohol abuse by subjects excessively exposed to Pb considerably increases the risk of bone damage."
],
"offsets": [
[
119,
2073
]
]
}
] | [
{
"id": "23376407_T1",
"type": "CHEMICAL",
"text": [
"Ca"
],
"offsets": [
[
1248,
1250
]
],
"normalized": []
},
{
"id": "23376407_T2",
"type": "CHEMICAL",
"text": [
"Pb"
],
"offsets": [
[
1288,
1290
]
],
"normalized": []
},
{
"id": "23376407_T3",
"type": "CHEMICAL",
"text": [
"Pb"
],
"offsets": [
[
1375,
1377
]
],
"normalized": []
},
{
"id": "23376407_T4",
"type": "CHEMICAL",
"text": [
"Pb"
],
"offsets": [
[
1416,
1418
]
],
"normalized": []
},
{
"id": "23376407_T5",
"type": "CHEMICAL",
"text": [
"alcohol"
],
"offsets": [
[
257,
264
]
],
"normalized": []
},
{
"id": "23376407_T6",
"type": "CHEMICAL",
"text": [
"Pb"
],
"offsets": [
[
1581,
1583
]
],
"normalized": []
},
{
"id": "23376407_T7",
"type": "CHEMICAL",
"text": [
"Pb"
],
"offsets": [
[
1924,
1926
]
],
"normalized": []
},
{
"id": "23376407_T8",
"type": "CHEMICAL",
"text": [
"alcohol"
],
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[
1974,
1981
]
],
"normalized": []
},
{
"id": "23376407_T9",
"type": "CHEMICAL",
"text": [
"Pb"
],
"offsets": [
[
2023,
2025
]
],
"normalized": []
},
{
"id": "23376407_T10",
"type": "CHEMICAL",
"text": [
"ethanol"
],
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[
147,
154
]
],
"normalized": []
},
{
"id": "23376407_T11",
"type": "CHEMICAL",
"text": [
"25-hydroxyvitamin D"
],
"offsets": [
[
598,
617
]
],
"normalized": []
},
{
"id": "23376407_T12",
"type": "CHEMICAL",
"text": [
"1,25-dihydroxyvitamin D"
],
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[
622,
645
]
],
"normalized": []
},
{
"id": "23376407_T13",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
705,
712
]
],
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},
{
"id": "23376407_T14",
"type": "CHEMICAL",
"text": [
"Ca"
],
"offsets": [
[
715,
717
]
],
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},
{
"id": "23376407_T15",
"type": "CHEMICAL",
"text": [
"phosphorus"
],
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[
732,
742
]
],
"normalized": []
},
{
"id": "23376407_T16",
"type": "CHEMICAL",
"text": [
"Pb"
],
"offsets": [
[
816,
818
]
],
"normalized": []
},
{
"id": "23376407_T17",
"type": "CHEMICAL",
"text": [
"Ca"
],
"offsets": [
[
908,
910
]
],
"normalized": []
},
{
"id": "23376407_T18",
"type": "CHEMICAL",
"text": [
"Pb"
],
"offsets": [
[
198,
200
]
],
"normalized": []
},
{
"id": "23376407_T19",
"type": "CHEMICAL",
"text": [
"Pb"
],
"offsets": [
[
986,
988
]
],
"normalized": []
},
{
"id": "23376407_T20",
"type": "CHEMICAL",
"text": [
"Pb"
],
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[
1045,
1047
]
],
"normalized": []
},
{
"id": "23376407_T21",
"type": "CHEMICAL",
"text": [
"ethanol"
],
"offsets": [
[
10,
17
]
],
"normalized": []
},
{
"id": "23376407_T22",
"type": "GENE-Y",
"text": [
"receptor activator nuclear factor-κB"
],
"offsets": [
[
1652,
1688
]
],
"normalized": []
},
{
"id": "23376407_T23",
"type": "GENE-Y",
"text": [
"RANK"
],
"offsets": [
[
1690,
1694
]
],
"normalized": []
},
{
"id": "23376407_T24",
"type": "GENE-Y",
"text": [
"RANK ligand"
],
"offsets": [
[
1696,
1707
]
],
"normalized": []
},
{
"id": "23376407_T25",
"type": "GENE-Y",
"text": [
"osteoprotegerin"
],
"offsets": [
[
1708,
1723
]
],
"normalized": []
},
{
"id": "23376407_T26",
"type": "GENE-Y",
"text": [
"osteocalcin"
],
"offsets": [
[
381,
392
]
],
"normalized": []
},
{
"id": "23376407_T27",
"type": "GENE-N",
"text": [
"procollagen I"
],
"offsets": [
[
394,
407
]
],
"normalized": []
},
{
"id": "23376407_T28",
"type": "GENE-Y",
"text": [
"osteoprotegerin"
],
"offsets": [
[
409,
424
]
],
"normalized": []
},
{
"id": "23376407_T29",
"type": "GENE-Y",
"text": [
"alkaline phosphatase"
],
"offsets": [
[
426,
446
]
],
"normalized": []
},
{
"id": "23376407_T30",
"type": "GENE-N",
"text": [
"collagen I"
],
"offsets": [
[
480,
490
]
],
"normalized": []
},
{
"id": "23376407_T31",
"type": "GENE-Y",
"text": [
"receptor activator of nuclear factor-κB ligand"
],
"offsets": [
[
500,
546
]
],
"normalized": []
},
{
"id": "23376407_T32",
"type": "GENE-Y",
"text": [
"parathormone"
],
"offsets": [
[
572,
584
]
],
"normalized": []
},
{
"id": "23376407_T33",
"type": "GENE-Y",
"text": [
"calcitonin"
],
"offsets": [
[
586,
596
]
],
"normalized": []
},
{
"id": "23376407_T34",
"type": "GENE-Y",
"text": [
"alkaline phosphatase"
],
"offsets": [
[
942,
962
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23376407_0",
"type": "INHIBITOR",
"arg1_id": "23376407_T6",
"arg2_id": "23376407_T22",
"normalized": []
},
{
"id": "23376407_1",
"type": "INHIBITOR",
"arg1_id": "23376407_T6",
"arg2_id": "23376407_T23",
"normalized": []
},
{
"id": "23376407_2",
"type": "INHIBITOR",
"arg1_id": "23376407_T6",
"arg2_id": "23376407_T24",
"normalized": []
},
{
"id": "23376407_3",
"type": "INHIBITOR",
"arg1_id": "23376407_T6",
"arg2_id": "23376407_T25",
"normalized": []
}
] |
9643444 | 9643444 | [
{
"id": "9643444_title",
"type": "title",
"text": [
"Investigation into the presence of insulin-degrading enzyme in cultured type II alveolar cells and the effects of enzyme inhibitors on pulmonary bioavailability of insulin in rats."
],
"offsets": [
[
0,
180
]
]
},
{
"id": "9643444_abstract",
"type": "abstract",
"text": [
"The purpose of this study was to investigate the role of insulin-degrading enzyme (IDE, EC 3.4.22.11) in insulin degradation in alveolar epithelium. The primary culture of isolated rat type-II pneumocytes was used for the in-vitro characterization of IDE. Insulin was then administered intratracheally with various inhibitors to assess the improvement in its pulmonary bioavailability. In cultured type-II pneumocytes, the cytosolic insulin-degrading activity contributed 81% of total insulin degradation, reached a maximum at pH 7.5 and had an apparent Michaelis-Menten constant (Km) of 135 nM. N-Ethylmaleimide, p-chloromercuribenzoic acid and 1,10-phenanthroline inhibited insulin-degrading activity almost completely in both crude homogenate and cytosol. An immunoprecipitation study showed that IDE contributed 74% of cytosolic insulin-degrading activity. Western blot analysis showing a single band of 110 kDa on reduced SDS (sodium dodecylsulphate) gels confirmed the presence of IDE in cultured type-II cells. When given intratracheally with insulin, inhibitors including N-ethylmaleimide, p-chloromercuribenzoic acid, and 1,10-phenanthroline significantly enhanced the absolute bioavailability of insulin and the compound's hypoglycaemic effects. These results suggest that IDE is present in alveolar epithelium and might be involved in limiting insulin absorption in the lung."
],
"offsets": [
[
181,
1567
]
]
}
] | [
{
"id": "9643444_T1",
"type": "CHEMICAL",
"text": [
"N-ethylmaleimide"
],
"offsets": [
[
1261,
1277
]
],
"normalized": []
},
{
"id": "9643444_T2",
"type": "CHEMICAL",
"text": [
"p-chloromercuribenzoic acid"
],
"offsets": [
[
1279,
1306
]
],
"normalized": []
},
{
"id": "9643444_T3",
"type": "CHEMICAL",
"text": [
"1,10-phenanthroline"
],
"offsets": [
[
1312,
1331
]
],
"normalized": []
},
{
"id": "9643444_T4",
"type": "CHEMICAL",
"text": [
"N-Ethylmaleimide"
],
"offsets": [
[
777,
793
]
],
"normalized": []
},
{
"id": "9643444_T5",
"type": "CHEMICAL",
"text": [
"p-chloromercuribenzoic acid"
],
"offsets": [
[
795,
822
]
],
"normalized": []
},
{
"id": "9643444_T6",
"type": "CHEMICAL",
"text": [
"1,10-phenanthroline"
],
"offsets": [
[
827,
846
]
],
"normalized": []
},
{
"id": "9643444_T7",
"type": "CHEMICAL",
"text": [
"sodium dodecylsulphate"
],
"offsets": [
[
1113,
1135
]
],
"normalized": []
},
{
"id": "9643444_T8",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1231,
1238
]
],
"normalized": []
},
{
"id": "9643444_T9",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
286,
293
]
],
"normalized": []
},
{
"id": "9643444_T10",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1387,
1394
]
],
"normalized": []
},
{
"id": "9643444_T11",
"type": "GENE-Y",
"text": [
"IDE"
],
"offsets": [
[
1464,
1467
]
],
"normalized": []
},
{
"id": "9643444_T12",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1536,
1543
]
],
"normalized": []
},
{
"id": "9643444_T13",
"type": "GENE-Y",
"text": [
"IDE"
],
"offsets": [
[
432,
435
]
],
"normalized": []
},
{
"id": "9643444_T14",
"type": "GENE-N",
"text": [
"Insulin"
],
"offsets": [
[
437,
444
]
],
"normalized": []
},
{
"id": "9643444_T15",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
614,
621
]
],
"normalized": []
},
{
"id": "9643444_T16",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
666,
673
]
],
"normalized": []
},
{
"id": "9643444_T17",
"type": "GENE-Y",
"text": [
"insulin-degrading enzyme"
],
"offsets": [
[
238,
262
]
],
"normalized": []
},
{
"id": "9643444_T18",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
857,
864
]
],
"normalized": []
},
{
"id": "9643444_T19",
"type": "GENE-Y",
"text": [
"IDE"
],
"offsets": [
[
981,
984
]
],
"normalized": []
},
{
"id": "9643444_T20",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1014,
1021
]
],
"normalized": []
},
{
"id": "9643444_T21",
"type": "GENE-Y",
"text": [
"IDE"
],
"offsets": [
[
264,
267
]
],
"normalized": []
},
{
"id": "9643444_T22",
"type": "GENE-Y",
"text": [
"EC 3.4.22.11"
],
"offsets": [
[
269,
281
]
],
"normalized": []
},
{
"id": "9643444_T23",
"type": "GENE-Y",
"text": [
"IDE"
],
"offsets": [
[
1168,
1171
]
],
"normalized": []
},
{
"id": "9643444_T24",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
164,
171
]
],
"normalized": []
},
{
"id": "9643444_T25",
"type": "GENE-Y",
"text": [
"insulin-degrading enzyme"
],
"offsets": [
[
35,
59
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "9643444_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "9643444_T4",
"arg2_id": "9643444_T18",
"normalized": []
},
{
"id": "9643444_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "9643444_T5",
"arg2_id": "9643444_T18",
"normalized": []
},
{
"id": "9643444_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "9643444_T6",
"arg2_id": "9643444_T18",
"normalized": []
},
{
"id": "9643444_3",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "9643444_T1",
"arg2_id": "9643444_T10",
"normalized": []
},
{
"id": "9643444_4",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "9643444_T2",
"arg2_id": "9643444_T10",
"normalized": []
},
{
"id": "9643444_5",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "9643444_T3",
"arg2_id": "9643444_T10",
"normalized": []
}
] |
17652426 | 17652426 | [
{
"id": "17652426_title",
"type": "title",
"text": [
"Bone growth retardation in mouse embryos expressing human collagenase 1."
],
"offsets": [
[
0,
72
]
]
},
{
"id": "17652426_abstract",
"type": "abstract",
"text": [
"Cellular growth and differentiation are readouts of multiple signaling pathways from the intercellular and/or extracellular milieu. The extracellular matrix through the activation of cellular receptors transmits these signals. Therefore, extracellular matrix proteolysis could affect cell fate in a variety of biological events. However, the biological consequence of inadequate extracellular matrix degradation in vivo is not clear. We developed a mouse model expressing human collagenase (matrix metalloproteinase-1, MMP-1) under the control of Col2a1 promoter. The mice showed significant growth retardation during embryogenesis and a loss of the demarcation of zonal structure and columnar array of the cartilage. Immunological examination revealed increased degradation of type II collagen and upregulation of fibronectin and alpha(5)-integrin subunit in the transgenic cartilage. The resting zone and proliferating zone of the growth plate cartilage exhibited a simultaneous increase in bromodeoxyuridine (BrdU)-incorporated proliferating cells and terminal deoxynucleotidyl transferase-mediated X-dUTP nick-end labeling-positive apoptotic cells, respectively. Chondrocyte differentiation was not disturbed in the transgenic mice as evidenced by normal expression of the Ihh and type X collagen expression. These data demonstrate that type II collagen proteolysis is an important determinant for the skeletal outgrowth through modulation of chondrocyte survival and cartilagenous growth."
],
"offsets": [
[
73,
1566
]
]
}
] | [
{
"id": "17652426_T1",
"type": "CHEMICAL",
"text": [
"BrdU"
],
"offsets": [
[
1085,
1089
]
],
"normalized": []
},
{
"id": "17652426_T2",
"type": "CHEMICAL",
"text": [
"bromodeoxyuridine"
],
"offsets": [
[
1066,
1083
]
],
"normalized": []
},
{
"id": "17652426_T3",
"type": "GENE-N",
"text": [
"type X collagen"
],
"offsets": [
[
1358,
1373
]
],
"normalized": []
},
{
"id": "17652426_T4",
"type": "GENE-N",
"text": [
"type II collagen"
],
"offsets": [
[
1414,
1430
]
],
"normalized": []
},
{
"id": "17652426_T5",
"type": "GENE-Y",
"text": [
"human collagenase"
],
"offsets": [
[
545,
562
]
],
"normalized": []
},
{
"id": "17652426_T6",
"type": "GENE-Y",
"text": [
"matrix metalloproteinase-1"
],
"offsets": [
[
564,
590
]
],
"normalized": []
},
{
"id": "17652426_T7",
"type": "GENE-Y",
"text": [
"MMP-1"
],
"offsets": [
[
592,
597
]
],
"normalized": []
},
{
"id": "17652426_T8",
"type": "GENE-N",
"text": [
"Col2a1 promoter"
],
"offsets": [
[
620,
635
]
],
"normalized": []
},
{
"id": "17652426_T9",
"type": "GENE-N",
"text": [
"type II collagen"
],
"offsets": [
[
851,
867
]
],
"normalized": []
},
{
"id": "17652426_T10",
"type": "GENE-Y",
"text": [
"fibronectin"
],
"offsets": [
[
888,
899
]
],
"normalized": []
},
{
"id": "17652426_T11",
"type": "GENE-Y",
"text": [
"alpha(5)-integrin"
],
"offsets": [
[
904,
921
]
],
"normalized": []
},
{
"id": "17652426_T12",
"type": "GENE-Y",
"text": [
"human collagenase 1"
],
"offsets": [
[
52,
71
]
],
"normalized": []
}
] | [] | [] | [] |
15700891 | 15700891 | [
{
"id": "15700891_title",
"type": "title",
"text": [
"Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus."
],
"offsets": [
[
0,
102
]
]
},
{
"id": "15700891_abstract",
"type": "abstract",
"text": [
"PURPOSE: The pharmacology and tolerability of exenatide in patients with type 2 diabetes mellitus were studied. METHODS: Two randomized, single-blind, placebo-controlled studies were conducted. Treatment with oral antidiabetic agents was stopped 14 days before study initiation. In the first study (study A), eight subjects received placebo, 0.1-, 0.2-, 0.3-, and either 0.4-microg/kg exenatide or placebo five minutes before a meal combined with liquid acetaminophen (to assess the rate of gastric emptying) on days 1, 3, 5, 7, and 9. In the second study (study B), subjects received a single s.c. dose of exenatide or placebo on consecutive days. Part 1 of study B used exenatide doses of 0.01 and 0.1 microg/ kg; 0.02-, 0.05-, and 0.1-microg/kg doses were given in part 2. After an overnight fast, the study drug was injected 15 minutes before a meal (part 1) and before a meal and acetaminophen (part 2). Parts 1 and 2 of study B enrolled six and eight patients, respectively. RESULTS: In both studies, plasma exenatide pharmacokinetic profiles appeared dose proportional. Exenatide doses of 0.02-0.2 microg/kg dose-dependently lowered postprandial glucose excursions. Exenatide suppressed postprandial plasma glucagon and slowed gastric emptying. There were no serious adverse events and no patient withdrawals related to treatment. Nausea and vomiting were the most common adverse events and were mild to moderate in severity at doses ranging from 0.02 to 0.2 microg/kg. CONCLUSION: Administration of preprandial exenatide by s.c. injection resulted in dose-proportional exenatide pharmacokinetics and antidiabetic pharmacodynamic activity. At doses ranging from 0.02 to 0.2 microg/kg, exenatide dose-dependently reduced postprandial plasma glucose excursion by insulinotropism, suppression of plasma glucagon, and slowing of gastric emptying."
],
"offsets": [
[
103,
1952
]
]
}
] | [
{
"id": "15700891_T1",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
1256,
1263
]
],
"normalized": []
},
{
"id": "15700891_T2",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
1850,
1857
]
],
"normalized": []
},
{
"id": "15700891_T3",
"type": "CHEMICAL",
"text": [
"acetaminophen"
],
"offsets": [
[
557,
570
]
],
"normalized": []
},
{
"id": "15700891_T4",
"type": "CHEMICAL",
"text": [
"acetaminophen"
],
"offsets": [
[
988,
1001
]
],
"normalized": []
},
{
"id": "15700891_T5",
"type": "GENE-Y",
"text": [
"glucagon"
],
"offsets": [
[
1317,
1325
]
],
"normalized": []
},
{
"id": "15700891_T6",
"type": "GENE-Y",
"text": [
"glucagon"
],
"offsets": [
[
1910,
1918
]
],
"normalized": []
}
] | [] | [] | [] |
23601990 | 23601990 | [
{
"id": "23601990_title",
"type": "title",
"text": [
"Synthesis and biological evaluation of phosphorylated flavonoids as potent and selective inhibitors of cholesterol esterase."
],
"offsets": [
[
0,
124
]
]
},
{
"id": "23601990_abstract",
"type": "abstract",
"text": [
"A series of phosphorylated flavonoids were synthesized and investigated in vitro as inhibitors of pancreatic cholesterol esterase (CEase) and acetylcholinesterase (AChE). The results showed that most of the synthesized compounds exhibited nanomolar potency against CEase, much better than the parent flavonoids. Furthermore, these phosphorylated flavonoids demonstrated good to high selectivity for CEase over AChE, which only showed micromolar potency inhibition of AChE. The most selective and potent inhibitor of CEase (3e) had IC50 value of 0.72 nM and 11800-fold selectivity for CEase over AChE. The structure-activity relationships revealed that the free hydroxyl group at position 5 and phosphate group at position 7 of the phosphorylated flavonoids are favorable to the inhibition of CEase. The inhibition mechanism and kinetic characterization studies indicated that they are irreversible competitive inhibitors of CEase."
],
"offsets": [
[
125,
1055
]
]
}
] | [
{
"id": "23601990_T1",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
234,
245
]
],
"normalized": []
},
{
"id": "23601990_T2",
"type": "CHEMICAL",
"text": [
"phosphorylated flavonoids"
],
"offsets": [
[
137,
162
]
],
"normalized": []
},
{
"id": "23601990_T3",
"type": "CHEMICAL",
"text": [
"flavonoids"
],
"offsets": [
[
425,
435
]
],
"normalized": []
},
{
"id": "23601990_T4",
"type": "CHEMICAL",
"text": [
"phosphorylated flavonoids"
],
"offsets": [
[
456,
481
]
],
"normalized": []
},
{
"id": "23601990_T5",
"type": "CHEMICAL",
"text": [
"hydroxyl"
],
"offsets": [
[
786,
794
]
],
"normalized": []
},
{
"id": "23601990_T6",
"type": "CHEMICAL",
"text": [
"phosphate"
],
"offsets": [
[
819,
828
]
],
"normalized": []
},
{
"id": "23601990_T7",
"type": "CHEMICAL",
"text": [
"phosphorylated flavonoids"
],
"offsets": [
[
856,
881
]
],
"normalized": []
},
{
"id": "23601990_T8",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
103,
114
]
],
"normalized": []
},
{
"id": "23601990_T9",
"type": "CHEMICAL",
"text": [
"phosphorylated flavonoids"
],
"offsets": [
[
39,
64
]
],
"normalized": []
},
{
"id": "23601990_T10",
"type": "GENE-Y",
"text": [
"cholesterol esterase"
],
"offsets": [
[
234,
254
]
],
"normalized": []
},
{
"id": "23601990_T11",
"type": "GENE-Y",
"text": [
"CEase"
],
"offsets": [
[
256,
261
]
],
"normalized": []
},
{
"id": "23601990_T12",
"type": "GENE-Y",
"text": [
"acetylcholinesterase"
],
"offsets": [
[
267,
287
]
],
"normalized": []
},
{
"id": "23601990_T13",
"type": "GENE-Y",
"text": [
"AChE"
],
"offsets": [
[
289,
293
]
],
"normalized": []
},
{
"id": "23601990_T14",
"type": "GENE-Y",
"text": [
"CEase"
],
"offsets": [
[
390,
395
]
],
"normalized": []
},
{
"id": "23601990_T15",
"type": "GENE-Y",
"text": [
"CEase"
],
"offsets": [
[
524,
529
]
],
"normalized": []
},
{
"id": "23601990_T16",
"type": "GENE-Y",
"text": [
"AChE"
],
"offsets": [
[
535,
539
]
],
"normalized": []
},
{
"id": "23601990_T17",
"type": "GENE-Y",
"text": [
"AChE"
],
"offsets": [
[
592,
596
]
],
"normalized": []
},
{
"id": "23601990_T18",
"type": "GENE-Y",
"text": [
"CEase"
],
"offsets": [
[
641,
646
]
],
"normalized": []
},
{
"id": "23601990_T19",
"type": "GENE-Y",
"text": [
"CEase"
],
"offsets": [
[
709,
714
]
],
"normalized": []
},
{
"id": "23601990_T20",
"type": "GENE-Y",
"text": [
"AChE"
],
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720,
724
]
],
"normalized": []
},
{
"id": "23601990_T21",
"type": "GENE-Y",
"text": [
"CEase"
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917,
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]
],
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{
"id": "23601990_T22",
"type": "GENE-Y",
"text": [
"CEase"
],
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[
1049,
1054
]
],
"normalized": []
},
{
"id": "23601990_T23",
"type": "GENE-Y",
"text": [
"cholesterol esterase"
],
"offsets": [
[
103,
123
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23601990_0",
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"normalized": []
},
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},
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},
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"type": "INHIBITOR",
"arg1_id": "23601990_T2",
"arg2_id": "23601990_T12",
"normalized": []
},
{
"id": "23601990_4",
"type": "INHIBITOR",
"arg1_id": "23601990_T2",
"arg2_id": "23601990_T13",
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},
{
"id": "23601990_5",
"type": "INHIBITOR",
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"arg2_id": "23601990_T14",
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},
{
"id": "23601990_6",
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},
{
"id": "23601990_7",
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},
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"type": "INHIBITOR",
"arg1_id": "23601990_T7",
"arg2_id": "23601990_T21",
"normalized": []
}
] |
14711372 | 14711372 | [
{
"id": "14711372_title",
"type": "title",
"text": [
"Structural model of carnitine palmitoyltransferase I based on the carnitine acetyltransferase crystal."
],
"offsets": [
[
0,
102
]
]
},
{
"id": "14711372_abstract",
"type": "abstract",
"text": [
"CPT I (carnitine palmitoyltransferase I) catalyses the conversion of palmitoyl-CoA into palmitoylcarnitine in the presence of L-carnitine, facilitating the entry of fatty acids into mitochondria. We propose a 3-D (three-dimensional) structural model for L-CPT I (liver CPT I), based on the similarity of this enzyme to the recently crystallized mouse carnitine acetyltransferase. The model includes 607 of the 773 amino acids of L-CPT I, and the positions of carnitine, CoA and the palmitoyl group were assigned by superposition and docking analysis. Functional analysis of this 3-D model included the mutagenesis of several amino acids in order to identify putative catalytic residues. Mutants D477A, D567A and E590D showed reduced L-CPT I activity. In addition, individual mutation of amino acids forming the conserved Ser685-Thr686-Ser687 motif abolished enzyme activity in mutants T686A and S687A and altered K(m) and the catalytic efficiency for carnitine in mutant S685A. We conclude that the catalytic residues are His473 and Asp477, while Ser687 probably stabilizes the transition state. Several conserved lysines, i.e. Lys455, Lys505, Lys560 and Lys561, were also mutated. Only mutants K455A and K560A showed decreases in activity of 50%. The model rationalizes the finding of nine natural mutations in patients with hereditary L-CPT I deficiencies."
],
"offsets": [
[
103,
1461
]
]
}
] | [
{
"id": "14711372_T1",
"type": "CHEMICAL",
"text": [
"L-carnitine"
],
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[
229,
240
]
],
"normalized": []
},
{
"id": "14711372_T2",
"type": "CHEMICAL",
"text": [
"fatty acids"
],
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[
268,
279
]
],
"normalized": []
},
{
"id": "14711372_T3",
"type": "CHEMICAL",
"text": [
"carnitine"
],
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[
454,
463
]
],
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{
"id": "14711372_T4",
"type": "CHEMICAL",
"text": [
"amino acids"
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[
517,
528
]
],
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},
{
"id": "14711372_T5",
"type": "CHEMICAL",
"text": [
"carnitine"
],
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[
562,
571
]
],
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},
{
"id": "14711372_T6",
"type": "CHEMICAL",
"text": [
"CoA"
],
"offsets": [
[
573,
576
]
],
"normalized": []
},
{
"id": "14711372_T7",
"type": "CHEMICAL",
"text": [
"palmitoyl"
],
"offsets": [
[
585,
594
]
],
"normalized": []
},
{
"id": "14711372_T8",
"type": "CHEMICAL",
"text": [
"amino acids"
],
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[
728,
739
]
],
"normalized": []
},
{
"id": "14711372_T9",
"type": "CHEMICAL",
"text": [
"palmitoyl-CoA"
],
"offsets": [
[
172,
185
]
],
"normalized": []
},
{
"id": "14711372_T10",
"type": "CHEMICAL",
"text": [
"carnitine"
],
"offsets": [
[
110,
119
]
],
"normalized": []
},
{
"id": "14711372_T11",
"type": "CHEMICAL",
"text": [
"amino acids"
],
"offsets": [
[
890,
901
]
],
"normalized": []
},
{
"id": "14711372_T12",
"type": "CHEMICAL",
"text": [
"palmitoylcarnitine"
],
"offsets": [
[
191,
209
]
],
"normalized": []
},
{
"id": "14711372_T13",
"type": "CHEMICAL",
"text": [
"carnitine"
],
"offsets": [
[
1054,
1063
]
],
"normalized": []
},
{
"id": "14711372_T14",
"type": "CHEMICAL",
"text": [
"carnitine"
],
"offsets": [
[
20,
29
]
],
"normalized": []
},
{
"id": "14711372_T15",
"type": "CHEMICAL",
"text": [
"carnitine"
],
"offsets": [
[
66,
75
]
],
"normalized": []
},
{
"id": "14711372_T16",
"type": "GENE-Y",
"text": [
"CPT I"
],
"offsets": [
[
103,
108
]
],
"normalized": []
},
{
"id": "14711372_T17",
"type": "GENE-N",
"text": [
"K455A"
],
"offsets": [
[
1298,
1303
]
],
"normalized": []
},
{
"id": "14711372_T18",
"type": "GENE-N",
"text": [
"K560A"
],
"offsets": [
[
1308,
1313
]
],
"normalized": []
},
{
"id": "14711372_T19",
"type": "GENE-Y",
"text": [
"L-CPT I"
],
"offsets": [
[
1440,
1447
]
],
"normalized": []
},
{
"id": "14711372_T20",
"type": "GENE-Y",
"text": [
"L-CPT I"
],
"offsets": [
[
357,
364
]
],
"normalized": []
},
{
"id": "14711372_T21",
"type": "GENE-Y",
"text": [
"liver CPT I"
],
"offsets": [
[
366,
377
]
],
"normalized": []
},
{
"id": "14711372_T22",
"type": "GENE-Y",
"text": [
"mouse carnitine acetyltransferase"
],
"offsets": [
[
448,
481
]
],
"normalized": []
},
{
"id": "14711372_T23",
"type": "GENE-Y",
"text": [
"L-CPT I"
],
"offsets": [
[
532,
539
]
],
"normalized": []
},
{
"id": "14711372_T24",
"type": "GENE-N",
"text": [
"D477A"
],
"offsets": [
[
798,
803
]
],
"normalized": []
},
{
"id": "14711372_T25",
"type": "GENE-N",
"text": [
"D567A"
],
"offsets": [
[
805,
810
]
],
"normalized": []
},
{
"id": "14711372_T26",
"type": "GENE-N",
"text": [
"E590D"
],
"offsets": [
[
815,
820
]
],
"normalized": []
},
{
"id": "14711372_T27",
"type": "GENE-Y",
"text": [
"L-CPT I"
],
"offsets": [
[
836,
843
]
],
"normalized": []
},
{
"id": "14711372_T28",
"type": "GENE-Y",
"text": [
"carnitine palmitoyltransferase I"
],
"offsets": [
[
110,
142
]
],
"normalized": []
},
{
"id": "14711372_T29",
"type": "GENE-N",
"text": [
"T686A"
],
"offsets": [
[
988,
993
]
],
"normalized": []
},
{
"id": "14711372_T30",
"type": "GENE-N",
"text": [
"S687"
],
"offsets": [
[
998,
1002
]
],
"normalized": []
},
{
"id": "14711372_T31",
"type": "GENE-N",
"text": [
"S685A"
],
"offsets": [
[
1074,
1079
]
],
"normalized": []
},
{
"id": "14711372_T32",
"type": "GENE-Y",
"text": [
"carnitine palmitoyltransferase I"
],
"offsets": [
[
20,
52
]
],
"normalized": []
},
{
"id": "14711372_T33",
"type": "GENE-Y",
"text": [
"carnitine acetyltransferase"
],
"offsets": [
[
66,
93
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "14711372_0",
"type": "SUBSTRATE",
"arg1_id": "14711372_T9",
"arg2_id": "14711372_T16",
"normalized": []
},
{
"id": "14711372_1",
"type": "SUBSTRATE",
"arg1_id": "14711372_T9",
"arg2_id": "14711372_T28",
"normalized": []
},
{
"id": "14711372_2",
"type": "PRODUCT-OF",
"arg1_id": "14711372_T12",
"arg2_id": "14711372_T16",
"normalized": []
},
{
"id": "14711372_3",
"type": "PRODUCT-OF",
"arg1_id": "14711372_T12",
"arg2_id": "14711372_T28",
"normalized": []
},
{
"id": "14711372_4",
"type": "SUBSTRATE",
"arg1_id": "14711372_T1",
"arg2_id": "14711372_T16",
"normalized": []
},
{
"id": "14711372_5",
"type": "SUBSTRATE",
"arg1_id": "14711372_T1",
"arg2_id": "14711372_T28",
"normalized": []
},
{
"id": "14711372_6",
"type": "PART-OF",
"arg1_id": "14711372_T4",
"arg2_id": "14711372_T23",
"normalized": []
},
{
"id": "14711372_7",
"type": "PART-OF",
"arg1_id": "14711372_T11",
"arg2_id": "14711372_T29",
"normalized": []
},
{
"id": "14711372_8",
"type": "PART-OF",
"arg1_id": "14711372_T11",
"arg2_id": "14711372_T30",
"normalized": []
},
{
"id": "14711372_9",
"type": "SUBSTRATE",
"arg1_id": "14711372_T13",
"arg2_id": "14711372_T31",
"normalized": []
}
] |
22867529 | 22867529 | [
{
"id": "22867529_title",
"type": "title",
"text": [
"Synthesis, characterization, screening and docking analysis of 4-anilinoquinazoline derivatives as tyrosine kinase inhibitors."
],
"offsets": [
[
0,
126
]
]
},
{
"id": "22867529_abstract",
"type": "abstract",
"text": [
"We report here the design and synthesis of a series of 4-anilinoquinazoline derivatives, of which 7 compounds were crystallographically characterized, as epidermal growth factor receptor (EGFR) inhibitors by modifications on the aniline ring or at the 6-alkoxy site of the 6,7-dimethoxy-4-anilinoquinazoline pharmacophore. The relative inhibition efficiency on EGFR of all as-prepared compounds were measured and ordered, and the IC50 values of nine highly active compounds were determined by ELISA. Docking studies indicated that all 4-anilinoquinazoline derivatives could be inserted into the ATP-binding pocket of the EGFR via indirect docking, and that the modifications at the 3'-position of the anilino group and 6-alkoxy site of the quinazoline ring have little interference with the formation of the two essential H-bonds between the N3 of the quinazoline ring and Thr766 through a water molecule, and the N1 of the quinazoline ring and N-H of Met769. The displacing of the phenyl at 4-position with pyridinyl dramatically reduces the activity of the quinazoline pharmacophore, the resulting derivative (10) being the least active compound. The docking results also showed that the formation of new H-bonds between the N-H of the ethylenediamine group linked to the 6-alkoxy site and Asp776/Cys773 in the binding pocket of EGFR makes compounds 19 (IC50=12.1±1.6 nM) and 20 (IC50=13.6±0.8 nM) the most potent EGFR inhibitors in this class and worthy of further modification to obtain more potent anticancer compounds."
],
"offsets": [
[
127,
1651
]
]
}
] | [
{
"id": "22867529_T1",
"type": "CHEMICAL",
"text": [
"pyridinyl"
],
"offsets": [
[
1135,
1144
]
],
"normalized": []
},
{
"id": "22867529_T2",
"type": "CHEMICAL",
"text": [
"quinazoline"
],
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[
1186,
1197
]
],
"normalized": []
},
{
"id": "22867529_T3",
"type": "CHEMICAL",
"text": [
"H"
],
"offsets": [
[
1334,
1335
]
],
"normalized": []
},
{
"id": "22867529_T4",
"type": "CHEMICAL",
"text": [
"N-H"
],
"offsets": [
[
1354,
1357
]
],
"normalized": []
},
{
"id": "22867529_T5",
"type": "CHEMICAL",
"text": [
"ethylenediamine"
],
"offsets": [
[
1365,
1380
]
],
"normalized": []
},
{
"id": "22867529_T6",
"type": "CHEMICAL",
"text": [
"6-alkoxy"
],
"offsets": [
[
1401,
1409
]
],
"normalized": []
},
{
"id": "22867529_T7",
"type": "CHEMICAL",
"text": [
"Asp"
],
"offsets": [
[
1419,
1422
]
],
"normalized": []
},
{
"id": "22867529_T8",
"type": "CHEMICAL",
"text": [
"Cys"
],
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[
1426,
1429
]
],
"normalized": []
},
{
"id": "22867529_T9",
"type": "CHEMICAL",
"text": [
"aniline"
],
"offsets": [
[
356,
363
]
],
"normalized": []
},
{
"id": "22867529_T10",
"type": "CHEMICAL",
"text": [
"6-alkoxy"
],
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[
379,
387
]
],
"normalized": []
},
{
"id": "22867529_T11",
"type": "CHEMICAL",
"text": [
"6,7-dimethoxy-4-anilinoquinazoline"
],
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[
400,
434
]
],
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},
{
"id": "22867529_T12",
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"4-anilinoquinazoline"
],
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662,
682
]
],
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},
{
"id": "22867529_T13",
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"4-anilinoquinazoline"
],
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[
182,
202
]
],
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},
{
"id": "22867529_T14",
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"text": [
"ATP"
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[
722,
725
]
],
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},
{
"id": "22867529_T15",
"type": "CHEMICAL",
"text": [
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],
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[
828,
835
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],
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},
{
"id": "22867529_T16",
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"text": [
"6-alkoxy"
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[
846,
854
]
],
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"id": "22867529_T17",
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"quinazoline"
],
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[
867,
878
]
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{
"id": "22867529_T18",
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"H"
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[
949,
950
]
],
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},
{
"id": "22867529_T19",
"type": "CHEMICAL",
"text": [
"quinazoline"
],
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[
979,
990
]
],
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},
{
"id": "22867529_T20",
"type": "CHEMICAL",
"text": [
"Thr"
],
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[
1000,
1003
]
],
"normalized": []
},
{
"id": "22867529_T21",
"type": "CHEMICAL",
"text": [
"quinazoline"
],
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[
1051,
1062
]
],
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},
{
"id": "22867529_T22",
"type": "CHEMICAL",
"text": [
"N-H"
],
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[
1072,
1075
]
],
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},
{
"id": "22867529_T23",
"type": "CHEMICAL",
"text": [
"Met"
],
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[
1079,
1082
]
],
"normalized": []
},
{
"id": "22867529_T24",
"type": "CHEMICAL",
"text": [
"phenyl"
],
"offsets": [
[
1109,
1115
]
],
"normalized": []
},
{
"id": "22867529_T25",
"type": "CHEMICAL",
"text": [
"4-anilinoquinazoline"
],
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[
63,
83
]
],
"normalized": []
},
{
"id": "22867529_T26",
"type": "CHEMICAL",
"text": [
"tyrosine"
],
"offsets": [
[
99,
107
]
],
"normalized": []
},
{
"id": "22867529_T27",
"type": "GENE-Y",
"text": [
"EGFR"
],
"offsets": [
[
1458,
1462
]
],
"normalized": []
},
{
"id": "22867529_T28",
"type": "GENE-Y",
"text": [
"EGFR"
],
"offsets": [
[
1543,
1547
]
],
"normalized": []
},
{
"id": "22867529_T29",
"type": "GENE-Y",
"text": [
"epidermal growth factor receptor"
],
"offsets": [
[
281,
313
]
],
"normalized": []
},
{
"id": "22867529_T30",
"type": "GENE-Y",
"text": [
"EGFR"
],
"offsets": [
[
315,
319
]
],
"normalized": []
},
{
"id": "22867529_T31",
"type": "GENE-Y",
"text": [
"EGFR"
],
"offsets": [
[
488,
492
]
],
"normalized": []
},
{
"id": "22867529_T32",
"type": "GENE-Y",
"text": [
"EGFR"
],
"offsets": [
[
748,
752
]
],
"normalized": []
},
{
"id": "22867529_T33",
"type": "GENE-N",
"text": [
"tyrosine kinase"
],
"offsets": [
[
99,
114
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "22867529_0",
"type": "INHIBITOR",
"arg1_id": "22867529_T25",
"arg2_id": "22867529_T33",
"normalized": []
},
{
"id": "22867529_1",
"type": "INHIBITOR",
"arg1_id": "22867529_T13",
"arg2_id": "22867529_T29",
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},
{
"id": "22867529_2",
"type": "INHIBITOR",
"arg1_id": "22867529_T13",
"arg2_id": "22867529_T30",
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},
{
"id": "22867529_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "22867529_T14",
"arg2_id": "22867529_T32",
"normalized": []
},
{
"id": "22867529_4",
"type": "PART-OF",
"arg1_id": "22867529_T20",
"arg2_id": "22867529_T32",
"normalized": []
},
{
"id": "22867529_5",
"type": "PART-OF",
"arg1_id": "22867529_T23",
"arg2_id": "22867529_T32",
"normalized": []
},
{
"id": "22867529_6",
"type": "PART-OF",
"arg1_id": "22867529_T8",
"arg2_id": "22867529_T27",
"normalized": []
},
{
"id": "22867529_7",
"type": "PART-OF",
"arg1_id": "22867529_T7",
"arg2_id": "22867529_T27",
"normalized": []
},
{
"id": "22867529_8",
"type": "INHIBITOR",
"arg1_id": "22867529_T5",
"arg2_id": "22867529_T28",
"normalized": []
}
] |
10901669 | 10901669 | [
{
"id": "10901669_title",
"type": "title",
"text": [
"Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin or 2,2',4,4',5,5'-hexachlorobiphenyl on vitamin K-dependent blood coagulation in male and female WAG/Rij-rats."
],
"offsets": [
[
0,
157
]
]
},
{
"id": "10901669_abstract",
"type": "abstract",
"text": [
"Newborns are susceptible to hemorrhages (hemorrhagic disease of the newborn or HDN) due to vitamin K deficiency. Induction of cytochrome P450 in the fetal liver by maternal anticonvulsant therapy such as phenobarbital or phenytoin is considered to be a major cause. An observed increase in late hemorrhagic disease (LHD) in breast fed neonates gave rise to the hypothesis that PCBs and dioxins, P450-inducing contaminants present in human milk, might effect vitamin K-dependent blood coagulation. This hypothesis was studied in rats. Administration of a single oral dose of 0.003, 0.03, 0.3, 3 or 30 nmol 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) per kg bodyweight or 0.75, 4, 20, 100 or 500 micromol 2,2',4,4',5,5'-hexachlorobiphenyl/kg bw (HxCB) to female and male rats resulted in dose-related reductions of the vitamin K-dependent coagulation factor VII. The highest factor VII reduction in female rats was 44%, observed after TCDD exposure. The Lowest Observed Adverse Effect Level (LOAEL) of TCDD on female factor VII levels was 0.3 nmol/kg bw (96 ng/kg). There was a significant inverse correlation between Factor VII levels and induction of hepatic ethoxyresorufin O-deethylating (EROD) activity, reflecting CYP1A1, and total P450 content. HxCB had no effect on female coagulation factors. In contrast, in male rats only exposure to HxCB, which induces mainly CYP2B1 and 2B2, decreased both coagulation factors dramatically up to 88%. The LOAEL of HxCB on factor VII in male rats was 100 micromol/kg bw (36 mg/kg). In general, effects on coagulation factors in male rats exceeded those in females. In addition, sex-dependent differences of TCDD and HxCB were observed on the hepatic vitamin K cycle enzyme activities in female and male rats. Vitamin K-dependent (gamma-glutamyl carboxylase activity was mainly induced in female rats; 2.3-fold in the highest dose group of TCDD. In male rats only vitamin K 2,3-epoxide reductase (KO-reductase) activity was induced 1.7-fold by the highest dose of HxCB. KO-reductase activity in female rats was also increased by TCDD, however, less pronounced than the carboxylase activity. Concluding, the hepatic vitamin K cycle still functions and is not blocked by TCDD or HxCB, thus explaining the observed reduction in factor VII. Finally, the possible role of P450 in vitamin K deficiency is discussed. Based on these results it is suggested to investigate the possible role of PCBs and dioxin-like compounds in LHD in more detail."
],
"offsets": [
[
158,
2637
]
]
}
] | [
{
"id": "10901669_T1",
"type": "CHEMICAL",
"text": [
"ethoxyresorufin"
],
"offsets": [
[
1316,
1331
]
],
"normalized": []
},
{
"id": "10901669_T2",
"type": "CHEMICAL",
"text": [
"O"
],
"offsets": [
[
1332,
1333
]
],
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},
{
"id": "10901669_T3",
"type": "CHEMICAL",
"text": [
"HxCB"
],
"offsets": [
[
1407,
1411
]
],
"normalized": []
},
{
"id": "10901669_T4",
"type": "CHEMICAL",
"text": [
"HxCB"
],
"offsets": [
[
1500,
1504
]
],
"normalized": []
},
{
"id": "10901669_T5",
"type": "CHEMICAL",
"text": [
"HxCB"
],
"offsets": [
[
1615,
1619
]
],
"normalized": []
},
{
"id": "10901669_T6",
"type": "CHEMICAL",
"text": [
"TCDD"
],
"offsets": [
[
1807,
1811
]
],
"normalized": []
},
{
"id": "10901669_T7",
"type": "CHEMICAL",
"text": [
"HxCB"
],
"offsets": [
[
1816,
1820
]
],
"normalized": []
},
{
"id": "10901669_T8",
"type": "CHEMICAL",
"text": [
"vitamin K"
],
"offsets": [
[
1850,
1859
]
],
"normalized": []
},
{
"id": "10901669_T9",
"type": "CHEMICAL",
"text": [
"Vitamin K"
],
"offsets": [
[
1909,
1918
]
],
"normalized": []
},
{
"id": "10901669_T10",
"type": "CHEMICAL",
"text": [
"gamma-glutamyl"
],
"offsets": [
[
1930,
1944
]
],
"normalized": []
},
{
"id": "10901669_T11",
"type": "CHEMICAL",
"text": [
"TCDD"
],
"offsets": [
[
2039,
2043
]
],
"normalized": []
},
{
"id": "10901669_T12",
"type": "CHEMICAL",
"text": [
"vitamin K 2,3-epoxide"
],
"offsets": [
[
2063,
2084
]
],
"normalized": []
},
{
"id": "10901669_T13",
"type": "CHEMICAL",
"text": [
"HxCB"
],
"offsets": [
[
2163,
2167
]
],
"normalized": []
},
{
"id": "10901669_T14",
"type": "CHEMICAL",
"text": [
"phenobarbital"
],
"offsets": [
[
362,
375
]
],
"normalized": []
},
{
"id": "10901669_T15",
"type": "CHEMICAL",
"text": [
"TCDD"
],
"offsets": [
[
2228,
2232
]
],
"normalized": []
},
{
"id": "10901669_T16",
"type": "CHEMICAL",
"text": [
"vitamin K"
],
"offsets": [
[
2314,
2323
]
],
"normalized": []
},
{
"id": "10901669_T17",
"type": "CHEMICAL",
"text": [
"TCDD"
],
"offsets": [
[
2368,
2372
]
],
"normalized": []
},
{
"id": "10901669_T18",
"type": "CHEMICAL",
"text": [
"phenytoin"
],
"offsets": [
[
379,
388
]
],
"normalized": []
},
{
"id": "10901669_T19",
"type": "CHEMICAL",
"text": [
"HxCB"
],
"offsets": [
[
2376,
2380
]
],
"normalized": []
},
{
"id": "10901669_T20",
"type": "CHEMICAL",
"text": [
"vitamin K"
],
"offsets": [
[
2474,
2483
]
],
"normalized": []
},
{
"id": "10901669_T21",
"type": "CHEMICAL",
"text": [
"PCBs"
],
"offsets": [
[
2584,
2588
]
],
"normalized": []
},
{
"id": "10901669_T22",
"type": "CHEMICAL",
"text": [
"dioxin"
],
"offsets": [
[
2593,
2599
]
],
"normalized": []
},
{
"id": "10901669_T23",
"type": "CHEMICAL",
"text": [
"PCBs"
],
"offsets": [
[
535,
539
]
],
"normalized": []
},
{
"id": "10901669_T24",
"type": "CHEMICAL",
"text": [
"dioxins"
],
"offsets": [
[
544,
551
]
],
"normalized": []
},
{
"id": "10901669_T25",
"type": "CHEMICAL",
"text": [
"vitamin K"
],
"offsets": [
[
616,
625
]
],
"normalized": []
},
{
"id": "10901669_T26",
"type": "CHEMICAL",
"text": [
"2,3,7,8-tetrachlorodibenzo-p-dioxin"
],
"offsets": [
[
763,
798
]
],
"normalized": []
},
{
"id": "10901669_T27",
"type": "CHEMICAL",
"text": [
"TCDD"
],
"offsets": [
[
800,
804
]
],
"normalized": []
},
{
"id": "10901669_T28",
"type": "CHEMICAL",
"text": [
"2,2',4,4',5,5'-hexachlorobiphenyl"
],
"offsets": [
[
860,
893
]
],
"normalized": []
},
{
"id": "10901669_T29",
"type": "CHEMICAL",
"text": [
"HxCB"
],
"offsets": [
[
901,
905
]
],
"normalized": []
},
{
"id": "10901669_T30",
"type": "CHEMICAL",
"text": [
"vitamin K"
],
"offsets": [
[
974,
983
]
],
"normalized": []
},
{
"id": "10901669_T31",
"type": "CHEMICAL",
"text": [
"vitamin K"
],
"offsets": [
[
249,
258
]
],
"normalized": []
},
{
"id": "10901669_T32",
"type": "CHEMICAL",
"text": [
"TCDD"
],
"offsets": [
[
1090,
1094
]
],
"normalized": []
},
{
"id": "10901669_T33",
"type": "CHEMICAL",
"text": [
"TCDD"
],
"offsets": [
[
1157,
1161
]
],
"normalized": []
},
{
"id": "10901669_T34",
"type": "CHEMICAL",
"text": [
"2,3,7,8-tetrachlorodibenzo-p-dioxin"
],
"offsets": [
[
11,
46
]
],
"normalized": []
},
{
"id": "10901669_T35",
"type": "CHEMICAL",
"text": [
"2,2',4,4',5,5'-hexachlorobiphenyl"
],
"offsets": [
[
50,
83
]
],
"normalized": []
},
{
"id": "10901669_T36",
"type": "CHEMICAL",
"text": [
"vitamin K"
],
"offsets": [
[
87,
96
]
],
"normalized": []
},
{
"id": "10901669_T37",
"type": "GENE-Y",
"text": [
"factor VII"
],
"offsets": [
[
1172,
1182
]
],
"normalized": []
},
{
"id": "10901669_T38",
"type": "GENE-Y",
"text": [
"Factor VII"
],
"offsets": [
[
1273,
1283
]
],
"normalized": []
},
{
"id": "10901669_T39",
"type": "GENE-Y",
"text": [
"CYP1A1"
],
"offsets": [
[
1375,
1381
]
],
"normalized": []
},
{
"id": "10901669_T40",
"type": "GENE-N",
"text": [
"P450"
],
"offsets": [
[
1393,
1397
]
],
"normalized": []
},
{
"id": "10901669_T41",
"type": "GENE-N",
"text": [
"cytochrome P450"
],
"offsets": [
[
284,
299
]
],
"normalized": []
},
{
"id": "10901669_T42",
"type": "GENE-N",
"text": [
"coagulation factors"
],
"offsets": [
[
1436,
1455
]
],
"normalized": []
},
{
"id": "10901669_T43",
"type": "GENE-N",
"text": [
"CYP2B1 and 2B2"
],
"offsets": [
[
1527,
1541
]
],
"normalized": []
},
{
"id": "10901669_T44",
"type": "GENE-N",
"text": [
"coagulation factors"
],
"offsets": [
[
1558,
1577
]
],
"normalized": []
},
{
"id": "10901669_T45",
"type": "GENE-Y",
"text": [
"factor VII"
],
"offsets": [
[
1623,
1633
]
],
"normalized": []
},
{
"id": "10901669_T46",
"type": "GENE-Y",
"text": [
"gamma-glutamyl carboxylase"
],
"offsets": [
[
1930,
1956
]
],
"normalized": []
},
{
"id": "10901669_T47",
"type": "GENE-N",
"text": [
"vitamin K 2,3-epoxide reductase"
],
"offsets": [
[
2063,
2094
]
],
"normalized": []
},
{
"id": "10901669_T48",
"type": "GENE-N",
"text": [
"KO-reductase"
],
"offsets": [
[
2096,
2108
]
],
"normalized": []
},
{
"id": "10901669_T49",
"type": "GENE-N",
"text": [
"KO-reductase"
],
"offsets": [
[
2169,
2181
]
],
"normalized": []
},
{
"id": "10901669_T50",
"type": "GENE-N",
"text": [
"carboxylase"
],
"offsets": [
[
2268,
2279
]
],
"normalized": []
},
{
"id": "10901669_T51",
"type": "GENE-Y",
"text": [
"factor VII"
],
"offsets": [
[
2424,
2434
]
],
"normalized": []
},
{
"id": "10901669_T52",
"type": "GENE-N",
"text": [
"P450"
],
"offsets": [
[
2466,
2470
]
],
"normalized": []
},
{
"id": "10901669_T53",
"type": "GENE-Y",
"text": [
"coagulation factor VII"
],
"offsets": [
[
994,
1016
]
],
"normalized": []
},
{
"id": "10901669_T54",
"type": "GENE-Y",
"text": [
"factor VII"
],
"offsets": [
[
1030,
1040
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "10901669_0",
"type": "ACTIVATOR",
"arg1_id": "10901669_T11",
"arg2_id": "10901669_T46",
"normalized": []
},
{
"id": "10901669_1",
"type": "ACTIVATOR",
"arg1_id": "10901669_T13",
"arg2_id": "10901669_T47",
"normalized": []
},
{
"id": "10901669_2",
"type": "ACTIVATOR",
"arg1_id": "10901669_T13",
"arg2_id": "10901669_T48",
"normalized": []
},
{
"id": "10901669_3",
"type": "ACTIVATOR",
"arg1_id": "10901669_T15",
"arg2_id": "10901669_T49",
"normalized": []
},
{
"id": "10901669_4",
"type": "ACTIVATOR",
"arg1_id": "10901669_T15",
"arg2_id": "10901669_T50",
"normalized": []
},
{
"id": "10901669_5",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "10901669_T4",
"arg2_id": "10901669_T44",
"normalized": []
}
] |
23576111 | 23576111 | [
{
"id": "23576111_title",
"type": "title",
"text": [
"Protective effects of green tea on antioxidative biomarkers in chemical laboratory workers."
],
"offsets": [
[
0,
91
]
]
},
{
"id": "23576111_abstract",
"type": "abstract",
"text": [
"Chemical materials are environmental contaminants, are extensively used in laboratories, and may cause various forms of health hazards in laboratory workers. Therefore, this toxicity most likely is a result of the oxidative metabolism of chemical to reactive products. As green tea (GT) possesses antioxidant effects, the objective of this study was to examine any amelioration oxidative stress in chemical laboratory workers drinking one cup (3 g/300 ml water) of freshly prepared tea once daily. Baseline characteristics including age, sex, smoking, fruit consumption, and duration of exposure were recorded via questionnaire to the subjects. Saliva level oxidative stress parameters such as total antioxidant capacity (TAC), glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) were estimated before and after consumption of GT in these workers. Treatment of subjects with GT induced a significant reduction in saliva GPx activity (406.61 ± 22.07 vs. 238.96 ± 16.26 U/l p = 0.001) and induction in TAC (0.46 ± 0.029 μmol/ml vs. 0.56 ± 0.031, p = 0.016). No statistically significant alteration was found for saliva SOD (0.080 ± 0.0019 vs. 0.079 ± 0.0014, p > 0.05) and CAT (20.36 ± 0.69 vs. 19.78 ± 0.71, p > 0.05) after 28 days treatment by GT. These results demonstrate that drinking GT during chemical exposure can reduce several parameters indicative of oxidative stress. In conclusion, using GT as a dietary supplement can be a rational protocol to control source of hazards in chemical laboratory workers."
],
"offsets": [
[
92,
1630
]
]
}
] | [
{
"id": "23576111_T1",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
820,
831
]
],
"normalized": []
},
{
"id": "23576111_T2",
"type": "CHEMICAL",
"text": [
"superoxide"
],
"offsets": [
[
870,
880
]
],
"normalized": []
},
{
"id": "23576111_T3",
"type": "GENE-N",
"text": [
"SOD"
],
"offsets": [
[
1234,
1237
]
],
"normalized": []
},
{
"id": "23576111_T4",
"type": "GENE-Y",
"text": [
"CAT"
],
"offsets": [
[
1288,
1291
]
],
"normalized": []
},
{
"id": "23576111_T5",
"type": "GENE-N",
"text": [
"glutathione peroxidase"
],
"offsets": [
[
820,
842
]
],
"normalized": []
},
{
"id": "23576111_T6",
"type": "GENE-N",
"text": [
"GPx"
],
"offsets": [
[
844,
847
]
],
"normalized": []
},
{
"id": "23576111_T7",
"type": "GENE-Y",
"text": [
"catalase"
],
"offsets": [
[
850,
858
]
],
"normalized": []
},
{
"id": "23576111_T8",
"type": "GENE-Y",
"text": [
"CAT"
],
"offsets": [
[
860,
863
]
],
"normalized": []
},
{
"id": "23576111_T9",
"type": "GENE-N",
"text": [
"superoxide dismutase"
],
"offsets": [
[
870,
890
]
],
"normalized": []
},
{
"id": "23576111_T10",
"type": "GENE-N",
"text": [
"SOD"
],
"offsets": [
[
892,
895
]
],
"normalized": []
},
{
"id": "23576111_T11",
"type": "GENE-N",
"text": [
"GPx"
],
"offsets": [
[
1037,
1040
]
],
"normalized": []
}
] | [] | [] | [] |
9480923 | 9480923 | [
{
"id": "9480923_title",
"type": "title",
"text": [
"Exogenous C2-ceramide activates c-fos serum response element via Rac-dependent signalling pathway."
],
"offsets": [
[
0,
98
]
]
},
{
"id": "9480923_abstract",
"type": "abstract",
"text": [
"Ceramide is an important regulatory molecule implicated in a variety of biological processes in response to stress and cytokines. To understand the signal transduction pathway of ceramide to the nucleus, in the present study, we examined whether C2-ceramide, a cell permeable ceramide, activates c-fos serum response element (SRE). Treatment of Rat-2 fibroblast cells with C2-ceramide caused the stimulation of c-fos SRE-dependent reporter gene activity in a dose- and time-dependent manner by transient transfection analysis. Next, we examined the role of Rho family GTPases in the ceramide-induced signalling to SRE activation. By reporter gene analysis following transient transfections with various plasmids expressing a dominant negative mutant form of Cdc42, Rac1 or RhoA, C2-ceramide-induced SRE activation was shown to be selectively repressed by pEXV-RacN17 encoding a dominant negative mutant of Rac1, suggesting that Rac activity is essential for the signalling cascade of ceramide to the nucleus. In a further study to analyse the downstream mediator of Rac in the ceramide-signalling pathway, we observed that either pretreatment with mepacrine, a potent and specific inhibitor of phospholipase A2, or co-transfection with antisense cytosolic phospholipase A2 (cPLA2) oligonucleotide repressed the C2-ceramide-induced SRE activation selectively, implying a critical role of cPLA2 in C2-ceramide-induced signalling to nucleus. Consistent with these results, the translocation of cPLA2 protein as well as the release of arachidonic acid, a principal product of phospholipase A2, was rapidly induced by the addition of C2-ceramide in a Rac-dependent manner. Together, our findings suggest the critical role of 'Rac and subsequent activation of phospholipase A2' in ceramide-signalling to nucleus."
],
"offsets": [
[
99,
1905
]
]
}
] | [
{
"id": "9480923_T1",
"type": "CHEMICAL",
"text": [
"Ceramide"
],
"offsets": [
[
99,
107
]
],
"normalized": []
},
{
"id": "9480923_T2",
"type": "CHEMICAL",
"text": [
"ceramide"
],
"offsets": [
[
1176,
1184
]
],
"normalized": []
},
{
"id": "9480923_T3",
"type": "CHEMICAL",
"text": [
"mepacrine"
],
"offsets": [
[
1247,
1256
]
],
"normalized": []
},
{
"id": "9480923_T4",
"type": "CHEMICAL",
"text": [
"C2-ceramide"
],
"offsets": [
[
1410,
1421
]
],
"normalized": []
},
{
"id": "9480923_T5",
"type": "CHEMICAL",
"text": [
"C2-ceramide"
],
"offsets": [
[
1495,
1506
]
],
"normalized": []
},
{
"id": "9480923_T6",
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"arachidonic acid"
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345,
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375,
383
]
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"id": "9480923_T12",
"type": "CHEMICAL",
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"C2-ceramide"
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472,
483
]
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"ceramide"
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682,
690
]
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"id": "9480923_T14",
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"C2-ceramide"
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878,
889
]
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"id": "9480923_T15",
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"ceramide"
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1083,
1091
]
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"id": "9480923_T16",
"type": "CHEMICAL",
"text": [
"C2-ceramide"
],
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[
10,
21
]
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},
{
"id": "9480923_T17",
"type": "GENE-N",
"text": [
"Rac"
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1165,
1168
]
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},
{
"id": "9480923_T18",
"type": "GENE-N",
"text": [
"cytokines"
],
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218,
227
]
],
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},
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"id": "9480923_T19",
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"text": [
"cytosolic phospholipase A2"
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1345,
1371
]
],
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},
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"id": "9480923_T20",
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"text": [
"cPLA2"
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1373,
1378
]
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},
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"SRE"
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1430,
1433
]
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},
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"id": "9480923_T22",
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"cPLA2"
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1486,
1491
]
],
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},
{
"id": "9480923_T23",
"type": "GENE-Y",
"text": [
"cPLA2"
],
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1590,
1595
]
],
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},
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"id": "9480923_T24",
"type": "GENE-Y",
"text": [
"phospholipase A2"
],
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1671,
1687
]
],
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},
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"id": "9480923_T25",
"type": "GENE-N",
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"Rac"
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1745,
1748
]
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},
{
"id": "9480923_T26",
"type": "GENE-N",
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"Rac"
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1820,
1823
]
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"id": "9480923_T27",
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"phospholipase A2"
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1853,
1869
]
],
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},
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"id": "9480923_T28",
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"c-fos serum response element"
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395,
423
]
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"SRE"
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425,
428
]
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},
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"id": "9480923_T30",
"type": "GENE-N",
"text": [
"c-fos SRE"
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510,
519
]
],
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},
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"id": "9480923_T31",
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"text": [
"Rho"
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656,
659
]
],
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},
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"id": "9480923_T32",
"type": "GENE-N",
"text": [
"GTPases"
],
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667,
674
]
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},
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"id": "9480923_T33",
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713,
716
]
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"Cdc42"
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857,
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]
],
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},
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"id": "9480923_T35",
"type": "GENE-Y",
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"Rac1"
],
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864,
868
]
],
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},
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"id": "9480923_T36",
"type": "GENE-Y",
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"RhoA"
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872,
876
]
],
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},
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"id": "9480923_T37",
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"SRE"
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898,
901
]
],
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},
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"id": "9480923_T38",
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"Rac1"
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1005,
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]
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},
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"id": "9480923_T39",
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"Rac"
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1030
]
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},
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"id": "9480923_T40",
"type": "GENE-N",
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"c-fos serum response element"
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32,
60
]
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},
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"id": "9480923_T41",
"type": "GENE-N",
"text": [
"Rac"
],
"offsets": [
[
65,
68
]
],
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}
] | [] | [] | [
{
"id": "9480923_0",
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"arg2_id": "9480923_T40",
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},
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},
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},
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"id": "9480923_4",
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},
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"id": "9480923_5",
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},
{
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"type": "PRODUCT-OF",
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"arg2_id": "9480923_T24",
"normalized": []
}
] |
12488248 | 12488248 | [
{
"id": "12488248_title",
"type": "title",
"text": [
"Organic anion transporter 3 (Slc22a8) is a dicarboxylate exchanger indirectly coupled to the Na+ gradient."
],
"offsets": [
[
0,
106
]
]
},
{
"id": "12488248_abstract",
"type": "abstract",
"text": [
"Basolateral uptake of organic anions in renal proximal tubule cells is indirectly coupled to the Na(+) gradient through Na(+)-dicarboxylate cotransport and organic anion/dicarboxylate exchange. One member of the organic anion transporter (OAT) family, Oat1, is expressed in the proximal tubule and is an organic anion/dicarboxylate exchanger. However, a second organic anion carrier, Oat3, is also highly expressed in the renal proximal tubule, but its mechanism is unclear. Thus we have assessed Oat3 function in Xenopus laevis oocytes and rat renal cortical slices. Probenecid-sensitive uptake of p-aminohippurate (PAH, an Oat1 and Oat3 substrate) and estrone sulfate (ES, an Oat3 substrate) in rat Oat3-expressing oocytes was significantly trans-stimulated by preloading the oocytes with the dicarboxylate glutarate (GA). GA stimulation of ES transport by oocytes coexpressing rabbit Na(+)-dicarboxylate cotransporter 1 and rat Oat3 was significantly inhibited when the preloading medium contained Li(+) or methylsuccinate (MS) or when Na(+) was absent. All these treatments inhibit the Na(+)-dicarboxylate cotransporter, but not rat Oat3. Li(+), MS, and Na(+) removal had no effect when applied during the ES uptake step, rather than during the GA preloading step. Concentrative ES uptake in rat renal cortical slices was also demonstrated to be probenecid and Na(+) sensitive. Accumulation of ES was stimulated by GA, and this stimulation was completely blocked by probenecid, Li(+), MS, taurocholate, and removal of Na(+). Thus Oat3 functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the Na(+) gradient."
],
"offsets": [
[
107,
1767
]
]
}
] | [
{
"id": "12488248_T1",
"type": "CHEMICAL",
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"Li(+)"
],
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[
1108,
1113
]
],
"normalized": []
},
{
"id": "12488248_T2",
"type": "CHEMICAL",
"text": [
"methylsuccinate"
],
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[
1117,
1132
]
],
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},
{
"id": "12488248_T3",
"type": "CHEMICAL",
"text": [
"Na(+)"
],
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[
1146,
1151
]
],
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},
{
"id": "12488248_T4",
"type": "CHEMICAL",
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"Na(+)-dicarboxylate"
],
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[
1197,
1216
]
],
"normalized": []
},
{
"id": "12488248_T5",
"type": "CHEMICAL",
"text": [
"Li(+)"
],
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[
1250,
1255
]
],
"normalized": []
},
{
"id": "12488248_T6",
"type": "CHEMICAL",
"text": [
"Na(+)"
],
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[
1265,
1270
]
],
"normalized": []
},
{
"id": "12488248_T7",
"type": "CHEMICAL",
"text": [
"Na(+)-dicarboxylate"
],
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[
227,
246
]
],
"normalized": []
},
{
"id": "12488248_T8",
"type": "CHEMICAL",
"text": [
"ES"
],
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[
1317,
1319
]
],
"normalized": []
},
{
"id": "12488248_T9",
"type": "CHEMICAL",
"text": [
"GA"
],
"offsets": [
[
1356,
1358
]
],
"normalized": []
},
{
"id": "12488248_T10",
"type": "CHEMICAL",
"text": [
"ES"
],
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[
1390,
1392
]
],
"normalized": []
},
{
"id": "12488248_T11",
"type": "CHEMICAL",
"text": [
"probenecid"
],
"offsets": [
[
1457,
1467
]
],
"normalized": []
},
{
"id": "12488248_T12",
"type": "CHEMICAL",
"text": [
"Na(+)"
],
"offsets": [
[
1472,
1477
]
],
"normalized": []
},
{
"id": "12488248_T13",
"type": "CHEMICAL",
"text": [
"ES"
],
"offsets": [
[
1505,
1507
]
],
"normalized": []
},
{
"id": "12488248_T14",
"type": "CHEMICAL",
"text": [
"GA"
],
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[
1526,
1528
]
],
"normalized": []
},
{
"id": "12488248_T15",
"type": "CHEMICAL",
"text": [
"probenecid"
],
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[
1577,
1587
]
],
"normalized": []
},
{
"id": "12488248_T16",
"type": "CHEMICAL",
"text": [
"Li(+)"
],
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[
1589,
1594
]
],
"normalized": []
},
{
"id": "12488248_T17",
"type": "CHEMICAL",
"text": [
"taurocholate"
],
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[
1600,
1612
]
],
"normalized": []
},
{
"id": "12488248_T18",
"type": "CHEMICAL",
"text": [
"Na(+)"
],
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[
1629,
1634
]
],
"normalized": []
},
{
"id": "12488248_T19",
"type": "CHEMICAL",
"text": [
"dicarboxylate"
],
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[
1676,
1689
]
],
"normalized": []
},
{
"id": "12488248_T20",
"type": "CHEMICAL",
"text": [
"Na(+)"
],
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[
1752,
1757
]
],
"normalized": []
},
{
"id": "12488248_T21",
"type": "CHEMICAL",
"text": [
"dicarboxylate"
],
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[
277,
290
]
],
"normalized": []
},
{
"id": "12488248_T22",
"type": "CHEMICAL",
"text": [
"dicarboxylate"
],
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[
425,
438
]
],
"normalized": []
},
{
"id": "12488248_T23",
"type": "CHEMICAL",
"text": [
"Probenecid"
],
"offsets": [
[
675,
685
]
],
"normalized": []
},
{
"id": "12488248_T24",
"type": "CHEMICAL",
"text": [
"p-aminohippurate"
],
"offsets": [
[
706,
722
]
],
"normalized": []
},
{
"id": "12488248_T25",
"type": "CHEMICAL",
"text": [
"estrone sulfate"
],
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[
761,
776
]
],
"normalized": []
},
{
"id": "12488248_T26",
"type": "CHEMICAL",
"text": [
"ES"
],
"offsets": [
[
778,
780
]
],
"normalized": []
},
{
"id": "12488248_T27",
"type": "CHEMICAL",
"text": [
"dicarboxylate"
],
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[
902,
915
]
],
"normalized": []
},
{
"id": "12488248_T28",
"type": "CHEMICAL",
"text": [
"glutarate"
],
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[
916,
925
]
],
"normalized": []
},
{
"id": "12488248_T29",
"type": "CHEMICAL",
"text": [
"GA"
],
"offsets": [
[
927,
929
]
],
"normalized": []
},
{
"id": "12488248_T30",
"type": "CHEMICAL",
"text": [
"GA"
],
"offsets": [
[
932,
934
]
],
"normalized": []
},
{
"id": "12488248_T31",
"type": "CHEMICAL",
"text": [
"ES"
],
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[
950,
952
]
],
"normalized": []
},
{
"id": "12488248_T32",
"type": "CHEMICAL",
"text": [
"Na(+)-dicarboxylate"
],
"offsets": [
[
994,
1013
]
],
"normalized": []
},
{
"id": "12488248_T33",
"type": "CHEMICAL",
"text": [
"Na(+)"
],
"offsets": [
[
204,
209
]
],
"normalized": []
},
{
"id": "12488248_T34",
"type": "CHEMICAL",
"text": [
"dicarboxylate"
],
"offsets": [
[
43,
56
]
],
"normalized": []
},
{
"id": "12488248_T35",
"type": "CHEMICAL",
"text": [
"Na+"
],
"offsets": [
[
93,
96
]
],
"normalized": []
},
{
"id": "12488248_T36",
"type": "GENE-N",
"text": [
"Na(+)-dicarboxylate cotransporter"
],
"offsets": [
[
1197,
1230
]
],
"normalized": []
},
{
"id": "12488248_T37",
"type": "GENE-Y",
"text": [
"rat Oat3"
],
"offsets": [
[
1240,
1248
]
],
"normalized": []
},
{
"id": "12488248_T38",
"type": "GENE-Y",
"text": [
"Oat3"
],
"offsets": [
[
1641,
1645
]
],
"normalized": []
},
{
"id": "12488248_T39",
"type": "GENE-N",
"text": [
"organic anion/dicarboxylate exchanger"
],
"offsets": [
[
1662,
1699
]
],
"normalized": []
},
{
"id": "12488248_T40",
"type": "GENE-N",
"text": [
"organic anion transporter"
],
"offsets": [
[
319,
344
]
],
"normalized": []
},
{
"id": "12488248_T41",
"type": "GENE-N",
"text": [
"OAT"
],
"offsets": [
[
346,
349
]
],
"normalized": []
},
{
"id": "12488248_T42",
"type": "GENE-Y",
"text": [
"Oat1"
],
"offsets": [
[
359,
363
]
],
"normalized": []
},
{
"id": "12488248_T43",
"type": "GENE-N",
"text": [
"organic anion/dicarboxylate exchanger"
],
"offsets": [
[
411,
448
]
],
"normalized": []
},
{
"id": "12488248_T44",
"type": "GENE-N",
"text": [
"organic anion carrier"
],
"offsets": [
[
468,
489
]
],
"normalized": []
},
{
"id": "12488248_T45",
"type": "GENE-Y",
"text": [
"Oat3"
],
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[
491,
495
]
],
"normalized": []
},
{
"id": "12488248_T46",
"type": "GENE-Y",
"text": [
"Oat3"
],
"offsets": [
[
604,
608
]
],
"normalized": []
},
{
"id": "12488248_T47",
"type": "GENE-Y",
"text": [
"Oat1"
],
"offsets": [
[
732,
736
]
],
"normalized": []
},
{
"id": "12488248_T48",
"type": "GENE-Y",
"text": [
"Oat3"
],
"offsets": [
[
741,
745
]
],
"normalized": []
},
{
"id": "12488248_T49",
"type": "GENE-Y",
"text": [
"Oat3"
],
"offsets": [
[
785,
789
]
],
"normalized": []
},
{
"id": "12488248_T50",
"type": "GENE-Y",
"text": [
"rat Oat3"
],
"offsets": [
[
804,
812
]
],
"normalized": []
},
{
"id": "12488248_T51",
"type": "GENE-Y",
"text": [
"rabbit Na(+)-dicarboxylate cotransporter 1"
],
"offsets": [
[
987,
1029
]
],
"normalized": []
},
{
"id": "12488248_T52",
"type": "GENE-Y",
"text": [
"rat Oat3"
],
"offsets": [
[
1034,
1042
]
],
"normalized": []
},
{
"id": "12488248_T53",
"type": "GENE-Y",
"text": [
"Organic anion transporter 3"
],
"offsets": [
[
0,
27
]
],
"normalized": []
},
{
"id": "12488248_T54",
"type": "GENE-Y",
"text": [
"Slc22a8"
],
"offsets": [
[
29,
36
]
],
"normalized": []
},
{
"id": "12488248_T55",
"type": "GENE-N",
"text": [
"dicarboxylate exchanger"
],
"offsets": [
[
43,
66
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12488248_0",
"type": "SUBSTRATE",
"arg1_id": "12488248_T24",
"arg2_id": "12488248_T47",
"normalized": []
},
{
"id": "12488248_1",
"type": "SUBSTRATE",
"arg1_id": "12488248_T24",
"arg2_id": "12488248_T48",
"normalized": []
},
{
"id": "12488248_2",
"type": "SUBSTRATE",
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"arg2_id": "12488248_T49",
"normalized": []
},
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"id": "12488248_3",
"type": "SUBSTRATE",
"arg1_id": "12488248_T26",
"arg2_id": "12488248_T49",
"normalized": []
},
{
"id": "12488248_4",
"type": "SUBSTRATE",
"arg1_id": "12488248_T25",
"arg2_id": "12488248_T50",
"normalized": []
},
{
"id": "12488248_5",
"type": "SUBSTRATE",
"arg1_id": "12488248_T26",
"arg2_id": "12488248_T50",
"normalized": []
},
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"id": "12488248_6",
"type": "INHIBITOR",
"arg1_id": "12488248_T23",
"arg2_id": "12488248_T47",
"normalized": []
},
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"id": "12488248_7",
"type": "INHIBITOR",
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"arg2_id": "12488248_T48",
"normalized": []
},
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"id": "12488248_8",
"type": "INHIBITOR",
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"arg2_id": "12488248_T49",
"normalized": []
},
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"id": "12488248_9",
"type": "INHIBITOR",
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"arg2_id": "12488248_T50",
"normalized": []
},
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"type": "SUBSTRATE",
"arg1_id": "12488248_T31",
"arg2_id": "12488248_T51",
"normalized": []
},
{
"id": "12488248_11",
"type": "SUBSTRATE",
"arg1_id": "12488248_T31",
"arg2_id": "12488248_T52",
"normalized": []
},
{
"id": "12488248_12",
"type": "ACTIVATOR",
"arg1_id": "12488248_T30",
"arg2_id": "12488248_T51",
"normalized": []
},
{
"id": "12488248_13",
"type": "ACTIVATOR",
"arg1_id": "12488248_T30",
"arg2_id": "12488248_T52",
"normalized": []
},
{
"id": "12488248_14",
"type": "INHIBITOR",
"arg1_id": "12488248_T1",
"arg2_id": "12488248_T51",
"normalized": []
},
{
"id": "12488248_15",
"type": "INHIBITOR",
"arg1_id": "12488248_T2",
"arg2_id": "12488248_T51",
"normalized": []
},
{
"id": "12488248_16",
"type": "INHIBITOR",
"arg1_id": "12488248_T1",
"arg2_id": "12488248_T52",
"normalized": []
},
{
"id": "12488248_17",
"type": "INHIBITOR",
"arg1_id": "12488248_T2",
"arg2_id": "12488248_T52",
"normalized": []
}
] |
12023506 | 12023506 | [
{
"id": "12023506_title",
"type": "title",
"text": [
"Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors."
],
"offsets": [
[
0,
96
]
]
},
{
"id": "12023506_abstract",
"type": "abstract",
"text": [
"The organic anion transport system is involved in the tubular excretion and reabsorption of various drugs and substances. The purpose of this study was to characterize the effects of various organic anion transport inhibitors on renal organic anion transport using proximal tubule cells stably expressing human organic anion transporter 2 (hOAT2) and hOAT4. Immunohistochemical analysis revealed that hOAT2 is localized to the basolateral side of the proximal tubule in the kidney. hOAT2 mediated a time- and concentration-dependent increase in prostaglandin F(2alpha) (PGF(2alpha)) uptake. The organic anion transport inhibitors used for this study were probenecid, 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902), betamipron, and cilastatin. Probenecid, but not KW-3902, betamipron, and cilastatin, significantly inhibited hOAT2-mediated PGF(2alpha) uptake. In contrast, probenecid, KW-3902, and betamipron, but not cilastatin, inhibited hOAT4-mediated estrone sulfate (ES) uptake. Kinetic analyses revealed that these inhibitions were competitive. The K(i) value of probenecid for hOAT2 was 766 microM, whereas those of probenecid, KW-3902, and betamipron for hOAT4 were 54.9, 20.7, and 502 microM, respectively. These results suggest that probenecid, KW-3902, and betamipron could inhibit hOAT4-mediated ES uptake in vitro, whereas probenecid alone could inhibit the hOAT2-mediated PGF(2alpha) uptake. Comparing the K(i) values with the therapeutically relevant concentrations of unbound inhibitors in the plasma, probenecid alone was predicted to inhibit hOAT4-mediated organic anion transport in vivo."
],
"offsets": [
[
97,
1709
]
]
}
] | [
{
"id": "12023506_T1",
"type": "CHEMICAL",
"text": [
"probenecid"
],
"offsets": [
[
1225,
1235
]
],
"normalized": []
},
{
"id": "12023506_T2",
"type": "CHEMICAL",
"text": [
"KW-3902"
],
"offsets": [
[
1237,
1244
]
],
"normalized": []
},
{
"id": "12023506_T3",
"type": "CHEMICAL",
"text": [
"betamipron"
],
"offsets": [
[
1250,
1260
]
],
"normalized": []
},
{
"id": "12023506_T4",
"type": "CHEMICAL",
"text": [
"probenecid"
],
"offsets": [
[
1345,
1355
]
],
"normalized": []
},
{
"id": "12023506_T5",
"type": "CHEMICAL",
"text": [
"KW-3902"
],
"offsets": [
[
1357,
1364
]
],
"normalized": []
},
{
"id": "12023506_T6",
"type": "CHEMICAL",
"text": [
"betamipron"
],
"offsets": [
[
1370,
1380
]
],
"normalized": []
},
{
"id": "12023506_T7",
"type": "CHEMICAL",
"text": [
"probenecid"
],
"offsets": [
[
1438,
1448
]
],
"normalized": []
},
{
"id": "12023506_T8",
"type": "CHEMICAL",
"text": [
"probenecid"
],
"offsets": [
[
1620,
1630
]
],
"normalized": []
},
{
"id": "12023506_T9",
"type": "CHEMICAL",
"text": [
"prostaglandin F(2alpha)"
],
"offsets": [
[
642,
665
]
],
"normalized": []
},
{
"id": "12023506_T10",
"type": "CHEMICAL",
"text": [
"PGF(2alpha)"
],
"offsets": [
[
667,
678
]
],
"normalized": []
},
{
"id": "12023506_T11",
"type": "CHEMICAL",
"text": [
"8-(noradamantan-3-yl)-1,3-dipropylxanthine"
],
"offsets": [
[
764,
806
]
],
"normalized": []
},
{
"id": "12023506_T12",
"type": "CHEMICAL",
"text": [
"KW-3902"
],
"offsets": [
[
808,
815
]
],
"normalized": []
},
{
"id": "12023506_T13",
"type": "CHEMICAL",
"text": [
"betamipron"
],
"offsets": [
[
818,
828
]
],
"normalized": []
},
{
"id": "12023506_T14",
"type": "CHEMICAL",
"text": [
"cilastatin"
],
"offsets": [
[
834,
844
]
],
"normalized": []
},
{
"id": "12023506_T15",
"type": "CHEMICAL",
"text": [
"Probenecid"
],
"offsets": [
[
846,
856
]
],
"normalized": []
},
{
"id": "12023506_T16",
"type": "CHEMICAL",
"text": [
"KW-3902"
],
"offsets": [
[
866,
873
]
],
"normalized": []
},
{
"id": "12023506_T17",
"type": "CHEMICAL",
"text": [
"betamipron"
],
"offsets": [
[
875,
885
]
],
"normalized": []
},
{
"id": "12023506_T18",
"type": "CHEMICAL",
"text": [
"cilastatin"
],
"offsets": [
[
891,
901
]
],
"normalized": []
},
{
"id": "12023506_T19",
"type": "CHEMICAL",
"text": [
"probenecid"
],
"offsets": [
[
975,
985
]
],
"normalized": []
},
{
"id": "12023506_T20",
"type": "CHEMICAL",
"text": [
"KW-3902"
],
"offsets": [
[
987,
994
]
],
"normalized": []
},
{
"id": "12023506_T21",
"type": "CHEMICAL",
"text": [
"betamipron"
],
"offsets": [
[
1000,
1010
]
],
"normalized": []
},
{
"id": "12023506_T22",
"type": "CHEMICAL",
"text": [
"cilastatin"
],
"offsets": [
[
1020,
1030
]
],
"normalized": []
},
{
"id": "12023506_T23",
"type": "GENE-Y",
"text": [
"hOAT2"
],
"offsets": [
[
1186,
1191
]
],
"normalized": []
},
{
"id": "12023506_T24",
"type": "GENE-Y",
"text": [
"hOAT4"
],
"offsets": [
[
1265,
1270
]
],
"normalized": []
},
{
"id": "12023506_T25",
"type": "GENE-Y",
"text": [
"hOAT4"
],
"offsets": [
[
1395,
1400
]
],
"normalized": []
},
{
"id": "12023506_T26",
"type": "GENE-Y",
"text": [
"hOAT2"
],
"offsets": [
[
1473,
1478
]
],
"normalized": []
},
{
"id": "12023506_T27",
"type": "GENE-Y",
"text": [
"hOAT4"
],
"offsets": [
[
1662,
1667
]
],
"normalized": []
},
{
"id": "12023506_T28",
"type": "GENE-Y",
"text": [
"human organic anion transporter 2"
],
"offsets": [
[
402,
435
]
],
"normalized": []
},
{
"id": "12023506_T29",
"type": "GENE-Y",
"text": [
"hOAT2"
],
"offsets": [
[
437,
442
]
],
"normalized": []
},
{
"id": "12023506_T30",
"type": "GENE-Y",
"text": [
"hOAT4"
],
"offsets": [
[
448,
453
]
],
"normalized": []
},
{
"id": "12023506_T31",
"type": "GENE-Y",
"text": [
"hOAT2"
],
"offsets": [
[
498,
503
]
],
"normalized": []
},
{
"id": "12023506_T32",
"type": "GENE-N",
"text": [
"organic anion transport system"
],
"offsets": [
[
101,
131
]
],
"normalized": []
},
{
"id": "12023506_T33",
"type": "GENE-Y",
"text": [
"hOAT2"
],
"offsets": [
[
579,
584
]
],
"normalized": []
},
{
"id": "12023506_T34",
"type": "GENE-Y",
"text": [
"hOAT2"
],
"offsets": [
[
927,
932
]
],
"normalized": []
},
{
"id": "12023506_T35",
"type": "GENE-Y",
"text": [
"hOAT4"
],
"offsets": [
[
1042,
1047
]
],
"normalized": []
},
{
"id": "12023506_T36",
"type": "GENE-N",
"text": [
"human organic anion transporters 2 and 4"
],
"offsets": [
[
15,
55
]
],
"normalized": []
},
{
"id": "12023506_T37",
"type": "GENE-N",
"text": [
"organic anion transport"
],
"offsets": [
[
61,
84
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12023506_0",
"type": "SUBSTRATE",
"arg1_id": "12023506_T9",
"arg2_id": "12023506_T33",
"normalized": []
},
{
"id": "12023506_1",
"type": "SUBSTRATE",
"arg1_id": "12023506_T10",
"arg2_id": "12023506_T33",
"normalized": []
},
{
"id": "12023506_2",
"type": "INHIBITOR",
"arg1_id": "12023506_T15",
"arg2_id": "12023506_T34",
"normalized": []
},
{
"id": "12023506_3",
"type": "INHIBITOR",
"arg1_id": "12023506_T19",
"arg2_id": "12023506_T35",
"normalized": []
},
{
"id": "12023506_4",
"type": "INHIBITOR",
"arg1_id": "12023506_T20",
"arg2_id": "12023506_T35",
"normalized": []
},
{
"id": "12023506_5",
"type": "INHIBITOR",
"arg1_id": "12023506_T21",
"arg2_id": "12023506_T35",
"normalized": []
},
{
"id": "12023506_6",
"type": "INHIBITOR",
"arg1_id": "12023506_T1",
"arg2_id": "12023506_T24",
"normalized": []
},
{
"id": "12023506_7",
"type": "INHIBITOR",
"arg1_id": "12023506_T2",
"arg2_id": "12023506_T24",
"normalized": []
},
{
"id": "12023506_8",
"type": "INHIBITOR",
"arg1_id": "12023506_T3",
"arg2_id": "12023506_T24",
"normalized": []
},
{
"id": "12023506_9",
"type": "INHIBITOR",
"arg1_id": "12023506_T4",
"arg2_id": "12023506_T25",
"normalized": []
},
{
"id": "12023506_10",
"type": "INHIBITOR",
"arg1_id": "12023506_T5",
"arg2_id": "12023506_T25",
"normalized": []
},
{
"id": "12023506_11",
"type": "INHIBITOR",
"arg1_id": "12023506_T6",
"arg2_id": "12023506_T25",
"normalized": []
},
{
"id": "12023506_12",
"type": "INHIBITOR",
"arg1_id": "12023506_T7",
"arg2_id": "12023506_T26",
"normalized": []
},
{
"id": "12023506_13",
"type": "INHIBITOR",
"arg1_id": "12023506_T8",
"arg2_id": "12023506_T27",
"normalized": []
}
] |
23494481 | 23494481 | [
{
"id": "23494481_title",
"type": "title",
"text": [
"Neuroprotection against neuroblastoma cell death induced by depletion of mitochondrial glutathione."
],
"offsets": [
[
0,
99
]
]
},
{
"id": "23494481_abstract",
"type": "abstract",
"text": [
"Mitochondrial glutathione pool is vital in protecting cells against oxidative stress as the majority of the cellular reactive oxygen species are generated in mitochondria. Oxidative stress is implicated as a causative factor in neuronal death in neurodegenerative disorders. We hypothesized that depletion of mitochondrial glutathione leads to mitochondrial dysfunction and apoptotic death of SK-N-SH (human neuroblastoma) cells and investigated the neuroprotective strategies against GSH depletion. SK-N-SH cells were treated with two distinct inhibitors of glutathione metabolism: L-buthionine-(S, R)-sulfoximine (BSO) and ethacrynic acid (EA). EA treatment caused depletion of both the total and mitochondrial glutathione (while BSO had no effect on mitochondrial glutathione), enhanced rotenone-induced ROS production, and reduced the viability of SK-N-SH cells. Glutathione depletion by BSO or EA demonstrated positive features of mitochondria-mediated apoptosis in neuroblastoma cell death. Prevention of apoptosis by Bcl2 overexpression or use of antioxidant ebselen did not confer neuroprotection. Co-culture with U-87 (human glioblastoma) cells protected SK-N-SH cells from the cell death. Our data suggest that depletion of mitochondrial glutathione leads to mitochondrial dysfunction and apoptosis. The study indicates that preventing mitochondrial glutathione depletion could become a novel strategy for the development of neuroprotective therapeutics in neurodegenerative disorders."
],
"offsets": [
[
100,
1595
]
]
}
] | [
{
"id": "23494481_T1",
"type": "CHEMICAL",
"text": [
"ebselen"
],
"offsets": [
[
1166,
1173
]
],
"normalized": []
},
{
"id": "23494481_T2",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
1348,
1359
]
],
"normalized": []
},
{
"id": "23494481_T3",
"type": "CHEMICAL",
"text": [
"oxygen"
],
"offsets": [
[
226,
232
]
],
"normalized": []
},
{
"id": "23494481_T4",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
1460,
1471
]
],
"normalized": []
},
{
"id": "23494481_T5",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
114,
125
]
],
"normalized": []
},
{
"id": "23494481_T6",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
423,
434
]
],
"normalized": []
},
{
"id": "23494481_T7",
"type": "CHEMICAL",
"text": [
"GSH"
],
"offsets": [
[
585,
588
]
],
"normalized": []
},
{
"id": "23494481_T8",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
659,
670
]
],
"normalized": []
},
{
"id": "23494481_T9",
"type": "CHEMICAL",
"text": [
"L-buthionine-(S, R)-sulfoximine"
],
"offsets": [
[
683,
714
]
],
"normalized": []
},
{
"id": "23494481_T10",
"type": "CHEMICAL",
"text": [
"BSO"
],
"offsets": [
[
716,
719
]
],
"normalized": []
},
{
"id": "23494481_T11",
"type": "CHEMICAL",
"text": [
"ethacrynic acid"
],
"offsets": [
[
725,
740
]
],
"normalized": []
},
{
"id": "23494481_T12",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
813,
824
]
],
"normalized": []
},
{
"id": "23494481_T13",
"type": "CHEMICAL",
"text": [
"BSO"
],
"offsets": [
[
832,
835
]
],
"normalized": []
},
{
"id": "23494481_T14",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
867,
878
]
],
"normalized": []
},
{
"id": "23494481_T15",
"type": "CHEMICAL",
"text": [
"rotenone"
],
"offsets": [
[
890,
898
]
],
"normalized": []
},
{
"id": "23494481_T16",
"type": "CHEMICAL",
"text": [
"Glutathione"
],
"offsets": [
[
967,
978
]
],
"normalized": []
},
{
"id": "23494481_T17",
"type": "CHEMICAL",
"text": [
"BSO"
],
"offsets": [
[
992,
995
]
],
"normalized": []
},
{
"id": "23494481_T18",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
87,
98
]
],
"normalized": []
},
{
"id": "23494481_T19",
"type": "GENE-Y",
"text": [
"Bcl2"
],
"offsets": [
[
1124,
1128
]
],
"normalized": []
}
] | [] | [] | [] |
19498041 | 19498041 | [
{
"id": "19498041_title",
"type": "title",
"text": [
"Exploring the mechanism of agonist efficacy: a relationship between efficacy and agonist dissociation rate at the muscarinic M3 receptor."
],
"offsets": [
[
0,
137
]
]
},
{
"id": "19498041_abstract",
"type": "abstract",
"text": [
"Although there are several empirical approaches that enable the comparison of relative agonist efficacy, the molecular basis that underlies differences in the ability of G protein-coupled receptor agonists to elicit a response is still largely unexplained. Several models have been described that incorporate the kinetics of receptor-mediated initiation of the G protein cycle, but these have not directly addressed the influence of agonist-binding kinetics. To test this, we investigated the relationship between the efficacy of seven M(3) muscarinic receptor agonists and their rate of dissociation (k(off)) from the M(3) receptor. The association and dissociation rate constants of the agonists were determined using a l-[N-methyl]-[(3)H]scopolamine methyl chloride competition binding assay in the presence of GTP. The agonists displayed a range of association and dissociation rates. Relative agonist efficacy was measured at two points after M(3) receptor activation: the stimulation of guanosine 5'-O-(3-[(35)S]thio)triphosphate binding to G alpha subunits, and the subsequent increase in intracellular calcium levels. These experiments revealed a range of intrinsic efficacy, from the low-efficacy pilocarpine and oxotremorine to high-efficacy acetylcholine. There was no relationship between agonist efficacy and the equilibrium binding affinity of each agonist (K(d)). When efficacy was compared with the dissociation rate constant, however, the two were highly correlated, suggesting a relationship between the duration of agonist binding at the receptor and the intrinsic efficacy. These data suggest that kinetic models incorporating the mean lifetime of specific complexes will be required to fully explain the nature of agonist efficacy."
],
"offsets": [
[
138,
1890
]
]
}
] | [
{
"id": "19498041_T1",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
1248,
1255
]
],
"normalized": []
},
{
"id": "19498041_T2",
"type": "CHEMICAL",
"text": [
"pilocarpine"
],
"offsets": [
[
1344,
1355
]
],
"normalized": []
},
{
"id": "19498041_T3",
"type": "CHEMICAL",
"text": [
"oxotremorine"
],
"offsets": [
[
1360,
1372
]
],
"normalized": []
},
{
"id": "19498041_T4",
"type": "CHEMICAL",
"text": [
"acetylcholine"
],
"offsets": [
[
1390,
1403
]
],
"normalized": []
},
{
"id": "19498041_T5",
"type": "CHEMICAL",
"text": [
"l-[N-methyl]-[(3)H]scopolamine methyl chloride"
],
"offsets": [
[
860,
906
]
],
"normalized": []
},
{
"id": "19498041_T6",
"type": "CHEMICAL",
"text": [
"guanosine 5'-O-(3-[(35)S]thio)triphosphate"
],
"offsets": [
[
1131,
1173
]
],
"normalized": []
},
{
"id": "19498041_T7",
"type": "GENE-N",
"text": [
"G alpha"
],
"offsets": [
[
1185,
1192
]
],
"normalized": []
},
{
"id": "19498041_T8",
"type": "GENE-N",
"text": [
"G protein-coupled receptor"
],
"offsets": [
[
308,
334
]
],
"normalized": []
},
{
"id": "19498041_T9",
"type": "GENE-N",
"text": [
"G protein"
],
"offsets": [
[
499,
508
]
],
"normalized": []
},
{
"id": "19498041_T10",
"type": "GENE-Y",
"text": [
"M(3) muscarinic receptor"
],
"offsets": [
[
674,
698
]
],
"normalized": []
},
{
"id": "19498041_T11",
"type": "GENE-Y",
"text": [
"M(3) receptor"
],
"offsets": [
[
757,
770
]
],
"normalized": []
},
{
"id": "19498041_T12",
"type": "GENE-Y",
"text": [
"M(3) receptor"
],
"offsets": [
[
1086,
1099
]
],
"normalized": []
},
{
"id": "19498041_T13",
"type": "GENE-Y",
"text": [
"muscarinic M3 receptor"
],
"offsets": [
[
114,
136
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "19498041_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "19498041_T6",
"arg2_id": "19498041_T7",
"normalized": []
}
] |
16929463 | 16929463 | [
{
"id": "16929463_title",
"type": "title",
"text": [
"Effects of vitamin K1 supplementation on vascular responsiveness and oxidative stress in a rat femoral osteotomy model."
],
"offsets": [
[
0,
119
]
]
},
{
"id": "16929463_abstract",
"type": "abstract",
"text": [
"The main function of vitamin K1 is to act a co-factor for gamma-glutamyl carboxylase. However, it has also been shown to lessen oxidative stress. This study was aimed to evaluate the effect of vitamin K1 supplementation on vascular responsiveness and oxidative status in rats that underwent femoral osteotomy. Twenty-four male rats were divided into three groups to serve as sham, osteotomy and vitamin K1 groups. Indices of oxidative stress (catalase), and oxidative damage (malondialdehyde) were analysed in erythrocytes. In order to evaluate vascular reactivity, concentration-response curves to phenylephrine, angiotensin II, 5-hydroxytryptamine, bradykinin and histamine were constructed. The findings of this study clearly show that oxidative stress clearly increases after femoral osteotomy in rats. Also, this operation causes a significant depression in vascular responsiveness to contracting agents and endothelium-dependent vasodilators. However, vitamin K1 supplementation prevents vascular hyporeactivity by reducing oxidative stress and may represent a novel approach during osteotomy healing."
],
"offsets": [
[
120,
1227
]
]
}
] | [
{
"id": "16929463_T1",
"type": "CHEMICAL",
"text": [
"vitamin K1"
],
"offsets": [
[
313,
323
]
],
"normalized": []
},
{
"id": "16929463_T2",
"type": "CHEMICAL",
"text": [
"vitamin K1"
],
"offsets": [
[
141,
151
]
],
"normalized": []
},
{
"id": "16929463_T3",
"type": "CHEMICAL",
"text": [
"vitamin K1"
],
"offsets": [
[
515,
525
]
],
"normalized": []
},
{
"id": "16929463_T4",
"type": "CHEMICAL",
"text": [
"malondialdehyde"
],
"offsets": [
[
596,
611
]
],
"normalized": []
},
{
"id": "16929463_T5",
"type": "CHEMICAL",
"text": [
"gamma-glutamyl"
],
"offsets": [
[
178,
192
]
],
"normalized": []
},
{
"id": "16929463_T6",
"type": "CHEMICAL",
"text": [
"phenylephrine"
],
"offsets": [
[
719,
732
]
],
"normalized": []
},
{
"id": "16929463_T7",
"type": "CHEMICAL",
"text": [
"angiotensin II"
],
"offsets": [
[
734,
748
]
],
"normalized": []
},
{
"id": "16929463_T8",
"type": "CHEMICAL",
"text": [
"5-hydroxytryptamine"
],
"offsets": [
[
750,
769
]
],
"normalized": []
},
{
"id": "16929463_T9",
"type": "CHEMICAL",
"text": [
"bradykinin"
],
"offsets": [
[
771,
781
]
],
"normalized": []
},
{
"id": "16929463_T10",
"type": "CHEMICAL",
"text": [
"histamine"
],
"offsets": [
[
786,
795
]
],
"normalized": []
},
{
"id": "16929463_T11",
"type": "CHEMICAL",
"text": [
"vitamin K1"
],
"offsets": [
[
1078,
1088
]
],
"normalized": []
},
{
"id": "16929463_T12",
"type": "CHEMICAL",
"text": [
"vitamin K1"
],
"offsets": [
[
11,
21
]
],
"normalized": []
},
{
"id": "16929463_T13",
"type": "GENE-Y",
"text": [
"catalase"
],
"offsets": [
[
563,
571
]
],
"normalized": []
},
{
"id": "16929463_T14",
"type": "GENE-Y",
"text": [
"gamma-glutamyl carboxylase"
],
"offsets": [
[
178,
204
]
],
"normalized": []
},
{
"id": "16929463_T15",
"type": "GENE-Y",
"text": [
"angiotensin II"
],
"offsets": [
[
734,
748
]
],
"normalized": []
},
{
"id": "16929463_T16",
"type": "GENE-Y",
"text": [
"bradykinin"
],
"offsets": [
[
771,
781
]
],
"normalized": []
}
] | [] | [] | [] |
23282998 | 23282998 | [
{
"id": "23282998_title",
"type": "title",
"text": [
"Characterization of arsenic induced cytotoxicity in liver with stress in erythrocytes and its reversibility with Pleurotus florida lectin."
],
"offsets": [
[
0,
138
]
]
},
{
"id": "23282998_abstract",
"type": "abstract",
"text": [
"Arsenic is one of the most hazardous substances in the environment known to cause toxicity in multiple organs. Cell adhesion, morphological alterations, cell proliferation, terminal deoxyuridine triphosphate nick-end labeling (TUNEL) and caspase-3/CPP32 fluorometric protease assay were important biomarkers to assess apoptosis in cells. This study aimed to evaluate arsenic-induced apoptosis in the hepatocytes of rat and its protective efficacy with coadministration of ascorbic acid (AA) and Pleurotus florida lectin (PFL) individually. Results of the present study also showed that arsenic caused cytotoxicity by elevating morphological alterations, TUNEL-positive nuclei, caspase-3 activity and DNA damage and reducing cell adhesion and cell proliferation in a time-dependent manner. The apoptosis in hepatocytes was reverted to normal value after coadministration of mushroom lectin in arsenic-exposed rat. The study provided significant evidence that PFL has antiapoptotic property against arsenic-induced toxicity. The beneficial effect of PFL was proportional to its duration of exposure. Retard activities of superoxide dismutase and catalase, enhanced lipid peroxidation as well as protein carbonyl in erythrocytes caused by arsenic could also be maintained toward normalcy by supplementation of AA and PFL. These antioxidative effects were exhibited in a time-dependant manner. In rat, treatment with AA and PFL prevented alteration of plasma enzyme activities caused by arsenic. The results concluded that treatment with PFL has significant role in protecting animals from arsenic-induced erythrocytic damage. This finding might be of therapeutic benefit in people suffering from chronic exposure to arsenic from natural sources, a global problem especially relevant to millions of people on the Indian subcontinent."
],
"offsets": [
[
139,
1968
]
]
}
] | [
{
"id": "23282998_T1",
"type": "CHEMICAL",
"text": [
"Arsenic"
],
"offsets": [
[
139,
146
]
],
"normalized": []
},
{
"id": "23282998_T2",
"type": "CHEMICAL",
"text": [
"superoxide"
],
"offsets": [
[
1258,
1268
]
],
"normalized": []
},
{
"id": "23282998_T3",
"type": "CHEMICAL",
"text": [
"carbonyl"
],
"offsets": [
[
1340,
1348
]
],
"normalized": []
},
{
"id": "23282998_T4",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1375,
1382
]
],
"normalized": []
},
{
"id": "23282998_T5",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1622,
1629
]
],
"normalized": []
},
{
"id": "23282998_T6",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1725,
1732
]
],
"normalized": []
},
{
"id": "23282998_T7",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1852,
1859
]
],
"normalized": []
},
{
"id": "23282998_T8",
"type": "CHEMICAL",
"text": [
"deoxyuridine triphosphate"
],
"offsets": [
[
321,
346
]
],
"normalized": []
},
{
"id": "23282998_T9",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
506,
513
]
],
"normalized": []
},
{
"id": "23282998_T10",
"type": "CHEMICAL",
"text": [
"ascorbic acid"
],
"offsets": [
[
611,
624
]
],
"normalized": []
},
{
"id": "23282998_T11",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
725,
732
]
],
"normalized": []
},
{
"id": "23282998_T12",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1031,
1038
]
],
"normalized": []
},
{
"id": "23282998_T13",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1136,
1143
]
],
"normalized": []
},
{
"id": "23282998_T14",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
20,
27
]
],
"normalized": []
},
{
"id": "23282998_T15",
"type": "GENE-N",
"text": [
"PFL"
],
"offsets": [
[
1187,
1190
]
],
"normalized": []
},
{
"id": "23282998_T16",
"type": "GENE-N",
"text": [
"superoxide dismutase"
],
"offsets": [
[
1258,
1278
]
],
"normalized": []
},
{
"id": "23282998_T17",
"type": "GENE-Y",
"text": [
"catalase"
],
"offsets": [
[
1283,
1291
]
],
"normalized": []
},
{
"id": "23282998_T18",
"type": "GENE-N",
"text": [
"PFL"
],
"offsets": [
[
1453,
1456
]
],
"normalized": []
},
{
"id": "23282998_T19",
"type": "GENE-N",
"text": [
"PFL"
],
"offsets": [
[
1559,
1562
]
],
"normalized": []
},
{
"id": "23282998_T20",
"type": "GENE-N",
"text": [
"PFL"
],
"offsets": [
[
1673,
1676
]
],
"normalized": []
},
{
"id": "23282998_T21",
"type": "GENE-N",
"text": [
"Pleurotus florida lectin"
],
"offsets": [
[
634,
658
]
],
"normalized": []
},
{
"id": "23282998_T22",
"type": "GENE-N",
"text": [
"PFL"
],
"offsets": [
[
660,
663
]
],
"normalized": []
},
{
"id": "23282998_T23",
"type": "GENE-Y",
"text": [
"caspase-3"
],
"offsets": [
[
816,
825
]
],
"normalized": []
},
{
"id": "23282998_T24",
"type": "GENE-N",
"text": [
"mushroom lectin"
],
"offsets": [
[
1012,
1027
]
],
"normalized": []
},
{
"id": "23282998_T25",
"type": "GENE-N",
"text": [
"PFL"
],
"offsets": [
[
1097,
1100
]
],
"normalized": []
},
{
"id": "23282998_T26",
"type": "GENE-N",
"text": [
"Pleurotus florida lectin"
],
"offsets": [
[
113,
137
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23282998_0",
"type": "ACTIVATOR",
"arg1_id": "23282998_T11",
"arg2_id": "23282998_T23",
"normalized": []
}
] |
16905533 | 16905533 | [
{
"id": "16905533_title",
"type": "title",
"text": [
"Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma."
],
"offsets": [
[
0,
113
]
]
},
{
"id": "16905533_abstract",
"type": "abstract",
"text": [
"Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by gammaPKC resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by gammaPKC could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and DAG signaling."
],
"offsets": [
[
114,
1459
]
]
}
] | [
{
"id": "16905533_T1",
"type": "CHEMICAL",
"text": [
"Diacylglycerol"
],
"offsets": [
[
114,
128
]
],
"normalized": []
},
{
"id": "16905533_T2",
"type": "CHEMICAL",
"text": [
"DAG"
],
"offsets": [
[
130,
133
]
],
"normalized": []
},
{
"id": "16905533_T3",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
"offsets": [
[
492,
496
]
],
"normalized": []
},
{
"id": "16905533_T4",
"type": "CHEMICAL",
"text": [
"phosphatidylserine"
],
"offsets": [
[
508,
526
]
],
"normalized": []
},
{
"id": "16905533_T5",
"type": "CHEMICAL",
"text": [
"diolein"
],
"offsets": [
[
527,
534
]
],
"normalized": []
},
{
"id": "16905533_T6",
"type": "CHEMICAL",
"text": [
"phosphorylated Ser"
],
"offsets": [
[
617,
635
]
],
"normalized": []
},
{
"id": "16905533_T7",
"type": "CHEMICAL",
"text": [
"Ser"
],
"offsets": [
[
644,
647
]
],
"normalized": []
},
{
"id": "16905533_T8",
"type": "CHEMICAL",
"text": [
"Ser"
],
"offsets": [
[
777,
780
]
],
"normalized": []
},
{
"id": "16905533_T9",
"type": "CHEMICAL",
"text": [
"Ser"
],
"offsets": [
[
789,
792
]
],
"normalized": []
},
{
"id": "16905533_T10",
"type": "CHEMICAL",
"text": [
"glutamic acid"
],
"offsets": [
[
819,
832
]
],
"normalized": []
},
{
"id": "16905533_T11",
"type": "CHEMICAL",
"text": [
"phosphatidic acid"
],
"offsets": [
[
213,
230
]
],
"normalized": []
},
{
"id": "16905533_T12",
"type": "CHEMICAL",
"text": [
"diacylglycerol"
],
"offsets": [
[
37,
51
]
],
"normalized": []
},
{
"id": "16905533_T13",
"type": "GENE-Y",
"text": [
"DGKgamma"
],
"offsets": [
[
1130,
1138
]
],
"normalized": []
},
{
"id": "16905533_T14",
"type": "GENE-Y",
"text": [
"gammaPKC"
],
"offsets": [
[
1169,
1177
]
],
"normalized": []
},
{
"id": "16905533_T15",
"type": "GENE-N",
"text": [
"kinases"
],
"offsets": [
[
1269,
1276
]
],
"normalized": []
},
{
"id": "16905533_T16",
"type": "GENE-Y",
"text": [
"gammaPKC"
],
"offsets": [
[
1278,
1286
]
],
"normalized": []
},
{
"id": "16905533_T17",
"type": "GENE-Y",
"text": [
"DGKgamma"
],
"offsets": [
[
1291,
1299
]
],
"normalized": []
},
{
"id": "16905533_T18",
"type": "GENE-N",
"text": [
"DAG kinase"
],
"offsets": [
[
234,
244
]
],
"normalized": []
},
{
"id": "16905533_T19",
"type": "GENE-Y",
"text": [
"DGKgamma"
],
"offsets": [
[
1432,
1440
]
],
"normalized": []
},
{
"id": "16905533_T20",
"type": "GENE-N",
"text": [
"DGK"
],
"offsets": [
[
246,
249
]
],
"normalized": []
},
{
"id": "16905533_T21",
"type": "GENE-N",
"text": [
"DGK"
],
"offsets": [
[
263,
266
]
],
"normalized": []
},
{
"id": "16905533_T22",
"type": "GENE-N",
"text": [
"PKC"
],
"offsets": [
[
308,
311
]
],
"normalized": []
},
{
"id": "16905533_T23",
"type": "GENE-N",
"text": [
"kinases"
],
"offsets": [
[
392,
399
]
],
"normalized": []
},
{
"id": "16905533_T24",
"type": "GENE-Y",
"text": [
"gammaPKC"
],
"offsets": [
[
401,
409
]
],
"normalized": []
},
{
"id": "16905533_T25",
"type": "GENE-Y",
"text": [
"DGKgamma"
],
"offsets": [
[
435,
443
]
],
"normalized": []
},
{
"id": "16905533_T26",
"type": "GENE-Y",
"text": [
"gammaPKC"
],
"offsets": [
[
608,
616
]
],
"normalized": []
},
{
"id": "16905533_T27",
"type": "GENE-Y",
"text": [
"DGKgamma"
],
"offsets": [
[
665,
673
]
],
"normalized": []
},
{
"id": "16905533_T28",
"type": "GENE-N",
"text": [
"protein kinase C"
],
"offsets": [
[
170,
186
]
],
"normalized": []
},
{
"id": "16905533_T29",
"type": "GENE-Y",
"text": [
"gammaPKC"
],
"offsets": [
[
698,
706
]
],
"normalized": []
},
{
"id": "16905533_T30",
"type": "GENE-Y",
"text": [
"DGKgamma"
],
"offsets": [
[
733,
741
]
],
"normalized": []
},
{
"id": "16905533_T31",
"type": "GENE-Y",
"text": [
"DGKgamma"
],
"offsets": [
[
752,
760
]
],
"normalized": []
},
{
"id": "16905533_T32",
"type": "GENE-N",
"text": [
"PKC"
],
"offsets": [
[
188,
191
]
],
"normalized": []
},
{
"id": "16905533_T33",
"type": "GENE-Y",
"text": [
"DGKgamma"
],
"offsets": [
[
922,
930
]
],
"normalized": []
},
{
"id": "16905533_T34",
"type": "GENE-Y",
"text": [
"DGKgamma"
],
"offsets": [
[
957,
965
]
],
"normalized": []
},
{
"id": "16905533_T35",
"type": "GENE-N",
"text": [
"kinases"
],
"offsets": [
[
1014,
1021
]
],
"normalized": []
},
{
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"type": "GENE-Y",
"text": [
"protein kinase C gamma"
],
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90,
112
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] | [] | [] | [
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}
] |
23536519 | 23536519 | [
{
"id": "23536519_title",
"type": "title",
"text": [
"Resveratrol inhibits proliferation, angiogenesis and induces apoptosis in colon cancer cells: Calorie restriction is the force to the cytotoxicity."
],
"offsets": [
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0,
147
]
]
},
{
"id": "23536519_abstract",
"type": "abstract",
"text": [
"The aim of this study was to examine the antitumour activity of resveratrol in human colorectal cancer cell lines (HCT116 and Caco2) and to explore its mechanism of action assuming that it is by calorie-restriction effect. Resveratrol inhibited the proliferation of colon cancer cells with half maximal inhibitory concentration (IC50) equal to 50 and 130 μM for HCT116 and Caco2, respectively. Caco2 cells appeared with significant time-dependent increase in the glycolytic pathway, a behaviour that was absent in HCT116 cells. Resveratrol (100 μM) significantly decreased the glycolytic enzymes (pyruvate kinase and lactate dehydrogenase) in Caco2 cells, while an increase in citrate synthase activity and a decrease in glucose consumption were observed in both cell lines. Moreover, resveratrol downregulated the expressions of leptin and c-Myc, and decreased the content of vascular endothelial growth factor. The apoptotic markers, caspases 3 and 8, were activated and the Bax/BCl2 ratio was increased. The study suggested a promising anticancer activity of resveratrol, calorie-restriction pathway may be one of the driving forces for this activity."
],
"offsets": [
[
148,
1302
]
]
}
] | [
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371,
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676,
687
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212,
223
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{
"id": "23536519_T5",
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"text": [
"citrate"
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825,
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]
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{
"id": "23536519_T6",
"type": "CHEMICAL",
"text": [
"glucose"
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869,
876
]
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0,
11
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{
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"glycolytic enzymes"
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725,
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},
{
"id": "23536519_T10",
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"pyruvate kinase"
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745,
760
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{
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765,
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"id": "23536519_T12",
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825,
841
]
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"id": "23536519_T13",
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"text": [
"leptin"
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978,
984
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"c-Myc"
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989,
994
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1025,
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1084,
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"text": [
"Bax"
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1125,
1128
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{
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"text": [
"BCl2"
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1129,
1133
]
],
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}
] | [] | [] | [
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},
{
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},
{
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{
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"arg2_id": "23536519_T15",
"normalized": []
}
] |
23566269 | 23566269 | [
{
"id": "23566269_title",
"type": "title",
"text": [
"4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors."
],
"offsets": [
[
0,
82
]
]
},
{
"id": "23566269_abstract",
"type": "abstract",
"text": [
"d-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze."
],
"offsets": [
[
83,
1295
]
]
}
] | [
{
"id": "23566269_T1",
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"d-Amino acid"
],
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83,
95
]
],
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},
{
"id": "23566269_T2",
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"3-hydroxy-pyridine-2(1H)-one"
],
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1093,
1121
]
],
"normalized": []
},
{
"id": "23566269_T3",
"type": "CHEMICAL",
"text": [
"6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one"
],
"offsets": [
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1153,
1213
]
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{
"id": "23566269_T4",
"type": "CHEMICAL",
"text": [
"N-methyl-d-aspartate"
],
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191,
211
]
],
"normalized": []
},
{
"id": "23566269_T5",
"type": "CHEMICAL",
"text": [
"MK-801"
],
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1248,
1254
]
],
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},
{
"id": "23566269_T6",
"type": "CHEMICAL",
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"4-hydroxypyridazin-3(2H)-one"
],
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248,
276
]
],
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},
{
"id": "23566269_T7",
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"text": [
"Tyr"
],
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619,
622
]
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{
"id": "23566269_T8",
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"text": [
"d-amino acids"
],
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138,
151
]
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{
"id": "23566269_T9",
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"3-hydroxy-pyridine-2(1H)-one"
],
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713,
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]
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},
{
"id": "23566269_T10",
"type": "CHEMICAL",
"text": [
"3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one"
],
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813,
858
]
],
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{
"id": "23566269_T11",
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"text": [
"d-serine"
],
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162,
170
]
],
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"id": "23566269_T12",
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1023,
1051
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"id": "23566269_T13",
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"4-Hydroxypyridazin-3(2H)-one"
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0,
28
]
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"id": "23566269_T14",
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"text": [
"d-Amino Acid"
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50,
62
]
],
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},
{
"id": "23566269_T15",
"type": "GENE-Y",
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"d-Amino acid oxidase"
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83,
103
]
],
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{
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"type": "GENE-N",
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"N-methyl-d-aspartate receptor"
],
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191,
220
]
],
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},
{
"id": "23566269_T17",
"type": "GENE-Y",
"text": [
"DAAO"
],
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298,
302
]
],
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},
{
"id": "23566269_T18",
"type": "GENE-Y",
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"DAAO"
],
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105,
109
]
],
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},
{
"id": "23566269_T19",
"type": "GENE-Y",
"text": [
"human DAAO"
],
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[
942,
952
]
],
"normalized": []
},
{
"id": "23566269_T20",
"type": "GENE-Y",
"text": [
"d-Amino Acid Oxidase"
],
"offsets": [
[
50,
70
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23566269_0",
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"arg2_id": "23566269_T20",
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},
{
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"arg2_id": "23566269_T15",
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},
{
"id": "23566269_2",
"type": "SUBSTRATE",
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"arg2_id": "23566269_T18",
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},
{
"id": "23566269_3",
"type": "SUBSTRATE",
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"arg2_id": "23566269_T15",
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},
{
"id": "23566269_4",
"type": "SUBSTRATE",
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"arg2_id": "23566269_T18",
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},
{
"id": "23566269_5",
"type": "AGONIST",
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"arg2_id": "23566269_T16",
"normalized": []
},
{
"id": "23566269_6",
"type": "INHIBITOR",
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},
{
"id": "23566269_7",
"type": "INHIBITOR",
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"arg2_id": "23566269_T19",
"normalized": []
},
{
"id": "23566269_8",
"type": "DIRECT-REGULATOR",
"arg1_id": "23566269_T10",
"arg2_id": "23566269_T19",
"normalized": []
}
] |
17565005 | 17565005 | [
{
"id": "17565005_title",
"type": "title",
"text": [
"The impact of hypoxic treatment on the expression of phosphoglycerate kinase and the cytotoxicity of troxacitabine and gemcitabine."
],
"offsets": [
[
0,
131
]
]
},
{
"id": "17565005_abstract",
"type": "abstract",
"text": [
"beta-L-Dioxolane-cytidine (L-OddC, Troxacitabine, BCH-4556), a novel L-configuration deoxycytidine analog, is under clinical trials for treating cancer. The cytotoxicity of L-OddC is dependent on the amount of the triphosphate form (L-OddCTP) in nuclear DNA. Phosphoglycerate kinase (PGK), a downstream protein of hypoxia-inducible-factor-1alpha (HIF-1alpha), is responsible for the phosphorylation of the diphosphate to the triphosphate of L-OddC. In this study, we studied the impact of hypoxia on the metabolism and the cytotoxicity of L-OddC and beta-d-2',2'-difluorodeoxycytidine (dFdC) in several human tumor cell lines including HepG2, Hep3B, A673, Panc-1, and RKO. Hypoxic treatment induced the protein expression of PGK 3-fold but had no effect on the protein expression of APE-1, dCK, CMPK, and nM23 H1. Hypoxic treatment increased L-OddCTP formation and incorporation of L-OddC into DNA, but it decreased the uptake and incorporation of dFdC, which correlated with the reduction of hENT1, hENT2, and hCNT2 expression. Using a clonogenic assay, hypoxic treatment of cells made them 2- to 3-fold more susceptible to L-OddC but not to dFdC after exposure to drugs for one generation. Dimethyloxallyl glycine enhanced the cytotoxicity of L-OddC but not dFdC in Panc-1 cells under normoxic conditions. Overexpression or down-regulation of PGK using transient transfection of pcDNA5-PGK or inducible shRNA in RKO cells affected the cytotoxicity of L-OddC but not that of dFdC. The knockdown of HIF-1alpha in inducible shRNA in RKO cells reduced the cytotoxicity of L-OddC but not dFdC under hypoxic conditions. In conclusion, hypoxia is an important factor that may potentiate the activity of L-OddC."
],
"offsets": [
[
132,
1837
]
]
}
] | [
{
"id": "17565005_T1",
"type": "CHEMICAL",
"text": [
"beta-L-Dioxolane-cytidine"
],
"offsets": [
[
132,
157
]
],
"normalized": []
},
{
"id": "17565005_T2",
"type": "CHEMICAL",
"text": [
"L-OddC"
],
"offsets": [
[
1257,
1263
]
],
"normalized": []
},
{
"id": "17565005_T3",
"type": "CHEMICAL",
"text": [
"dFdC"
],
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[
1275,
1279
]
],
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},
{
"id": "17565005_T4",
"type": "CHEMICAL",
"text": [
"Dimethyloxallyl glycine"
],
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[
1324,
1347
]
],
"normalized": []
},
{
"id": "17565005_T5",
"type": "CHEMICAL",
"text": [
"L-OddC"
],
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[
1377,
1383
]
],
"normalized": []
},
{
"id": "17565005_T6",
"type": "CHEMICAL",
"text": [
"dFdC"
],
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[
1392,
1396
]
],
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},
{
"id": "17565005_T7",
"type": "CHEMICAL",
"text": [
"L-OddC"
],
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[
1585,
1591
]
],
"normalized": []
},
{
"id": "17565005_T8",
"type": "CHEMICAL",
"text": [
"dFdC"
],
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[
1608,
1612
]
],
"normalized": []
},
{
"id": "17565005_T9",
"type": "CHEMICAL",
"text": [
"L-OddC"
],
"offsets": [
[
1702,
1708
]
],
"normalized": []
},
{
"id": "17565005_T10",
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"text": [
"dFdC"
],
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[
1717,
1721
]
],
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},
{
"id": "17565005_T11",
"type": "CHEMICAL",
"text": [
"L-OddC"
],
"offsets": [
[
1830,
1836
]
],
"normalized": []
},
{
"id": "17565005_T12",
"type": "CHEMICAL",
"text": [
"L-OddC"
],
"offsets": [
[
305,
311
]
],
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},
{
"id": "17565005_T13",
"type": "CHEMICAL",
"text": [
"triphosphate"
],
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[
346,
358
]
],
"normalized": []
},
{
"id": "17565005_T14",
"type": "CHEMICAL",
"text": [
"L-OddCTP"
],
"offsets": [
[
365,
373
]
],
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},
{
"id": "17565005_T15",
"type": "CHEMICAL",
"text": [
"Phosphoglycerate"
],
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[
391,
407
]
],
"normalized": []
},
{
"id": "17565005_T16",
"type": "CHEMICAL",
"text": [
"L-OddC"
],
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[
159,
165
]
],
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},
{
"id": "17565005_T17",
"type": "CHEMICAL",
"text": [
"Troxacitabine"
],
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[
167,
180
]
],
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},
{
"id": "17565005_T18",
"type": "CHEMICAL",
"text": [
"diphosphate"
],
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[
538,
549
]
],
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},
{
"id": "17565005_T19",
"type": "CHEMICAL",
"text": [
"triphosphate"
],
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[
557,
569
]
],
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},
{
"id": "17565005_T20",
"type": "CHEMICAL",
"text": [
"L-OddC"
],
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[
573,
579
]
],
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},
{
"id": "17565005_T21",
"type": "CHEMICAL",
"text": [
"BCH-4556"
],
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[
182,
190
]
],
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},
{
"id": "17565005_T22",
"type": "CHEMICAL",
"text": [
"L-OddC"
],
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[
671,
677
]
],
"normalized": []
},
{
"id": "17565005_T23",
"type": "CHEMICAL",
"text": [
"beta-d-2',2'-difluorodeoxycytidine"
],
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682,
716
]
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},
{
"id": "17565005_T24",
"type": "CHEMICAL",
"text": [
"dFdC"
],
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[
718,
722
]
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{
"id": "17565005_T25",
"type": "CHEMICAL",
"text": [
"L-configuration deoxycytidine"
],
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201,
230
]
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{
"id": "17565005_T26",
"type": "CHEMICAL",
"text": [
"L-OddCTP"
],
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[
974,
982
]
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{
"id": "17565005_T27",
"type": "CHEMICAL",
"text": [
"L-OddC"
],
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[
1014,
1020
]
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},
{
"id": "17565005_T28",
"type": "CHEMICAL",
"text": [
"dFdC"
],
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[
1080,
1084
]
],
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},
{
"id": "17565005_T29",
"type": "CHEMICAL",
"text": [
"troxacitabine"
],
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[
101,
114
]
],
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{
"id": "17565005_T30",
"type": "CHEMICAL",
"text": [
"gemcitabine"
],
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119,
130
]
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},
{
"id": "17565005_T31",
"type": "CHEMICAL",
"text": [
"phosphoglycerate"
],
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[
53,
69
]
],
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},
{
"id": "17565005_T32",
"type": "GENE-Y",
"text": [
"hENT2"
],
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1132,
1137
]
],
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},
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"id": "17565005_T33",
"type": "GENE-Y",
"text": [
"hCNT2"
],
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1143,
1148
]
],
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},
{
"id": "17565005_T34",
"type": "GENE-N",
"text": [
"PGK"
],
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1477,
1480
]
],
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},
{
"id": "17565005_T35",
"type": "GENE-N",
"text": [
"PGK"
],
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1520,
1523
]
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},
{
"id": "17565005_T36",
"type": "GENE-Y",
"text": [
"HIF-1alpha"
],
"offsets": [
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1631,
1641
]
],
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},
{
"id": "17565005_T37",
"type": "GENE-N",
"text": [
"Phosphoglycerate kinase"
],
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391,
414
]
],
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},
{
"id": "17565005_T38",
"type": "GENE-N",
"text": [
"PGK"
],
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416,
419
]
],
"normalized": []
},
{
"id": "17565005_T39",
"type": "GENE-Y",
"text": [
"hypoxia-inducible-factor-1alpha"
],
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446,
477
]
],
"normalized": []
},
{
"id": "17565005_T40",
"type": "GENE-Y",
"text": [
"HIF-1alpha"
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479,
489
]
],
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},
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"id": "17565005_T41",
"type": "GENE-N",
"text": [
"PGK"
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857,
860
]
],
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},
{
"id": "17565005_T42",
"type": "GENE-Y",
"text": [
"APE-1"
],
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915,
920
]
],
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},
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"id": "17565005_T43",
"type": "GENE-Y",
"text": [
"dCK"
],
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922,
925
]
],
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},
{
"id": "17565005_T44",
"type": "GENE-Y",
"text": [
"CMPK"
],
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927,
931
]
],
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},
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"id": "17565005_T45",
"type": "GENE-Y",
"text": [
"nM23 H1"
],
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[
937,
944
]
],
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},
{
"id": "17565005_T46",
"type": "GENE-Y",
"text": [
"hENT1"
],
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1125,
1130
]
],
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},
{
"id": "17565005_T47",
"type": "GENE-N",
"text": [
"phosphoglycerate kinase"
],
"offsets": [
[
53,
76
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17565005_0",
"type": "SUBSTRATE",
"arg1_id": "17565005_T20",
"arg2_id": "17565005_T37",
"normalized": []
},
{
"id": "17565005_1",
"type": "SUBSTRATE",
"arg1_id": "17565005_T20",
"arg2_id": "17565005_T38",
"normalized": []
}
] |
23643730 | 23643730 | [
{
"id": "23643730_title",
"type": "title",
"text": [
"Juglone, isolated from Juglans mandshurica Maxim, induces apoptosis via down-regulation of AR expression in human prostate cancer LNCaP cells."
],
"offsets": [
[
0,
142
]
]
},
{
"id": "23643730_abstract",
"type": "abstract",
"text": [
"Juglone is a natural compound which has been isolated from Juglans mandshurica Maxim. Recent studies have shown that juglone had various pharmacological effects such as anti-viral, anti-bacterial and anti-cancer. However, its anti-cancer activity on human prostate cancer LNCaP cell has not been examined. Thus, the current study was designed to elucidate the molecular mechanism of apoptosis induced by juglone in androgen-sensitive prostate cancer LNCaP cells. MTT assay was performed to examine the anti-proliferative effect of juglone. Occurrence of apoptosis was detected by Hoechst 33342 staining and flow cytometry in LNCaP cells treated with juglone for 24h. The result shown that juglone inhibited the growth of LNCaP cells in a dose-dependent manner. Morphological changes of apoptotic body formation after juglone treatment were observed by Hoechst 33342 staining. This apoptotic induction was associated with loss of mitochondrial membrane potential, and caspase-3, -9 activation. Moreover, we found that juglone significantly inhibited the expression levels of androgen receptor (AR) and prostate-specific antigen (PSA) in a dose-dependent manner, as well as abrogated up-regulation of AR and PSA genes with and/or without dihydrotestosterone (DHT). Take together, our results demonstrated that juglone might induce the apoptosis in LNCaP cell via down-regulation of AR expression. Therefore, our results indicated that juglone may be a potential candidate of drug for androgen-sensitive prostate cancer."
],
"offsets": [
[
143,
1660
]
]
}
] | [
{
"id": "23643730_T1",
"type": "CHEMICAL",
"text": [
"Juglone"
],
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[
143,
150
]
],
"normalized": []
},
{
"id": "23643730_T2",
"type": "CHEMICAL",
"text": [
"juglone"
],
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[
1160,
1167
]
],
"normalized": []
},
{
"id": "23643730_T3",
"type": "CHEMICAL",
"text": [
"androgen"
],
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[
1217,
1225
]
],
"normalized": []
},
{
"id": "23643730_T4",
"type": "CHEMICAL",
"text": [
"juglone"
],
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[
260,
267
]
],
"normalized": []
},
{
"id": "23643730_T5",
"type": "CHEMICAL",
"text": [
"dihydrotestosterone"
],
"offsets": [
[
1379,
1398
]
],
"normalized": []
},
{
"id": "23643730_T6",
"type": "CHEMICAL",
"text": [
"DHT"
],
"offsets": [
[
1400,
1403
]
],
"normalized": []
},
{
"id": "23643730_T7",
"type": "CHEMICAL",
"text": [
"juglone"
],
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[
1451,
1458
]
],
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},
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"id": "23643730_T8",
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"text": [
"juglone"
],
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[
1576,
1583
]
],
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},
{
"id": "23643730_T9",
"type": "CHEMICAL",
"text": [
"androgen"
],
"offsets": [
[
1625,
1633
]
],
"normalized": []
},
{
"id": "23643730_T10",
"type": "CHEMICAL",
"text": [
"juglone"
],
"offsets": [
[
547,
554
]
],
"normalized": []
},
{
"id": "23643730_T11",
"type": "CHEMICAL",
"text": [
"androgen"
],
"offsets": [
[
558,
566
]
],
"normalized": []
},
{
"id": "23643730_T12",
"type": "CHEMICAL",
"text": [
"MTT"
],
"offsets": [
[
606,
609
]
],
"normalized": []
},
{
"id": "23643730_T13",
"type": "CHEMICAL",
"text": [
"juglone"
],
"offsets": [
[
674,
681
]
],
"normalized": []
},
{
"id": "23643730_T14",
"type": "CHEMICAL",
"text": [
"Hoechst 33342"
],
"offsets": [
[
723,
736
]
],
"normalized": []
},
{
"id": "23643730_T15",
"type": "CHEMICAL",
"text": [
"juglone"
],
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[
793,
800
]
],
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},
{
"id": "23643730_T16",
"type": "CHEMICAL",
"text": [
"juglone"
],
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[
832,
839
]
],
"normalized": []
},
{
"id": "23643730_T17",
"type": "CHEMICAL",
"text": [
"juglone"
],
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[
960,
967
]
],
"normalized": []
},
{
"id": "23643730_T18",
"type": "CHEMICAL",
"text": [
"Hoechst 33342"
],
"offsets": [
[
995,
1008
]
],
"normalized": []
},
{
"id": "23643730_T19",
"type": "CHEMICAL",
"text": [
"Juglone"
],
"offsets": [
[
0,
7
]
],
"normalized": []
},
{
"id": "23643730_T20",
"type": "GENE-Y",
"text": [
"androgen receptor"
],
"offsets": [
[
1217,
1234
]
],
"normalized": []
},
{
"id": "23643730_T21",
"type": "GENE-Y",
"text": [
"AR"
],
"offsets": [
[
1236,
1238
]
],
"normalized": []
},
{
"id": "23643730_T22",
"type": "GENE-Y",
"text": [
"prostate-specific antigen"
],
"offsets": [
[
1244,
1269
]
],
"normalized": []
},
{
"id": "23643730_T23",
"type": "GENE-Y",
"text": [
"PSA"
],
"offsets": [
[
1271,
1274
]
],
"normalized": []
},
{
"id": "23643730_T24",
"type": "GENE-Y",
"text": [
"AR"
],
"offsets": [
[
1342,
1344
]
],
"normalized": []
},
{
"id": "23643730_T25",
"type": "GENE-Y",
"text": [
"PSA"
],
"offsets": [
[
1349,
1352
]
],
"normalized": []
},
{
"id": "23643730_T26",
"type": "GENE-Y",
"text": [
"AR"
],
"offsets": [
[
1523,
1525
]
],
"normalized": []
},
{
"id": "23643730_T27",
"type": "GENE-N",
"text": [
"caspase-3, -9"
],
"offsets": [
[
1110,
1123
]
],
"normalized": []
},
{
"id": "23643730_T28",
"type": "GENE-Y",
"text": [
"AR"
],
"offsets": [
[
91,
93
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23643730_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23643730_T19",
"arg2_id": "23643730_T28",
"normalized": []
},
{
"id": "23643730_1",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23643730_T2",
"arg2_id": "23643730_T20",
"normalized": []
},
{
"id": "23643730_2",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23643730_T2",
"arg2_id": "23643730_T21",
"normalized": []
},
{
"id": "23643730_3",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23643730_T2",
"arg2_id": "23643730_T22",
"normalized": []
},
{
"id": "23643730_4",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23643730_T2",
"arg2_id": "23643730_T23",
"normalized": []
},
{
"id": "23643730_5",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23643730_T2",
"arg2_id": "23643730_T24",
"normalized": []
},
{
"id": "23643730_6",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23643730_T2",
"arg2_id": "23643730_T25",
"normalized": []
},
{
"id": "23643730_7",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23643730_T7",
"arg2_id": "23643730_T26",
"normalized": []
}
] |
7853212 | 7853212 | [
{
"id": "7853212_title",
"type": "title",
"text": [
"Mepyramine, a histamine H1 receptor antagonist, inhibits the metabolic activity of rat and human P450 2D forms."
],
"offsets": [
[
0,
111
]
]
},
{
"id": "7853212_abstract",
"type": "abstract",
"text": [
"The interaction of antihistaminics, including mepyramine, with rat hepatic cytochrome P450s (P450s) was investigated. We first investigated mepyramine binding to eight forms of rat hepatic P450s. Mepyramine bound specifically to P450 2D1, which suggests that it inhibits P450 2D activity. Histamine H1 receptor antagonists (mepyramine, diphenhydramine, chlorpheniramine and triprolidine) inhibited the lidocaine 3-hydroxylation activity catalyzed by P450 2D1 but did not inhibit the testosterone hydroxylation activities catalyzed by P450s other than P450 2D forms. The Ki values of these antagonists for the catalytic activity of P450 2D1 were low and were similar to those of quinine and quinidine, which are specific inhibitors of P450 2D forms. The Ki value of mepyramine was especially low, at 34 nM. Furthermore, the effects of mepyramine on human P450 2D6 were investigated. Among the ten forms of human P450 expressed in yeast, mepyramine bound specifically to P450 2D6 in a binding assay. In human hepatic microsomes, mepyramine inhibited the debrisoquine 4-hydroxylation activity catalyzed by P450 2D6. These results indicate that histamine H1 receptor antagonists such as mepyramine are potent inhibitors of P450 2D forms because of their high affinity for these enzymes."
],
"offsets": [
[
112,
1394
]
]
}
] | [
{
"id": "7853212_T1",
"type": "CHEMICAL",
"text": [
"mepyramine"
],
"offsets": [
[
1139,
1149
]
],
"normalized": []
},
{
"id": "7853212_T2",
"type": "CHEMICAL",
"text": [
"debrisoquine"
],
"offsets": [
[
1164,
1176
]
],
"normalized": []
},
{
"id": "7853212_T3",
"type": "CHEMICAL",
"text": [
"histamine"
],
"offsets": [
[
1253,
1262
]
],
"normalized": []
},
{
"id": "7853212_T4",
"type": "CHEMICAL",
"text": [
"mepyramine"
],
"offsets": [
[
1295,
1305
]
],
"normalized": []
},
{
"id": "7853212_T5",
"type": "CHEMICAL",
"text": [
"mepyramine"
],
"offsets": [
[
252,
262
]
],
"normalized": []
},
{
"id": "7853212_T6",
"type": "CHEMICAL",
"text": [
"Mepyramine"
],
"offsets": [
[
308,
318
]
],
"normalized": []
},
{
"id": "7853212_T7",
"type": "CHEMICAL",
"text": [
"Histamine"
],
"offsets": [
[
401,
410
]
],
"normalized": []
},
{
"id": "7853212_T8",
"type": "CHEMICAL",
"text": [
"mepyramine"
],
"offsets": [
[
436,
446
]
],
"normalized": []
},
{
"id": "7853212_T9",
"type": "CHEMICAL",
"text": [
"diphenhydramine"
],
"offsets": [
[
448,
463
]
],
"normalized": []
},
{
"id": "7853212_T10",
"type": "CHEMICAL",
"text": [
"chlorpheniramine"
],
"offsets": [
[
465,
481
]
],
"normalized": []
},
{
"id": "7853212_T11",
"type": "CHEMICAL",
"text": [
"triprolidine"
],
"offsets": [
[
486,
498
]
],
"normalized": []
},
{
"id": "7853212_T12",
"type": "CHEMICAL",
"text": [
"lidocaine"
],
"offsets": [
[
514,
523
]
],
"normalized": []
},
{
"id": "7853212_T13",
"type": "CHEMICAL",
"text": [
"mepyramine"
],
"offsets": [
[
158,
168
]
],
"normalized": []
},
{
"id": "7853212_T14",
"type": "CHEMICAL",
"text": [
"testosterone"
],
"offsets": [
[
595,
607
]
],
"normalized": []
},
{
"id": "7853212_T15",
"type": "CHEMICAL",
"text": [
"quinine"
],
"offsets": [
[
790,
797
]
],
"normalized": []
},
{
"id": "7853212_T16",
"type": "CHEMICAL",
"text": [
"quinidine"
],
"offsets": [
[
802,
811
]
],
"normalized": []
},
{
"id": "7853212_T17",
"type": "CHEMICAL",
"text": [
"mepyramine"
],
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[
877,
887
]
],
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},
{
"id": "7853212_T18",
"type": "CHEMICAL",
"text": [
"mepyramine"
],
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[
946,
956
]
],
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},
{
"id": "7853212_T19",
"type": "CHEMICAL",
"text": [
"mepyramine"
],
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[
1048,
1058
]
],
"normalized": []
},
{
"id": "7853212_T20",
"type": "CHEMICAL",
"text": [
"Mepyramine"
],
"offsets": [
[
0,
10
]
],
"normalized": []
},
{
"id": "7853212_T21",
"type": "CHEMICAL",
"text": [
"histamine"
],
"offsets": [
[
14,
23
]
],
"normalized": []
},
{
"id": "7853212_T22",
"type": "GENE-Y",
"text": [
"P450 2D6"
],
"offsets": [
[
1215,
1223
]
],
"normalized": []
},
{
"id": "7853212_T23",
"type": "GENE-Y",
"text": [
"histamine H1 receptor"
],
"offsets": [
[
1253,
1274
]
],
"normalized": []
},
{
"id": "7853212_T24",
"type": "GENE-N",
"text": [
"P450 2D"
],
"offsets": [
[
1331,
1338
]
],
"normalized": []
},
{
"id": "7853212_T25",
"type": "GENE-N",
"text": [
"rat hepatic P450s"
],
"offsets": [
[
289,
306
]
],
"normalized": []
},
{
"id": "7853212_T26",
"type": "GENE-Y",
"text": [
"P450 2D1"
],
"offsets": [
[
341,
349
]
],
"normalized": []
},
{
"id": "7853212_T27",
"type": "GENE-N",
"text": [
"P450 2D"
],
"offsets": [
[
383,
390
]
],
"normalized": []
},
{
"id": "7853212_T28",
"type": "GENE-Y",
"text": [
"Histamine H1 receptor"
],
"offsets": [
[
401,
422
]
],
"normalized": []
},
{
"id": "7853212_T29",
"type": "GENE-Y",
"text": [
"P450 2D1"
],
"offsets": [
[
562,
570
]
],
"normalized": []
},
{
"id": "7853212_T30",
"type": "GENE-N",
"text": [
"P450s"
],
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646,
651
]
],
"normalized": []
},
{
"id": "7853212_T31",
"type": "GENE-N",
"text": [
"P450 2D"
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663,
670
]
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},
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"id": "7853212_T32",
"type": "GENE-Y",
"text": [
"P450 2D1"
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743,
751
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},
{
"id": "7853212_T33",
"type": "GENE-N",
"text": [
"rat hepatic cytochrome P450s"
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175,
203
]
],
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},
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"id": "7853212_T34",
"type": "GENE-N",
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"P450 2D"
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846,
853
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"id": "7853212_T35",
"type": "GENE-Y",
"text": [
"human P450 2D6"
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960,
974
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{
"id": "7853212_T36",
"type": "GENE-N",
"text": [
"human P450"
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1017,
1027
]
],
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},
{
"id": "7853212_T37",
"type": "GENE-N",
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"P450s"
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205,
210
]
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{
"id": "7853212_T38",
"type": "GENE-Y",
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"P450 2D6"
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1081,
1089
]
],
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},
{
"id": "7853212_T39",
"type": "GENE-N",
"text": [
"histamine H1 receptor"
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14,
35
]
],
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},
{
"id": "7853212_T40",
"type": "GENE-N",
"text": [
"rat and human P450 2D"
],
"offsets": [
[
83,
104
]
],
"normalized": []
}
] | [] | [] | [
{
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},
{
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{
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{
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},
{
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},
{
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},
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},
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},
{
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},
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},
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},
{
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},
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},
{
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{
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"arg2_id": "7853212_T34",
"normalized": []
}
] |
23142558 | 23142558 | [
{
"id": "23142558_title",
"type": "title",
"text": [
"The 17-β-oestradiol inhibits osteoclast activity by increasing the cannabinoid CB2 receptor expression."
],
"offsets": [
[
0,
103
]
]
},
{
"id": "23142558_abstract",
"type": "abstract",
"text": [
"Bone is a highly metabolically active tissue and its formation and resorption is at the base of bone remodelling. The critical importance of a balanced bone remodelling is demonstrated by human diseases, i.e. osteoporosis, in which a net increase in bone resorption is responsible of skeleton weakening and fracture risk. Oestrogens display anti-resorptive properties on bone metabolism. Indeed, the so-called post-menopausal osteoporosis occurs after interruption of gonad function and benefits from hormonal replacement treatment. Recently, an important role for the endocannabinoid system in the regulation of skeletal remodelling in human has also been shown. In particular, we showed that CB2 stimulation is able to reduce the number of human OCs in vitro. Here, we provide unprecedented evidence that 17-β-oestradiol administration inhibits activity and formation of human OCs in vitro, demonstrating that oestrogens are able to induce an increase of CB2 expression probably through the recruitment of a putative oestrogens responsive element in the CB2 encoding for gene."
],
"offsets": [
[
104,
1182
]
]
}
] | [
{
"id": "23142558_T1",
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"text": [
"oestrogens"
],
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[
1123,
1133
]
],
"normalized": []
},
{
"id": "23142558_T2",
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"text": [
"Oestrogens"
],
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426,
436
]
],
"normalized": []
},
{
"id": "23142558_T3",
"type": "CHEMICAL",
"text": [
"17-β-oestradiol"
],
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[
911,
926
]
],
"normalized": []
},
{
"id": "23142558_T4",
"type": "CHEMICAL",
"text": [
"oestrogens"
],
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[
1016,
1026
]
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},
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"id": "23142558_T5",
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"17-β-oestradiol"
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4,
19
]
],
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},
{
"id": "23142558_T6",
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"text": [
"oestrogens responsive element"
],
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[
1123,
1152
]
],
"normalized": []
},
{
"id": "23142558_T7",
"type": "GENE-Y",
"text": [
"CB2"
],
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1160,
1163
]
],
"normalized": []
},
{
"id": "23142558_T8",
"type": "GENE-Y",
"text": [
"CB2"
],
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798,
801
]
],
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},
{
"id": "23142558_T9",
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"CB2"
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1061,
1064
]
],
"normalized": []
},
{
"id": "23142558_T10",
"type": "GENE-Y",
"text": [
"cannabinoid CB2 receptor"
],
"offsets": [
[
67,
91
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23142558_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23142558_T5",
"arg2_id": "23142558_T10",
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},
{
"id": "23142558_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23142558_T4",
"arg2_id": "23142558_T9",
"normalized": []
}
] |
23220413 | 23220413 | [
{
"id": "23220413_title",
"type": "title",
"text": [
"Exposure of zebrafish embryos/larvae to TDCPP alters concentrations of thyroid hormones and transcriptions of genes involved in the hypothalamic-pituitary-thyroid axis."
],
"offsets": [
[
0,
168
]
]
},
{
"id": "23220413_abstract",
"type": "abstract",
"text": [
"Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) has been frequently detected in the environment and in various biota, including fish, and has been implicated in disruption of the thyroid endocrine system. In the present study, zebrafish (Danio rerio) embryos were exposed to different concentrations of TDCPP (10, 50, 100, 300 and 600 μg/L) from 2 h post-fertilization (hpf) to 144 hpf. Developmental endpoints, and whole-body concentrations of thyroid hormones and transcriptional profiles of genes involved in the hypothalamic-pituitary-thyroid (HPT) axis were examined. Exposure to TDCPP caused a dose-dependent developmental toxicity, including decreased body weight, reduced hatching, survival and heartbeat rates, and increased malformation (spinal curvature). Treatment with the positive control chemical 3,3',5-triiodo-l-thyronine (T3) significantly decreased whole-body thyroxin (T4) concentrations, increased whole-body T3 concentrations, and upregulated mRNA expression involved in the HPT axis as a compensatory mechanism. These results suggested that the HPT axis in 144-hpf zebrafish larvae was responsive to chemical exposure and could be used to evaluate the effects of chemicals on the thyroid endocrine system. TDCPP exposure significantly decreased whole-body T4 concentrations and increased whole-body T3 concentrations, indicating thyroid endocrine disruption. The upregulation of genes related to thyroid hormone metabolism (dio1 and ugt1ab) might be responsible for decreased T4 concentrations. Treatment with TDCPP also significantly increased transcription of genes involved in thyroid hormone synthesis (tshβ, slc5a5 and tg) and thyroid development (hhex, nkx2.1 and pax8) as a compensatory mechanism for decreased T4 concentrations. Taken together, these results suggest that TDCPP alters the transcription of genes involved in the HPT axis and changes whole-body concentrations of thyroid hormones in zebrafish embryos/larvae, thus causing an endocrine disruption of the thyroid system."
],
"offsets": [
[
169,
2181
]
]
}
] | [
{
"id": "23220413_T1",
"type": "CHEMICAL",
"text": [
"Tris(1,3-dichloro-2-propyl) phosphate"
],
"offsets": [
[
169,
206
]
],
"normalized": []
},
{
"id": "23220413_T2",
"type": "CHEMICAL",
"text": [
"TDCPP"
],
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[
1396,
1401
]
],
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},
{
"id": "23220413_T3",
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"text": [
"TDCPP"
],
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[
1700,
1705
]
],
"normalized": []
},
{
"id": "23220413_T4",
"type": "CHEMICAL",
"text": [
"TDCPP"
],
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[
1970,
1975
]
],
"normalized": []
},
{
"id": "23220413_T5",
"type": "CHEMICAL",
"text": [
"TDCPP"
],
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[
470,
475
]
],
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},
{
"id": "23220413_T6",
"type": "CHEMICAL",
"text": [
"TDCPP"
],
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[
208,
213
]
],
"normalized": []
},
{
"id": "23220413_T7",
"type": "CHEMICAL",
"text": [
"TDCPP"
],
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[
752,
757
]
],
"normalized": []
},
{
"id": "23220413_T8",
"type": "CHEMICAL",
"text": [
"3,3',5-triiodo-l-thyronine"
],
"offsets": [
[
979,
1005
]
],
"normalized": []
},
{
"id": "23220413_T9",
"type": "CHEMICAL",
"text": [
"thyroxin (T4)"
],
"offsets": [
[
1046,
1059
]
],
"normalized": []
},
{
"id": "23220413_T10",
"type": "CHEMICAL",
"text": [
"TDCPP"
],
"offsets": [
[
40,
45
]
],
"normalized": []
},
{
"id": "23220413_T11",
"type": "GENE-Y",
"text": [
"dio1"
],
"offsets": [
[
1614,
1618
]
],
"normalized": []
},
{
"id": "23220413_T12",
"type": "GENE-Y",
"text": [
"ugt1ab"
],
"offsets": [
[
1623,
1629
]
],
"normalized": []
},
{
"id": "23220413_T13",
"type": "GENE-N",
"text": [
"tshβ"
],
"offsets": [
[
1797,
1801
]
],
"normalized": []
},
{
"id": "23220413_T14",
"type": "GENE-Y",
"text": [
"slc5a5"
],
"offsets": [
[
1803,
1809
]
],
"normalized": []
},
{
"id": "23220413_T15",
"type": "GENE-Y",
"text": [
"tg"
],
"offsets": [
[
1814,
1816
]
],
"normalized": []
},
{
"id": "23220413_T16",
"type": "GENE-Y",
"text": [
"hhex"
],
"offsets": [
[
1843,
1847
]
],
"normalized": []
},
{
"id": "23220413_T17",
"type": "GENE-Y",
"text": [
"nkx2.1"
],
"offsets": [
[
1849,
1855
]
],
"normalized": []
},
{
"id": "23220413_T18",
"type": "GENE-Y",
"text": [
"pax8"
],
"offsets": [
[
1860,
1864
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23220413_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23220413_T3",
"arg2_id": "23220413_T13",
"normalized": []
},
{
"id": "23220413_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23220413_T3",
"arg2_id": "23220413_T14",
"normalized": []
},
{
"id": "23220413_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23220413_T3",
"arg2_id": "23220413_T15",
"normalized": []
},
{
"id": "23220413_3",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23220413_T3",
"arg2_id": "23220413_T16",
"normalized": []
},
{
"id": "23220413_4",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23220413_T3",
"arg2_id": "23220413_T17",
"normalized": []
},
{
"id": "23220413_5",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23220413_T3",
"arg2_id": "23220413_T18",
"normalized": []
}
] |
16223973 | 16223973 | [
{
"id": "16223973_title",
"type": "title",
"text": [
"SOM230 inhibits insulin-like growth factor-I action in mammary gland development by pituitary independent mechanism: mediated through somatostatin subtype receptor 3?"
],
"offsets": [
[
0,
166
]
]
},
{
"id": "16223973_abstract",
"type": "abstract",
"text": [
"Somatostatin analogs (SAs) treat acromegaly by lowering pituitary GH secretion, which, in turn, lowers systemic IGF-I. The profound systemic effect is often greater than expected in the face of only partial GH suppression. Here we report that the SA SOM230 can also act by a nonpituitary-mediated inhibition of IGF-I action. SOM230 inhibited mammary development in intact and hypophysectomized female rats, a process requiring IGF-I. IGF-I overcame this inhibition. SOM230 also inhibited other actions of IGF-I (inhibition of apoptosis, phosphorylation of insulin receptor substrate-1, and cell division). SOM230 did not reduce IGF-I mRNA abundance in mammary gland but did stimulate IGF binding protein 5 (IGFBP5). IGFBP5 was 3.75 times higher in mammary epithelium of SOM230 than in placebo animals (P < 0.001). Administration of IGFBP-5 also inhibited GH-induced mammary development (P < 0.001). Measurement of sstr(1-5) (somatostatin subtype receptor) by real-time RT-PCR revealed that the mammary glands had an abundance of sstr(3) and lower amounts of sstr(4) and sstr(5) but no sstr(1) or sstr(2.) That mammary development was also inhibited to a lesser degree than SOM230 by octreotide, whose main action is through sstr(2), strongly suggests that sstr(3) is at least in part mediating the effects of the SAs. We conclude that 1) SAs inhibit IGF-I action in the mammary gland through a novel nonpituitary mechanism; 2) IGFBP-5, here shown to inhibit pubertal mammary development, might mediate the effect; and 3) Measurement of available sstr receptors in the mammary gland suggests that sstr(3) mediates the SA activity, but sstr(5) is also a possible mediator."
],
"offsets": [
[
167,
1837
]
]
}
] | [
{
"id": "16223973_T1",
"type": "CHEMICAL",
"text": [
"SOM230"
],
"offsets": [
[
417,
423
]
],
"normalized": []
},
{
"id": "16223973_T2",
"type": "CHEMICAL",
"text": [
"SOM230"
],
"offsets": [
[
492,
498
]
],
"normalized": []
},
{
"id": "16223973_T3",
"type": "CHEMICAL",
"text": [
"SOM230"
],
"offsets": [
[
773,
779
]
],
"normalized": []
},
{
"id": "16223973_T4",
"type": "CHEMICAL",
"text": [
"SOM230"
],
"offsets": [
[
937,
943
]
],
"normalized": []
},
{
"id": "16223973_T5",
"type": "CHEMICAL",
"text": [
"SOM230"
],
"offsets": [
[
0,
6
]
],
"normalized": []
},
{
"id": "16223973_T6",
"type": "GENE-Y",
"text": [
"Somatostatin"
],
"offsets": [
[
167,
179
]
],
"normalized": []
},
{
"id": "16223973_T7",
"type": "GENE-Y",
"text": [
"sstr(3)"
],
"offsets": [
[
1196,
1203
]
],
"normalized": []
},
{
"id": "16223973_T8",
"type": "GENE-Y",
"text": [
"sstr(4)"
],
"offsets": [
[
1225,
1232
]
],
"normalized": []
},
{
"id": "16223973_T9",
"type": "GENE-Y",
"text": [
"sstr(5)"
],
"offsets": [
[
1237,
1244
]
],
"normalized": []
},
{
"id": "16223973_T10",
"type": "GENE-Y",
"text": [
"sstr(1)"
],
"offsets": [
[
1252,
1259
]
],
"normalized": []
},
{
"id": "16223973_T11",
"type": "GENE-Y",
"text": [
"sstr(2.)"
],
"offsets": [
[
1263,
1271
]
],
"normalized": []
},
{
"id": "16223973_T12",
"type": "GENE-Y",
"text": [
"IGF-I"
],
"offsets": [
[
279,
284
]
],
"normalized": []
},
{
"id": "16223973_T13",
"type": "GENE-Y",
"text": [
"sstr(2)"
],
"offsets": [
[
1391,
1398
]
],
"normalized": []
},
{
"id": "16223973_T14",
"type": "GENE-Y",
"text": [
"sstr(3)"
],
"offsets": [
[
1423,
1430
]
],
"normalized": []
},
{
"id": "16223973_T15",
"type": "GENE-Y",
"text": [
"IGF-I"
],
"offsets": [
[
1517,
1522
]
],
"normalized": []
},
{
"id": "16223973_T16",
"type": "GENE-Y",
"text": [
"IGFBP-5"
],
"offsets": [
[
1594,
1601
]
],
"normalized": []
},
{
"id": "16223973_T17",
"type": "GENE-N",
"text": [
"sstr receptors"
],
"offsets": [
[
1713,
1727
]
],
"normalized": []
},
{
"id": "16223973_T18",
"type": "GENE-Y",
"text": [
"sstr(3)"
],
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[
1763,
1770
]
],
"normalized": []
},
{
"id": "16223973_T19",
"type": "GENE-Y",
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"sstr(5)"
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[
1801,
1808
]
],
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},
{
"id": "16223973_T20",
"type": "GENE-Y",
"text": [
"GH"
],
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[
374,
376
]
],
"normalized": []
},
{
"id": "16223973_T21",
"type": "GENE-Y",
"text": [
"IGF-I"
],
"offsets": [
[
478,
483
]
],
"normalized": []
},
{
"id": "16223973_T22",
"type": "GENE-Y",
"text": [
"IGF-I"
],
"offsets": [
[
594,
599
]
],
"normalized": []
},
{
"id": "16223973_T23",
"type": "GENE-Y",
"text": [
"IGF-I"
],
"offsets": [
[
601,
606
]
],
"normalized": []
},
{
"id": "16223973_T24",
"type": "GENE-Y",
"text": [
"IGF-I"
],
"offsets": [
[
672,
677
]
],
"normalized": []
},
{
"id": "16223973_T25",
"type": "GENE-Y",
"text": [
"insulin receptor substrate-1"
],
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[
723,
751
]
],
"normalized": []
},
{
"id": "16223973_T26",
"type": "GENE-Y",
"text": [
"IGF-I"
],
"offsets": [
[
795,
800
]
],
"normalized": []
},
{
"id": "16223973_T27",
"type": "GENE-Y",
"text": [
"GH"
],
"offsets": [
[
233,
235
]
],
"normalized": []
},
{
"id": "16223973_T28",
"type": "GENE-Y",
"text": [
"IGF binding protein 5"
],
"offsets": [
[
851,
872
]
],
"normalized": []
},
{
"id": "16223973_T29",
"type": "GENE-Y",
"text": [
"IGFBP5"
],
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[
874,
880
]
],
"normalized": []
},
{
"id": "16223973_T30",
"type": "GENE-Y",
"text": [
"IGFBP5"
],
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[
883,
889
]
],
"normalized": []
},
{
"id": "16223973_T31",
"type": "GENE-Y",
"text": [
"IGFBP-5"
],
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[
999,
1006
]
],
"normalized": []
},
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"id": "16223973_T32",
"type": "GENE-Y",
"text": [
"GH"
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1022,
1024
]
],
"normalized": []
},
{
"id": "16223973_T33",
"type": "GENE-N",
"text": [
"sstr(1-5)"
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"offsets": [
[
1081,
1090
]
],
"normalized": []
},
{
"id": "16223973_T34",
"type": "GENE-N",
"text": [
"somatostatin subtype receptor"
],
"offsets": [
[
1092,
1121
]
],
"normalized": []
},
{
"id": "16223973_T35",
"type": "GENE-Y",
"text": [
"somatostatin subtype receptor 3"
],
"offsets": [
[
134,
165
]
],
"normalized": []
},
{
"id": "16223973_T36",
"type": "GENE-Y",
"text": [
"insulin-like growth factor-I"
],
"offsets": [
[
16,
44
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16223973_0",
"type": "INHIBITOR",
"arg1_id": "16223973_T5",
"arg2_id": "16223973_T36",
"normalized": []
},
{
"id": "16223973_1",
"type": "INHIBITOR",
"arg1_id": "16223973_T1",
"arg2_id": "16223973_T21",
"normalized": []
}
] |
2653642 | 2653642 | [
{
"id": "2653642_title",
"type": "title",
"text": [
"Cysteamine and the endocrine pancreas: immunocytochemical, immunochemical, and functional aspects."
],
"offsets": [
[
0,
98
]
]
},
{
"id": "2653642_abstract",
"type": "abstract",
"text": [
"To evaluate the previously reported depletion of pancreatic somatostatin by cysteamine (beta-mercaptoethylamine), mice were injected subcutaneously with the drug at 300 mg/kg. Immunocytochemical analysis performed on sections from tissue taken at 4 h after the injection revealed an elimination of somatostatin-14-like immunoreactivity without alterations in the somatostatin-28(1-12)-like immunoreactivity. In sections from tissues taken at 24 h after injection, no differences between cysteamine-injected animals and controls were observed. Immunochemical analysis of somatostatin-14-like immunoreactivity in pancreatic extracts showed a significant reduction of the concentration (P less than 0.001). In contrast, no change in the insulin concentration was observed. Functionally, cysteamine lowered the plasma glucose levels at 1 h after injection; this effect persisted for 6 h. Plasma insulin levels were likewise reduced transiently by cysteamine. Concomitant administration of somatostatin did not influence these effects of cysteamine. The plasma glucose-lowering effect of cysteamine was seen also in alloxan-diabetic mice. We conclude that cysteamine alters the immunoreactive characteristics of pancreatic somatostatin without affecting the immunoreactivity of insulin, and that cysteamine transiently reduces plasma glucose and insulin levels."
],
"offsets": [
[
99,
1455
]
]
}
] | [
{
"id": "2653642_T1",
"type": "CHEMICAL",
"text": [
"cysteamine"
],
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[
1132,
1142
]
],
"normalized": []
},
{
"id": "2653642_T2",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
1155,
1162
]
],
"normalized": []
},
{
"id": "2653642_T3",
"type": "CHEMICAL",
"text": [
"cysteamine"
],
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[
1182,
1192
]
],
"normalized": []
},
{
"id": "2653642_T4",
"type": "CHEMICAL",
"text": [
"cysteamine"
],
"offsets": [
[
1250,
1260
]
],
"normalized": []
},
{
"id": "2653642_T5",
"type": "CHEMICAL",
"text": [
"somatostatin"
],
"offsets": [
[
1317,
1329
]
],
"normalized": []
},
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"id": "2653642_T6",
"type": "CHEMICAL",
"text": [
"cysteamine"
],
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[
1390,
1400
]
],
"normalized": []
},
{
"id": "2653642_T7",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
1428,
1435
]
],
"normalized": []
},
{
"id": "2653642_T8",
"type": "CHEMICAL",
"text": [
"somatostatin"
],
"offsets": [
[
397,
409
]
],
"normalized": []
},
{
"id": "2653642_T9",
"type": "CHEMICAL",
"text": [
"somatostatin"
],
"offsets": [
[
462,
474
]
],
"normalized": []
},
{
"id": "2653642_T10",
"type": "CHEMICAL",
"text": [
"cysteamine"
],
"offsets": [
[
586,
596
]
],
"normalized": []
},
{
"id": "2653642_T11",
"type": "CHEMICAL",
"text": [
"somatostatin-14"
],
"offsets": [
[
669,
684
]
],
"normalized": []
},
{
"id": "2653642_T12",
"type": "CHEMICAL",
"text": [
"somatostatin"
],
"offsets": [
[
159,
171
]
],
"normalized": []
},
{
"id": "2653642_T13",
"type": "CHEMICAL",
"text": [
"cysteamine"
],
"offsets": [
[
175,
185
]
],
"normalized": []
},
{
"id": "2653642_T14",
"type": "CHEMICAL",
"text": [
"cysteamine"
],
"offsets": [
[
883,
893
]
],
"normalized": []
},
{
"id": "2653642_T15",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
913,
920
]
],
"normalized": []
},
{
"id": "2653642_T16",
"type": "CHEMICAL",
"text": [
"beta-mercaptoethylamine"
],
"offsets": [
[
187,
210
]
],
"normalized": []
},
{
"id": "2653642_T17",
"type": "CHEMICAL",
"text": [
"cysteamine"
],
"offsets": [
[
1042,
1052
]
],
"normalized": []
},
{
"id": "2653642_T18",
"type": "CHEMICAL",
"text": [
"somatostatin"
],
"offsets": [
[
1084,
1096
]
],
"normalized": []
},
{
"id": "2653642_T19",
"type": "CHEMICAL",
"text": [
"Cysteamine"
],
"offsets": [
[
0,
10
]
],
"normalized": []
},
{
"id": "2653642_T20",
"type": "GENE-Y",
"text": [
"somatostatin"
],
"offsets": [
[
1317,
1329
]
],
"normalized": []
},
{
"id": "2653642_T21",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1372,
1379
]
],
"normalized": []
},
{
"id": "2653642_T22",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1440,
1447
]
],
"normalized": []
},
{
"id": "2653642_T23",
"type": "GENE-Y",
"text": [
"somatostatin-14"
],
"offsets": [
[
397,
412
]
],
"normalized": []
},
{
"id": "2653642_T24",
"type": "GENE-Y",
"text": [
"somatostatin-28(1-12)"
],
"offsets": [
[
462,
483
]
],
"normalized": []
},
{
"id": "2653642_T25",
"type": "GENE-Y",
"text": [
"somatostatin-14"
],
"offsets": [
[
669,
684
]
],
"normalized": []
},
{
"id": "2653642_T26",
"type": "GENE-Y",
"text": [
"somatostatin"
],
"offsets": [
[
159,
171
]
],
"normalized": []
},
{
"id": "2653642_T27",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
833,
840
]
],
"normalized": []
},
{
"id": "2653642_T28",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
990,
997
]
],
"normalized": []
},
{
"id": "2653642_T29",
"type": "GENE-Y",
"text": [
"somatostatin"
],
"offsets": [
[
1084,
1096
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "2653642_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "2653642_T17",
"arg2_id": "2653642_T28",
"normalized": []
},
{
"id": "2653642_1",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "2653642_T6",
"arg2_id": "2653642_T22",
"normalized": []
}
] |
12721093 | 12721093 | [
{
"id": "12721093_title",
"type": "title",
"text": [
"Crosstalk between presynaptic angiotensin receptors, bradykinin receptors and alpha 2-autoreceptors in sympathetic neurons: a study in alpha 2-adrenoceptor-deficient mice."
],
"offsets": [
[
0,
171
]
]
},
{
"id": "12721093_abstract",
"type": "abstract",
"text": [
"1. In mouse atria, angiotensin II and bradykinin lose much or all of their noradrenaline release-enhancing effect when presynaptic alpha(2)-autoinhibition does not operate either because of stimulation with very brief pulse trains or because of treatment with alpha(2) antagonists. We now studied this operational condition in alpha(2)-adrenoceptor-deficient mice. Release of (3)H-noradrenaline was elicited by electrical stimulation. 2. In tissues from wild-type (WT) mice, angiotensin II and bradykinin increased the overflow of tritium evoked by 120 pulses at 3 Hz. This enhancement did not occur or was much reduced when tissues were stimulated by 120 pulses at 3 Hz in the presence of rauwolscine and phentolamine, or when they were stimulated by 20 pulses at 50 Hz. 3. In tissues from mice lacking the alpha(2A)-adrenoceptor (alpha(2A)KO) or the alpha(2B)-adrenoceptor (alpha(2B)KO), the concentration-response curves of angiotensin II and bradykinin (120 pulses at 3 Hz) were unchanged. In tissues from mice lacking the alpha(2C)-adrenoceptor (alpha(2C)KO) or both the alpha(2A)- and the alpha(2C)-adrenoceptor (alpha(2AC)KO), the concentration-response curves were shifted to the same extent downwards. 4. As in WT tissues, angiotensin II and bradykinin lost most or all of their effect in alpha(2A)KO and alpha(2AC)KO tissues when rauwolscine and phentolamine were present or trains consisted of 20 pulses at 50 Hz. 5. Rauwolscine and phentolamine increased tritium overflow evoked by 120 pulses at 3 Hz up to seven-fold in WT and alpha(2B)KO tissues, three-fold in alpha(2A)KO and alpha(2C)KO tissues, and two-fold in alpha(2AC)KO tissues. 6. Results confirm that angiotensin II and bradykinin require ongoing alpha(2)-autoinhibition for the full extent of their release-enhancing effect. Specifically, they require ongoing alpha(2C)-autoinhibition. The peptide effects that remain in alpha(2C)-autoreceptor-deficient mice seem to be because of alpha(2B)-autoinhibition. The results hence also suggest that in addition to alpha(2A)- and alpha(2C)- mouse postganglionic sympathetic neurons possess alpha(2B)-autoreceptors."
],
"offsets": [
[
172,
2303
]
]
}
] | [
{
"id": "12721093_T1",
"type": "CHEMICAL",
"text": [
"rauwolscine"
],
"offsets": [
[
1512,
1523
]
],
"normalized": []
},
{
"id": "12721093_T2",
"type": "CHEMICAL",
"text": [
"phentolamine"
],
"offsets": [
[
1528,
1540
]
],
"normalized": []
},
{
"id": "12721093_T3",
"type": "CHEMICAL",
"text": [
"Rauwolscine"
],
"offsets": [
[
1600,
1611
]
],
"normalized": []
},
{
"id": "12721093_T4",
"type": "CHEMICAL",
"text": [
"phentolamine"
],
"offsets": [
[
1616,
1628
]
],
"normalized": []
},
{
"id": "12721093_T5",
"type": "CHEMICAL",
"text": [
"angiotensin II"
],
"offsets": [
[
1846,
1860
]
],
"normalized": []
},
{
"id": "12721093_T6",
"type": "CHEMICAL",
"text": [
"bradykinin"
],
"offsets": [
[
1865,
1875
]
],
"normalized": []
},
{
"id": "12721093_T7",
"type": "CHEMICAL",
"text": [
"angiotensin II"
],
"offsets": [
[
191,
205
]
],
"normalized": []
},
{
"id": "12721093_T8",
"type": "CHEMICAL",
"text": [
"(3)H-noradrenaline"
],
"offsets": [
[
548,
566
]
],
"normalized": []
},
{
"id": "12721093_T9",
"type": "CHEMICAL",
"text": [
"bradykinin"
],
"offsets": [
[
210,
220
]
],
"normalized": []
},
{
"id": "12721093_T10",
"type": "CHEMICAL",
"text": [
"angiotensin II"
],
"offsets": [
[
647,
661
]
],
"normalized": []
},
{
"id": "12721093_T11",
"type": "CHEMICAL",
"text": [
"bradykinin"
],
"offsets": [
[
666,
676
]
],
"normalized": []
},
{
"id": "12721093_T12",
"type": "CHEMICAL",
"text": [
"rauwolscine"
],
"offsets": [
[
862,
873
]
],
"normalized": []
},
{
"id": "12721093_T13",
"type": "CHEMICAL",
"text": [
"phentolamine"
],
"offsets": [
[
878,
890
]
],
"normalized": []
},
{
"id": "12721093_T14",
"type": "CHEMICAL",
"text": [
"noradrenaline"
],
"offsets": [
[
247,
260
]
],
"normalized": []
},
{
"id": "12721093_T15",
"type": "CHEMICAL",
"text": [
"angiotensin II"
],
"offsets": [
[
1099,
1113
]
],
"normalized": []
},
{
"id": "12721093_T16",
"type": "CHEMICAL",
"text": [
"bradykinin"
],
"offsets": [
[
1118,
1128
]
],
"normalized": []
},
{
"id": "12721093_T17",
"type": "CHEMICAL",
"text": [
"angiotensin"
],
"offsets": [
[
30,
41
]
],
"normalized": []
},
{
"id": "12721093_T18",
"type": "CHEMICAL",
"text": [
"bradykinin"
],
"offsets": [
[
53,
63
]
],
"normalized": []
},
{
"id": "12721093_T19",
"type": "GENE-Y",
"text": [
"alpha(2C)-adrenoceptor"
],
"offsets": [
[
1199,
1221
]
],
"normalized": []
},
{
"id": "12721093_T20",
"type": "GENE-Y",
"text": [
"alpha(2C)"
],
"offsets": [
[
1223,
1232
]
],
"normalized": []
},
{
"id": "12721093_T21",
"type": "GENE-N",
"text": [
"alpha(2A)- and the alpha(2C)-adrenoceptor"
],
"offsets": [
[
1248,
1289
]
],
"normalized": []
},
{
"id": "12721093_T22",
"type": "GENE-N",
"text": [
"alpha(2AC)"
],
"offsets": [
[
1291,
1301
]
],
"normalized": []
},
{
"id": "12721093_T23",
"type": "GENE-Y",
"text": [
"angiotensin II"
],
"offsets": [
[
1404,
1418
]
],
"normalized": []
},
{
"id": "12721093_T24",
"type": "GENE-Y",
"text": [
"bradykinin"
],
"offsets": [
[
1423,
1433
]
],
"normalized": []
},
{
"id": "12721093_T25",
"type": "GENE-Y",
"text": [
"alpha(2A)"
],
"offsets": [
[
1470,
1479
]
],
"normalized": []
},
{
"id": "12721093_T26",
"type": "GENE-N",
"text": [
"alpha(2)"
],
"offsets": [
[
303,
311
]
],
"normalized": []
},
{
"id": "12721093_T27",
"type": "GENE-N",
"text": [
"alpha(2AC)"
],
"offsets": [
[
1486,
1496
]
],
"normalized": []
},
{
"id": "12721093_T28",
"type": "GENE-Y",
"text": [
"alpha(2B)"
],
"offsets": [
[
1712,
1721
]
],
"normalized": []
},
{
"id": "12721093_T29",
"type": "GENE-Y",
"text": [
"alpha(2A)"
],
"offsets": [
[
1747,
1756
]
],
"normalized": []
},
{
"id": "12721093_T30",
"type": "GENE-Y",
"text": [
"alpha(2C)"
],
"offsets": [
[
1763,
1772
]
],
"normalized": []
},
{
"id": "12721093_T31",
"type": "GENE-N",
"text": [
"alpha(2AC)"
],
"offsets": [
[
1800,
1810
]
],
"normalized": []
},
{
"id": "12721093_T32",
"type": "GENE-Y",
"text": [
"angiotensin II"
],
"offsets": [
[
1846,
1860
]
],
"normalized": []
},
{
"id": "12721093_T33",
"type": "GENE-Y",
"text": [
"bradykinin"
],
"offsets": [
[
1865,
1875
]
],
"normalized": []
},
{
"id": "12721093_T34",
"type": "GENE-N",
"text": [
"alpha(2)"
],
"offsets": [
[
1892,
1900
]
],
"normalized": []
},
{
"id": "12721093_T35",
"type": "GENE-Y",
"text": [
"alpha(2C)"
],
"offsets": [
[
2006,
2015
]
],
"normalized": []
},
{
"id": "12721093_T36",
"type": "GENE-Y",
"text": [
"alpha(2C)-autoreceptor"
],
"offsets": [
[
2067,
2089
]
],
"normalized": []
},
{
"id": "12721093_T37",
"type": "GENE-Y",
"text": [
"angiotensin II"
],
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191,
205
]
],
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},
{
"id": "12721093_T38",
"type": "GENE-Y",
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"alpha(2B)"
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2127,
2136
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},
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"id": "12721093_T39",
"type": "GENE-Y",
"text": [
"alpha(2A)"
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2204,
2213
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},
{
"id": "12721093_T40",
"type": "GENE-Y",
"text": [
"alpha(2C)"
],
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[
2219,
2228
]
],
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},
{
"id": "12721093_T41",
"type": "GENE-Y",
"text": [
"alpha(2B)-autoreceptors"
],
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[
2279,
2302
]
],
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},
{
"id": "12721093_T42",
"type": "GENE-N",
"text": [
"alpha(2)"
],
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432,
440
]
],
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},
{
"id": "12721093_T43",
"type": "GENE-N",
"text": [
"alpha(2)-adrenoceptor"
],
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[
499,
520
]
],
"normalized": []
},
{
"id": "12721093_T44",
"type": "GENE-Y",
"text": [
"bradykinin"
],
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210,
220
]
],
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},
{
"id": "12721093_T45",
"type": "GENE-Y",
"text": [
"angiotensin II"
],
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[
647,
661
]
],
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},
{
"id": "12721093_T46",
"type": "GENE-Y",
"text": [
"bradykinin"
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666,
676
]
],
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},
{
"id": "12721093_T47",
"type": "GENE-Y",
"text": [
"alpha(2A)-adrenoceptor"
],
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980,
1002
]
],
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},
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"id": "12721093_T48",
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"alpha(2A)"
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1013
]
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},
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"type": "GENE-Y",
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"alpha(2B)-adrenoceptor"
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1024,
1046
]
],
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},
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"alpha(2B)"
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1048,
1057
]
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},
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"type": "GENE-Y",
"text": [
"angiotensin II"
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1099,
1113
]
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},
{
"id": "12721093_T52",
"type": "GENE-Y",
"text": [
"bradykinin"
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1118,
1128
]
],
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},
{
"id": "12721093_T53",
"type": "GENE-N",
"text": [
"alpha 2-adrenoceptor"
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135,
155
]
],
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},
{
"id": "12721093_T54",
"type": "GENE-N",
"text": [
"angiotensin receptors"
],
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30,
51
]
],
"normalized": []
},
{
"id": "12721093_T55",
"type": "GENE-N",
"text": [
"bradykinin receptors"
],
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53,
73
]
],
"normalized": []
},
{
"id": "12721093_T56",
"type": "GENE-N",
"text": [
"alpha 2-autoreceptors"
],
"offsets": [
[
78,
99
]
],
"normalized": []
}
] | [] | [] | [] |
16901636 | 16901636 | [
{
"id": "16901636_title",
"type": "title",
"text": [
"Reduction of cerebral infarct size by the AT1-receptor blocker candesartan, the HMG-CoA reductase inhibitor rosuvastatin and their combination. An experimental study in rats."
],
"offsets": [
[
0,
174
]
]
},
{
"id": "16901636_abstract",
"type": "abstract",
"text": [
"Our purpose was to test the impact of single and/or combined treatment with the AT(1)-receptor blocker candesartan and the HMG-CoA reductase inhibitor rosuvastatin on infarct size and neuroscore in transient cerebral ischemia in rats. L-NAME was used to test whether any potential effect was due to activation of endothelial nitric oxide synthase (eNOS). Therefore, the middle cerebral artery was occluded for 1 h (MCAO) followed by 7 days reperfusion. Rats received candesartan 2h before and daily after MCAO (pretreatment) or daily after MCAO (posttreatment); rosuvastatin was given daily for 7 days before MCAO without or with candesartan pre- and posttreatment. In addition, candesartan and rosuvastatin were combined with L-NAME. Infarct size and neuroscore at day 7 were compared to those of controls. As result, compared to controls (109+/-12 mm(3)) infarct size with candesartan (pretreatment: 21+/-5 mm(3); posttreatment: 68+/-29 mm(3); P<0.05) or rosuvastatin (69+/-14 mm(3); P<0.05) was smaller. Combined treatment also reduced infarct size (pretreatment: 37+/-15 mm(3); posttreatment 57+/-20mm(3); P<0.05); but there was no benefit of combined treatment over candesartan pretreatment alone. Compared to controls (2.08+/-0.28) only candesartan pretreatment and combined treatment improved the neuroscore (0.97+/-0.05, 1.10+/-0.33; P<0.05). L-NAME abolished the reduction in infarct size and improvement in neuroscore. In conclusion, both, candesartan or rosuvastatin treatment alone reduced infarct size in transient cerebral ischemia, and the best result was achieved with candesartan pretreatment. Combined treatment was superior to rosuvastatin alone, but not to candesartan. The therapeutic benefit of both agents was at least in parts mediated by eNOS-activation."
],
"offsets": [
[
175,
1954
]
]
}
] | [
{
"id": "16901636_T1",
"type": "CHEMICAL",
"text": [
"candesartan"
],
"offsets": [
[
278,
289
]
],
"normalized": []
},
{
"id": "16901636_T2",
"type": "CHEMICAL",
"text": [
"candesartan"
],
"offsets": [
[
1346,
1357
]
],
"normalized": []
},
{
"id": "16901636_T3",
"type": "CHEMICAL",
"text": [
"HMG-CoA"
],
"offsets": [
[
298,
305
]
],
"normalized": []
},
{
"id": "16901636_T4",
"type": "CHEMICAL",
"text": [
"candesartan"
],
"offsets": [
[
1418,
1429
]
],
"normalized": []
},
{
"id": "16901636_T5",
"type": "CHEMICAL",
"text": [
"L-NAME"
],
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[
1526,
1532
]
],
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},
{
"id": "16901636_T6",
"type": "CHEMICAL",
"text": [
"candesartan"
],
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[
1625,
1636
]
],
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},
{
"id": "16901636_T7",
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"text": [
"rosuvastatin"
],
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[
1640,
1652
]
],
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},
{
"id": "16901636_T8",
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"text": [
"rosuvastatin"
],
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[
326,
338
]
],
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},
{
"id": "16901636_T9",
"type": "CHEMICAL",
"text": [
"candesartan"
],
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[
1760,
1771
]
],
"normalized": []
},
{
"id": "16901636_T10",
"type": "CHEMICAL",
"text": [
"rosuvastatin"
],
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[
1821,
1833
]
],
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},
{
"id": "16901636_T11",
"type": "CHEMICAL",
"text": [
"candesartan"
],
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[
1852,
1863
]
],
"normalized": []
},
{
"id": "16901636_T12",
"type": "CHEMICAL",
"text": [
"L-NAME"
],
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[
410,
416
]
],
"normalized": []
},
{
"id": "16901636_T13",
"type": "CHEMICAL",
"text": [
"nitric oxide"
],
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[
500,
512
]
],
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},
{
"id": "16901636_T14",
"type": "CHEMICAL",
"text": [
"candesartan"
],
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642,
653
]
],
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},
{
"id": "16901636_T15",
"type": "CHEMICAL",
"text": [
"rosuvastatin"
],
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737,
749
]
],
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"id": "16901636_T16",
"type": "CHEMICAL",
"text": [
"candesartan"
],
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[
805,
816
]
],
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},
{
"id": "16901636_T17",
"type": "CHEMICAL",
"text": [
"candesartan"
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854,
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]
],
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},
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"type": "CHEMICAL",
"text": [
"rosuvastatin"
],
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870,
882
]
],
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},
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"id": "16901636_T19",
"type": "CHEMICAL",
"text": [
"L-NAME"
],
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902,
908
]
],
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},
{
"id": "16901636_T20",
"type": "CHEMICAL",
"text": [
"candesartan"
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1050,
1061
]
],
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},
{
"id": "16901636_T21",
"type": "CHEMICAL",
"text": [
"rosuvastatin"
],
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1132,
1144
]
],
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},
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"id": "16901636_T22",
"type": "CHEMICAL",
"text": [
"rosuvastatin"
],
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[
108,
120
]
],
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},
{
"id": "16901636_T23",
"type": "CHEMICAL",
"text": [
"candesartan"
],
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[
63,
74
]
],
"normalized": []
},
{
"id": "16901636_T24",
"type": "CHEMICAL",
"text": [
"HMG-CoA"
],
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[
80,
87
]
],
"normalized": []
},
{
"id": "16901636_T25",
"type": "GENE-Y",
"text": [
"HMG-CoA reductase"
],
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[
298,
315
]
],
"normalized": []
},
{
"id": "16901636_T26",
"type": "GENE-Y",
"text": [
"eNOS"
],
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[
1938,
1942
]
],
"normalized": []
},
{
"id": "16901636_T27",
"type": "GENE-Y",
"text": [
"endothelial nitric oxide synthase"
],
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[
488,
521
]
],
"normalized": []
},
{
"id": "16901636_T28",
"type": "GENE-Y",
"text": [
"eNOS"
],
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[
523,
527
]
],
"normalized": []
},
{
"id": "16901636_T29",
"type": "GENE-N",
"text": [
"AT(1)"
],
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[
255,
260
]
],
"normalized": []
},
{
"id": "16901636_T30",
"type": "GENE-N",
"text": [
"AT1"
],
"offsets": [
[
42,
45
]
],
"normalized": []
},
{
"id": "16901636_T31",
"type": "GENE-Y",
"text": [
"HMG-CoA reductase"
],
"offsets": [
[
80,
97
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16901636_0",
"type": "INHIBITOR",
"arg1_id": "16901636_T23",
"arg2_id": "16901636_T30",
"normalized": []
},
{
"id": "16901636_1",
"type": "INHIBITOR",
"arg1_id": "16901636_T22",
"arg2_id": "16901636_T31",
"normalized": []
},
{
"id": "16901636_2",
"type": "INHIBITOR",
"arg1_id": "16901636_T1",
"arg2_id": "16901636_T29",
"normalized": []
},
{
"id": "16901636_3",
"type": "INHIBITOR",
"arg1_id": "16901636_T8",
"arg2_id": "16901636_T25",
"normalized": []
}
] |
23357361 | 23357361 | [
{
"id": "23357361_title",
"type": "title",
"text": [
"β-Asarone induces senescence in colorectal cancer cells by inducing lamin B1 expression."
],
"offsets": [
[
0,
88
]
]
},
{
"id": "23357361_abstract",
"type": "abstract",
"text": [
"Colorectal cancer is a leading cause of cancer mortality with a complex carcinogenesis that includes reduced cellular senescence. Lamin proteins are decreased in senescing cells, and frequently decreased in malignancies. This study identified a new drug candidate for colorectal cancer that appears to target cell senescence via a lamin protein. β-Asarone (1-propenyl-2,4,5-methoxybenzol) is a compound from the traditional medical herb Acorus calamus Linn. This study tested the in vitro and in vivo effects of β-asarone on colorectal cancer cells by testing cell viability using human colorectal cell lines HT29 and SW480 in MTT assays; tumorigenesis using xenografts in nude mice and a mouse model of colorectal cancer; cell senescence using senescence-associated β-galactosidase activity; and expression of cancer and senescence-related proteins, specifically lamins, Oct-1, p53, p21, and p15, by Western blot. β-Asarone appeared to increase expression of lamin B1, p53, p21, but not lamin A/C. β-Asarone regulates p15 expression by regulation of Oct-1 binding. Collectively, the results suggested that β-asarone inhibits colon cancer formation in vivo and in vitro by inducing senescence. Since β-asarone induced lamin B1 expression, a model is proposed in which β-asarone inhibits colorectal cancer by inducing senescence through lamin B1."
],
"offsets": [
[
89,
1434
]
]
}
] | [
{
"id": "23357361_T1",
"type": "CHEMICAL",
"text": [
"β-asarone"
],
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[
1196,
1205
]
],
"normalized": []
},
{
"id": "23357361_T2",
"type": "CHEMICAL",
"text": [
"β-asarone"
],
"offsets": [
[
1289,
1298
]
],
"normalized": []
},
{
"id": "23357361_T3",
"type": "CHEMICAL",
"text": [
"β-asarone"
],
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[
1357,
1366
]
],
"normalized": []
},
{
"id": "23357361_T4",
"type": "CHEMICAL",
"text": [
"β-Asarone"
],
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[
435,
444
]
],
"normalized": []
},
{
"id": "23357361_T5",
"type": "CHEMICAL",
"text": [
"1-propenyl-2,4,5-methoxybenzol"
],
"offsets": [
[
446,
476
]
],
"normalized": []
},
{
"id": "23357361_T6",
"type": "CHEMICAL",
"text": [
"β-asarone"
],
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[
601,
610
]
],
"normalized": []
},
{
"id": "23357361_T7",
"type": "CHEMICAL",
"text": [
"MTT"
],
"offsets": [
[
716,
719
]
],
"normalized": []
},
{
"id": "23357361_T8",
"type": "CHEMICAL",
"text": [
"β-Asarone"
],
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[
1004,
1013
]
],
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},
{
"id": "23357361_T9",
"type": "CHEMICAL",
"text": [
"β-Asarone"
],
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[
1088,
1097
]
],
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},
{
"id": "23357361_T10",
"type": "CHEMICAL",
"text": [
"β-Asarone"
],
"offsets": [
[
0,
9
]
],
"normalized": []
},
{
"id": "23357361_T11",
"type": "GENE-Y",
"text": [
"p15"
],
"offsets": [
[
1108,
1111
]
],
"normalized": []
},
{
"id": "23357361_T12",
"type": "GENE-Y",
"text": [
"Oct-1"
],
"offsets": [
[
1140,
1145
]
],
"normalized": []
},
{
"id": "23357361_T13",
"type": "GENE-Y",
"text": [
"lamin B1"
],
"offsets": [
[
1307,
1315
]
],
"normalized": []
},
{
"id": "23357361_T14",
"type": "GENE-N",
"text": [
"Lamin"
],
"offsets": [
[
219,
224
]
],
"normalized": []
},
{
"id": "23357361_T15",
"type": "GENE-Y",
"text": [
"lamin B1"
],
"offsets": [
[
1425,
1433
]
],
"normalized": []
},
{
"id": "23357361_T16",
"type": "GENE-N",
"text": [
"lamin"
],
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[
420,
425
]
],
"normalized": []
},
{
"id": "23357361_T17",
"type": "GENE-N",
"text": [
"β-galactosidase"
],
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[
856,
871
]
],
"normalized": []
},
{
"id": "23357361_T18",
"type": "GENE-N",
"text": [
"lamins"
],
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[
953,
959
]
],
"normalized": []
},
{
"id": "23357361_T19",
"type": "GENE-Y",
"text": [
"Oct-1"
],
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[
961,
966
]
],
"normalized": []
},
{
"id": "23357361_T20",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
968,
971
]
],
"normalized": []
},
{
"id": "23357361_T21",
"type": "GENE-Y",
"text": [
"p21"
],
"offsets": [
[
973,
976
]
],
"normalized": []
},
{
"id": "23357361_T22",
"type": "GENE-Y",
"text": [
"p15"
],
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[
982,
985
]
],
"normalized": []
},
{
"id": "23357361_T23",
"type": "GENE-Y",
"text": [
"lamin B1"
],
"offsets": [
[
1049,
1057
]
],
"normalized": []
},
{
"id": "23357361_T24",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
1059,
1062
]
],
"normalized": []
},
{
"id": "23357361_T25",
"type": "GENE-Y",
"text": [
"p21"
],
"offsets": [
[
1064,
1067
]
],
"normalized": []
},
{
"id": "23357361_T26",
"type": "GENE-N",
"text": [
"lamin A/C"
],
"offsets": [
[
1077,
1086
]
],
"normalized": []
},
{
"id": "23357361_T27",
"type": "GENE-Y",
"text": [
"lamin B1"
],
"offsets": [
[
68,
76
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23357361_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23357361_T10",
"arg2_id": "23357361_T27",
"normalized": []
},
{
"id": "23357361_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23357361_T8",
"arg2_id": "23357361_T23",
"normalized": []
},
{
"id": "23357361_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23357361_T8",
"arg2_id": "23357361_T24",
"normalized": []
},
{
"id": "23357361_3",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23357361_T8",
"arg2_id": "23357361_T25",
"normalized": []
},
{
"id": "23357361_4",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23357361_T9",
"arg2_id": "23357361_T11",
"normalized": []
},
{
"id": "23357361_5",
"type": "DIRECT-REGULATOR",
"arg1_id": "23357361_T9",
"arg2_id": "23357361_T12",
"normalized": []
},
{
"id": "23357361_6",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23357361_T2",
"arg2_id": "23357361_T13",
"normalized": []
},
{
"id": "23357361_7",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23357361_T3",
"arg2_id": "23357361_T15",
"normalized": []
}
] |
11393267 | 11393267 | [
{
"id": "11393267_title",
"type": "title",
"text": [
"Neuroparalysis and oxime efficacy in organophosphate poisoning: a study of butyrylcholinesterase."
],
"offsets": [
[
0,
97
]
]
},
{
"id": "11393267_abstract",
"type": "abstract",
"text": [
"The temporal profile of butyrylcholinesterase (BuChE) and in vitro pralidoxime-reactivated BuChE was studied in a cohort of 25 organophosphate-poisoned patients to examine their relationship to the development of intermediate syndrome and to understand reasons for lack of efficacy of oxime treatment. The clinical severity of poisoning (assessed by the Namba Scale) correlated significantly with the severity of intermediate syndrome. BuChE activity increased significantly over time and showed significant relationship to muscle power. The temporal profile of the enzyme was correlated to the clinical severity of poisoning. Reactivation potentials of BuChE (the difference between oxime-reactivated and -unreactivated enzyme activity) declined significantly with time after organophosphate ingestion. The reactivation potential of the enzyme at admission decreased significantly with increasing severity of poisoning and was lower in patients who developed intermediate syndrome. Patients who received oxime prior to hospitalization had a higher rate of intermediate syndrome and lower levels of BuChE at admission than those who had not. The study suggests that (i) BuChE reflects the clinical course of poisoning, confirming earlier studies; (ii) intermediate syndrome may be associated with a persistent inhibition of BuChE; and (iii) the lack of oxime efficacy in our patients maybe due to their severity of poisoning and the timing of oxime treatment."
],
"offsets": [
[
98,
1557
]
]
}
] | [
{
"id": "11393267_T1",
"type": "CHEMICAL",
"text": [
"oxime"
],
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[
1103,
1108
]
],
"normalized": []
},
{
"id": "11393267_T2",
"type": "CHEMICAL",
"text": [
"organophosphate"
],
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[
225,
240
]
],
"normalized": []
},
{
"id": "11393267_T3",
"type": "CHEMICAL",
"text": [
"oxime"
],
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[
1451,
1456
]
],
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{
"id": "11393267_T4",
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"text": [
"oxime"
],
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1541,
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"id": "11393267_T5",
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"oxime"
],
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383,
388
]
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},
{
"id": "11393267_T6",
"type": "CHEMICAL",
"text": [
"pralidoxime"
],
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[
165,
176
]
],
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},
{
"id": "11393267_T7",
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"oxime"
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782,
787
]
],
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},
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"id": "11393267_T8",
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"text": [
"organophosphate"
],
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875,
890
]
],
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{
"id": "11393267_T9",
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"text": [
"oxime"
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19,
24
]
],
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},
{
"id": "11393267_T10",
"type": "CHEMICAL",
"text": [
"organophosphate"
],
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[
37,
52
]
],
"normalized": []
},
{
"id": "11393267_T11",
"type": "GENE-Y",
"text": [
"BuChE"
],
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[
1197,
1202
]
],
"normalized": []
},
{
"id": "11393267_T12",
"type": "GENE-Y",
"text": [
"BuChE"
],
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[
1268,
1273
]
],
"normalized": []
},
{
"id": "11393267_T13",
"type": "GENE-Y",
"text": [
"BuChE"
],
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[
1422,
1427
]
],
"normalized": []
},
{
"id": "11393267_T14",
"type": "GENE-Y",
"text": [
"butyrylcholinesterase"
],
"offsets": [
[
122,
143
]
],
"normalized": []
},
{
"id": "11393267_T15",
"type": "GENE-Y",
"text": [
"BuChE"
],
"offsets": [
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534,
539
]
],
"normalized": []
},
{
"id": "11393267_T16",
"type": "GENE-Y",
"text": [
"BuChE"
],
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[
145,
150
]
],
"normalized": []
},
{
"id": "11393267_T17",
"type": "GENE-Y",
"text": [
"BuChE"
],
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[
752,
757
]
],
"normalized": []
},
{
"id": "11393267_T18",
"type": "GENE-Y",
"text": [
"BuChE"
],
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[
189,
194
]
],
"normalized": []
},
{
"id": "11393267_T19",
"type": "GENE-Y",
"text": [
"butyrylcholinesterase"
],
"offsets": [
[
75,
96
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "11393267_0",
"type": "ACTIVATOR",
"arg1_id": "11393267_T6",
"arg2_id": "11393267_T18",
"normalized": []
},
{
"id": "11393267_1",
"type": "ACTIVATOR",
"arg1_id": "11393267_T7",
"arg2_id": "11393267_T17",
"normalized": []
},
{
"id": "11393267_2",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "11393267_T1",
"arg2_id": "11393267_T11",
"normalized": []
}
] |
15562257 | 15562257 | [
{
"id": "15562257_title",
"type": "title",
"text": [
"State-dependent mibefradil block of Na+ channels."
],
"offsets": [
[
0,
49
]
]
},
{
"id": "15562257_abstract",
"type": "abstract",
"text": [
"Mibefradil is a T-type Ca2+ channel antagonist with reported cross-reactivity with other classes of ion channels, including K+, Cl-, and Na+ channels. Using whole-cell voltage clamp, we examined mibefradil block of four Na+ channel isoforms expressed in human embryonic kidney cells: Nav1.5 (cardiac), Nav1.4 (skeletal muscle), Nav1.2 (brain), and Nav1.7 (peripheral nerve). Mibefradil blocked Nav1.5 in a use/frequency-dependent manner, indicating preferential binding to states visited during depolarization. Mibefradil blocked currents of all Na+ channel isoforms with similar affinity and a dependence on holding potential, and drug off-rate was slowed at depolarized potentials (k(off) was 0.024/s at -130 mV and 0.007/s at -100 mV for Nav1.5). We further probed the interaction of mibefradil with inactivated Nav1.5 channels. Neither the degree nor the time course of block was dependent on the stimulus duration, which dramatically changed the residency time of channels in the fast-inactivated state. In addition, inhibiting the binding of the fast inactivation lid (Nav1.5 ICM + MTSET) did not alter mibefradil block, confirming that the drug does not preferentially interact with the fast-inactivated state. We also tested whether mibefradil interacted with slow-inactivated state(s). When selectively applied to channels after inducing slow inactivation with a 60-s pulse to -10 mV, mibefradil (1 microM) produced 45% fractional block in Nav1.5 and greater block (88%) in an isoform (Nav1.4) that slow-inactivates more completely. Our results suggest that mibefradil blocks Na+ channels in a state-dependent manner that does not depend on fast inactivation but probably involves interaction with one or more slow-inactivated state(s)."
],
"offsets": [
[
50,
1795
]
]
}
] | [
{
"id": "15562257_T1",
"type": "CHEMICAL",
"text": [
"Mibefradil"
],
"offsets": [
[
50,
60
]
],
"normalized": []
},
{
"id": "15562257_T2",
"type": "CHEMICAL",
"text": [
"mibefradil"
],
"offsets": [
[
1159,
1169
]
],
"normalized": []
},
{
"id": "15562257_T3",
"type": "CHEMICAL",
"text": [
"mibefradil"
],
"offsets": [
[
1291,
1301
]
],
"normalized": []
},
{
"id": "15562257_T4",
"type": "CHEMICAL",
"text": [
"K+"
],
"offsets": [
[
174,
176
]
],
"normalized": []
},
{
"id": "15562257_T5",
"type": "CHEMICAL",
"text": [
"Cl-"
],
"offsets": [
[
178,
181
]
],
"normalized": []
},
{
"id": "15562257_T6",
"type": "CHEMICAL",
"text": [
"Na+"
],
"offsets": [
[
187,
190
]
],
"normalized": []
},
{
"id": "15562257_T7",
"type": "CHEMICAL",
"text": [
"mibefradil"
],
"offsets": [
[
1444,
1454
]
],
"normalized": []
},
{
"id": "15562257_T8",
"type": "CHEMICAL",
"text": [
"mibefradil"
],
"offsets": [
[
1617,
1627
]
],
"normalized": []
},
{
"id": "15562257_T9",
"type": "CHEMICAL",
"text": [
"Na+"
],
"offsets": [
[
1635,
1638
]
],
"normalized": []
},
{
"id": "15562257_T10",
"type": "CHEMICAL",
"text": [
"mibefradil"
],
"offsets": [
[
245,
255
]
],
"normalized": []
},
{
"id": "15562257_T11",
"type": "CHEMICAL",
"text": [
"Na+"
],
"offsets": [
[
270,
273
]
],
"normalized": []
},
{
"id": "15562257_T12",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
"offsets": [
[
73,
77
]
],
"normalized": []
},
{
"id": "15562257_T13",
"type": "CHEMICAL",
"text": [
"Mibefradil"
],
"offsets": [
[
425,
435
]
],
"normalized": []
},
{
"id": "15562257_T14",
"type": "CHEMICAL",
"text": [
"Mibefradil"
],
"offsets": [
[
561,
571
]
],
"normalized": []
},
{
"id": "15562257_T15",
"type": "CHEMICAL",
"text": [
"Na+"
],
"offsets": [
[
596,
599
]
],
"normalized": []
},
{
"id": "15562257_T16",
"type": "CHEMICAL",
"text": [
"mibefradil"
],
"offsets": [
[
837,
847
]
],
"normalized": []
},
{
"id": "15562257_T17",
"type": "CHEMICAL",
"text": [
"mibefradil"
],
"offsets": [
[
16,
26
]
],
"normalized": []
},
{
"id": "15562257_T18",
"type": "CHEMICAL",
"text": [
"Na+"
],
"offsets": [
[
36,
39
]
],
"normalized": []
},
{
"id": "15562257_T19",
"type": "GENE-Y",
"text": [
"Nav1.5"
],
"offsets": [
[
1125,
1131
]
],
"normalized": []
},
{
"id": "15562257_T20",
"type": "GENE-N",
"text": [
"K+, Cl-, and Na+ channels"
],
"offsets": [
[
174,
199
]
],
"normalized": []
},
{
"id": "15562257_T21",
"type": "GENE-Y",
"text": [
"Nav1.5"
],
"offsets": [
[
1499,
1505
]
],
"normalized": []
},
{
"id": "15562257_T22",
"type": "GENE-Y",
"text": [
"Nav1.4"
],
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[
1545,
1551
]
],
"normalized": []
},
{
"id": "15562257_T23",
"type": "GENE-N",
"text": [
"Na+ channels"
],
"offsets": [
[
1635,
1647
]
],
"normalized": []
},
{
"id": "15562257_T24",
"type": "GENE-N",
"text": [
"T-type Ca2+ channel"
],
"offsets": [
[
66,
85
]
],
"normalized": []
},
{
"id": "15562257_T25",
"type": "GENE-N",
"text": [
"Na+ channel"
],
"offsets": [
[
270,
281
]
],
"normalized": []
},
{
"id": "15562257_T26",
"type": "GENE-Y",
"text": [
"Nav1.5"
],
"offsets": [
[
334,
340
]
],
"normalized": []
},
{
"id": "15562257_T27",
"type": "GENE-Y",
"text": [
"Nav1.4"
],
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[
352,
358
]
],
"normalized": []
},
{
"id": "15562257_T28",
"type": "GENE-Y",
"text": [
"Nav1.2"
],
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[
378,
384
]
],
"normalized": []
},
{
"id": "15562257_T29",
"type": "GENE-Y",
"text": [
"Nav1.7"
],
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[
398,
404
]
],
"normalized": []
},
{
"id": "15562257_T30",
"type": "GENE-Y",
"text": [
"Nav1.5"
],
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[
444,
450
]
],
"normalized": []
},
{
"id": "15562257_T31",
"type": "GENE-N",
"text": [
"Na+ channel"
],
"offsets": [
[
596,
607
]
],
"normalized": []
},
{
"id": "15562257_T32",
"type": "GENE-Y",
"text": [
"Nav1.5"
],
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[
791,
797
]
],
"normalized": []
},
{
"id": "15562257_T33",
"type": "GENE-Y",
"text": [
"Nav1.5"
],
"offsets": [
[
865,
871
]
],
"normalized": []
},
{
"id": "15562257_T34",
"type": "GENE-N",
"text": [
"Na+ channels"
],
"offsets": [
[
36,
48
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "15562257_0",
"type": "INHIBITOR",
"arg1_id": "15562257_T17",
"arg2_id": "15562257_T34",
"normalized": []
},
{
"id": "15562257_1",
"type": "ANTAGONIST",
"arg1_id": "15562257_T1",
"arg2_id": "15562257_T24",
"normalized": []
},
{
"id": "15562257_2",
"type": "INHIBITOR",
"arg1_id": "15562257_T10",
"arg2_id": "15562257_T25",
"normalized": []
},
{
"id": "15562257_3",
"type": "INHIBITOR",
"arg1_id": "15562257_T10",
"arg2_id": "15562257_T26",
"normalized": []
},
{
"id": "15562257_4",
"type": "INHIBITOR",
"arg1_id": "15562257_T10",
"arg2_id": "15562257_T27",
"normalized": []
},
{
"id": "15562257_5",
"type": "INHIBITOR",
"arg1_id": "15562257_T10",
"arg2_id": "15562257_T28",
"normalized": []
},
{
"id": "15562257_6",
"type": "INHIBITOR",
"arg1_id": "15562257_T10",
"arg2_id": "15562257_T29",
"normalized": []
},
{
"id": "15562257_7",
"type": "INHIBITOR",
"arg1_id": "15562257_T13",
"arg2_id": "15562257_T30",
"normalized": []
},
{
"id": "15562257_8",
"type": "INHIBITOR",
"arg1_id": "15562257_T14",
"arg2_id": "15562257_T31",
"normalized": []
},
{
"id": "15562257_9",
"type": "INHIBITOR",
"arg1_id": "15562257_T14",
"arg2_id": "15562257_T32",
"normalized": []
},
{
"id": "15562257_10",
"type": "DIRECT-REGULATOR",
"arg1_id": "15562257_T16",
"arg2_id": "15562257_T33",
"normalized": []
},
{
"id": "15562257_11",
"type": "INHIBITOR",
"arg1_id": "15562257_T2",
"arg2_id": "15562257_T19",
"normalized": []
},
{
"id": "15562257_12",
"type": "INHIBITOR",
"arg1_id": "15562257_T7",
"arg2_id": "15562257_T21",
"normalized": []
},
{
"id": "15562257_13",
"type": "INHIBITOR",
"arg1_id": "15562257_T7",
"arg2_id": "15562257_T22",
"normalized": []
},
{
"id": "15562257_14",
"type": "INHIBITOR",
"arg1_id": "15562257_T8",
"arg2_id": "15562257_T23",
"normalized": []
}
] |
23017389 | 23017389 | [
{
"id": "23017389_title",
"type": "title",
"text": [
"Studies on the antioxidant potential of flavones of Allium vineale isolated from its water-soluble fraction."
],
"offsets": [
[
0,
108
]
]
},
{
"id": "23017389_abstract",
"type": "abstract",
"text": [
"The aim of this work was to examine the chemical constituents and antioxidant potential of water-soluble fractions from the commonly consumed vegetable, Allium vineale. The water-soluble fraction, containing phenolic compounds, was extracted with ethyl acetate to obtain flavonoids which were separated and purified by repeated column chromatography over Sephadex LH-20, RP C18 and silica gel. The isolated compounds were identified according to their physicochemical properties and spectral data (UV, HPLC-TOF/MS, (1)H NMR, (13)C NMR and 2D NMR). Three flavonoids were isolated and identified as chrysoeriol-7-O-[2″-O-E-feruloyl]-β-d-glucoside (1), chrysoeriol (2), and isorhamnetin-3-β-d-glucoside (3). Antioxidant studies of the aqueous extract and three isolated compounds, 1, 2, 3, were undertaken and they were found to have significant antioxidant activity. Antioxidant activities were evaluated for total antioxidant activity by the ferric thiocyanate method, ferric ion (Fe(3+)) reducing antioxidant power assay (FRAP), ferrous ion (Fe(2+)) metal chelating activity, and DPPH free radical-scavenging activity. The water-soluble ethyl acetate and methanol extraction methods were also compared using HPLC-TOF/MS."
],
"offsets": [
[
109,
1329
]
]
}
] | [
{
"id": "23017389_T1",
"type": "CHEMICAL",
"text": [
"ferrous"
],
"offsets": [
[
1138,
1145
]
],
"normalized": []
},
{
"id": "23017389_T2",
"type": "CHEMICAL",
"text": [
"Fe(2+)"
],
"offsets": [
[
1151,
1157
]
],
"normalized": []
},
{
"id": "23017389_T3",
"type": "CHEMICAL",
"text": [
"DPPH"
],
"offsets": [
[
1189,
1193
]
],
"normalized": []
},
{
"id": "23017389_T4",
"type": "CHEMICAL",
"text": [
"ethyl acetate"
],
"offsets": [
[
1246,
1259
]
],
"normalized": []
},
{
"id": "23017389_T5",
"type": "CHEMICAL",
"text": [
"methanol"
],
"offsets": [
[
1264,
1272
]
],
"normalized": []
},
{
"id": "23017389_T6",
"type": "CHEMICAL",
"text": [
"ethyl acetate"
],
"offsets": [
[
356,
369
]
],
"normalized": []
},
{
"id": "23017389_T7",
"type": "CHEMICAL",
"text": [
"flavonoids"
],
"offsets": [
[
380,
390
]
],
"normalized": []
},
{
"id": "23017389_T8",
"type": "CHEMICAL",
"text": [
"silica gel"
],
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[
491,
501
]
],
"normalized": []
},
{
"id": "23017389_T9",
"type": "CHEMICAL",
"text": [
"(1)H"
],
"offsets": [
[
624,
628
]
],
"normalized": []
},
{
"id": "23017389_T10",
"type": "CHEMICAL",
"text": [
"(13)C"
],
"offsets": [
[
634,
639
]
],
"normalized": []
},
{
"id": "23017389_T11",
"type": "CHEMICAL",
"text": [
"chrysoeriol-7-O-[2″-O-E-feruloyl]-β-d-glucoside"
],
"offsets": [
[
706,
753
]
],
"normalized": []
},
{
"id": "23017389_T12",
"type": "CHEMICAL",
"text": [
"chrysoeriol"
],
"offsets": [
[
759,
770
]
],
"normalized": []
},
{
"id": "23017389_T13",
"type": "CHEMICAL",
"text": [
"isorhamnetin-3-β-d-glucoside"
],
"offsets": [
[
780,
808
]
],
"normalized": []
},
{
"id": "23017389_T14",
"type": "CHEMICAL",
"text": [
"ferric thiocyanate"
],
"offsets": [
[
1050,
1068
]
],
"normalized": []
},
{
"id": "23017389_T15",
"type": "CHEMICAL",
"text": [
"ferric"
],
"offsets": [
[
1077,
1083
]
],
"normalized": []
},
{
"id": "23017389_T16",
"type": "CHEMICAL",
"text": [
"Fe(3+)"
],
"offsets": [
[
1089,
1095
]
],
"normalized": []
},
{
"id": "23017389_T17",
"type": "CHEMICAL",
"text": [
"flavones"
],
"offsets": [
[
40,
48
]
],
"normalized": []
}
] | [] | [] | [] |
17524933 | 17524933 | [
{
"id": "17524933_title",
"type": "title",
"text": [
"An assay for the determination of sirolimus levels in the lymphocyte of transplant patients."
],
"offsets": [
[
0,
92
]
]
},
{
"id": "17524933_abstract",
"type": "abstract",
"text": [
"UNLABELLED: Both tacrolimus (TAC) and sirolimus (SRL) bind to the same immunophilin FKBP12; however, their mechanisms of action are distinct. SRL inhibits mammalian target of rapamycin (TOR), which is an enzyme critical to the immune function. TOR inhibition blocks the signal that mediates T-cell proliferation by preventing cell-cycle progression from G1 to S phase. Moreover, TOR inhibition results in a decrease in antibody production by blocking B-cell proliferation and maturation into antibody producing cells. The use of SRL has resulted in a decrease in the number of rejection episodes. As with other immunosuppressive agents, SRL can cause dose-related side effects, the most notable of which are hypercholesterolemia, hyperlipidemia, anemia, and thrombocytopenia. Thus, therapeutic drug monitoring to assess efficacy and toxicity has became a necessity. SRL blood levels do not correlate with its bioactivity and are affected by the concomitant use of other immunosuppressive drugs. To determine the bioactivity of SRL we have developed an assay to determine the level of Sirolimus per lymphocyte of transplant patients. The levels were correlated with lymphocyte count. METHODS: Whole blood samples from patients on SRL were collected in Ethylene Diamine Tetra-acetic acid (EDTA) vacutainer tubes. Immediately the lymphocytes from 2 mL of blood were separated using 1.5 mL of Ficoll gradient, by centrifugation for 30 minutes at 2500 RPM. The lymphocytes were washed three times with phosphate-bufferd saline and the pellet suspended in 150 microL of Middle East research institute (MERI) drug extraction solution (Beirut, Lebanon), which was then added to 300 microL of IMx solublizing reagent. The cytoplasmic SRL concentrations in lymphocytes were measured using kits supplied from Abbott diagnostics or by high-performance liquid tomography. A corresponding whole blood sample from each patient was used to measure blood levels. To determine the level per lymphocyte, the value obtained was divided by the number of lymphocytes and expressed as Pg/cell. A pharmacokinetic profile for both blood and lymphocytes was constructed for each patient using data corresponding to predose C(0), 1 hour (C(1)) and 2 hours (C(2)) after the dose. The lymphocyte enumeration for C(0), C(1), and C(2) was performed using the FACS Calibur Flow Cytometer from Becton Dickinson. The average dose was 2.86 +/- 1.27 mg/d with a C(0) = 8.05 +/- 4.24, C(1) = 21.9 +/- 8.9 ng/mL, and C(2) = 23 +/- 0.03 ng/mL. Although there was a significant correlation (P=.0975) between the dose and C(0), there was no correlation between the dose and C(0) level on the lymphocyte count P=.897. However, there was a strong correlation between SRL lymphocyte levels (pg/cell) and the lymphocyte count (r(2)=.6.06). The higher the concentration of the drug the lower the lymphocyte counts. The assay is sensitive to within 0.45 pg/cell, reproducible with a coefficient of variance (CV) of 6.4% within assay and 7.5% for intraassay."
],
"offsets": [
[
93,
3103
]
]
}
] | [
{
"id": "17524933_T1",
"type": "CHEMICAL",
"text": [
"SRL"
],
"offsets": [
[
1120,
1123
]
],
"normalized": []
},
{
"id": "17524933_T2",
"type": "CHEMICAL",
"text": [
"Sirolimus"
],
"offsets": [
[
1177,
1186
]
],
"normalized": []
},
{
"id": "17524933_T3",
"type": "CHEMICAL",
"text": [
"SRL"
],
"offsets": [
[
1322,
1325
]
],
"normalized": []
},
{
"id": "17524933_T4",
"type": "CHEMICAL",
"text": [
"Ethylene Diamine Tetra-acetic acid"
],
"offsets": [
[
1344,
1378
]
],
"normalized": []
},
{
"id": "17524933_T5",
"type": "CHEMICAL",
"text": [
"EDTA"
],
"offsets": [
[
1380,
1384
]
],
"normalized": []
},
{
"id": "17524933_T6",
"type": "CHEMICAL",
"text": [
"phosphate"
],
"offsets": [
[
1590,
1599
]
],
"normalized": []
},
{
"id": "17524933_T7",
"type": "CHEMICAL",
"text": [
"SRL"
],
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[
1818,
1821
]
],
"normalized": []
},
{
"id": "17524933_T8",
"type": "CHEMICAL",
"text": [
"tacrolimus"
],
"offsets": [
[
110,
120
]
],
"normalized": []
},
{
"id": "17524933_T9",
"type": "CHEMICAL",
"text": [
"rapamycin"
],
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[
268,
277
]
],
"normalized": []
},
{
"id": "17524933_T10",
"type": "CHEMICAL",
"text": [
"SRL"
],
"offsets": [
[
2817,
2820
]
],
"normalized": []
},
{
"id": "17524933_T11",
"type": "CHEMICAL",
"text": [
"TAC"
],
"offsets": [
[
122,
125
]
],
"normalized": []
},
{
"id": "17524933_T12",
"type": "CHEMICAL",
"text": [
"sirolimus"
],
"offsets": [
[
131,
140
]
],
"normalized": []
},
{
"id": "17524933_T13",
"type": "CHEMICAL",
"text": [
"SRL"
],
"offsets": [
[
142,
145
]
],
"normalized": []
},
{
"id": "17524933_T14",
"type": "CHEMICAL",
"text": [
"SRL"
],
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[
622,
625
]
],
"normalized": []
},
{
"id": "17524933_T15",
"type": "CHEMICAL",
"text": [
"SRL"
],
"offsets": [
[
730,
733
]
],
"normalized": []
},
{
"id": "17524933_T16",
"type": "CHEMICAL",
"text": [
"SRL"
],
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[
959,
962
]
],
"normalized": []
},
{
"id": "17524933_T17",
"type": "CHEMICAL",
"text": [
"sirolimus"
],
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[
34,
43
]
],
"normalized": []
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{
"id": "17524933_T18",
"type": "GENE-Y",
"text": [
"mammalian target of rapamycin"
],
"offsets": [
[
248,
277
]
],
"normalized": []
},
{
"id": "17524933_T19",
"type": "GENE-Y",
"text": [
"TOR"
],
"offsets": [
[
279,
282
]
],
"normalized": []
},
{
"id": "17524933_T20",
"type": "GENE-Y",
"text": [
"TOR"
],
"offsets": [
[
337,
340
]
],
"normalized": []
},
{
"id": "17524933_T21",
"type": "GENE-Y",
"text": [
"TOR"
],
"offsets": [
[
472,
475
]
],
"normalized": []
},
{
"id": "17524933_T22",
"type": "GENE-Y",
"text": [
"immunophilin FKBP12"
],
"offsets": [
[
164,
183
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17524933_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "17524933_T8",
"arg2_id": "17524933_T22",
"normalized": []
},
{
"id": "17524933_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "17524933_T11",
"arg2_id": "17524933_T22",
"normalized": []
},
{
"id": "17524933_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "17524933_T12",
"arg2_id": "17524933_T22",
"normalized": []
},
{
"id": "17524933_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "17524933_T13",
"arg2_id": "17524933_T22",
"normalized": []
}
] |
19281809 | 19281809 | [
{
"id": "19281809_title",
"type": "title",
"text": [
"Sergliflozin etabonate, a selective SGLT2 inhibitor, improves glycemic control in streptozotocin-induced diabetic rats and Zucker fatty rats."
],
"offsets": [
[
0,
141
]
]
},
{
"id": "19281809_abstract",
"type": "abstract",
"text": [
"The low-affinity sodium glucose cotransporter (SGLT2) is responsible for most of the glucose reabsorption in the kidney and has been highlighted as a novel therapeutic target for the treatment of diabetes. We discovered sergliflozin etabonate, a novel selective SGLT2 inhibitor, and found that selective inhibition of SGLT2 increased urinary glucose excretion and consequently decreased plasma glucose levels. In this report, we examined the antihyperglycemic effects of sergliflozin etabonate in normal and diabetic rats in comparison with those of a sulfonylurea (gliclazide) and an alpha-glucosidase inhibitor (voglibose). Sergliflozin etabonate increased urinary glucose excretion in a dose-dependent manner, and inhibited the increase in plasma glucose after sucrose loading independently of insulin secretion in normal rats. Sergliflozin etabonate also improved postprandial hyperglycemia in neonatal streptozotocin-induced diabetic rats; whereas gliclazide did not improve it. In rats with mild or moderate streptozotocin-induced diabetes, the degree of the antihyperglycemic effects of sergliflozin etabonate correlated with the severity of the diabetic condition. Sergliflozin etabonate did not affect the plasma glucose level of normal rats as seen with gliclazide. Chronic treatment with sergliflozin etabonate reduced the levels of glycated hemoglobin and fasting plasma glucose, and improved the glycemic response after glucose loading in Zucker fatty rats. In addition, sergliflozin etabonate did not affect the body weight or food intake. These data indicate that sergliflozin etabonate could improve glycemic control without its use resulting in insulin secretion, hypoglycemia, and body weight gain, and may provide a unique approach to the treatment of diabetes."
],
"offsets": [
[
142,
1922
]
]
}
] | [
{
"id": "19281809_T1",
"type": "CHEMICAL",
"text": [
"streptozotocin"
],
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[
1156,
1170
]
],
"normalized": []
},
{
"id": "19281809_T2",
"type": "CHEMICAL",
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"sergliflozin etabonate"
],
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]
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},
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"Sergliflozin etabonate"
],
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1315,
1337
]
],
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},
{
"id": "19281809_T4",
"type": "CHEMICAL",
"text": [
"glucose"
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[
1364,
1371
]
],
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},
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"id": "19281809_T5",
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"text": [
"gliclazide"
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[
1406,
1416
]
],
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},
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"id": "19281809_T6",
"type": "CHEMICAL",
"text": [
"sergliflozin etabonate"
],
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[
1441,
1463
]
],
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},
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"id": "19281809_T7",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
1525,
1532
]
],
"normalized": []
},
{
"id": "19281809_T8",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
1575,
1582
]
],
"normalized": []
},
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"id": "19281809_T9",
"type": "CHEMICAL",
"text": [
"sergliflozin etabonate"
],
"offsets": [
[
1626,
1648
]
],
"normalized": []
},
{
"id": "19281809_T10",
"type": "CHEMICAL",
"text": [
"sergliflozin etabonate"
],
"offsets": [
[
1721,
1743
]
],
"normalized": []
},
{
"id": "19281809_T11",
"type": "CHEMICAL",
"text": [
"sodium"
],
"offsets": [
[
159,
165
]
],
"normalized": []
},
{
"id": "19281809_T12",
"type": "CHEMICAL",
"text": [
"sergliflozin etabonate"
],
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[
362,
384
]
],
"normalized": []
},
{
"id": "19281809_T13",
"type": "CHEMICAL",
"text": [
"glucose"
],
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[
166,
173
]
],
"normalized": []
},
{
"id": "19281809_T14",
"type": "CHEMICAL",
"text": [
"glucose"
],
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[
484,
491
]
],
"normalized": []
},
{
"id": "19281809_T15",
"type": "CHEMICAL",
"text": [
"glucose"
],
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[
536,
543
]
],
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},
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"id": "19281809_T16",
"type": "CHEMICAL",
"text": [
"sergliflozin etabonate"
],
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613,
635
]
],
"normalized": []
},
{
"id": "19281809_T17",
"type": "CHEMICAL",
"text": [
"sulfonylurea"
],
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[
694,
706
]
],
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},
{
"id": "19281809_T18",
"type": "CHEMICAL",
"text": [
"gliclazide"
],
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[
708,
718
]
],
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},
{
"id": "19281809_T19",
"type": "CHEMICAL",
"text": [
"voglibose"
],
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[
756,
765
]
],
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},
{
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"type": "CHEMICAL",
"text": [
"Sergliflozin etabonate"
],
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768,
790
]
],
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},
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"text": [
"glucose"
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[
809,
816
]
],
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},
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"id": "19281809_T22",
"type": "CHEMICAL",
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"glucose"
],
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[
892,
899
]
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},
{
"id": "19281809_T23",
"type": "CHEMICAL",
"text": [
"sucrose"
],
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[
906,
913
]
],
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},
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"id": "19281809_T24",
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"Sergliflozin etabonate"
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973,
995
]
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},
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"id": "19281809_T25",
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"glucose"
],
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227,
234
]
],
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},
{
"id": "19281809_T26",
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"text": [
"streptozotocin"
],
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[
1049,
1063
]
],
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},
{
"id": "19281809_T27",
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"text": [
"gliclazide"
],
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[
1095,
1105
]
],
"normalized": []
},
{
"id": "19281809_T28",
"type": "CHEMICAL",
"text": [
"Sergliflozin etabonate"
],
"offsets": [
[
0,
22
]
],
"normalized": []
},
{
"id": "19281809_T29",
"type": "CHEMICAL",
"text": [
"streptozotocin"
],
"offsets": [
[
82,
96
]
],
"normalized": []
},
{
"id": "19281809_T30",
"type": "GENE-N",
"text": [
"glycated hemoglobin"
],
"offsets": [
[
1486,
1505
]
],
"normalized": []
},
{
"id": "19281809_T31",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1804,
1811
]
],
"normalized": []
},
{
"id": "19281809_T32",
"type": "GENE-N",
"text": [
"sodium glucose cotransporter"
],
"offsets": [
[
159,
187
]
],
"normalized": []
},
{
"id": "19281809_T33",
"type": "GENE-Y",
"text": [
"SGLT2"
],
"offsets": [
[
404,
409
]
],
"normalized": []
},
{
"id": "19281809_T34",
"type": "GENE-Y",
"text": [
"SGLT2"
],
"offsets": [
[
460,
465
]
],
"normalized": []
},
{
"id": "19281809_T35",
"type": "GENE-Y",
"text": [
"SGLT2"
],
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[
189,
194
]
],
"normalized": []
},
{
"id": "19281809_T36",
"type": "GENE-Y",
"text": [
"alpha-glucosidase"
],
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[
727,
744
]
],
"normalized": []
},
{
"id": "19281809_T37",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
939,
946
]
],
"normalized": []
},
{
"id": "19281809_T38",
"type": "GENE-Y",
"text": [
"SGLT2"
],
"offsets": [
[
36,
41
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "19281809_0",
"type": "INHIBITOR",
"arg1_id": "19281809_T28",
"arg2_id": "19281809_T38",
"normalized": []
},
{
"id": "19281809_1",
"type": "SUBSTRATE",
"arg1_id": "19281809_T25",
"arg2_id": "19281809_T35",
"normalized": []
},
{
"id": "19281809_2",
"type": "SUBSTRATE",
"arg1_id": "19281809_T25",
"arg2_id": "19281809_T32",
"normalized": []
},
{
"id": "19281809_3",
"type": "INHIBITOR",
"arg1_id": "19281809_T12",
"arg2_id": "19281809_T33",
"normalized": []
},
{
"id": "19281809_4",
"type": "INHIBITOR",
"arg1_id": "19281809_T12",
"arg2_id": "19281809_T34",
"normalized": []
},
{
"id": "19281809_5",
"type": "INHIBITOR",
"arg1_id": "19281809_T19",
"arg2_id": "19281809_T36",
"normalized": []
},
{
"id": "19281809_6",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "19281809_T6",
"arg2_id": "19281809_T30",
"normalized": []
}
] |
23234313 | 23234313 | [
{
"id": "23234313_title",
"type": "title",
"text": [
"Influence of surface groups on poly(propylene imine) dendrimers antiprion activity."
],
"offsets": [
[
0,
83
]
]
},
{
"id": "23234313_abstract",
"type": "abstract",
"text": [
"Prion diseases are characterized by the accumulation of PrP(Sc), an aberrantly folded isoform of the host protein PrP(C). Specific forms of synthetic molecules known as dendrimers are able to eliminate protease-resistant PrP(Sc) in both an intracellular and in vitro setting. The properties of a dendrimer which govern this ability are unknown. We addressed the issue by comparing the in vitro antiprion ability of numerous modified poly(propylene-imine) dendrimers, which varied in size, structure, charge, and surface group composition. Several of the modified dendrimers, including an anionic glycodendrimer, reduced the level of protease resistant PrP(Sc) in a prion strain-dependent manner. This led to the formulation of a new working model for dendrimer/prion interactions which proposes dendrimers eliminate PrP(Sc) by destabilizing the protein and rendering it susceptible to proteolysis. This ability is not dependent on any particular charge of dendrimer, but does require a high density of reactive surface groups."
],
"offsets": [
[
84,
1110
]
]
}
] | [
{
"id": "23234313_T1",
"type": "CHEMICAL",
"text": [
"poly(propylene-imine)"
],
"offsets": [
[
517,
538
]
],
"normalized": []
},
{
"id": "23234313_T2",
"type": "CHEMICAL",
"text": [
"poly(propylene imine)"
],
"offsets": [
[
31,
52
]
],
"normalized": []
},
{
"id": "23234313_T3",
"type": "GENE-N",
"text": [
"Prion"
],
"offsets": [
[
84,
89
]
],
"normalized": []
},
{
"id": "23234313_T4",
"type": "GENE-Y",
"text": [
"PrP(C)"
],
"offsets": [
[
198,
204
]
],
"normalized": []
},
{
"id": "23234313_T5",
"type": "GENE-Y",
"text": [
"PrP(Sc)"
],
"offsets": [
[
305,
312
]
],
"normalized": []
},
{
"id": "23234313_T6",
"type": "GENE-Y",
"text": [
"PrP(Sc)"
],
"offsets": [
[
140,
147
]
],
"normalized": []
},
{
"id": "23234313_T7",
"type": "GENE-N",
"text": [
"protease"
],
"offsets": [
[
717,
725
]
],
"normalized": []
},
{
"id": "23234313_T8",
"type": "GENE-Y",
"text": [
"PrP(Sc)"
],
"offsets": [
[
736,
743
]
],
"normalized": []
},
{
"id": "23234313_T9",
"type": "GENE-Y",
"text": [
"PrP(Sc)"
],
"offsets": [
[
900,
907
]
],
"normalized": []
}
] | [] | [] | [] |
12565907 | 12565907 | [
{
"id": "12565907_title",
"type": "title",
"text": [
"In situ and in vitro evidence for DCoH/HNF-1 alpha transcription of tyrosinase in human skin melanocytes."
],
"offsets": [
[
0,
105
]
]
},
{
"id": "12565907_abstract",
"type": "abstract",
"text": [
"Human epidermal melanocytes hold the full capacity for autocrine de novo synthesis/regulation/recycling of the essential cofactor 6-tetrahydrobiopterin (6BH(4)) for conversion of L-phenylalanine via phenylalanine hydroxylase to L-tyrosine and for production of L-Dopa via tyrosine hydroxylase to initiate both pigmentation and catecholamine synthesis in these neural crest-derived cells. Earlier we have demonstrated pterin-4a-carbinolamine dehydratase (PCD) mRNA and enzyme activities in epidermal melanocytes and keratinocytes. This protein dimerises also the transcription factor hepatocyte nuclear factor 1 (HNF-1), leading to activation of multiple genes. This study demonstrates for the first time DCoH/HNF-1 alpha expression and transcriptional activity in human epidermal melanocytes in vitro and in situ and identified tyrosinase, the key enzyme for pigmentation, as a new transcriptional target. Specific binding of DCoH/HNF-1 complex to the human tyrosinase promoter was confirmed by gel shift analysis. These results provide a novel mechanism in the regulation of skin pigmentation."
],
"offsets": [
[
106,
1200
]
]
}
] | [
{
"id": "12565907_T1",
"type": "CHEMICAL",
"text": [
"6-tetrahydrobiopterin"
],
"offsets": [
[
236,
257
]
],
"normalized": []
},
{
"id": "12565907_T2",
"type": "CHEMICAL",
"text": [
"6BH(4)"
],
"offsets": [
[
259,
265
]
],
"normalized": []
},
{
"id": "12565907_T3",
"type": "CHEMICAL",
"text": [
"L-phenylalanine"
],
"offsets": [
[
285,
300
]
],
"normalized": []
},
{
"id": "12565907_T4",
"type": "CHEMICAL",
"text": [
"phenylalanine"
],
"offsets": [
[
305,
318
]
],
"normalized": []
},
{
"id": "12565907_T5",
"type": "CHEMICAL",
"text": [
"L-tyrosine"
],
"offsets": [
[
334,
344
]
],
"normalized": []
},
{
"id": "12565907_T6",
"type": "CHEMICAL",
"text": [
"L-Dopa"
],
"offsets": [
[
367,
373
]
],
"normalized": []
},
{
"id": "12565907_T7",
"type": "CHEMICAL",
"text": [
"tyrosine"
],
"offsets": [
[
378,
386
]
],
"normalized": []
},
{
"id": "12565907_T8",
"type": "CHEMICAL",
"text": [
"catecholamine"
],
"offsets": [
[
433,
446
]
],
"normalized": []
},
{
"id": "12565907_T9",
"type": "CHEMICAL",
"text": [
"pterin-4a-carbinolamine"
],
"offsets": [
[
523,
546
]
],
"normalized": []
},
{
"id": "12565907_T10",
"type": "GENE-Y",
"text": [
"phenylalanine hydroxylase"
],
"offsets": [
[
305,
330
]
],
"normalized": []
},
{
"id": "12565907_T11",
"type": "GENE-Y",
"text": [
"tyrosine hydroxylase"
],
"offsets": [
[
378,
398
]
],
"normalized": []
},
{
"id": "12565907_T12",
"type": "GENE-Y",
"text": [
"pterin-4a-carbinolamine dehydratase"
],
"offsets": [
[
523,
558
]
],
"normalized": []
},
{
"id": "12565907_T13",
"type": "GENE-Y",
"text": [
"PCD"
],
"offsets": [
[
560,
563
]
],
"normalized": []
},
{
"id": "12565907_T14",
"type": "GENE-Y",
"text": [
"hepatocyte nuclear factor 1"
],
"offsets": [
[
689,
716
]
],
"normalized": []
},
{
"id": "12565907_T15",
"type": "GENE-Y",
"text": [
"HNF-1"
],
"offsets": [
[
718,
723
]
],
"normalized": []
},
{
"id": "12565907_T16",
"type": "GENE-Y",
"text": [
"DCoH"
],
"offsets": [
[
810,
814
]
],
"normalized": []
},
{
"id": "12565907_T17",
"type": "GENE-Y",
"text": [
"HNF-1 alpha"
],
"offsets": [
[
815,
826
]
],
"normalized": []
},
{
"id": "12565907_T18",
"type": "GENE-Y",
"text": [
"tyrosinase"
],
"offsets": [
[
934,
944
]
],
"normalized": []
},
{
"id": "12565907_T19",
"type": "GENE-Y",
"text": [
"DCoH"
],
"offsets": [
[
1032,
1036
]
],
"normalized": []
},
{
"id": "12565907_T20",
"type": "GENE-Y",
"text": [
"HNF-1"
],
"offsets": [
[
1037,
1042
]
],
"normalized": []
},
{
"id": "12565907_T21",
"type": "GENE-N",
"text": [
"human tyrosinase promoter"
],
"offsets": [
[
1058,
1083
]
],
"normalized": []
},
{
"id": "12565907_T22",
"type": "GENE-Y",
"text": [
"DCoH"
],
"offsets": [
[
34,
38
]
],
"normalized": []
},
{
"id": "12565907_T23",
"type": "GENE-Y",
"text": [
"HNF-1 alpha"
],
"offsets": [
[
39,
50
]
],
"normalized": []
},
{
"id": "12565907_T24",
"type": "GENE-Y",
"text": [
"tyrosinase"
],
"offsets": [
[
68,
78
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12565907_0",
"type": "SUBSTRATE",
"arg1_id": "12565907_T3",
"arg2_id": "12565907_T10",
"normalized": []
},
{
"id": "12565907_1",
"type": "SUBSTRATE",
"arg1_id": "12565907_T5",
"arg2_id": "12565907_T10",
"normalized": []
},
{
"id": "12565907_2",
"type": "PRODUCT-OF",
"arg1_id": "12565907_T6",
"arg2_id": "12565907_T11",
"normalized": []
},
{
"id": "12565907_3",
"type": "SUBSTRATE",
"arg1_id": "12565907_T3",
"arg2_id": "12565907_T11",
"normalized": []
},
{
"id": "12565907_4",
"type": "SUBSTRATE",
"arg1_id": "12565907_T1",
"arg2_id": "12565907_T10",
"normalized": []
},
{
"id": "12565907_5",
"type": "SUBSTRATE",
"arg1_id": "12565907_T2",
"arg2_id": "12565907_T10",
"normalized": []
},
{
"id": "12565907_6",
"type": "SUBSTRATE",
"arg1_id": "12565907_T1",
"arg2_id": "12565907_T11",
"normalized": []
},
{
"id": "12565907_7",
"type": "SUBSTRATE",
"arg1_id": "12565907_T2",
"arg2_id": "12565907_T11",
"normalized": []
},
{
"id": "12565907_8",
"type": "PRODUCT-OF",
"arg1_id": "12565907_T8",
"arg2_id": "12565907_T10",
"normalized": []
},
{
"id": "12565907_9",
"type": "PRODUCT-OF",
"arg1_id": "12565907_T8",
"arg2_id": "12565907_T11",
"normalized": []
}
] |
17853709 | 17853709 | [
{
"id": "17853709_title",
"type": "title",
"text": [
"[Lipoprotein(a): a link between thrombogenesis and atherogenesis]."
],
"offsets": [
[
0,
66
]
]
},
{
"id": "17853709_abstract",
"type": "abstract",
"text": [
"INTRODUCTION: It is well known that numerous mechanisms of thrombogenesis can participate in every stage of atherosclerotic disease. The discovery of Lp(a) lipoprotein and its structural similarity with plasminogen suggests another pathogenic link between atherogenesis and thrombogenesis. SOME CHARACTERISTICS OF LP(A) LIPOPROTEIN: This lipoprotein is present in the whole human population in a wide range of plasma concentrations. It has numerous different isoforms. Its synthesis occurs in the liver, but it is practically metabolically independent from other lipoproteins. Today, Lp(a) lipoprotein is considered to be an independent risk factor for heart and brain ischemic disease. FIBRINOLYTIC MECHANISMS: The primary role of the fibrinolytic mechanism is to prevent thrombus Jormation during circulation and to remove already formed ones. Plasmin has a central role in this process, due to the inactive proenzyme plasminogen. Its basic activators are tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). The most important inhibitors of plasminogen are alpha2-antiplasmin and plasminogen activator inhibitors 1 and 2 (PA-1 and PAI-2). Structural similarity of Lp(a) and plasminogen The apo(a) and plasminogen genes are very closely linked on the long arm of chromosome 6. Because of that they are structuraly very similar and they have a cross immunological reactivity. Their common elements are so-called \"kringle\" structures. The key difference in structure of Lp(a) and plasminogen is replacement of Arg with Ser at position 560. This prevents splitting of apo(a) by plasminogen activators. LP(A) AND FIBRINOLYSIS: Lp(a) lipoprotein inhibits activation of plasminogen by streptokinase. It is also a competitive inhibitor of plasminogen for its binding to plasminogen receptors. Furthermore, it successfully achieves competitive inhibition of plasminogen for binding to tetranectin and thrombospondin. Also, Lp(a) inhibits activation of transforming growth factor alpha (TGF-alpha). It positively correlates with PAI-1 and it is assumed that it promotes release of tissue factor pathway inhibitor (17FPI) from endothelial cell surfaces. CONCLUSION: In regulation of the hemostatic system via apolipoprotein(a) antifibrinolytic effects, Lp(a) lipoprotein ojfers a molecular solution to the link between thrombogenesis and atherogenesis."
],
"offsets": [
[
67,
2443
]
]
}
] | [
{
"id": "17853709_T1",
"type": "CHEMICAL",
"text": [
"Arg"
],
"offsets": [
[
1609,
1612
]
],
"normalized": []
},
{
"id": "17853709_T2",
"type": "CHEMICAL",
"text": [
"Ser"
],
"offsets": [
[
1618,
1621
]
],
"normalized": []
},
{
"id": "17853709_T3",
"type": "GENE-Y",
"text": [
"urokinase plasminogen activator"
],
"offsets": [
[
1070,
1101
]
],
"normalized": []
},
{
"id": "17853709_T4",
"type": "GENE-Y",
"text": [
"u-PA"
],
"offsets": [
[
1103,
1107
]
],
"normalized": []
},
{
"id": "17853709_T5",
"type": "GENE-Y",
"text": [
"plasminogen"
],
"offsets": [
[
1143,
1154
]
],
"normalized": []
},
{
"id": "17853709_T6",
"type": "GENE-Y",
"text": [
"alpha2-antiplasmin"
],
"offsets": [
[
1159,
1177
]
],
"normalized": []
},
{
"id": "17853709_T7",
"type": "GENE-N",
"text": [
"plasminogen activator inhibitors 1 and 2"
],
"offsets": [
[
1182,
1222
]
],
"normalized": []
},
{
"id": "17853709_T8",
"type": "GENE-Y",
"text": [
"PA-1"
],
"offsets": [
[
1224,
1228
]
],
"normalized": []
},
{
"id": "17853709_T9",
"type": "GENE-Y",
"text": [
"PAI-2"
],
"offsets": [
[
1233,
1238
]
],
"normalized": []
},
{
"id": "17853709_T10",
"type": "GENE-Y",
"text": [
"Lp(a)"
],
"offsets": [
[
1266,
1271
]
],
"normalized": []
},
{
"id": "17853709_T11",
"type": "GENE-Y",
"text": [
"plasminogen"
],
"offsets": [
[
1276,
1287
]
],
"normalized": []
},
{
"id": "17853709_T12",
"type": "GENE-N",
"text": [
"apo(a)"
],
"offsets": [
[
1292,
1298
]
],
"normalized": []
},
{
"id": "17853709_T13",
"type": "GENE-Y",
"text": [
"plasminogen"
],
"offsets": [
[
1303,
1314
]
],
"normalized": []
},
{
"id": "17853709_T14",
"type": "GENE-Y",
"text": [
"Lp(a)"
],
"offsets": [
[
217,
222
]
],
"normalized": []
},
{
"id": "17853709_T15",
"type": "GENE-Y",
"text": [
"Lp(a)"
],
"offsets": [
[
1569,
1574
]
],
"normalized": []
},
{
"id": "17853709_T16",
"type": "GENE-Y",
"text": [
"plasminogen"
],
"offsets": [
[
1579,
1590
]
],
"normalized": []
},
{
"id": "17853709_T17",
"type": "GENE-N",
"text": [
"lipoprotein"
],
"offsets": [
[
223,
234
]
],
"normalized": []
},
{
"id": "17853709_T18",
"type": "GENE-N",
"text": [
"apo(a)"
],
"offsets": [
[
1666,
1672
]
],
"normalized": []
},
{
"id": "17853709_T19",
"type": "GENE-N",
"text": [
"plasminogen activators"
],
"offsets": [
[
1676,
1698
]
],
"normalized": []
},
{
"id": "17853709_T20",
"type": "GENE-Y",
"text": [
"LP(A)"
],
"offsets": [
[
1700,
1705
]
],
"normalized": []
},
{
"id": "17853709_T21",
"type": "GENE-Y",
"text": [
"Lp(a)"
],
"offsets": [
[
1724,
1729
]
],
"normalized": []
},
{
"id": "17853709_T22",
"type": "GENE-N",
"text": [
"lipoprotein"
],
"offsets": [
[
1730,
1741
]
],
"normalized": []
},
{
"id": "17853709_T23",
"type": "GENE-Y",
"text": [
"plasminogen"
],
"offsets": [
[
1765,
1776
]
],
"normalized": []
},
{
"id": "17853709_T24",
"type": "GENE-N",
"text": [
"streptokinase"
],
"offsets": [
[
1780,
1793
]
],
"normalized": []
},
{
"id": "17853709_T25",
"type": "GENE-Y",
"text": [
"plasminogen"
],
"offsets": [
[
1833,
1844
]
],
"normalized": []
},
{
"id": "17853709_T26",
"type": "GENE-N",
"text": [
"plasminogen receptors"
],
"offsets": [
[
1864,
1885
]
],
"normalized": []
},
{
"id": "17853709_T27",
"type": "GENE-Y",
"text": [
"plasminogen"
],
"offsets": [
[
1951,
1962
]
],
"normalized": []
},
{
"id": "17853709_T28",
"type": "GENE-Y",
"text": [
"tetranectin"
],
"offsets": [
[
1978,
1989
]
],
"normalized": []
},
{
"id": "17853709_T29",
"type": "GENE-Y",
"text": [
"thrombospondin"
],
"offsets": [
[
1994,
2008
]
],
"normalized": []
},
{
"id": "17853709_T30",
"type": "GENE-Y",
"text": [
"Lp(a)"
],
"offsets": [
[
2016,
2021
]
],
"normalized": []
},
{
"id": "17853709_T31",
"type": "GENE-Y",
"text": [
"transforming growth factor alpha"
],
"offsets": [
[
2045,
2077
]
],
"normalized": []
},
{
"id": "17853709_T32",
"type": "GENE-Y",
"text": [
"TGF-alpha"
],
"offsets": [
[
2079,
2088
]
],
"normalized": []
},
{
"id": "17853709_T33",
"type": "GENE-Y",
"text": [
"plasminogen"
],
"offsets": [
[
270,
281
]
],
"normalized": []
},
{
"id": "17853709_T34",
"type": "GENE-Y",
"text": [
"PAI-1"
],
"offsets": [
[
2121,
2126
]
],
"normalized": []
},
{
"id": "17853709_T35",
"type": "GENE-Y",
"text": [
"tissue factor"
],
"offsets": [
[
2173,
2186
]
],
"normalized": []
},
{
"id": "17853709_T36",
"type": "GENE-N",
"text": [
"apolipoprotein(a)"
],
"offsets": [
[
2300,
2317
]
],
"normalized": []
},
{
"id": "17853709_T37",
"type": "GENE-Y",
"text": [
"Lp(a)"
],
"offsets": [
[
2344,
2349
]
],
"normalized": []
},
{
"id": "17853709_T38",
"type": "GENE-N",
"text": [
"lipoprotein"
],
"offsets": [
[
2350,
2361
]
],
"normalized": []
},
{
"id": "17853709_T39",
"type": "GENE-Y",
"text": [
"LP(A)"
],
"offsets": [
[
381,
386
]
],
"normalized": []
},
{
"id": "17853709_T40",
"type": "GENE-N",
"text": [
"LIPOPROTEIN"
],
"offsets": [
[
387,
398
]
],
"normalized": []
},
{
"id": "17853709_T41",
"type": "GENE-N",
"text": [
"lipoproteins"
],
"offsets": [
[
630,
642
]
],
"normalized": []
},
{
"id": "17853709_T42",
"type": "GENE-Y",
"text": [
"Lp(a)"
],
"offsets": [
[
651,
656
]
],
"normalized": []
},
{
"id": "17853709_T43",
"type": "GENE-N",
"text": [
"lipoprotein"
],
"offsets": [
[
657,
668
]
],
"normalized": []
},
{
"id": "17853709_T44",
"type": "GENE-Y",
"text": [
"Plasmin"
],
"offsets": [
[
913,
920
]
],
"normalized": []
},
{
"id": "17853709_T45",
"type": "GENE-Y",
"text": [
"plasminogen"
],
"offsets": [
[
987,
998
]
],
"normalized": []
},
{
"id": "17853709_T46",
"type": "GENE-Y",
"text": [
"tissue-type plasminogen activator"
],
"offsets": [
[
1025,
1058
]
],
"normalized": []
},
{
"id": "17853709_T47",
"type": "GENE-Y",
"text": [
"t-PA"
],
"offsets": [
[
1060,
1064
]
],
"normalized": []
},
{
"id": "17853709_T48",
"type": "GENE-Y",
"text": [
"Lipoprotein(a)"
],
"offsets": [
[
1,
15
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17853709_0",
"type": "PART-OF",
"arg1_id": "17853709_T1",
"arg2_id": "17853709_T15",
"normalized": []
},
{
"id": "17853709_1",
"type": "PART-OF",
"arg1_id": "17853709_T2",
"arg2_id": "17853709_T15",
"normalized": []
},
{
"id": "17853709_2",
"type": "PART-OF",
"arg1_id": "17853709_T1",
"arg2_id": "17853709_T16",
"normalized": []
},
{
"id": "17853709_3",
"type": "PART-OF",
"arg1_id": "17853709_T2",
"arg2_id": "17853709_T16",
"normalized": []
}
] |
12398910 | 12398910 | [
{
"id": "12398910_title",
"type": "title",
"text": [
"MDMA- and p-chlorophenylalanine-induced reduction in 5-HT concentrations: effects on serotonin transporter densities."
],
"offsets": [
[
0,
117
]
]
},
{
"id": "12398910_abstract",
"type": "abstract",
"text": [
"Low levels of serotonin may reduce the density of the serotonin transporter (SERT) by either increasing trafficking or reducing synthesis; a \"neuroadaptive response\". To determine whether 3,4-methylenedioxymethamphetamine (MDMA)-induced reductions in SERT density could be related to such a mechanism, p-chlorophenylalanine or MDMA was administered to rats, and brain serotonin and SERT density were measured. As expected, both treatments led to serotonin depletion 1, 7 and 14 days later. However, only MDMA reduced SERT density. This observation suggests that MDMA-induced reductions in SERT density do not represent neuroadaptive responses to decreased levels of brain serotonin, but may occur in response to some other stimulus or to the neurotoxic effects of MDMA."
],
"offsets": [
[
118,
887
]
]
}
] | [
{
"id": "12398910_T1",
"type": "CHEMICAL",
"text": [
"serotonin"
],
"offsets": [
[
132,
141
]
],
"normalized": []
},
{
"id": "12398910_T2",
"type": "CHEMICAL",
"text": [
"3,4-methylenedioxymethamphetamine"
],
"offsets": [
[
306,
339
]
],
"normalized": []
},
{
"id": "12398910_T3",
"type": "CHEMICAL",
"text": [
"MDMA"
],
"offsets": [
[
341,
345
]
],
"normalized": []
},
{
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85,
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"SERT"
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"SERT"
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"SERT"
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172,
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195,
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"serotonin transporter"
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85,
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}
] | [] | [] | [] |
23611338 | 23611338 | [
{
"id": "23611338_title",
"type": "title",
"text": [
"Reaction between peroxynitrite and triphenylphosphonium-substituted arylboronic acid isomers - Identification of diagnostic marker products and biological implications."
],
"offsets": [
[
0,
168
]
]
},
{
"id": "23611338_abstract",
"type": "abstract",
"text": [
"</i>Aromatic boronic acids react rapidly with peroxynitrite (ONOO<sup>-</sup>) to yield phenols as major products. This reaction was used to monitor ONOO<sup>-</sup> formation in cellular systems. Previously, we proposed that the reaction between ONOO<sup>-</sup> and arylboronates (PhB(OH)<sub>2</sub>) yields a phenolic product (major pathway) and a radical pair PhB(OH)<sub>2</sub>O<sup>•-</sup>…<sup>•</sup>NO<sub>2</sub> (minor pathway). [Sikora A. <i>et al., Chem Res Toxicol</i> 24, 687-97]. In this study, we investigated the influence of a bulky triphenylphosphonium (TPP) group on the reaction between ONOO<sup>-</sup> and mitochondria-targeted arylboronate isomers (<i>o</i>-, <i>m</i>-, and <i>p</i>-MitoPhB(OH)<sub>2</sub>). Results from the electron paramagnetic resonance (EPR) spin-trapping experiments unequivocally showed the presence of a phenyl radical intermediate from <i>meta</i> and <i>para</i> isomers, and not from the <i>ortho</i> isomer. The yield of <i>o</i>-MitoPhNO<sub>2</sub> formed from the reaction between <i>o</i>-MitoPhB(OH)<sub>2</sub> and ONOO<sup>-</sup> was not diminished by phenyl radical scavengers, suggesting a rapid fragmentation of the <i>o</i>-MitoPhB(OH)<sub>2</sub>O<sup>•-</sup> radical anion with subsequent reaction of the resulting phenyl radical with <sup>•</sup>NO<sub>2</sub> in the solvent cage. The DFT quantum mechanical calculations showed that the energy barrier for the dissociation of <i>o</i>-MitoPhB(OH)<sub>2</sub>O<sup>•-</sup> radical anion is significantly lower than that of <i>m</i>-MitoPhB(OH)<sub>2</sub>O<sup>•-</sup> and <i>p</i>-MitoPhB(OH)<sub>2</sub>O<sup>•-</sup> radical anions. We conclude that the reaction of ONOO<sup>-</sup> with <i>ortho</i>-MitoPhB(OH)<sub>2</sub> forming the minor nitrated product, <i>o</i>-MitoPhNO<sub>2</sub>, and the corresponding major phenolic product (<i>o</i>-MitoPhOH) can be employed as a diagnostic tool to specifically detect ONOO<sup>-</sup> in biological systems."
],
"offsets": [
[
169,
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]
]
}
] | [
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"id": "23611338_T1",
"type": "CHEMICAL",
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"<i>o</i>-MitoPhB(OH)<sub>2</sub>"
],
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1211,
1243
]
],
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},
{
"id": "23611338_T2",
"type": "CHEMICAL",
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"ONOO<sup>-</sup>"
],
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1248,
1264
]
],
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"id": "23611338_T3",
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"phenyl"
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1287,
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]
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"id": "23611338_T4",
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],
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1354,
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]
],
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"id": "23611338_T5",
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"phenyl"
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[
1457,
1463
]
],
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},
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"id": "23611338_T6",
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"<sup>•</sup>NO<sub>2</sub>"
],
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1477,
1503
]
],
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},
{
"id": "23611338_T7",
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"<i>o</i>-MitoPhB(OH)<sub>2</sub>O<sup>•-</sup>"
],
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[
1620,
1666
]
],
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},
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"id": "23611338_T8",
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"ONOO<sup>-</sup>"
],
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[
318,
334
]
],
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},
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"id": "23611338_T9",
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],
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1717,
1763
]
],
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},
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"id": "23611338_T10",
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"<i>p</i>-MitoPhB(OH)<sub>2</sub>O<sup>•-</sup>"
],
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1768,
1814
]
],
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"ONOO<sup>-</sup>"
],
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[
1864,
1880
]
],
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},
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"id": "23611338_T12",
"type": "CHEMICAL",
"text": [
"<i>ortho</i>-MitoPhB(OH)<sub>2</sub>"
],
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[
1886,
1922
]
],
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},
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"id": "23611338_T13",
"type": "CHEMICAL",
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"<i>o</i>-MitoPhNO<sub>2</sub>"
],
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[
1959,
1988
]
],
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},
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"phenolic"
],
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[
2018,
2026
]
],
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},
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"<i>o</i>-MitoPhOH"
],
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2036,
2053
]
],
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},
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"ONOO<sup>-</sup>"
],
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2115,
2131
]
],
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"ONOO<sup>-</sup>"
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416,
432
]
],
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"arylboronates"
],
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437,
450
]
],
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"PhB(OH)<sub>2</sub>"
],
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452,
471
]
],
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"phenolic"
],
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482,
490
]
],
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},
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"type": "CHEMICAL",
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"PhB(OH)<sub>2</sub>O<sup>•-</sup>"
],
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534,
567
]
],
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"id": "23611338_T22",
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"<sup>•</sup>NO<sub>2</sub>"
],
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568,
594
]
],
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"Aromatic boronic acids"
],
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173,
195
]
],
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},
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"id": "23611338_T24",
"type": "CHEMICAL",
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"peroxynitrite"
],
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[
215,
228
]
],
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},
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724,
744
]
],
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"TPP"
],
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746,
749
]
],
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},
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"ONOO<sup>-</sup>"
],
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[
781,
797
]
],
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},
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"ONOO<sup>-</sup>"
],
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[
230,
246
]
],
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},
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"type": "CHEMICAL",
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"arylboronate"
],
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[
824,
836
]
],
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},
{
"id": "23611338_T30",
"type": "CHEMICAL",
"text": [
"<i>o</i>-, <i>m</i>-, and <i>p</i>-MitoPhB(OH)<sub>2</sub>"
],
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[
846,
904
]
],
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},
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"id": "23611338_T31",
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"phenyl"
],
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[
1027,
1033
]
],
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},
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"id": "23611338_T32",
"type": "CHEMICAL",
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"phenols"
],
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[
257,
264
]
],
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},
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"id": "23611338_T33",
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"<i>o</i>-MitoPhNO<sub>2</sub>"
],
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1148,
1177
]
],
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},
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"id": "23611338_T34",
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"text": [
"peroxynitrite"
],
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[
17,
30
]
],
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},
{
"id": "23611338_T35",
"type": "CHEMICAL",
"text": [
"triphenylphosphonium-substituted arylboronic acid"
],
"offsets": [
[
35,
84
]
],
"normalized": []
}
] | [] | [] | [] |
11102491 | 11102491 | [
{
"id": "11102491_title",
"type": "title",
"text": [
"NMDA and glutamate evoke excitotoxicity at distinct cellular locations in rat cortical neurons in vitro."
],
"offsets": [
[
0,
104
]
]
},
{
"id": "11102491_abstract",
"type": "abstract",
"text": [
"The development of cortical neurons in vivo and in vitro is accompanied by alterations in NMDA receptor subunit expression and concomitant modifications in the pharmacological profile of NMDA-activated ionic currents. For example, we observed that with decreasing NR2B/NR2A subunit expression ratio, the block of NMDA receptor-mediated whole-cell responses by the NR2B-selective antagonist haloperidol was also decreased. In mature cultures (>22 d in vitro), however, NMDA responses obtained from excised nucleated macropatches, which comprised a large portion of the soma, remained strongly antagonized by haloperidol. These results suggest that in more mature neurons NR1/NR2B receptors appear to be preferentially expressed in the cell body. As predicted from the whole-cell recording pharmacological profile, NMDA-induced toxicity was largely unaffected by haloperidol in mature cultures. However, haloperidol effectively blocked glutamate toxicity in the same cultures, suggesting that the neurotoxic actions of this amino acid were mostly due to the activation of somatic NMDA receptors. In experiments in which the potency of glutamate toxicity was increased by the transport inhibitor l-trans-pyrrolidine-2,4-dicarboxylic acid, the neuroprotective effects of haloperidol were significantly diminished. This was likely because of the fact that glutamate, now toxic at much lower concentrations, was able to reach and activate dendritic receptors under these conditions. These results strongly argue that exogenous glutamate and NMDA normally induce excitotoxicity at distinct cellular locations in mature mixed neuronal cultures and that NR1/NR2B receptors remain an important component in the expression of glutamate, but not NMDA-induced excitotoxicity."
],
"offsets": [
[
105,
1867
]
]
}
] | [
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1127,
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"NMDA"
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1183,
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0,
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9,
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1183,
1197
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"NR1"
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1750,
1753
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"NR2B"
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1754,
1758
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"id": "11102491_T22",
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"NR2B"
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369,
373
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"id": "11102491_T23",
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"NR2A"
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[
374,
378
]
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},
{
"id": "11102491_T24",
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"NMDA receptor"
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418,
431
]
],
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},
{
"id": "11102491_T25",
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"NR2B"
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[
469,
473
]
],
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},
{
"id": "11102491_T26",
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"NR1"
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[
775,
778
]
],
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},
{
"id": "11102491_T27",
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"text": [
"NR2B"
],
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779,
783
]
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},
{
"id": "11102491_T28",
"type": "GENE-N",
"text": [
"NMDA receptor"
],
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[
195,
208
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "11102491_0",
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"arg2_id": "11102491_T25",
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},
{
"id": "11102491_1",
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},
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"id": "11102491_2",
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{
"id": "11102491_3",
"type": "INHIBITOR",
"arg1_id": "11102491_T14",
"arg2_id": "11102491_T19",
"normalized": []
},
{
"id": "11102491_4",
"type": "ACTIVATOR",
"arg1_id": "11102491_T16",
"arg2_id": "11102491_T19",
"normalized": []
}
] |
17141733 | 17141733 | [
{
"id": "17141733_title",
"type": "title",
"text": [
"The pH-dependent distribution of the photosensitizer chlorin e6 among plasma proteins and membranes: a physico-chemical approach."
],
"offsets": [
[
0,
129
]
]
},
{
"id": "17141733_abstract",
"type": "abstract",
"text": [
"Decrease in interstitial pH of the tumor stroma and over-expression of low density lipoprotein (LDL) receptors by several types of neoplastic cells have been suggested to be important determinants of selective retention of photosensitizers by proliferative tissues. The interactions of chlorin e6 (Ce6), a photosensitizer bearing three carboxylic groups, with plasma proteins and DOPC unilamellar vesicles are investigated by fluorescence spectroscopy. The binding constant to liposomes, with reference to the DOPC concentration, is 6 x 10(3) M(-1) at pH 7.4. Binding of Ce6 to LDL involves about ten high affinity sites close to the apoprotein and some solubilization in the lipid compartment. The overall association constant is 5.7 x 10(7) M(-1) at pH 7.4. Human serum albumin (HSA) is the major carrier (association constant 1.8 x 10(8) M(-1) at pH 7.4). Whereas the affinity of Ce6 for LDL and liposomes increases at lower pH, it decreases for albumin. Between pH 7.4 and 6.5, the relative affinities of Ce6 for LDL versus HSA, and for membranes versus HSA, are multiplied by 4.6 and 3.5, respectively. These effects are likely driven by the ionization equilibria of the photosensitizer carboxylic chains. Then, the cellular uptake of chlorin e6 may be facilitated by its pH-mediated redistribution within the tumor stroma."
],
"offsets": [
[
130,
1458
]
]
}
] | [
{
"id": "17141733_T1",
"type": "CHEMICAL",
"text": [
"Ce6"
],
"offsets": [
[
1139,
1142
]
],
"normalized": []
},
{
"id": "17141733_T2",
"type": "CHEMICAL",
"text": [
"carboxylic"
],
"offsets": [
[
1322,
1332
]
],
"normalized": []
},
{
"id": "17141733_T3",
"type": "CHEMICAL",
"text": [
"chlorin e6"
],
"offsets": [
[
1370,
1380
]
],
"normalized": []
},
{
"id": "17141733_T4",
"type": "CHEMICAL",
"text": [
"chlorin e6"
],
"offsets": [
[
416,
426
]
],
"normalized": []
},
{
"id": "17141733_T5",
"type": "CHEMICAL",
"text": [
"Ce6"
],
"offsets": [
[
428,
431
]
],
"normalized": []
},
{
"id": "17141733_T6",
"type": "CHEMICAL",
"text": [
"carboxylic"
],
"offsets": [
[
466,
476
]
],
"normalized": []
},
{
"id": "17141733_T7",
"type": "CHEMICAL",
"text": [
"Ce6"
],
"offsets": [
[
701,
704
]
],
"normalized": []
},
{
"id": "17141733_T8",
"type": "CHEMICAL",
"text": [
"Ce6"
],
"offsets": [
[
1013,
1016
]
],
"normalized": []
},
{
"id": "17141733_T9",
"type": "CHEMICAL",
"text": [
"chlorin e6"
],
"offsets": [
[
53,
63
]
],
"normalized": []
},
{
"id": "17141733_T10",
"type": "GENE-N",
"text": [
"LDL"
],
"offsets": [
[
1147,
1150
]
],
"normalized": []
},
{
"id": "17141733_T11",
"type": "GENE-Y",
"text": [
"HSA"
],
"offsets": [
[
1158,
1161
]
],
"normalized": []
},
{
"id": "17141733_T12",
"type": "GENE-Y",
"text": [
"HSA"
],
"offsets": [
[
1188,
1191
]
],
"normalized": []
},
{
"id": "17141733_T13",
"type": "GENE-N",
"text": [
"LDL"
],
"offsets": [
[
708,
711
]
],
"normalized": []
},
{
"id": "17141733_T14",
"type": "GENE-Y",
"text": [
"low density lipoprotein (LDL) receptors"
],
"offsets": [
[
201,
240
]
],
"normalized": []
},
{
"id": "17141733_T15",
"type": "GENE-Y",
"text": [
"Human serum albumin"
],
"offsets": [
[
890,
909
]
],
"normalized": []
},
{
"id": "17141733_T16",
"type": "GENE-Y",
"text": [
"HSA"
],
"offsets": [
[
911,
914
]
],
"normalized": []
},
{
"id": "17141733_T17",
"type": "GENE-N",
"text": [
"LDL"
],
"offsets": [
[
1021,
1024
]
],
"normalized": []
},
{
"id": "17141733_T18",
"type": "GENE-Y",
"text": [
"albumin"
],
"offsets": [
[
1079,
1086
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17141733_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "17141733_T7",
"arg2_id": "17141733_T13",
"normalized": []
},
{
"id": "17141733_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "17141733_T8",
"arg2_id": "17141733_T17",
"normalized": []
},
{
"id": "17141733_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "17141733_T1",
"arg2_id": "17141733_T10",
"normalized": []
},
{
"id": "17141733_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "17141733_T1",
"arg2_id": "17141733_T11",
"normalized": []
},
{
"id": "17141733_4",
"type": "DIRECT-REGULATOR",
"arg1_id": "17141733_T1",
"arg2_id": "17141733_T12",
"normalized": []
}
] |
20512624 | 20512624 | [
{
"id": "20512624_title",
"type": "title",
"text": [
"A possible role of the non-GAT1 GABA transporters in transfer of GABA from GABAergic to glutamatergic neurons in mouse cerebellar neuronal cultures."
],
"offsets": [
[
0,
148
]
]
},
{
"id": "20512624_abstract",
"type": "abstract",
"text": [
"Cultures of dissociated cerebellum from 7-day-old mice were used to investigate the mechanism involved in synthesis and cellular redistribution of GABA in these cultures consisting primarily of glutamatergic granule neurons and a smaller population of GABAergic Golgi and stellate neurons. The distribution of GAD, GABA and the vesicular glutamate transporter VGlut-1 was assessed using specific antibodies combined with immunofluorescence microscopy. Additionally, tiagabine, SKF 89976-A, betaine, beta-alanine, nipecotic acid and guvacine were used to inhibit the GAT1, betaine/GABA (BGT1), GAT2 and GAT3 transporters. Only a small population of cells were immuno-stained for GAD while many cells exhibited VGlut-1 like immuno-reactivity which, however, never co-localized with GAD positive neurons. This likely reflects the small number of GABAergic neurons compared to the glutamatergic granule neurons constituting the majority of the cells. GABA uptake exhibited the kinetics of high affinity transport and could be partly (20%) inhibited by betaine (IC(50) 142 microM), beta-alanine (30%) and almost fully (90%) inhibited by SKF 89976-A (IC(50) 0.8 microM) or nipecotic acid and guvacine at 1 mM concentrations (95%). Essentially all neurons showed GABA like immunostaining albeit with differences in intensity. The results indicate that GABA which is synthesized in a small population of GAD-positive neurons is redistributed to essentially all neurons including the glutamatergic granule cells. GAT1 is not likely involved in this redistribution since addition of 15 microM tiagabine (GAT1 inhibitor) to the culture medium had no effect on the overall GABA content of the cells. Likewise the BGT1 transporter cannot alone account for the redistribution since inclusion of 3 mM betaine in the culture medium had no effect on the overall GABA content. The inhibitory action of beta-alanine and high concentrations of nipecotic acid and guvacine on GABA transport strongly suggests that also GAT2 or GAT3 (HUGO nomenclature) could play a role."
],
"offsets": [
[
149,
2198
]
]
}
] | [
{
"id": "20512624_T1",
"type": "CHEMICAL",
"text": [
"betaine"
],
"offsets": [
[
1197,
1204
]
],
"normalized": []
},
{
"id": "20512624_T2",
"type": "CHEMICAL",
"text": [
"beta-alanine"
],
"offsets": [
[
1226,
1238
]
],
"normalized": []
},
{
"id": "20512624_T3",
"type": "CHEMICAL",
"text": [
"SKF 89976-A"
],
"offsets": [
[
1281,
1292
]
],
"normalized": []
},
{
"id": "20512624_T4",
"type": "CHEMICAL",
"text": [
"nipecotic acid"
],
"offsets": [
[
1316,
1330
]
],
"normalized": []
},
{
"id": "20512624_T5",
"type": "CHEMICAL",
"text": [
"guvacine"
],
"offsets": [
[
1335,
1343
]
],
"normalized": []
},
{
"id": "20512624_T6",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
1405,
1409
]
],
"normalized": []
},
{
"id": "20512624_T7",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
1494,
1498
]
],
"normalized": []
},
{
"id": "20512624_T8",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
296,
300
]
],
"normalized": []
},
{
"id": "20512624_T9",
"type": "CHEMICAL",
"text": [
"tiagabine"
],
"offsets": [
[
1732,
1741
]
],
"normalized": []
},
{
"id": "20512624_T10",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
1810,
1814
]
],
"normalized": []
},
{
"id": "20512624_T11",
"type": "CHEMICAL",
"text": [
"betaine"
],
"offsets": [
[
1935,
1942
]
],
"normalized": []
},
{
"id": "20512624_T12",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
1994,
1998
]
],
"normalized": []
},
{
"id": "20512624_T13",
"type": "CHEMICAL",
"text": [
"beta-alanine"
],
"offsets": [
[
2033,
2045
]
],
"normalized": []
},
{
"id": "20512624_T14",
"type": "CHEMICAL",
"text": [
"nipecotic acid"
],
"offsets": [
[
2073,
2087
]
],
"normalized": []
},
{
"id": "20512624_T15",
"type": "CHEMICAL",
"text": [
"guvacine"
],
"offsets": [
[
2092,
2100
]
],
"normalized": []
},
{
"id": "20512624_T16",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
2104,
2108
]
],
"normalized": []
},
{
"id": "20512624_T17",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
464,
468
]
],
"normalized": []
},
{
"id": "20512624_T18",
"type": "CHEMICAL",
"text": [
"glutamate"
],
"offsets": [
[
487,
496
]
],
"normalized": []
},
{
"id": "20512624_T19",
"type": "CHEMICAL",
"text": [
"tiagabine"
],
"offsets": [
[
615,
624
]
],
"normalized": []
},
{
"id": "20512624_T20",
"type": "CHEMICAL",
"text": [
"SKF 89976-A"
],
"offsets": [
[
626,
637
]
],
"normalized": []
},
{
"id": "20512624_T21",
"type": "CHEMICAL",
"text": [
"betaine"
],
"offsets": [
[
639,
646
]
],
"normalized": []
},
{
"id": "20512624_T22",
"type": "CHEMICAL",
"text": [
"beta-alanine"
],
"offsets": [
[
648,
660
]
],
"normalized": []
},
{
"id": "20512624_T23",
"type": "CHEMICAL",
"text": [
"nipecotic acid"
],
"offsets": [
[
662,
676
]
],
"normalized": []
},
{
"id": "20512624_T24",
"type": "CHEMICAL",
"text": [
"guvacine"
],
"offsets": [
[
681,
689
]
],
"normalized": []
},
{
"id": "20512624_T25",
"type": "CHEMICAL",
"text": [
"betaine"
],
"offsets": [
[
721,
728
]
],
"normalized": []
},
{
"id": "20512624_T26",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
729,
733
]
],
"normalized": []
},
{
"id": "20512624_T27",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
1096,
1100
]
],
"normalized": []
},
{
"id": "20512624_T28",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
32,
36
]
],
"normalized": []
},
{
"id": "20512624_T29",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
65,
69
]
],
"normalized": []
},
{
"id": "20512624_T30",
"type": "GENE-N",
"text": [
"GAD"
],
"offsets": [
[
1545,
1548
]
],
"normalized": []
},
{
"id": "20512624_T31",
"type": "GENE-Y",
"text": [
"GAT1"
],
"offsets": [
[
1653,
1657
]
],
"normalized": []
},
{
"id": "20512624_T32",
"type": "GENE-Y",
"text": [
"GAT1"
],
"offsets": [
[
1743,
1747
]
],
"normalized": []
},
{
"id": "20512624_T33",
"type": "GENE-Y",
"text": [
"BGT1"
],
"offsets": [
[
1850,
1854
]
],
"normalized": []
},
{
"id": "20512624_T34",
"type": "GENE-Y",
"text": [
"GAT2"
],
"offsets": [
[
2147,
2151
]
],
"normalized": []
},
{
"id": "20512624_T35",
"type": "GENE-Y",
"text": [
"GAT3"
],
"offsets": [
[
2155,
2159
]
],
"normalized": []
},
{
"id": "20512624_T36",
"type": "GENE-N",
"text": [
"GAD"
],
"offsets": [
[
459,
462
]
],
"normalized": []
},
{
"id": "20512624_T37",
"type": "GENE-N",
"text": [
"vesicular glutamate transporter"
],
"offsets": [
[
477,
508
]
],
"normalized": []
},
{
"id": "20512624_T38",
"type": "GENE-Y",
"text": [
"VGlut-1"
],
"offsets": [
[
509,
516
]
],
"normalized": []
},
{
"id": "20512624_T39",
"type": "GENE-Y",
"text": [
"GAT1"
],
"offsets": [
[
715,
719
]
],
"normalized": []
},
{
"id": "20512624_T40",
"type": "GENE-Y",
"text": [
"BGT1"
],
"offsets": [
[
735,
739
]
],
"normalized": []
},
{
"id": "20512624_T41",
"type": "GENE-Y",
"text": [
"GAT2"
],
"offsets": [
[
742,
746
]
],
"normalized": []
},
{
"id": "20512624_T42",
"type": "GENE-Y",
"text": [
"GAT3"
],
"offsets": [
[
751,
755
]
],
"normalized": []
},
{
"id": "20512624_T43",
"type": "GENE-N",
"text": [
"GAD"
],
"offsets": [
[
827,
830
]
],
"normalized": []
},
{
"id": "20512624_T44",
"type": "GENE-Y",
"text": [
"VGlut-1"
],
"offsets": [
[
858,
865
]
],
"normalized": []
},
{
"id": "20512624_T45",
"type": "GENE-N",
"text": [
"GAD"
],
"offsets": [
[
929,
932
]
],
"normalized": []
},
{
"id": "20512624_T46",
"type": "GENE-Y",
"text": [
"GAT1"
],
"offsets": [
[
27,
31
]
],
"normalized": []
},
{
"id": "20512624_T47",
"type": "GENE-Y",
"text": [
"GABA transporters"
],
"offsets": [
[
32,
49
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "20512624_0",
"type": "SUBSTRATE",
"arg1_id": "20512624_T29",
"arg2_id": "20512624_T46",
"normalized": []
},
{
"id": "20512624_1",
"type": "SUBSTRATE",
"arg1_id": "20512624_T29",
"arg2_id": "20512624_T47",
"normalized": []
},
{
"id": "20512624_2",
"type": "INHIBITOR",
"arg1_id": "20512624_T19",
"arg2_id": "20512624_T39",
"normalized": []
},
{
"id": "20512624_3",
"type": "INHIBITOR",
"arg1_id": "20512624_T20",
"arg2_id": "20512624_T39",
"normalized": []
},
{
"id": "20512624_4",
"type": "INHIBITOR",
"arg1_id": "20512624_T21",
"arg2_id": "20512624_T39",
"normalized": []
},
{
"id": "20512624_5",
"type": "INHIBITOR",
"arg1_id": "20512624_T22",
"arg2_id": "20512624_T39",
"normalized": []
},
{
"id": "20512624_6",
"type": "INHIBITOR",
"arg1_id": "20512624_T23",
"arg2_id": "20512624_T39",
"normalized": []
},
{
"id": "20512624_7",
"type": "INHIBITOR",
"arg1_id": "20512624_T24",
"arg2_id": "20512624_T39",
"normalized": []
},
{
"id": "20512624_8",
"type": "INHIBITOR",
"arg1_id": "20512624_T19",
"arg2_id": "20512624_T40",
"normalized": []
},
{
"id": "20512624_9",
"type": "INHIBITOR",
"arg1_id": "20512624_T20",
"arg2_id": "20512624_T40",
"normalized": []
},
{
"id": "20512624_10",
"type": "INHIBITOR",
"arg1_id": "20512624_T21",
"arg2_id": "20512624_T40",
"normalized": []
},
{
"id": "20512624_11",
"type": "INHIBITOR",
"arg1_id": "20512624_T22",
"arg2_id": "20512624_T40",
"normalized": []
},
{
"id": "20512624_12",
"type": "INHIBITOR",
"arg1_id": "20512624_T23",
"arg2_id": "20512624_T40",
"normalized": []
},
{
"id": "20512624_13",
"type": "INHIBITOR",
"arg1_id": "20512624_T24",
"arg2_id": "20512624_T40",
"normalized": []
},
{
"id": "20512624_14",
"type": "INHIBITOR",
"arg1_id": "20512624_T19",
"arg2_id": "20512624_T41",
"normalized": []
},
{
"id": "20512624_15",
"type": "INHIBITOR",
"arg1_id": "20512624_T20",
"arg2_id": "20512624_T41",
"normalized": []
},
{
"id": "20512624_16",
"type": "INHIBITOR",
"arg1_id": "20512624_T21",
"arg2_id": "20512624_T41",
"normalized": []
},
{
"id": "20512624_17",
"type": "INHIBITOR",
"arg1_id": "20512624_T22",
"arg2_id": "20512624_T41",
"normalized": []
},
{
"id": "20512624_18",
"type": "INHIBITOR",
"arg1_id": "20512624_T23",
"arg2_id": "20512624_T41",
"normalized": []
},
{
"id": "20512624_19",
"type": "INHIBITOR",
"arg1_id": "20512624_T24",
"arg2_id": "20512624_T41",
"normalized": []
},
{
"id": "20512624_20",
"type": "INHIBITOR",
"arg1_id": "20512624_T19",
"arg2_id": "20512624_T42",
"normalized": []
},
{
"id": "20512624_21",
"type": "INHIBITOR",
"arg1_id": "20512624_T20",
"arg2_id": "20512624_T42",
"normalized": []
},
{
"id": "20512624_22",
"type": "INHIBITOR",
"arg1_id": "20512624_T21",
"arg2_id": "20512624_T42",
"normalized": []
},
{
"id": "20512624_23",
"type": "INHIBITOR",
"arg1_id": "20512624_T22",
"arg2_id": "20512624_T42",
"normalized": []
},
{
"id": "20512624_24",
"type": "INHIBITOR",
"arg1_id": "20512624_T23",
"arg2_id": "20512624_T42",
"normalized": []
},
{
"id": "20512624_25",
"type": "INHIBITOR",
"arg1_id": "20512624_T24",
"arg2_id": "20512624_T42",
"normalized": []
},
{
"id": "20512624_26",
"type": "PRODUCT-OF",
"arg1_id": "20512624_T7",
"arg2_id": "20512624_T30",
"normalized": []
},
{
"id": "20512624_27",
"type": "INHIBITOR",
"arg1_id": "20512624_T9",
"arg2_id": "20512624_T32",
"normalized": []
},
{
"id": "20512624_28",
"type": "SUBSTRATE",
"arg1_id": "20512624_T10",
"arg2_id": "20512624_T32",
"normalized": []
},
{
"id": "20512624_29",
"type": "INHIBITOR",
"arg1_id": "20512624_T11",
"arg2_id": "20512624_T33",
"normalized": []
},
{
"id": "20512624_30",
"type": "INHIBITOR",
"arg1_id": "20512624_T13",
"arg2_id": "20512624_T34",
"normalized": []
},
{
"id": "20512624_31",
"type": "INHIBITOR",
"arg1_id": "20512624_T14",
"arg2_id": "20512624_T34",
"normalized": []
},
{
"id": "20512624_32",
"type": "INHIBITOR",
"arg1_id": "20512624_T15",
"arg2_id": "20512624_T34",
"normalized": []
},
{
"id": "20512624_33",
"type": "SUBSTRATE",
"arg1_id": "20512624_T16",
"arg2_id": "20512624_T34",
"normalized": []
},
{
"id": "20512624_34",
"type": "SUBSTRATE",
"arg1_id": "20512624_T16",
"arg2_id": "20512624_T35",
"normalized": []
},
{
"id": "20512624_35",
"type": "INHIBITOR",
"arg1_id": "20512624_T13",
"arg2_id": "20512624_T35",
"normalized": []
},
{
"id": "20512624_36",
"type": "INHIBITOR",
"arg1_id": "20512624_T14",
"arg2_id": "20512624_T35",
"normalized": []
},
{
"id": "20512624_37",
"type": "INHIBITOR",
"arg1_id": "20512624_T15",
"arg2_id": "20512624_T35",
"normalized": []
}
] |
8384226 | 8384226 | [
{
"id": "8384226_title",
"type": "title",
"text": [
"Inhibition of cytokine-primed eosinophil chemotaxis by nedocromil sodium."
],
"offsets": [
[
0,
73
]
]
},
{
"id": "8384226_abstract",
"type": "abstract",
"text": [
"BACKGROUND: Eosinophil influx into the lung tissue is considered to be relevant for the pathogenesis of asthma. Various chemotactic factors may be responsible for this influx. Recently it has been demonstrated that the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) are present in the circulation of individuals with allergic asthma. These cytokines have the capacity to modulate chemotactic responses of eosinophils toward platelet-activating factor, formyl-methionyl-leucyl-phenylalanine, (FMLP) and neutrophil-activating factor (NAF)/IL-8, but not toward complement fragment C5a (C5a). Here the effect of nedocromil sodium on the chemotactic response of eosinophils from allergic asthmatic individuals and from normal donors preincubated with GM-CSF or IL-3 toward FMLP, NAF/IL-8 was evaluated. RESULTS: Nedocromil sodium inhibited the chemotactic response toward FMLP and NAF/IL-8 of GM-CSF primed eosinophils approximately 60% (inhibitory concentration of 50% [IC50] approximately 1 to 10 nmol/L), whereas these responses of IL-3 primed eosinophils was completely inhibited (IC50 approximately 1 nmol/L). CONCLUSIONS: The chemotactic responses toward C5a were inhibited by nedocromil sodium at higher concentrations than were required in the priming studies (IC50 approximately 10 to 100 nmol/L). Nedocromil sodium (0.1 mumol/L) was also effective in inhibiting the chemotactic response toward FMLP (10 nmol/L) of eosinophils isolated from the circulation of patients with allergic asthma 3 hours after allergen challenge. These findings might explain in part the antiinflammatory action of nedocromil sodium."
],
"offsets": [
[
74,
1757
]
]
}
] | [
{
"id": "8384226_T1",
"type": "CHEMICAL",
"text": [
"nedocromil sodium"
],
"offsets": [
[
1321,
1338
]
],
"normalized": []
},
{
"id": "8384226_T2",
"type": "CHEMICAL",
"text": [
"Nedocromil sodium"
],
"offsets": [
[
1445,
1462
]
],
"normalized": []
},
{
"id": "8384226_T3",
"type": "CHEMICAL",
"text": [
"FMLP"
],
"offsets": [
[
1542,
1546
]
],
"normalized": []
},
{
"id": "8384226_T4",
"type": "CHEMICAL",
"text": [
"nedocromil sodium"
],
"offsets": [
[
1739,
1756
]
],
"normalized": []
},
{
"id": "8384226_T5",
"type": "CHEMICAL",
"text": [
"formyl-methionyl-leucyl-phenylalanine"
],
"offsets": [
[
595,
632
]
],
"normalized": []
},
{
"id": "8384226_T6",
"type": "CHEMICAL",
"text": [
"FMLP"
],
"offsets": [
[
635,
639
]
],
"normalized": []
},
{
"id": "8384226_T7",
"type": "CHEMICAL",
"text": [
"nedocromil sodium"
],
"offsets": [
[
751,
768
]
],
"normalized": []
},
{
"id": "8384226_T8",
"type": "CHEMICAL",
"text": [
"Nedocromil sodium"
],
"offsets": [
[
950,
967
]
],
"normalized": []
},
{
"id": "8384226_T9",
"type": "CHEMICAL",
"text": [
"FMLP"
],
"offsets": [
[
1010,
1014
]
],
"normalized": []
},
{
"id": "8384226_T10",
"type": "CHEMICAL",
"text": [
"nedocromil sodium"
],
"offsets": [
[
55,
72
]
],
"normalized": []
},
{
"id": "8384226_T11",
"type": "GENE-Y",
"text": [
"IL-3"
],
"offsets": [
[
1173,
1177
]
],
"normalized": []
},
{
"id": "8384226_T12",
"type": "GENE-Y",
"text": [
"C5a"
],
"offsets": [
[
1299,
1302
]
],
"normalized": []
},
{
"id": "8384226_T13",
"type": "GENE-N",
"text": [
"cytokines"
],
"offsets": [
[
293,
302
]
],
"normalized": []
},
{
"id": "8384226_T14",
"type": "GENE-Y",
"text": [
"granulocyte-macrophage colony-stimulating factor"
],
"offsets": [
[
303,
351
]
],
"normalized": []
},
{
"id": "8384226_T15",
"type": "GENE-Y",
"text": [
"GM-CSF"
],
"offsets": [
[
353,
359
]
],
"normalized": []
},
{
"id": "8384226_T16",
"type": "GENE-Y",
"text": [
"interleukin-3"
],
"offsets": [
[
362,
375
]
],
"normalized": []
},
{
"id": "8384226_T17",
"type": "GENE-Y",
"text": [
"IL-3"
],
"offsets": [
[
377,
381
]
],
"normalized": []
},
{
"id": "8384226_T18",
"type": "GENE-Y",
"text": [
"interleukin-5"
],
"offsets": [
[
388,
401
]
],
"normalized": []
},
{
"id": "8384226_T19",
"type": "GENE-Y",
"text": [
"IL-5"
],
"offsets": [
[
403,
407
]
],
"normalized": []
},
{
"id": "8384226_T20",
"type": "GENE-N",
"text": [
"cytokines"
],
"offsets": [
[
483,
492
]
],
"normalized": []
},
{
"id": "8384226_T21",
"type": "GENE-Y",
"text": [
"neutrophil-activating factor"
],
"offsets": [
[
645,
673
]
],
"normalized": []
},
{
"id": "8384226_T22",
"type": "GENE-Y",
"text": [
"NAF"
],
"offsets": [
[
675,
678
]
],
"normalized": []
},
{
"id": "8384226_T23",
"type": "GENE-Y",
"text": [
"IL-8"
],
"offsets": [
[
680,
684
]
],
"normalized": []
},
{
"id": "8384226_T24",
"type": "GENE-Y",
"text": [
"complement fragment C5a"
],
"offsets": [
[
701,
724
]
],
"normalized": []
},
{
"id": "8384226_T25",
"type": "GENE-Y",
"text": [
"C5a"
],
"offsets": [
[
726,
729
]
],
"normalized": []
},
{
"id": "8384226_T26",
"type": "GENE-Y",
"text": [
"GM-CSF"
],
"offsets": [
[
889,
895
]
],
"normalized": []
},
{
"id": "8384226_T27",
"type": "GENE-N",
"text": [
"IL-3"
],
"offsets": [
[
899,
903
]
],
"normalized": []
},
{
"id": "8384226_T28",
"type": "GENE-Y",
"text": [
"NAF"
],
"offsets": [
[
917,
920
]
],
"normalized": []
},
{
"id": "8384226_T29",
"type": "GENE-Y",
"text": [
"IL-8"
],
"offsets": [
[
921,
925
]
],
"normalized": []
},
{
"id": "8384226_T30",
"type": "GENE-Y",
"text": [
"NAF"
],
"offsets": [
[
1019,
1022
]
],
"normalized": []
},
{
"id": "8384226_T31",
"type": "GENE-Y",
"text": [
"IL-8"
],
"offsets": [
[
1023,
1027
]
],
"normalized": []
},
{
"id": "8384226_T32",
"type": "GENE-Y",
"text": [
"GM-CSF"
],
"offsets": [
[
1031,
1037
]
],
"normalized": []
},
{
"id": "8384226_T33",
"type": "GENE-N",
"text": [
"cytokine"
],
"offsets": [
[
14,
22
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "8384226_0",
"type": "INHIBITOR",
"arg1_id": "8384226_T10",
"arg2_id": "8384226_T33",
"normalized": []
},
{
"id": "8384226_1",
"type": "INHIBITOR",
"arg1_id": "8384226_T1",
"arg2_id": "8384226_T12",
"normalized": []
},
{
"id": "8384226_2",
"type": "INHIBITOR",
"arg1_id": "8384226_T8",
"arg2_id": "8384226_T30",
"normalized": []
},
{
"id": "8384226_3",
"type": "INHIBITOR",
"arg1_id": "8384226_T8",
"arg2_id": "8384226_T31",
"normalized": []
},
{
"id": "8384226_4",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "8384226_T8",
"arg2_id": "8384226_T32",
"normalized": []
},
{
"id": "8384226_5",
"type": "INHIBITOR",
"arg1_id": "8384226_T8",
"arg2_id": "8384226_T11",
"normalized": []
}
] |
16437532 | 16437532 | [
{
"id": "16437532_title",
"type": "title",
"text": [
"Cholinesterase inhibitors for Alzheimer's disease."
],
"offsets": [
[
0,
50
]
]
},
{
"id": "16437532_abstract",
"type": "abstract",
"text": [
"BACKGROUND: Since the introduction of the first cholinesterase inhibitor (ChEI) in 1997, most clinicians and probably most patients would consider the cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line pharmacotherapy for mild to moderate Alzheimer's disease.The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve is to modify the manifestations of Alzheimer's disease. Cochrane reviews of each ChEI for Alzheimer's disease have been completed (Birks 2005, Birks 2005b and Loy 2005). Despite the evidence from the clinical studies and the intervening clinical experience the debate on whether ChEIs are effective continues. OBJECTIVES: To assess the effects of donepezil, galantamine and rivastigmine in people with mild, moderate or severe dementia due to Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' , 'Aricept' , galanthamin* galantamin* reminyl, rivastigmine, exelon, \"ENA 713\" and ENA-713 on 12 June 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases. SELECTION CRITERIA: All unconfounded, blinded, randomized trials in which treatment with a ChEI was compared with placebo or another ChEI for patients with mild, moderate or severe dementia due to Alzheimer's disease. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment estimated. MAIN RESULTS: The results of 13 randomized, double blind, placebo controlled trials demonstrate that treatment for periods of 6 months and one year, with donepezil, galantamine or rivastigmine at the recommended dose for people with mild, moderate or severe dementia due to Alzheimer's disease produced improvements in cognitive function, on average -2.7 points (95%CI -3.0 to -2.3), in the midrange of the 70 point ADAS-Cog Scale. Study clinicians blind to other measures rated global clinical state more positively in treated patients. Benefits of treatment were also seen on measures of activities of daily living and behaviour. None of these treatment effects are large. There is nothing to suggest the effects are less for patients with severe dementia or mild dementia, although there is very little evidence for other than mild to moderate dementia.More patients leave ChEI treatment groups, approximately 29 %, on account of adverse events than leave the placebo groups (18%). There is evidence of more adverse events in total in the patients treated with a ChEI than with placebo. Although many types of adverse event were reported, nausea, vomiting, diarrhoea, were significantly more frequent in the ChEI groups than in placebo. There are four studies, all supported by one of the pharmaceutical companies, in which two ChEIs were compared, two studies of donepezil compared with galantamine, and two of donepezil compared with rivastigmine. In three studies the patients were not blinded to treatment, only the fourth, DON vs RIV/Bullock is double blind. Two of the studies provide little evidence, they are of 12 weeks duration, which is barely long enough to complete the drug titration. There is no evidence from DON vs GAL/Wilcock of a treatment difference between donepezil and galantamine at 52 weeks for cognition, activities of daily living, the numbers who leave the trial before the end of treatment, the number who suffer any adverse event, or any specific adverse event. There is no evidence from DON vs RIV/Bullock of a difference between donepezil and rivastigmine for cognitive function, activities of daily living and behavioural disturbance at two years. Fewer patients suffer adverse events on donepezil than rivastigmine. AUTHORS' CONCLUSIONS: The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease. It is not possible to identify those who will respond to treatment prior to treatment. There is no evidence that treatment with a ChEI is not cost effective. Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. There appears to be less adverse effects associated with donepezil compared with rivastigmine. It may be that galantamine and rivastigmine match donepezil in tolerability if a careful and gradual titration routine over more than three months is used. Titration with donepezil is more straightforward and the lower dose may be worth consideration."
],
"offsets": [
[
51,
4890
]
]
}
] | [
{
"id": "16437532_T1",
"type": "CHEMICAL",
"text": [
"donepezil"
],
"offsets": [
[
1193,
1202
]
],
"normalized": []
},
{
"id": "16437532_T2",
"type": "CHEMICAL",
"text": [
"E2020"
],
"offsets": [
[
1206,
1211
]
],
"normalized": []
},
{
"id": "16437532_T3",
"type": "CHEMICAL",
"text": [
"Aricept"
],
"offsets": [
[
1216,
1223
]
],
"normalized": []
},
{
"id": "16437532_T4",
"type": "CHEMICAL",
"text": [
"galanthamin"
],
"offsets": [
[
1227,
1238
]
],
"normalized": []
},
{
"id": "16437532_T5",
"type": "CHEMICAL",
"text": [
"galantamin"
],
"offsets": [
[
1240,
1250
]
],
"normalized": []
},
{
"id": "16437532_T6",
"type": "CHEMICAL",
"text": [
"reminyl"
],
"offsets": [
[
1252,
1259
]
],
"normalized": []
},
{
"id": "16437532_T7",
"type": "CHEMICAL",
"text": [
"rivastigmine"
],
"offsets": [
[
1261,
1273
]
],
"normalized": []
},
{
"id": "16437532_T8",
"type": "CHEMICAL",
"text": [
"exelon"
],
"offsets": [
[
1275,
1281
]
],
"normalized": []
},
{
"id": "16437532_T9",
"type": "CHEMICAL",
"text": [
"ENA 713"
],
"offsets": [
[
1284,
1291
]
],
"normalized": []
},
{
"id": "16437532_T10",
"type": "CHEMICAL",
"text": [
"ENA-713"
],
"offsets": [
[
1297,
1304
]
],
"normalized": []
},
{
"id": "16437532_T11",
"type": "CHEMICAL",
"text": [
"donepezil"
],
"offsets": [
[
221,
230
]
],
"normalized": []
},
{
"id": "16437532_T12",
"type": "CHEMICAL",
"text": [
"galantamine"
],
"offsets": [
[
232,
243
]
],
"normalized": []
},
{
"id": "16437532_T13",
"type": "CHEMICAL",
"text": [
"donepezil"
],
"offsets": [
[
2001,
2010
]
],
"normalized": []
},
{
"id": "16437532_T14",
"type": "CHEMICAL",
"text": [
"galantamine"
],
"offsets": [
[
2012,
2023
]
],
"normalized": []
},
{
"id": "16437532_T15",
"type": "CHEMICAL",
"text": [
"rivastigmine"
],
"offsets": [
[
248,
260
]
],
"normalized": []
},
{
"id": "16437532_T16",
"type": "CHEMICAL",
"text": [
"rivastigmine"
],
"offsets": [
[
2027,
2039
]
],
"normalized": []
},
{
"id": "16437532_T17",
"type": "CHEMICAL",
"text": [
"donepezil"
],
"offsets": [
[
3214,
3223
]
],
"normalized": []
},
{
"id": "16437532_T18",
"type": "CHEMICAL",
"text": [
"galantamine"
],
"offsets": [
[
3238,
3249
]
],
"normalized": []
},
{
"id": "16437532_T19",
"type": "CHEMICAL",
"text": [
"donepezil"
],
"offsets": [
[
3262,
3271
]
],
"normalized": []
},
{
"id": "16437532_T20",
"type": "CHEMICAL",
"text": [
"rivastigmine"
],
"offsets": [
[
3286,
3298
]
],
"normalized": []
},
{
"id": "16437532_T21",
"type": "CHEMICAL",
"text": [
"donepezil"
],
"offsets": [
[
3628,
3637
]
],
"normalized": []
},
{
"id": "16437532_T22",
"type": "CHEMICAL",
"text": [
"galantamine"
],
"offsets": [
[
3642,
3653
]
],
"normalized": []
},
{
"id": "16437532_T23",
"type": "CHEMICAL",
"text": [
"donepezil"
],
"offsets": [
[
3911,
3920
]
],
"normalized": []
},
{
"id": "16437532_T24",
"type": "CHEMICAL",
"text": [
"rivastigmine"
],
"offsets": [
[
3925,
3937
]
],
"normalized": []
},
{
"id": "16437532_T25",
"type": "CHEMICAL",
"text": [
"acetylcholine"
],
"offsets": [
[
451,
464
]
],
"normalized": []
},
{
"id": "16437532_T26",
"type": "CHEMICAL",
"text": [
"donepezil"
],
"offsets": [
[
4071,
4080
]
],
"normalized": []
},
{
"id": "16437532_T27",
"type": "CHEMICAL",
"text": [
"rivastigmine"
],
"offsets": [
[
4086,
4098
]
],
"normalized": []
},
{
"id": "16437532_T28",
"type": "CHEMICAL",
"text": [
"donepezil"
],
"offsets": [
[
4601,
4610
]
],
"normalized": []
},
{
"id": "16437532_T29",
"type": "CHEMICAL",
"text": [
"rivastigmine"
],
"offsets": [
[
4625,
4637
]
],
"normalized": []
},
{
"id": "16437532_T30",
"type": "CHEMICAL",
"text": [
"galantamine"
],
"offsets": [
[
4654,
4665
]
],
"normalized": []
},
{
"id": "16437532_T31",
"type": "CHEMICAL",
"text": [
"rivastigmine"
],
"offsets": [
[
4670,
4682
]
],
"normalized": []
},
{
"id": "16437532_T32",
"type": "CHEMICAL",
"text": [
"donepezil"
],
"offsets": [
[
4689,
4698
]
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{
"id": "16437532_T33",
"type": "CHEMICAL",
"text": [
"donepezil"
],
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"id": "16437532_T34",
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"donepezil"
],
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952,
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"text": [
"galantamine"
],
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963,
974
]
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"rivastigmine"
],
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"cholinesterase"
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99,
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"acetylcholinesterase"
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543,
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"type": "GENE-Y",
"text": [
"Cholinesterase"
],
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[
0,
14
]
],
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}
] | [] | [] | [
{
"id": "16437532_0",
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},
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}
] |
12401318 | 12401318 | [
{
"id": "12401318_title",
"type": "title",
"text": [
"Chemical responsiveness and histochemical phenotype of electrophysiologically classified cells of the adult rat dorsal root ganglion."
],
"offsets": [
[
0,
133
]
]
},
{
"id": "12401318_abstract",
"type": "abstract",
"text": [
"Whole cell patch recordings were obtained from medium diameter (35-45 microm) dorsal root ganglion neurons. Using electrophysiological parameters, we were able to subclassify acutely dissociated dorsal root ganglion cells into three uniform (types 5, 6 and 9) and one mixed class (type 8) of neurons. All subtypes (types 5, 6, 8 and 9) had broad action potentials (7.0+/-0.2, 5.2+/-0.4, 7.3+/-0.5 and 6.0+/-0.4 ms) and exceptionally long afterhyperpolarizations (112+/-9, 178+/-19, 124+/-31 and 204+/-33 ms). Long afterhyperpolarizations have been linked to mechanically insensitive (silent) nociceptors by other laboratories [Djouhri et al., J. Physiol. 513 (1998) 857-872]. Chemosensitivity varied among cell classes. Cell types 5, 8 and 9 were capsaicin sensitive (45+/-13, 87+/-30 and 28+/-13 pA/pF; 5 microM) groups, while the type 6 cell was capsaicin insensitive. All cell types expressed ASIC-like (acid sensing ion channel) amiloride sensitive, proton-activated currents with a threshold of pH 6.8 and a peak near pH 5.0. All medium sized cells were sensitive to ATP (50 microM) and exhibited the 'mixed' form of ATP-gated current [Burgard et al., J. Neurophysiol. 82 (1999) 1590-1598; Grubb and Evans, Eur. J. Neurosci. 11 (1999) 149-154]. Immunohistochemistry performed on individual cells indicated the expression of both P2X(1) and P2X(3) subunits. Electrophysiologically defined classes were histochemically uniform. All types were examined for the presence of substance P (SP), calcitonin gene related peptide (CGRP) and binding of isolectin B4 (IB4). All subtypes expressed CGRP immunoreactivity. Types 5 and 8 co-expressed SP and CGRP immunoreactivity and also bound IB4. Subtypes 6 and 9 were positive for neurofilament m. It is likely that these cells represent major classes of myelinated and unmyelinated peptide expressing nociceptors."
],
"offsets": [
[
134,
1991
]
]
}
] | [
{
"id": "12401318_T1",
"type": "CHEMICAL",
"text": [
"ATP"
],
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[
1206,
1209
]
],
"normalized": []
},
{
"id": "12401318_T2",
"type": "CHEMICAL",
"text": [
"ATP"
],
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[
1256,
1259
]
],
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},
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"id": "12401318_T3",
"type": "CHEMICAL",
"text": [
"substance P"
],
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[
1609,
1620
]
],
"normalized": []
},
{
"id": "12401318_T4",
"type": "CHEMICAL",
"text": [
"SP"
],
"offsets": [
[
1622,
1624
]
],
"normalized": []
},
{
"id": "12401318_T5",
"type": "CHEMICAL",
"text": [
"SP"
],
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[
1774,
1776
]
],
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},
{
"id": "12401318_T6",
"type": "CHEMICAL",
"text": [
"capsaicin"
],
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[
881,
890
]
],
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},
{
"id": "12401318_T7",
"type": "CHEMICAL",
"text": [
"capsaicin"
],
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[
982,
991
]
],
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},
{
"id": "12401318_T8",
"type": "CHEMICAL",
"text": [
"amiloride"
],
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[
1067,
1076
]
],
"normalized": []
},
{
"id": "12401318_T9",
"type": "GENE-Y",
"text": [
"P2X(1)"
],
"offsets": [
[
1468,
1474
]
],
"normalized": []
},
{
"id": "12401318_T10",
"type": "GENE-Y",
"text": [
"P2X(3)"
],
"offsets": [
[
1479,
1485
]
],
"normalized": []
},
{
"id": "12401318_T11",
"type": "GENE-Y",
"text": [
"substance P"
],
"offsets": [
[
1609,
1620
]
],
"normalized": []
},
{
"id": "12401318_T12",
"type": "GENE-Y",
"text": [
"SP"
],
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[
1622,
1624
]
],
"normalized": []
},
{
"id": "12401318_T13",
"type": "GENE-N",
"text": [
"calcitonin gene related peptide"
],
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[
1627,
1658
]
],
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},
{
"id": "12401318_T14",
"type": "GENE-N",
"text": [
"CGRP"
],
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[
1660,
1664
]
],
"normalized": []
},
{
"id": "12401318_T15",
"type": "GENE-Y",
"text": [
"isolectin B4"
],
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[
1681,
1693
]
],
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},
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"id": "12401318_T16",
"type": "GENE-Y",
"text": [
"IB4"
],
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[
1695,
1698
]
],
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},
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"id": "12401318_T17",
"type": "GENE-N",
"text": [
"CGRP"
],
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[
1724,
1728
]
],
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},
{
"id": "12401318_T18",
"type": "GENE-Y",
"text": [
"SP"
],
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[
1774,
1776
]
],
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},
{
"id": "12401318_T19",
"type": "GENE-N",
"text": [
"CGRP"
],
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[
1781,
1785
]
],
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},
{
"id": "12401318_T20",
"type": "GENE-Y",
"text": [
"IB4"
],
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[
1818,
1821
]
],
"normalized": []
},
{
"id": "12401318_T21",
"type": "GENE-Y",
"text": [
"neurofilament m"
],
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[
1858,
1873
]
],
"normalized": []
},
{
"id": "12401318_T22",
"type": "GENE-N",
"text": [
"nociceptors"
],
"offsets": [
[
1979,
1990
]
],
"normalized": []
},
{
"id": "12401318_T23",
"type": "GENE-N",
"text": [
"nociceptors"
],
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[
726,
737
]
],
"normalized": []
},
{
"id": "12401318_T24",
"type": "GENE-N",
"text": [
"ASIC"
],
"offsets": [
[
1030,
1034
]
],
"normalized": []
},
{
"id": "12401318_T25",
"type": "GENE-N",
"text": [
"acid sensing ion channel"
],
"offsets": [
[
1041,
1065
]
],
"normalized": []
}
] | [] | [] | [] |
23229509 | 23229509 | [
{
"id": "23229509_title",
"type": "title",
"text": [
"Regions on adenylyl cyclase VII required for selective regulation by the G13 pathway."
],
"offsets": [
[
0,
85
]
]
},
{
"id": "23229509_abstract",
"type": "abstract",
"text": [
"Regulation of multiple adenylyl cyclases (AC) provides unique inputs to mediate the synthesis of cAMP, a ubiquitous second messenger that controls many aspects of cellular function. On stimulation by G(s), the activities of ACs can be further selectively modulated by other pathways to ensure precise control of intracellular cAMP responses to specific stimuli. Recently, we reported that one of the AC isoforms, AC7, is uniquely regulated by the G(13) pathway. To understand more fully the molecular mechanism of this regulation, we compared the regulation of AC7 with that of AC2 in bone marrow-derived macrophages devoid of AC7. Although both enzymes could fully restore regulation of cAMP by Gβγ, activation of the G(13) pathway preferentially synergized with AC7. Exchange of domains between the two isoforms indicates that the C1b domain and the N-terminus of the C1a domain are important for directing selective regulation of AC7 by the G(13) pathway. A mutagenesis screen identified more specific regions of AC7 that differentially mediate its regulation by distinct pathways."
],
"offsets": [
[
86,
1170
]
]
}
] | [
{
"id": "23229509_T1",
"type": "CHEMICAL",
"text": [
"adenylyl"
],
"offsets": [
[
109,
117
]
],
"normalized": []
},
{
"id": "23229509_T2",
"type": "CHEMICAL",
"text": [
"cAMP"
],
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[
412,
416
]
],
"normalized": []
},
{
"id": "23229509_T3",
"type": "CHEMICAL",
"text": [
"cAMP"
],
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[
774,
778
]
],
"normalized": []
},
{
"id": "23229509_T4",
"type": "CHEMICAL",
"text": [
"N"
],
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938,
939
]
],
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},
{
"id": "23229509_T5",
"type": "CHEMICAL",
"text": [
"cAMP"
],
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[
183,
187
]
],
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},
{
"id": "23229509_T6",
"type": "CHEMICAL",
"text": [
"adenylyl"
],
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[
11,
19
]
],
"normalized": []
},
{
"id": "23229509_T7",
"type": "GENE-Y",
"text": [
"AC7"
],
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[
1102,
1105
]
],
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},
{
"id": "23229509_T8",
"type": "GENE-N",
"text": [
"G(s)"
],
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[
286,
290
]
],
"normalized": []
},
{
"id": "23229509_T9",
"type": "GENE-N",
"text": [
"ACs"
],
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[
310,
313
]
],
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},
{
"id": "23229509_T10",
"type": "GENE-N",
"text": [
"adenylyl cyclases"
],
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[
109,
126
]
],
"normalized": []
},
{
"id": "23229509_T11",
"type": "GENE-N",
"text": [
"AC"
],
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[
486,
488
]
],
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},
{
"id": "23229509_T12",
"type": "GENE-Y",
"text": [
"AC7"
],
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[
499,
502
]
],
"normalized": []
},
{
"id": "23229509_T13",
"type": "GENE-N",
"text": [
"AC"
],
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[
128,
130
]
],
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},
{
"id": "23229509_T14",
"type": "GENE-Y",
"text": [
"G(13)"
],
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533,
538
]
],
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},
{
"id": "23229509_T15",
"type": "GENE-Y",
"text": [
"AC7"
],
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[
647,
650
]
],
"normalized": []
},
{
"id": "23229509_T16",
"type": "GENE-Y",
"text": [
"AC2"
],
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[
664,
667
]
],
"normalized": []
},
{
"id": "23229509_T17",
"type": "GENE-Y",
"text": [
"AC7"
],
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[
713,
716
]
],
"normalized": []
},
{
"id": "23229509_T18",
"type": "GENE-N",
"text": [
"Gβγ"
],
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[
782,
785
]
],
"normalized": []
},
{
"id": "23229509_T19",
"type": "GENE-Y",
"text": [
"G(13)"
],
"offsets": [
[
805,
810
]
],
"normalized": []
},
{
"id": "23229509_T20",
"type": "GENE-Y",
"text": [
"AC7"
],
"offsets": [
[
850,
853
]
],
"normalized": []
},
{
"id": "23229509_T21",
"type": "GENE-N",
"text": [
"C1b domain"
],
"offsets": [
[
919,
929
]
],
"normalized": []
},
{
"id": "23229509_T22",
"type": "GENE-N",
"text": [
"C1a domain"
],
"offsets": [
[
956,
966
]
],
"normalized": []
},
{
"id": "23229509_T23",
"type": "GENE-Y",
"text": [
"AC7"
],
"offsets": [
[
1019,
1022
]
],
"normalized": []
},
{
"id": "23229509_T24",
"type": "GENE-Y",
"text": [
"G(13)"
],
"offsets": [
[
1030,
1035
]
],
"normalized": []
},
{
"id": "23229509_T25",
"type": "GENE-Y",
"text": [
"adenylyl cyclase VII"
],
"offsets": [
[
11,
31
]
],
"normalized": []
},
{
"id": "23229509_T26",
"type": "GENE-Y",
"text": [
"G13"
],
"offsets": [
[
73,
76
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23229509_0",
"type": "PRODUCT-OF",
"arg1_id": "23229509_T5",
"arg2_id": "23229509_T10",
"normalized": []
},
{
"id": "23229509_1",
"type": "PRODUCT-OF",
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"arg2_id": "23229509_T13",
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},
{
"id": "23229509_2",
"type": "PRODUCT-OF",
"arg1_id": "23229509_T2",
"arg2_id": "23229509_T9",
"normalized": []
},
{
"id": "23229509_3",
"type": "PART-OF",
"arg1_id": "23229509_T4",
"arg2_id": "23229509_T22",
"normalized": []
}
] |
22849656 | 22849656 | [
{
"id": "22849656_title",
"type": "title",
"text": [
"NT, NPY and PGP 9.5 presence in myomeytrium and in fibroid pseudocapsule and their possible impact on muscular physiology."
],
"offsets": [
[
0,
122
]
]
},
{
"id": "22849656_abstract",
"type": "abstract",
"text": [
"The uterine myoma pseudocapsule is a neurovascular bundle surrounding fibroid, containing neuropeptides, probably involved in uterine scar healing. We studied neurotensin (NT), neuropeptide tyrosine (NPY), and protein gene product 9.5 (PGP 9.5) nerve fibres in the pseudocapsule neurovascular bundle of intramural uterine fibroids on 67 no pregnant women by intracapsular myomectomy sparing the neurovascular bundle, sampling full thickness specimens of the pseudocapsule of uterine fibroids (PUF) and normal myometrium (NM) obtained from the fundus uteri (FU) and the uterine body (UB). The samples were sent for histological and immunofluorescent analyses and compared by morphometrical quantification. The Conventional Unit (C.U.) difference of NT, NPY, and PGP 9.5 nerve fibres was statistically analyzed. Our results showed that NT, NPY, and PGP 9.5 neurofibers are almost equally present in PUF as in NM of a no pregnant uterus. As all of these neuropeptides are present in the uterine muscle and can affect muscle contractility, uterine peristalsis and muscular healing. A myomectomy respecting the pseudocapsule neurofibers should facilitate smooth muscle scarring and promote restoration of normal uterine peristalsis with a possible positive influence on fertility."
],
"offsets": [
[
123,
1398
]
]
}
] | [
{
"id": "22849656_T1",
"type": "CHEMICAL",
"text": [
"neurotensin"
],
"offsets": [
[
282,
293
]
],
"normalized": []
},
{
"id": "22849656_T2",
"type": "CHEMICAL",
"text": [
"tyrosine"
],
"offsets": [
[
313,
321
]
],
"normalized": []
},
{
"id": "22849656_T3",
"type": "GENE-Y",
"text": [
"neurotensin"
],
"offsets": [
[
282,
293
]
],
"normalized": []
},
{
"id": "22849656_T4",
"type": "GENE-Y",
"text": [
"NT"
],
"offsets": [
[
295,
297
]
],
"normalized": []
},
{
"id": "22849656_T5",
"type": "GENE-Y",
"text": [
"neuropeptide tyrosine"
],
"offsets": [
[
300,
321
]
],
"normalized": []
},
{
"id": "22849656_T6",
"type": "GENE-Y",
"text": [
"NPY"
],
"offsets": [
[
323,
326
]
],
"normalized": []
},
{
"id": "22849656_T7",
"type": "GENE-Y",
"text": [
"protein gene product 9.5"
],
"offsets": [
[
333,
357
]
],
"normalized": []
},
{
"id": "22849656_T8",
"type": "GENE-Y",
"text": [
"PGP 9.5"
],
"offsets": [
[
359,
366
]
],
"normalized": []
},
{
"id": "22849656_T9",
"type": "GENE-Y",
"text": [
"NT"
],
"offsets": [
[
871,
873
]
],
"normalized": []
},
{
"id": "22849656_T10",
"type": "GENE-Y",
"text": [
"NPY"
],
"offsets": [
[
875,
878
]
],
"normalized": []
},
{
"id": "22849656_T11",
"type": "GENE-Y",
"text": [
"PGP 9.5"
],
"offsets": [
[
884,
891
]
],
"normalized": []
},
{
"id": "22849656_T12",
"type": "GENE-Y",
"text": [
"NT"
],
"offsets": [
[
957,
959
]
],
"normalized": []
},
{
"id": "22849656_T13",
"type": "GENE-Y",
"text": [
"NPY"
],
"offsets": [
[
961,
964
]
],
"normalized": []
},
{
"id": "22849656_T14",
"type": "GENE-Y",
"text": [
"PGP 9.5"
],
"offsets": [
[
970,
977
]
],
"normalized": []
},
{
"id": "22849656_T15",
"type": "GENE-Y",
"text": [
"NT"
],
"offsets": [
[
0,
2
]
],
"normalized": []
},
{
"id": "22849656_T16",
"type": "GENE-Y",
"text": [
"PGP 9.5"
],
"offsets": [
[
12,
19
]
],
"normalized": []
},
{
"id": "22849656_T17",
"type": "GENE-Y",
"text": [
"NPY"
],
"offsets": [
[
4,
7
]
],
"normalized": []
}
] | [] | [] | [] |
16546990 | 16546990 | [
{
"id": "16546990_title",
"type": "title",
"text": [
"Sulindac independently modulates extracellular signal-regulated kinase 1/2 and cyclic GMP-dependent protein kinase signaling pathways."
],
"offsets": [
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0,
134
]
]
},
{
"id": "16546990_abstract",
"type": "abstract",
"text": [
"Colorectal cancer is the second leading cause of cancer mortality in the United States. Substantial human and animal data support the ability of nonsteroidal anti-inflammatory drugs to cause regression of existing colon tumors and prevent new tumor formation. The mechanism by which the nonsteroidal anti-inflammatory drug sulindac prevents tumor growth is poorly understood and seems complex as sulindac can modulate several growth-related signaling pathways. Sulindac metabolites simultaneously (a) increase cellular cyclic GMP and subsequently activate cyclic GMP-dependent protein kinase (PKG); (b) activate c-jun NH2-terminal kinase (JNK); (c) inhibit extracellular signal-regulated kinase 1/2 (ERK1/2); and (d) decrease beta-catenin protein expression at times and doses consistent with apoptosis. The purpose of this study was to determine if PKG, ERK1/2, JNK, and beta-catenin are independent targets for sulindac in vitro. Pharmacologic activation of PKG with YC-1 increases JNK phosphorylation and induces apoptosis in colon cancer cells without modulating ERK1/2 phosphorylation or beta-catenin protein expression. Inhibition of ERK1/2 with U0126 induces apoptosis but fails to activate JNK phosphorylation or down-regulate beta-catenin protein expression. Cotreatment with U0126 and YC-1 synergistically increases apoptosis in colorectal cancer cells and recapitulates the effects of sulindac treatment on ERK1/2, JNK, and beta-catenin. These results indicate that sulindac metabolites modulate ERK1/2 and PKG pathways independently in colon cancer cells and suggest that the full apoptotic effect of sulindac is mediated by more than one pathway. Using similar combinatorial approaches in vivo may provide more effective, less toxic chemopreventive and chemotherapeutic strategies. Such therapies could dramatically reduce the incidence and death rate from colorectal cancer."
],
"offsets": [
[
135,
2023
]
]
}
] | [
{
"id": "16546990_T1",
"type": "CHEMICAL",
"text": [
"U0126"
],
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[
1287,
1292
]
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"id": "16546990_T2",
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"text": [
"U0126"
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1420,
1425
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"id": "16546990_T3",
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"text": [
"YC-1"
],
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1430,
1434
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"id": "16546990_T4",
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"sulindac"
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1531,
1539
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"sulindac"
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1612,
1620
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"sulindac"
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1748,
1756
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458,
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"id": "16546990_T8",
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539
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596,
604
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654,
664
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"id": "16546990_T11",
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"cyclic GMP"
],
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691,
701
]
],
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"id": "16546990_T12",
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"text": [
"NH2"
],
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753,
756
]
],
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"id": "16546990_T13",
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"text": [
"sulindac"
],
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1048,
1056
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],
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},
{
"id": "16546990_T14",
"type": "CHEMICAL",
"text": [
"YC-1"
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1104,
1108
]
],
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"id": "16546990_T15",
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"Sulindac"
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0,
8
]
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"id": "16546990_T16",
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"text": [
"cyclic GMP"
],
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79,
89
]
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},
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"id": "16546990_T17",
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"ERK1/2"
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1202,
1208
]
],
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},
{
"id": "16546990_T18",
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"beta-catenin"
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1228,
1240
]
],
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},
{
"id": "16546990_T19",
"type": "GENE-N",
"text": [
"ERK1/2"
],
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[
1275,
1281
]
],
"normalized": []
},
{
"id": "16546990_T20",
"type": "GENE-N",
"text": [
"JNK"
],
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[
1333,
1336
]
],
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},
{
"id": "16546990_T21",
"type": "GENE-Y",
"text": [
"beta-catenin"
],
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[
1370,
1382
]
],
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},
{
"id": "16546990_T22",
"type": "GENE-N",
"text": [
"ERK1/2"
],
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[
1553,
1559
]
],
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},
{
"id": "16546990_T23",
"type": "GENE-N",
"text": [
"JNK"
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[
1561,
1564
]
],
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},
{
"id": "16546990_T24",
"type": "GENE-Y",
"text": [
"beta-catenin"
],
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1570,
1582
]
],
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},
{
"id": "16546990_T25",
"type": "GENE-N",
"text": [
"ERK1/2"
],
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[
1642,
1648
]
],
"normalized": []
},
{
"id": "16546990_T26",
"type": "GENE-N",
"text": [
"PKG"
],
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[
1653,
1656
]
],
"normalized": []
},
{
"id": "16546990_T27",
"type": "GENE-N",
"text": [
"cyclic GMP-dependent protein kinase"
],
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691,
726
]
],
"normalized": []
},
{
"id": "16546990_T28",
"type": "GENE-N",
"text": [
"PKG"
],
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728,
731
]
],
"normalized": []
},
{
"id": "16546990_T29",
"type": "GENE-N",
"text": [
"c-jun NH2-terminal kinase"
],
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747,
772
]
],
"normalized": []
},
{
"id": "16546990_T30",
"type": "GENE-N",
"text": [
"JNK"
],
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774,
777
]
],
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},
{
"id": "16546990_T31",
"type": "GENE-N",
"text": [
"extracellular signal-regulated kinase 1/2"
],
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[
792,
833
]
],
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},
{
"id": "16546990_T32",
"type": "GENE-N",
"text": [
"ERK1/2"
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835,
841
]
],
"normalized": []
},
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"id": "16546990_T33",
"type": "GENE-Y",
"text": [
"beta-catenin"
],
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[
861,
873
]
],
"normalized": []
},
{
"id": "16546990_T34",
"type": "GENE-N",
"text": [
"PKG"
],
"offsets": [
[
985,
988
]
],
"normalized": []
},
{
"id": "16546990_T35",
"type": "GENE-N",
"text": [
"ERK1/2"
],
"offsets": [
[
990,
996
]
],
"normalized": []
},
{
"id": "16546990_T36",
"type": "GENE-N",
"text": [
"JNK"
],
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998,
1001
]
],
"normalized": []
},
{
"id": "16546990_T37",
"type": "GENE-Y",
"text": [
"beta-catenin"
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1007,
1019
]
],
"normalized": []
},
{
"id": "16546990_T38",
"type": "GENE-N",
"text": [
"PKG"
],
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[
1095,
1098
]
],
"normalized": []
},
{
"id": "16546990_T39",
"type": "GENE-N",
"text": [
"JNK"
],
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1119,
1122
]
],
"normalized": []
},
{
"id": "16546990_T40",
"type": "GENE-N",
"text": [
"extracellular signal-regulated kinase 1/2"
],
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33,
74
]
],
"normalized": []
},
{
"id": "16546990_T41",
"type": "GENE-N",
"text": [
"cyclic GMP-dependent protein kinase"
],
"offsets": [
[
79,
114
]
],
"normalized": []
}
] | [] | [] | [
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"arg2_id": "16546990_T27",
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},
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"arg1_id": "16546990_T3",
"arg2_id": "16546990_T24",
"normalized": []
}
] |
1712335 | 1712335 | [
{
"id": "1712335_title",
"type": "title",
"text": [
"Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol."
],
"offsets": [
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0,
107
]
]
},
{
"id": "1712335_abstract",
"type": "abstract",
"text": [
"The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. Carvedilol produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)"
],
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[
108,
2821
]
]
}
] | [
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1423,
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1528,
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1554,
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1635,
1645
]
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"id": "1712335_T7",
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"calcium"
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1799,
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]
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"id": "1712335_T8",
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1826,
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]
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},
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"id": "1712335_T9",
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"calcium"
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1897,
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]
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},
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"id": "1712335_T10",
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"calcium"
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1964,
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]
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},
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"id": "1712335_T11",
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"carvedilol"
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"calcium"
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2349,
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2424,
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2745,
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771,
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"id": "1712335_T24",
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902,
915
]
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"carvedilol"
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935,
945
]
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},
{
"id": "1712335_T26",
"type": "CHEMICAL",
"text": [
"salbutamol"
],
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[
1045,
1055
]
],
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},
{
"id": "1712335_T27",
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"racemic carvedilol"
],
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[
206,
224
]
],
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},
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"id": "1712335_T28",
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"carvedilol"
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96,
106
]
],
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},
{
"id": "1712335_T29",
"type": "GENE-Y",
"text": [
"angiotensin II"
],
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[
1143,
1157
]
],
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},
{
"id": "1712335_T30",
"type": "GENE-N",
"text": [
"beta 1 and beta 2 adrenoceptors"
],
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[
1188,
1219
]
],
"normalized": []
},
{
"id": "1712335_T31",
"type": "GENE-Y",
"text": [
"beta 1 adrenoceptor"
],
"offsets": [
[
1294,
1313
]
],
"normalized": []
},
{
"id": "1712335_T32",
"type": "GENE-N",
"text": [
"alpha 1 adrenoceptor"
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[
1373,
1393
]
],
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},
{
"id": "1712335_T33",
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"text": [
"alpha 2 adrenoceptor"
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[
1478,
1498
]
],
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},
{
"id": "1712335_T34",
"type": "GENE-N",
"text": [
"beta adrenoceptor"
],
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246,
263
]
],
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},
{
"id": "1712335_T35",
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"text": [
"alpha 1 adrenoceptor"
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[
1576,
1596
]
],
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},
{
"id": "1712335_T36",
"type": "GENE-Y",
"text": [
"angiotensin II"
],
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[
1696,
1710
]
],
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},
{
"id": "1712335_T37",
"type": "GENE-N",
"text": [
"calcium channel"
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1799,
1814
]
],
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},
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"id": "1712335_T38",
"type": "GENE-N",
"text": [
"voltage dependent calcium channels"
],
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1879,
1913
]
],
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},
{
"id": "1712335_T39",
"type": "GENE-N",
"text": [
"calcium channel"
],
"offsets": [
[
2067,
2082
]
],
"normalized": []
},
{
"id": "1712335_T40",
"type": "GENE-N",
"text": [
"alpha 1 adrenoceptor"
],
"offsets": [
[
2316,
2336
]
],
"normalized": []
},
{
"id": "1712335_T41",
"type": "GENE-N",
"text": [
"beta adrenoceptor"
],
"offsets": [
[
2394,
2411
]
],
"normalized": []
},
{
"id": "1712335_T42",
"type": "GENE-N",
"text": [
"beta and alpha 1 adrenoceptors"
],
"offsets": [
[
2572,
2602
]
],
"normalized": []
},
{
"id": "1712335_T43",
"type": "GENE-N",
"text": [
"beta 1, beta 2, and alpha 1 adrenoceptors"
],
"offsets": [
[
2690,
2731
]
],
"normalized": []
},
{
"id": "1712335_T44",
"type": "GENE-N",
"text": [
"calcium channels"
],
"offsets": [
[
2745,
2761
]
],
"normalized": []
},
{
"id": "1712335_T45",
"type": "GENE-Y",
"text": [
"beta 1 adrenoceptor"
],
"offsets": [
[
839,
858
]
],
"normalized": []
},
{
"id": "1712335_T46",
"type": "GENE-Y",
"text": [
"beta 2 adrenoceptor"
],
"offsets": [
[
990,
1009
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "1712335_0",
"type": "ANTAGONIST",
"arg1_id": "1712335_T27",
"arg2_id": "1712335_T34",
"normalized": []
},
{
"id": "1712335_1",
"type": "INHIBITOR",
"arg1_id": "1712335_T23",
"arg2_id": "1712335_T45",
"normalized": []
},
{
"id": "1712335_2",
"type": "ACTIVATOR",
"arg1_id": "1712335_T24",
"arg2_id": "1712335_T45",
"normalized": []
},
{
"id": "1712335_3",
"type": "INHIBITOR",
"arg1_id": "1712335_T25",
"arg2_id": "1712335_T46",
"normalized": []
},
{
"id": "1712335_4",
"type": "INHIBITOR",
"arg1_id": "1712335_T1",
"arg2_id": "1712335_T31",
"normalized": []
},
{
"id": "1712335_5",
"type": "INHIBITOR",
"arg1_id": "1712335_T2",
"arg2_id": "1712335_T32",
"normalized": []
},
{
"id": "1712335_6",
"type": "ANTAGONIST",
"arg1_id": "1712335_T5",
"arg2_id": "1712335_T35",
"normalized": []
},
{
"id": "1712335_7",
"type": "ACTIVATOR",
"arg1_id": "1712335_T8",
"arg2_id": "1712335_T37",
"normalized": []
},
{
"id": "1712335_8",
"type": "ACTIVATOR",
"arg1_id": "1712335_T8",
"arg2_id": "1712335_T38",
"normalized": []
},
{
"id": "1712335_9",
"type": "SUBSTRATE",
"arg1_id": "1712335_T10",
"arg2_id": "1712335_T38",
"normalized": []
},
{
"id": "1712335_10",
"type": "INHIBITOR",
"arg1_id": "1712335_T11",
"arg2_id": "1712335_T38",
"normalized": []
},
{
"id": "1712335_11",
"type": "ANTAGONIST",
"arg1_id": "1712335_T12",
"arg2_id": "1712335_T39",
"normalized": []
},
{
"id": "1712335_12",
"type": "ANTAGONIST",
"arg1_id": "1712335_T15",
"arg2_id": "1712335_T40",
"normalized": []
},
{
"id": "1712335_13",
"type": "ANTAGONIST",
"arg1_id": "1712335_T16",
"arg2_id": "1712335_T41",
"normalized": []
},
{
"id": "1712335_14",
"type": "ANTAGONIST",
"arg1_id": "1712335_T19",
"arg2_id": "1712335_T44",
"normalized": []
}
] |
23200253 | 23200253 | [
{
"id": "23200253_title",
"type": "title",
"text": [
"Further exploration of M₁ allosteric agonists: subtle structural changes abolish M₁ allosteric agonism and result in pan-mAChR orthosteric antagonism."
],
"offsets": [
[
0,
150
]
]
},
{
"id": "23200253_abstract",
"type": "abstract",
"text": [
"This letter describes the further exploration of two series of M(1) allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M(1) allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M(1) allosteric agonist family (VU0357017) identified similar, subtle 'molecular switches' that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M(1) activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and mAChR antagonism."
],
"offsets": [
[
151,
1072
]
]
}
] | [
{
"id": "23200253_T1",
"type": "CHEMICAL",
"text": [
"TPBP"
],
"offsets": [
[
305,
309
]
],
"normalized": []
},
{
"id": "23200253_T2",
"type": "CHEMICAL",
"text": [
"piperidine"
],
"offsets": [
[
377,
387
]
],
"normalized": []
},
{
"id": "23200253_T3",
"type": "CHEMICAL",
"text": [
"VU0357017"
],
"offsets": [
[
607,
616
]
],
"normalized": []
},
{
"id": "23200253_T4",
"type": "CHEMICAL",
"text": [
"TBPB"
],
"offsets": [
[
240,
244
]
],
"normalized": []
},
{
"id": "23200253_T5",
"type": "CHEMICAL",
"text": [
"VU0357017"
],
"offsets": [
[
249,
258
]
],
"normalized": []
},
{
"id": "23200253_T6",
"type": "GENE-N",
"text": [
"mAChR"
],
"offsets": [
[
461,
466
]
],
"normalized": []
},
{
"id": "23200253_T7",
"type": "GENE-N",
"text": [
"mAChR"
],
"offsets": [
[
734,
739
]
],
"normalized": []
},
{
"id": "23200253_T8",
"type": "GENE-N",
"text": [
"mAChR"
],
"offsets": [
[
1055,
1060
]
],
"normalized": []
},
{
"id": "23200253_T9",
"type": "GENE-N",
"text": [
"mAChR"
],
"offsets": [
[
121,
126
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23200253_0",
"type": "ANTAGONIST",
"arg1_id": "23200253_T2",
"arg2_id": "23200253_T6",
"normalized": []
},
{
"id": "23200253_1",
"type": "ANTAGONIST",
"arg1_id": "23200253_T1",
"arg2_id": "23200253_T6",
"normalized": []
},
{
"id": "23200253_2",
"type": "ANTAGONIST",
"arg1_id": "23200253_T3",
"arg2_id": "23200253_T7",
"normalized": []
}
] |
23411172 | 23411172 | [
{
"id": "23411172_title",
"type": "title",
"text": [
"Apple polyphenols suppress antigen presentation of ovalbumin by THP-1-derived dendritic cells."
],
"offsets": [
[
0,
94
]
]
},
{
"id": "23411172_abstract",
"type": "abstract",
"text": [
"Apple polyphenol extract (AP) and procyanidin contained in AP were investigated for their immunomodulatory effects using THP-1-derived human dendritic cells (TDDCs). The expression levels of HLA-DR (MHC class II) and CD86 (costimulatory molecule) were measured as an indicator of antigen presentation in TDDCs. A significant decrease in HLA-DR expression was observed in the AP and fractionated procyanidin-treated cells in the presence of ovalbumin (OVA), but no effect on CD86 expression was observed. The uptake of OVA was not inhibited by AP treatment, and the gene expression of membrane-associated RING-CH ubiquitin E3 ligase, MARCH1, was up-regulated by AP treatment. It can therefore be presumed that AP suppresses HLA-DR expression via the ubiquitin-proteasome pathway. Furthermore, the up-regulation of IL-12 and TNF-α was found in the procyanidin trimers-treated cells in the presence of OVA. These results suggest that apple polyphenols would be an effective factor for the development of immunomodulatory agents with suppressive effects of antigen presentation."
],
"offsets": [
[
95,
1169
]
]
}
] | [
{
"id": "23411172_T1",
"type": "CHEMICAL",
"text": [
"procyanidin"
],
"offsets": [
[
129,
140
]
],
"normalized": []
},
{
"id": "23411172_T2",
"type": "CHEMICAL",
"text": [
"procyanidin"
],
"offsets": [
[
490,
501
]
],
"normalized": []
},
{
"id": "23411172_T3",
"type": "CHEMICAL",
"text": [
"polyphenol"
],
"offsets": [
[
101,
111
]
],
"normalized": []
},
{
"id": "23411172_T4",
"type": "CHEMICAL",
"text": [
"procyanidin"
],
"offsets": [
[
941,
952
]
],
"normalized": []
},
{
"id": "23411172_T5",
"type": "CHEMICAL",
"text": [
"polyphenols"
],
"offsets": [
[
1032,
1043
]
],
"normalized": []
},
{
"id": "23411172_T6",
"type": "CHEMICAL",
"text": [
"polyphenols"
],
"offsets": [
[
6,
17
]
],
"normalized": []
},
{
"id": "23411172_T7",
"type": "GENE-N",
"text": [
"HLA-DR"
],
"offsets": [
[
286,
292
]
],
"normalized": []
},
{
"id": "23411172_T8",
"type": "GENE-N",
"text": [
"MHC class II"
],
"offsets": [
[
294,
306
]
],
"normalized": []
},
{
"id": "23411172_T9",
"type": "GENE-N",
"text": [
"CD86"
],
"offsets": [
[
312,
316
]
],
"normalized": []
},
{
"id": "23411172_T10",
"type": "GENE-N",
"text": [
"HLA-DR"
],
"offsets": [
[
432,
438
]
],
"normalized": []
},
{
"id": "23411172_T11",
"type": "GENE-N",
"text": [
"ovalbumin"
],
"offsets": [
[
535,
544
]
],
"normalized": []
},
{
"id": "23411172_T12",
"type": "GENE-N",
"text": [
"OVA"
],
"offsets": [
[
546,
549
]
],
"normalized": []
},
{
"id": "23411172_T13",
"type": "GENE-N",
"text": [
"CD86"
],
"offsets": [
[
569,
573
]
],
"normalized": []
},
{
"id": "23411172_T14",
"type": "GENE-N",
"text": [
"OVA"
],
"offsets": [
[
613,
616
]
],
"normalized": []
},
{
"id": "23411172_T15",
"type": "GENE-N",
"text": [
"RING-CH"
],
"offsets": [
[
699,
706
]
],
"normalized": []
},
{
"id": "23411172_T16",
"type": "GENE-N",
"text": [
"ubiquitin E3 ligase"
],
"offsets": [
[
707,
726
]
],
"normalized": []
},
{
"id": "23411172_T17",
"type": "GENE-N",
"text": [
"MARCH1"
],
"offsets": [
[
728,
734
]
],
"normalized": []
},
{
"id": "23411172_T18",
"type": "GENE-N",
"text": [
"HLA-DR"
],
"offsets": [
[
818,
824
]
],
"normalized": []
},
{
"id": "23411172_T19",
"type": "GENE-N",
"text": [
"ubiquitin"
],
"offsets": [
[
844,
853
]
],
"normalized": []
},
{
"id": "23411172_T20",
"type": "GENE-N",
"text": [
"proteasome"
],
"offsets": [
[
854,
864
]
],
"normalized": []
},
{
"id": "23411172_T21",
"type": "GENE-N",
"text": [
"IL-12"
],
"offsets": [
[
908,
913
]
],
"normalized": []
},
{
"id": "23411172_T22",
"type": "GENE-N",
"text": [
"TNF-α"
],
"offsets": [
[
918,
923
]
],
"normalized": []
},
{
"id": "23411172_T23",
"type": "GENE-N",
"text": [
"OVA"
],
"offsets": [
[
994,
997
]
],
"normalized": []
},
{
"id": "23411172_T24",
"type": "GENE-N",
"text": [
"ovalbumin"
],
"offsets": [
[
51,
60
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23411172_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23411172_T2",
"arg2_id": "23411172_T10",
"normalized": []
},
{
"id": "23411172_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23411172_T4",
"arg2_id": "23411172_T21",
"normalized": []
},
{
"id": "23411172_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23411172_T4",
"arg2_id": "23411172_T22",
"normalized": []
}
] |
23597099 | 23597099 | [
{
"id": "23597099_title",
"type": "title",
"text": [
"2-Methoxyjuglone Induces Apoptosis in HepG2 Human Hepatocellular Carcinoma Cells and Exhibits in Vivo Antitumor Activity in a H22 Mouse Hepatocellular Carcinoma Model."
],
"offsets": [
[
0,
167
]
]
},
{
"id": "23597099_abstract",
"type": "abstract",
"text": [
"In order to discover anticancer agents from natural sources, an ethanol-soluble extract of the root bark of Juglans cathayensis was investigated and showed cytotoxic effects against various human cancer cell lines. A subsequent phytochemical study on the EtOAc-soluble fraction determined 2-methoxyjuglone (1) as one of the main active constituents. Compound 1 was shown to be cytotoxic against HepG2 cells. Morphological features of apoptosis were observed in 1-treated HepG2 cells, including cell shrinkage, membrane blebbing, nuclear condensation, and apoptotic body formation. Cell cycle analysis with propidium iodide staining showed that 1 induced cell cycle arrest at the S phase in HepG2 cells. Flow cytometric analysis with annexin V and propidium iodide staining demonstrated that 1 induced HepG2 cell apoptotic events in a dose-dependent manner (0-8 μg/mL). Western blot analysis of apoptosis-related proteins revealed that 1 induces HepG2 cell apoptosis through mitochondrial cytochrome c-dependent activation of the caspase-9 and caspase-3 cascade pathway (intrinsic pathway). An in vivo experiment using tumor-bearing mice showed that treatment with 1 at 0.5 and 1.0 mg/kg per day decreased the tumor mass by 56% and 67%, respectively."
],
"offsets": [
[
168,
1417
]
]
}
] | [
{
"id": "23597099_T1",
"type": "CHEMICAL",
"text": [
"EtOAc"
],
"offsets": [
[
423,
428
]
],
"normalized": []
},
{
"id": "23597099_T2",
"type": "CHEMICAL",
"text": [
"2-methoxyjuglone"
],
"offsets": [
[
457,
473
]
],
"normalized": []
},
{
"id": "23597099_T3",
"type": "CHEMICAL",
"text": [
"propidium iodide"
],
"offsets": [
[
774,
790
]
],
"normalized": []
},
{
"id": "23597099_T4",
"type": "CHEMICAL",
"text": [
"ethanol"
],
"offsets": [
[
232,
239
]
],
"normalized": []
},
{
"id": "23597099_T5",
"type": "CHEMICAL",
"text": [
"propidium iodide"
],
"offsets": [
[
915,
931
]
],
"normalized": []
},
{
"id": "23597099_T6",
"type": "CHEMICAL",
"text": [
"2-Methoxyjuglone"
],
"offsets": [
[
0,
16
]
],
"normalized": []
},
{
"id": "23597099_T7",
"type": "GENE-Y",
"text": [
"caspase-9"
],
"offsets": [
[
1197,
1206
]
],
"normalized": []
},
{
"id": "23597099_T8",
"type": "GENE-Y",
"text": [
"caspase-3"
],
"offsets": [
[
1211,
1220
]
],
"normalized": []
},
{
"id": "23597099_T9",
"type": "GENE-N",
"text": [
"apoptosis-related proteins"
],
"offsets": [
[
1062,
1088
]
],
"normalized": []
},
{
"id": "23597099_T10",
"type": "GENE-Y",
"text": [
"cytochrome c"
],
"offsets": [
[
1156,
1168
]
],
"normalized": []
}
] | [] | [] | [] |
23276627 | 23276627 | [
{
"id": "23276627_title",
"type": "title",
"text": [
"Methylation damage to RNA induced in vivo in Escherichia coli is repaired by endogenous AlkB as part of the adaptive response."
],
"offsets": [
[
0,
126
]
]
},
{
"id": "23276627_abstract",
"type": "abstract",
"text": [
"Cytotoxic 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) lesions induced in DNA and RNA in vitro and in pre-damaged DNA and RNA bacteriophages in vivo are repaired by the Escherichia coli (E. coli) protein AlkB and a human homolog, ALKBH3. However, it is not known whether endogenous RNA is repaired in vivo by repair proteins present at physiological concentrations. The concept of RNA repair as a biologically relevant process has therefore remained elusive. Here, we demonstrate AlkB-mediated repair of endogenous RNA in vivo by measuring differences in lesion-accumulation in two independent AlkB-proficient and deficient E. coli strains during exposure to methyl methanesulfonate (MMS). Repair was observed both in AlkB-overproducing strains and in the wild-type strains after AlkB induction. RNA repair appeared to be highest in RNA species below 200 nucleotides in size, mainly comprising tRNAs. Strikingly, at least 10-fold more lesions were repaired in RNA than in DNA. This may be a consequence of some 30-fold higher levels of aberrant methylation in RNA than in DNA after exposure to MMS. A high primary kinetic isotope effect (>10) was measured using a deuterated methylated RNA substrate, D3-1me(rA), demonstrating that it is the catalytic step, and not the search step that is rate-limiting. Our results demonstrate that RNA repair by AlkB takes place in endogenous RNA as part of an adaptive response in wild-type E. coli cells."
],
"offsets": [
[
127,
1577
]
]
}
] | [
{
"id": "23276627_T1",
"type": "CHEMICAL",
"text": [
"1-methyladenine"
],
"offsets": [
[
137,
152
]
],
"normalized": []
},
{
"id": "23276627_T2",
"type": "CHEMICAL",
"text": [
"MMS"
],
"offsets": [
[
1229,
1232
]
],
"normalized": []
},
{
"id": "23276627_T3",
"type": "CHEMICAL",
"text": [
"1-meA"
],
"offsets": [
[
154,
159
]
],
"normalized": []
},
{
"id": "23276627_T4",
"type": "CHEMICAL",
"text": [
"3-methylcytosine"
],
"offsets": [
[
165,
181
]
],
"normalized": []
},
{
"id": "23276627_T5",
"type": "CHEMICAL",
"text": [
"3-meC"
],
"offsets": [
[
183,
188
]
],
"normalized": []
},
{
"id": "23276627_T6",
"type": "CHEMICAL",
"text": [
"methyl methanesulfonate"
],
"offsets": [
[
794,
817
]
],
"normalized": []
},
{
"id": "23276627_T7",
"type": "CHEMICAL",
"text": [
"MMS"
],
"offsets": [
[
819,
822
]
],
"normalized": []
},
{
"id": "23276627_T8",
"type": "CHEMICAL",
"text": [
"nucleotides"
],
"offsets": [
[
990,
1001
]
],
"normalized": []
},
{
"id": "23276627_T9",
"type": "GENE-Y",
"text": [
"AlkB"
],
"offsets": [
[
1483,
1487
]
],
"normalized": []
},
{
"id": "23276627_T10",
"type": "GENE-Y",
"text": [
"Escherichia coli (E. coli) protein AlkB"
],
"offsets": [
[
304,
343
]
],
"normalized": []
},
{
"id": "23276627_T11",
"type": "GENE-Y",
"text": [
"human homolog, ALKBH3"
],
"offsets": [
[
350,
371
]
],
"normalized": []
},
{
"id": "23276627_T12",
"type": "GENE-Y",
"text": [
"AlkB"
],
"offsets": [
[
615,
619
]
],
"normalized": []
},
{
"id": "23276627_T13",
"type": "GENE-Y",
"text": [
"AlkB"
],
"offsets": [
[
729,
733
]
],
"normalized": []
},
{
"id": "23276627_T14",
"type": "GENE-Y",
"text": [
"AlkB"
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853,
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]
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"normalized": []
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{
"id": "23276627_T15",
"type": "GENE-Y",
"text": [
"AlkB"
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915,
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]
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"id": "23276627_T16",
"type": "GENE-Y",
"text": [
"AlkB"
],
"offsets": [
[
88,
92
]
],
"normalized": []
}
] | [] | [] | [] |
16449355 | 16449355 | [
{
"id": "16449355_title",
"type": "title",
"text": [
"Overexpression of kidney neutral endopeptidase (EC 3.4.24.11) and renal function in experimental cirrhosis."
],
"offsets": [
[
0,
107
]
]
},
{
"id": "16449355_abstract",
"type": "abstract",
"text": [
"Neutral endopeptidase degrades atrial natriuretic peptide (ANP) and bradykinin and may generate endothelin-1 from big-endothelin. In advanced cirrhosis, sodium retention is accompanied by elevated plasma ANP levels, and infusion of ANP causes hypotension, but in normal humans increasing the concentration of ANP through the inhibition of neutral endopeptidase, localized in renal proximal tubule cells, causes natriuresis without any arterial pressure drop. The purpose of this study was the assessment of kidney neutral endopeptidase expression and responses to candoxatrilat (a specific inhibitor of this enzyme) in rats with CCl4-induced cirrhosis. Two groups of control rats (n = 5) were injected with vehicle or 3 mg/kg candoxatrilat. Three groups of cirrhotic rats with ascites (n = 10) received vehicle alone or 3 or 10 mg/kg candoxatrilat. In cirrhotic rats, Western blot analysis revealed a 170% increase in renal neutral endopeptidase protein content (P < 0.03), mainly in the proximal nephron and macula densa, and both candoxatrilat dosages increased plasma ANP levels, urinary volume, and urinary excretion of sodium, ANP, and cGMP compared with vehicle alone (all P < 0.03). Candoxatrilat (10 mg/kg) also reduced tubular solute-free water reabsorption (P < 0.03) in cirrhotic rats, but renal blood flow, arterial pressure, and plasma renin activity were unaffected. Neutral endopeptidase inhibition has natriuretic and aquaretic actions in cirrhosis without any effect on blood pressure and kidney perfusion due to a significant overexpression of this enzyme in renal cortex."
],
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]
]
}
] | [
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"candoxatrilat"
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"id": "16449355_T2",
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"text": [
"sodium"
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1232,
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]
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{
"id": "16449355_T3",
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"text": [
"cGMP"
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1249,
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"id": "16449355_T4",
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"sodium"
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261,
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]
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"id": "16449355_T6",
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"candoxatrilat"
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]
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"id": "16449355_T7",
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"text": [
"CCl4"
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737,
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]
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"id": "16449355_T8",
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"candoxatrilat"
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"id": "16449355_T10",
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"text": [
"Neutral endopeptidase"
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108,
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]
],
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},
{
"id": "16449355_T11",
"type": "GENE-Y",
"text": [
"ANP"
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1179,
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]
],
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},
{
"id": "16449355_T12",
"type": "GENE-Y",
"text": [
"ANP"
],
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[
1240,
1243
]
],
"normalized": []
},
{
"id": "16449355_T13",
"type": "GENE-Y",
"text": [
"big-endothelin"
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222,
236
]
],
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},
{
"id": "16449355_T14",
"type": "GENE-Y",
"text": [
"renin"
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1457,
1462
]
],
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},
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"id": "16449355_T15",
"type": "GENE-Y",
"text": [
"Neutral endopeptidase"
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1489,
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]
],
"normalized": []
},
{
"id": "16449355_T16",
"type": "GENE-Y",
"text": [
"ANP"
],
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312,
315
]
],
"normalized": []
},
{
"id": "16449355_T17",
"type": "GENE-Y",
"text": [
"ANP"
],
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340,
343
]
],
"normalized": []
},
{
"id": "16449355_T18",
"type": "GENE-Y",
"text": [
"ANP"
],
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417,
420
]
],
"normalized": []
},
{
"id": "16449355_T19",
"type": "GENE-Y",
"text": [
"atrial natriuretic peptide"
],
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[
139,
165
]
],
"normalized": []
},
{
"id": "16449355_T20",
"type": "GENE-Y",
"text": [
"neutral endopeptidase"
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447,
468
]
],
"normalized": []
},
{
"id": "16449355_T21",
"type": "GENE-Y",
"text": [
"neutral endopeptidase"
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[
622,
643
]
],
"normalized": []
},
{
"id": "16449355_T22",
"type": "GENE-Y",
"text": [
"ANP"
],
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[
167,
170
]
],
"normalized": []
},
{
"id": "16449355_T23",
"type": "GENE-Y",
"text": [
"bradykinin"
],
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[
176,
186
]
],
"normalized": []
},
{
"id": "16449355_T24",
"type": "GENE-Y",
"text": [
"neutral endopeptidase"
],
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[
1032,
1053
]
],
"normalized": []
},
{
"id": "16449355_T25",
"type": "GENE-Y",
"text": [
"endothelin-1"
],
"offsets": [
[
204,
216
]
],
"normalized": []
},
{
"id": "16449355_T26",
"type": "GENE-Y",
"text": [
"neutral endopeptidase"
],
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[
25,
46
]
],
"normalized": []
},
{
"id": "16449355_T27",
"type": "GENE-Y",
"text": [
"EC 3.4.24.11"
],
"offsets": [
[
48,
60
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16449355_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "16449355_T1",
"arg2_id": "16449355_T11",
"normalized": []
},
{
"id": "16449355_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "16449355_T1",
"arg2_id": "16449355_T12",
"normalized": []
}
] |
23589462 | 23589462 | [
{
"id": "23589462_title",
"type": "title",
"text": [
"(13) C-Detected Through-Bond Correlation Experiments for Protein Resonance Assignment by Ultra-Fast MAS Solid-State NMR."
],
"offsets": [
[
0,
120
]
]
},
{
"id": "23589462_abstract",
"type": "abstract",
"text": [
"We present two sequences which combine ((1) H,(15) N) and ((15) N,(13) C) selective cross-polarization steps with an efficient variant of the J-based homonuclear transfer scheme, in which a spin-state-selective (S(3) E) block is incorporated to improve both resolution and sensitivity in the direct (13) C dimension. We propose these two sequences as a part of a suite of four N-C correlation experiments allowing for the assignment of protein backbone resonances in the solid state. We illustrate these experiments under ultra-fast magic angle spinning conditions on two samples of microcrystalline dimeric human superoxide dismutase (SOD, 153×2 amino acids), in its diamagnetic (\"empty\", Zn(II) ) and paramagnetic (Cu(II) , Zn(II) ) states."
],
"offsets": [
[
121,
863
]
]
}
] | [
{
"id": "23589462_T1",
"type": "CHEMICAL",
"text": [
"(13) C"
],
"offsets": [
[
420,
426
]
],
"normalized": []
},
{
"id": "23589462_T2",
"type": "CHEMICAL",
"text": [
"N-C"
],
"offsets": [
[
498,
501
]
],
"normalized": []
},
{
"id": "23589462_T3",
"type": "CHEMICAL",
"text": [
"(1) H"
],
"offsets": [
[
161,
166
]
],
"normalized": []
},
{
"id": "23589462_T4",
"type": "CHEMICAL",
"text": [
"(15) N"
],
"offsets": [
[
167,
173
]
],
"normalized": []
},
{
"id": "23589462_T5",
"type": "CHEMICAL",
"text": [
"(15) N"
],
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[
180,
186
]
],
"normalized": []
},
{
"id": "23589462_T6",
"type": "CHEMICAL",
"text": [
"amino acids"
],
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[
768,
779
]
],
"normalized": []
},
{
"id": "23589462_T7",
"type": "CHEMICAL",
"text": [
"(13) C"
],
"offsets": [
[
187,
193
]
],
"normalized": []
},
{
"id": "23589462_T8",
"type": "CHEMICAL",
"text": [
"Zn(II)"
],
"offsets": [
[
811,
817
]
],
"normalized": []
},
{
"id": "23589462_T9",
"type": "CHEMICAL",
"text": [
"Cu(II)"
],
"offsets": [
[
838,
844
]
],
"normalized": []
},
{
"id": "23589462_T10",
"type": "CHEMICAL",
"text": [
"Zn(II)"
],
"offsets": [
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847,
853
]
],
"normalized": []
},
{
"id": "23589462_T11",
"type": "CHEMICAL",
"text": [
"(13) C"
],
"offsets": [
[
0,
6
]
],
"normalized": []
},
{
"id": "23589462_T12",
"type": "GENE-N",
"text": [
"human superoxide dismutase"
],
"offsets": [
[
729,
755
]
],
"normalized": []
},
{
"id": "23589462_T13",
"type": "GENE-N",
"text": [
"SOD, 153×2 amino acids"
],
"offsets": [
[
757,
779
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23589462_0",
"type": "PART-OF",
"arg1_id": "23589462_T6",
"arg2_id": "23589462_T12",
"normalized": []
}
] |
23248236 | 23248236 | [
{
"id": "23248236_title",
"type": "title",
"text": [
"Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione."
],
"offsets": [
[
0,
110
]
]
},
{
"id": "23248236_abstract",
"type": "abstract",
"text": [
"Increasing antibiotic resistance makes the identification of new antibacterial principles an urgent task. The thioredoxin system including thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH plays critical roles in cellular DNA synthesis and defense against oxidative stress. Notably, TrxR is very different in structure and mechanism in mammals and bacteria. Ebselen [2-phenyl-1,2 benzisoselenazol-3(2H)-one], a well-known antioxidant and a substrate for mammalian TrxR and Trx, is rapidly bacteriocidal for methicillin-resistant Staphylococcus aureus by an unknown mechanism. We have discovered that ebselen is a competitive inhibitor of Escherichia coli TrxR with a Ki of 0.52 ± 0.13 μM, through reaction with the active site dithiol of the enzyme. Bacteria lacking glutathione (GSH) and glutaredoxin, in which TrxR and Trx are essential for DNA synthesis, were particularly sensitive to ebselen. In growth-inhibited E. coli strains, Trx1 and Trx2 were oxidized, demonstrating that electron transfer via thioredoxin was blocked. Ebselen and its sulfur analog ebsulfur were bactericidal for GSH-negative pathogens. Ebsulfur inhibited a clinically isolated Helicobacter pylori strain with a minimum inhibitory concentration value as low as 0.39 μg/ml. These results demonstrate that bacterial Trx and TrxR are viable antibacterial drug targets using benzisoselenazol and benzisothiazol derivates.-Lu, J., Vlamis-Gardikas, A., Kandasamy, K., Zhao, R., Gustafsson, T. N., Engstrand, L., Hoffner, S., Engman, L., Holmgren, A. Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione."
],
"offsets": [
[
111,
1752
]
]
}
] | [
{
"id": "23248236_T1",
"type": "CHEMICAL",
"text": [
"Ebselen"
],
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[
1150,
1157
]
],
"normalized": []
},
{
"id": "23248236_T2",
"type": "CHEMICAL",
"text": [
"sulfur"
],
"offsets": [
[
1166,
1172
]
],
"normalized": []
},
{
"id": "23248236_T3",
"type": "CHEMICAL",
"text": [
"ebsulfur"
],
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[
1180,
1188
]
],
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},
{
"id": "23248236_T4",
"type": "CHEMICAL",
"text": [
"GSH"
],
"offsets": [
[
1211,
1214
]
],
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},
{
"id": "23248236_T5",
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"Ebsulfur"
],
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1235,
1243
]
],
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},
{
"id": "23248236_T6",
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"text": [
"benzisoselenazol"
],
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[
1469,
1485
]
],
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},
{
"id": "23248236_T7",
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"text": [
"benzisothiazol"
],
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[
1490,
1504
]
],
"normalized": []
},
{
"id": "23248236_T8",
"type": "CHEMICAL",
"text": [
"NADPH"
],
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303,
308
]
],
"normalized": []
},
{
"id": "23248236_T9",
"type": "CHEMICAL",
"text": [
"Ebselen"
],
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[
478,
485
]
],
"normalized": []
},
{
"id": "23248236_T10",
"type": "CHEMICAL",
"text": [
"2-phenyl-1,2 benzisoselenazol-3(2H)-one"
],
"offsets": [
[
487,
526
]
],
"normalized": []
},
{
"id": "23248236_T11",
"type": "CHEMICAL",
"text": [
"methicillin"
],
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[
627,
638
]
],
"normalized": []
},
{
"id": "23248236_T12",
"type": "CHEMICAL",
"text": [
"ebselen"
],
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[
720,
727
]
],
"normalized": []
},
{
"id": "23248236_T13",
"type": "CHEMICAL",
"text": [
"dithiol"
],
"offsets": [
[
847,
854
]
],
"normalized": []
},
{
"id": "23248236_T14",
"type": "CHEMICAL",
"text": [
"glutathione"
],
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[
887,
898
]
],
"normalized": []
},
{
"id": "23248236_T15",
"type": "CHEMICAL",
"text": [
"GSH"
],
"offsets": [
[
900,
903
]
],
"normalized": []
},
{
"id": "23248236_T16",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
98,
109
]
],
"normalized": []
},
{
"id": "23248236_T17",
"type": "GENE-N",
"text": [
"thioredoxin"
],
"offsets": [
[
1125,
1136
]
],
"normalized": []
},
{
"id": "23248236_T18",
"type": "GENE-Y",
"text": [
"thioredoxin"
],
"offsets": [
[
221,
232
]
],
"normalized": []
},
{
"id": "23248236_T19",
"type": "GENE-N",
"text": [
"bacterial Trx"
],
"offsets": [
[
1402,
1415
]
],
"normalized": []
},
{
"id": "23248236_T20",
"type": "GENE-N",
"text": [
"TrxR"
],
"offsets": [
[
1420,
1424
]
],
"normalized": []
},
{
"id": "23248236_T21",
"type": "GENE-N",
"text": [
"thioredoxin reductase"
],
"offsets": [
[
250,
271
]
],
"normalized": []
},
{
"id": "23248236_T22",
"type": "GENE-N",
"text": [
"bacterial thioredoxin reductase"
],
"offsets": [
[
1656,
1687
]
],
"normalized": []
},
{
"id": "23248236_T23",
"type": "GENE-N",
"text": [
"TrxR"
],
"offsets": [
[
273,
277
]
],
"normalized": []
},
{
"id": "23248236_T24",
"type": "GENE-Y",
"text": [
"thioredoxin"
],
"offsets": [
[
280,
291
]
],
"normalized": []
},
{
"id": "23248236_T25",
"type": "GENE-Y",
"text": [
"Trx"
],
"offsets": [
[
293,
296
]
],
"normalized": []
},
{
"id": "23248236_T26",
"type": "GENE-N",
"text": [
"TrxR"
],
"offsets": [
[
403,
407
]
],
"normalized": []
},
{
"id": "23248236_T27",
"type": "GENE-N",
"text": [
"mammalian TrxR"
],
"offsets": [
[
574,
588
]
],
"normalized": []
},
{
"id": "23248236_T28",
"type": "GENE-N",
"text": [
"Trx"
],
"offsets": [
[
593,
596
]
],
"normalized": []
},
{
"id": "23248236_T29",
"type": "GENE-Y",
"text": [
"Escherichia coli TrxR"
],
"offsets": [
[
758,
779
]
],
"normalized": []
},
{
"id": "23248236_T30",
"type": "GENE-N",
"text": [
"glutaredoxin"
],
"offsets": [
[
909,
921
]
],
"normalized": []
},
{
"id": "23248236_T31",
"type": "GENE-N",
"text": [
"TrxR"
],
"offsets": [
[
932,
936
]
],
"normalized": []
},
{
"id": "23248236_T32",
"type": "GENE-N",
"text": [
"Trx"
],
"offsets": [
[
941,
944
]
],
"normalized": []
},
{
"id": "23248236_T33",
"type": "GENE-Y",
"text": [
"Trx1"
],
"offsets": [
[
1055,
1059
]
],
"normalized": []
},
{
"id": "23248236_T34",
"type": "GENE-Y",
"text": [
"Trx2"
],
"offsets": [
[
1064,
1068
]
],
"normalized": []
},
{
"id": "23248236_T35",
"type": "GENE-N",
"text": [
"bacterial thioredoxin reductase"
],
"offsets": [
[
14,
45
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23248236_0",
"type": "SUBSTRATE",
"arg1_id": "23248236_T9",
"arg2_id": "23248236_T27",
"normalized": []
},
{
"id": "23248236_1",
"type": "SUBSTRATE",
"arg1_id": "23248236_T10",
"arg2_id": "23248236_T27",
"normalized": []
},
{
"id": "23248236_2",
"type": "SUBSTRATE",
"arg1_id": "23248236_T9",
"arg2_id": "23248236_T28",
"normalized": []
},
{
"id": "23248236_3",
"type": "SUBSTRATE",
"arg1_id": "23248236_T10",
"arg2_id": "23248236_T28",
"normalized": []
},
{
"id": "23248236_4",
"type": "INHIBITOR",
"arg1_id": "23248236_T12",
"arg2_id": "23248236_T29",
"normalized": []
},
{
"id": "23248236_5",
"type": "PART-OF",
"arg1_id": "23248236_T13",
"arg2_id": "23248236_T29",
"normalized": []
}
] |
15236843 | 15236843 | [
{
"id": "15236843_title",
"type": "title",
"text": [
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"id": "15236843_abstract",
"type": "abstract",
"text": [
"To determine the role played by Tyr(356 (7.43)) in the rat beta(1)-adrenoceptor in binding the antagonists (+/-)cyanopindolol (4-[3-(t-butylamino]-3-(2'-cyano-indoloxy)-2-propanolol) and its iodinated analogue (+/-)[(125)Iodo]cyanopindolol (1-(t-butylamino]-3-(2'-cyano-3'-iodo-indoloxy)-2-propanolol), Tyr(356 (7.43)) was mutated to either Phe or Ala and binding affinities determined for wild type and mutant rat beta(1)-adrenoceptors. Our results indicate that Tyr(356 (7.43)) is important for (+/-)cyanopindolol, but not (+/-)[(125)Iodo]cyanopindolol, binding and that (+/-)cyanopindolol adopts a \"reverse\" binding orientation whereas (+/-)[(125)Iodo]cyanopindolol cannot be accommodated in this binding mode. We define a \"reverse\" antagonist binding mode as one where the aryloxy moiety interacts with residues on transmembrane helices 1, 2, 3 and 7. The beta(1)-adrenoceptor site-directed mutagenesis results are the first to support a \"reverse\" antagonist binding orientation and the involvement of Tyr(356 (7.43)) in this binding mode."
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] |
23231808 | 23231808 | [
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"type": "title",
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"Acetazolamide impairs fear memory consolidation in rodents."
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"id": "23231808_abstract",
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"Acetazolamide (AZ) is an carbonic anhydrase inhibitor, which has been used in the treatment of seizures, mountain sickness and glaucoma. Memory impairment by AZ has been reported in patient interviews; however, the related mechanism is unclear. We applied two fear conditioning paradigms, shuttle avoidance and passive avoidance, in both rats and mice to investigate this clinical anecdote. Adult Wistar rats receiving AZ 1 h before the shuttle avoidance test showed decreased avoidance rates, especially at high dosage. Adult ICR mice receiving AZ both before and after acquisition trials showed the decreased step-through latencies during the passive avoidance test. This impairment of fear memory was corroborated with decreased LTP by AZ in the amygdala. AZ only inhibited fear conditioning-induced ERK phosphorylation and had no effect on Akt phosphorylation. In conclusion, our study confirmed the adverse cognitive effect of AZ in animal and electrophysiological studies. In clinical practice, clinicians should be aware of this side effect in patients taking AZ. In addition, this inhibition of fear memory by AZ could potentially be applied to patients with posttraumatic stress disorder."
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17315049 | 17315049 | [
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"type": "title",
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"id": "17315049_abstract",
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"text": [
"Novel therapeutic strategies for type 2 diabetes are needed, since the current treatment options neither address all pathophysiological mechanisms nor achieve the glycemic target goals. A general islet-cell dysfunction including insulin- and glucagon-secretion defects contributes to the pathophysiology of type 2 diabetes. Improving islet function by incretin hormone action is a novel therapeutic approach. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are important incretin hormones contributing to 50-70% of the stimulation of insulin secretion after a meal. Dipeptidyl-peptidase IV (DPP-4) inhibitors inhibit the degradation of GLP-1 and GIP as well as that of other regulatory peptides. Sitagliptin, a DPP-4 inhibitor, is orally active and has been shown to be efficacious and safe in clinical studies. Sitagliptin has received approval in Mexico, the United States and other countries. Like other DPP-4 inhibitors, sitagliptin reduces hemoglobin A1c (HbA1c), fasting and postprandial glucose by glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. Sitagliptin is weight neutral. Indirect measures show a possible improvement of beta-cell function. Sitagliptin does not cause a higher rate of hypoglycemia in comparison to metformin or placebo. This article gives an overview of the mechanisms of action, pharmacology and clinical trial results of sitagliptin."
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