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12135320 | 12135320 | [
{
"id": "12135320_title",
"type": "title",
"text": [
"Decreased expression of arginase II in the kidneys of Dahl salt-sensitive rats."
],
"offsets": [
[
0,
79
]
]
},
{
"id": "12135320_abstract",
"type": "abstract",
"text": [
"Arginase catalyzes the hydrolysis of arginine to urea and ornithine. Urea is not only an important solute for concentrating urine but also inhibits Na-K-2Cl cotransport. To elucidate the roles of arginase in the development of salt-sensitive hypertension, we examined arginase activity and expression in the kidney and other organs of Dahl/Rapp salt-sensitive (SS) and salt-resistant (SR) rats before and after 4 weeks' administration of a 4% NaCl or control diet. At 4 weeks of age, arginase activity in the kidney was lower in SS rats than in SR rats. Kidney arginase activity was lower in SS rats than in SR rats at 8 weeks of age, and salt loading did not alter arginase activity. Arginase II (the dominant isoform in the kidney) mRNA and protein in the kidney of salt-loaded SS rats were also lower than those of salt-loaded SR rats. Arginase activities in the liver and cerebellum did not differ between SS and SR rats. To examine the effect of urea, the product of arginase reaction, on the development of hypertension, SS rats were given a 4% NaCl diet containing 5% kaolin or 5% urea. Six-week urea supplementation attenuated the development of hypertension in SS rats. These findings suggest that decreased arginase expression in the kidney may be at least partially responsible for the salt-sensitive hypertension in SS rats."
],
"offsets": [
[
80,
1416
]
]
}
] | [
{
"id": "12135320_T1",
"type": "CHEMICAL",
"text": [
"NaCl"
],
"offsets": [
[
1131,
1135
]
],
"normalized": []
},
{
"id": "12135320_T2",
"type": "CHEMICAL",
"text": [
"Na"
],
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[
228,
230
]
],
"normalized": []
},
{
"id": "12135320_T3",
"type": "CHEMICAL",
"text": [
"K"
],
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[
231,
232
]
],
"normalized": []
},
{
"id": "12135320_T4",
"type": "CHEMICAL",
"text": [
"2Cl"
],
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[
233,
236
]
],
"normalized": []
},
{
"id": "12135320_T5",
"type": "CHEMICAL",
"text": [
"arginine"
],
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[
117,
125
]
],
"normalized": []
},
{
"id": "12135320_T6",
"type": "CHEMICAL",
"text": [
"NaCl"
],
"offsets": [
[
523,
527
]
],
"normalized": []
},
{
"id": "12135320_T7",
"type": "CHEMICAL",
"text": [
"urea"
],
"offsets": [
[
129,
133
]
],
"normalized": []
},
{
"id": "12135320_T8",
"type": "CHEMICAL",
"text": [
"ornithine"
],
"offsets": [
[
138,
147
]
],
"normalized": []
},
{
"id": "12135320_T9",
"type": "CHEMICAL",
"text": [
"Urea"
],
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[
149,
153
]
],
"normalized": []
},
{
"id": "12135320_T10",
"type": "CHEMICAL",
"text": [
"urea"
],
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[
1031,
1035
]
],
"normalized": []
},
{
"id": "12135320_T11",
"type": "GENE-N",
"text": [
"Arginase"
],
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[
80,
88
]
],
"normalized": []
},
{
"id": "12135320_T12",
"type": "GENE-N",
"text": [
"arginase"
],
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[
348,
356
]
],
"normalized": []
},
{
"id": "12135320_T13",
"type": "GENE-N",
"text": [
"arginase"
],
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[
564,
572
]
],
"normalized": []
},
{
"id": "12135320_T14",
"type": "GENE-N",
"text": [
"arginase"
],
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[
746,
754
]
],
"normalized": []
},
{
"id": "12135320_T15",
"type": "GENE-N",
"text": [
"Arginase II"
],
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[
765,
776
]
],
"normalized": []
},
{
"id": "12135320_T16",
"type": "GENE-N",
"text": [
"Arginase"
],
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919,
927
]
],
"normalized": []
},
{
"id": "12135320_T17",
"type": "GENE-N",
"text": [
"arginase"
],
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[
1052,
1060
]
],
"normalized": []
},
{
"id": "12135320_T18",
"type": "GENE-N",
"text": [
"arginase II"
],
"offsets": [
[
24,
35
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12135320_0",
"type": "SUBSTRATE",
"arg1_id": "12135320_T5",
"arg2_id": "12135320_T11",
"normalized": []
},
{
"id": "12135320_1",
"type": "PRODUCT-OF",
"arg1_id": "12135320_T7",
"arg2_id": "12135320_T11",
"normalized": []
},
{
"id": "12135320_2",
"type": "PRODUCT-OF",
"arg1_id": "12135320_T8",
"arg2_id": "12135320_T11",
"normalized": []
},
{
"id": "12135320_3",
"type": "PRODUCT-OF",
"arg1_id": "12135320_T10",
"arg2_id": "12135320_T17",
"normalized": []
}
] |
17639997 | 17639997 | [
{
"id": "17639997_title",
"type": "title",
"text": [
"Solamargine upregulation of Fas, downregulation of HER2, and enhancement of cytotoxicity using epirubicin in NSCLC cells."
],
"offsets": [
[
0,
121
]
]
},
{
"id": "17639997_abstract",
"type": "abstract",
"text": [
"Nonsmall-cell lung cancer (NSCLC) is not generally a chemosensitive tumor, and the mechanism of resistance to the relevant anticancer drugs has not been fully elucidated. Solamargine (SM), the major steroidal glycoalkaloids extracted from the Chinese herb Solanum, inhibits the growth of human tumor cells. We have previously demonstrated that SM regulates tumor necrosis factor receptors (TNFRs)- and mitochondria-mediated pathways and sensitizes NSCLC cells to initiate apoptosis. Interestingly, this investigation reveals that SM up-regulated Fas expression and down-regulated the expression of HER2, whose overexpression is associated with resistance to drugs, and promotes chemotherapy-induced apoptosis in NSCLC A549 and H441 cells. After treatment with SM, the expression of HER2 mRNA was correlated with the expression of topoisomerase IIalpha (TOP2A) mRNA. The combinatory use of low concentrations of SM with low-toxic topoisomerase II inhibitor epirubicin accelerated apoptotic cell death. Therefore, the downregulation of the HER2 and TOP2A expression by SM with epirubicin may partially explain the SM and epirubicin cytotoxicity synergy effect in NSCLC. Results of this study suggest that SM induces Fas and TNFR-induced NSCLC cell apoptosis and reduces HER2 expression. These findings provide the synergistic therapeutic interaction between SM and epirubicin, suggesting that such combinations may be effectively exploited in future human cancer clinical trials."
],
"offsets": [
[
122,
1599
]
]
}
] | [
{
"id": "17639997_T1",
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"text": [
"epirubicin"
],
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[
1197,
1207
]
],
"normalized": []
},
{
"id": "17639997_T2",
"type": "CHEMICAL",
"text": [
"epirubicin"
],
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[
1241,
1251
]
],
"normalized": []
},
{
"id": "17639997_T3",
"type": "CHEMICAL",
"text": [
"epirubicin"
],
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[
1485,
1495
]
],
"normalized": []
},
{
"id": "17639997_T4",
"type": "CHEMICAL",
"text": [
"Solamargine"
],
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[
293,
304
]
],
"normalized": []
},
{
"id": "17639997_T5",
"type": "CHEMICAL",
"text": [
"SM"
],
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[
306,
308
]
],
"normalized": []
},
{
"id": "17639997_T6",
"type": "CHEMICAL",
"text": [
"steroidal glycoalkaloids"
],
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[
321,
345
]
],
"normalized": []
},
{
"id": "17639997_T7",
"type": "CHEMICAL",
"text": [
"epirubicin"
],
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[
1078,
1088
]
],
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},
{
"id": "17639997_T8",
"type": "CHEMICAL",
"text": [
"Solamargine"
],
"offsets": [
[
0,
11
]
],
"normalized": []
},
{
"id": "17639997_T9",
"type": "CHEMICAL",
"text": [
"epirubicin"
],
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[
95,
105
]
],
"normalized": []
},
{
"id": "17639997_T10",
"type": "GENE-Y",
"text": [
"HER2"
],
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[
1160,
1164
]
],
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},
{
"id": "17639997_T11",
"type": "GENE-Y",
"text": [
"TOP2A"
],
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[
1169,
1174
]
],
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},
{
"id": "17639997_T12",
"type": "GENE-N",
"text": [
"TNFR"
],
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1344,
1348
]
],
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},
{
"id": "17639997_T13",
"type": "GENE-Y",
"text": [
"HER2"
],
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1390,
1394
]
],
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},
{
"id": "17639997_T14",
"type": "GENE-N",
"text": [
"tumor necrosis factor receptors"
],
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[
479,
510
]
],
"normalized": []
},
{
"id": "17639997_T15",
"type": "GENE-N",
"text": [
"TNFRs"
],
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[
512,
517
]
],
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},
{
"id": "17639997_T16",
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"text": [
"Fas"
],
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[
668,
671
]
],
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},
{
"id": "17639997_T17",
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"HER2"
],
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[
720,
724
]
],
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},
{
"id": "17639997_T18",
"type": "GENE-Y",
"text": [
"HER2"
],
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[
904,
908
]
],
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},
{
"id": "17639997_T19",
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"text": [
"topoisomerase IIalpha"
],
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[
952,
973
]
],
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},
{
"id": "17639997_T20",
"type": "GENE-Y",
"text": [
"TOP2A"
],
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[
975,
980
]
],
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},
{
"id": "17639997_T21",
"type": "GENE-Y",
"text": [
"topoisomerase II"
],
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[
1051,
1067
]
],
"normalized": []
},
{
"id": "17639997_T22",
"type": "GENE-Y",
"text": [
"Fas"
],
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[
28,
31
]
],
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},
{
"id": "17639997_T23",
"type": "GENE-Y",
"text": [
"HER2"
],
"offsets": [
[
51,
55
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17639997_0",
"type": "INHIBITOR",
"arg1_id": "17639997_T7",
"arg2_id": "17639997_T21",
"normalized": []
},
{
"id": "17639997_1",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "17639997_T1",
"arg2_id": "17639997_T10",
"normalized": []
},
{
"id": "17639997_2",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "17639997_T1",
"arg2_id": "17639997_T11",
"normalized": []
}
] |
15936988 | 15936988 | [
{
"id": "15936988_title",
"type": "title",
"text": [
"Simvastatin induces interleukin-18 production in human peripheral blood mononuclear cells."
],
"offsets": [
[
0,
90
]
]
},
{
"id": "15936988_abstract",
"type": "abstract",
"text": [
"The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. Simvastatin, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by simvastatin. Moreover, simvastatin concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of IL-18, simvastatin suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of simvastatin. The effects of simvastatin were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of simvastatin."
],
"offsets": [
[
91,
1192
]
]
}
] | [
{
"id": "15936988_T1",
"type": "CHEMICAL",
"text": [
"mevalonate"
],
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[
1103,
1113
]
],
"normalized": []
},
{
"id": "15936988_T2",
"type": "CHEMICAL",
"text": [
"HMG-CoA"
],
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[
1145,
1152
]
],
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},
{
"id": "15936988_T3",
"type": "CHEMICAL",
"text": [
"simvastatin"
],
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[
1180,
1191
]
],
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},
{
"id": "15936988_T4",
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"HMG-CoA"
],
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[
200,
207
]
],
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},
{
"id": "15936988_T5",
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"text": [
"Simvastatin"
],
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[
333,
344
]
],
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},
{
"id": "15936988_T6",
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"HMG-CoA"
],
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349,
356
]
],
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},
{
"id": "15936988_T7",
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"simvastatin"
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646,
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]
],
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},
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"id": "15936988_T8",
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"simvastatin"
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669,
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]
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"id": "15936988_T9",
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],
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161,
198
]
],
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},
{
"id": "15936988_T10",
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"simvastatin"
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817,
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]
],
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},
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"id": "15936988_T11",
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"simvastatin"
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991,
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]
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},
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"id": "15936988_T12",
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"simvastatin"
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1019,
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]
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},
{
"id": "15936988_T13",
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"HMG-CoA"
],
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[
1084,
1091
]
],
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},
{
"id": "15936988_T14",
"type": "CHEMICAL",
"text": [
"Simvastatin"
],
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[
0,
11
]
],
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},
{
"id": "15936988_T15",
"type": "GENE-Y",
"text": [
"HMG-CoA reductase"
],
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[
1145,
1162
]
],
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},
{
"id": "15936988_T16",
"type": "GENE-Y",
"text": [
"leukocyte function-associated antigen (LFA)-1"
],
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[
223,
268
]
],
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},
{
"id": "15936988_T17",
"type": "GENE-Y",
"text": [
"intercellular adhesion molecule (ICAM)-1"
],
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[
291,
331
]
],
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},
{
"id": "15936988_T18",
"type": "GENE-Y",
"text": [
"HMG-CoA reductase"
],
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[
349,
366
]
],
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},
{
"id": "15936988_T19",
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"text": [
"LFA-1"
],
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[
401,
406
]
],
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},
{
"id": "15936988_T20",
"type": "GENE-Y",
"text": [
"interleukin (IL)-18"
],
"offsets": [
[
434,
453
]
],
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},
{
"id": "15936988_T21",
"type": "GENE-Y",
"text": [
"tumor necrosis factor (TNF)-alpha"
],
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[
455,
488
]
],
"normalized": []
},
{
"id": "15936988_T22",
"type": "GENE-Y",
"text": [
"interferon (IFN)-gamma"
],
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[
493,
515
]
],
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},
{
"id": "15936988_T23",
"type": "GENE-Y",
"text": [
"IL-18"
],
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[
572,
577
]
],
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},
{
"id": "15936988_T24",
"type": "GENE-N",
"text": [
"cytokine"
],
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[
616,
624
]
],
"normalized": []
},
{
"id": "15936988_T25",
"type": "GENE-Y",
"text": [
"ICAM-1"
],
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[
735,
741
]
],
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},
{
"id": "15936988_T26",
"type": "GENE-Y",
"text": [
"CD40"
],
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[
772,
776
]
],
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},
{
"id": "15936988_T27",
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"3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase"
],
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[
161,
218
]
],
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},
{
"id": "15936988_T28",
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"IL-18"
],
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[
810,
815
]
],
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},
{
"id": "15936988_T29",
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"ICAM-1"
],
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[
858,
864
]
],
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},
{
"id": "15936988_T30",
"type": "GENE-Y",
"text": [
"CD40"
],
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[
869,
873
]
],
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},
{
"id": "15936988_T31",
"type": "GENE-N",
"text": [
"IL-12"
],
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[
903,
908
]
],
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},
{
"id": "15936988_T32",
"type": "GENE-Y",
"text": [
"TNF-alpha"
],
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[
910,
919
]
],
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},
{
"id": "15936988_T33",
"type": "GENE-Y",
"text": [
"IFN-gamma"
],
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[
924,
933
]
],
"normalized": []
},
{
"id": "15936988_T34",
"type": "GENE-Y",
"text": [
"HMG-CoA reductase"
],
"offsets": [
[
1084,
1101
]
],
"normalized": []
},
{
"id": "15936988_T35",
"type": "GENE-Y",
"text": [
"interleukin-18"
],
"offsets": [
[
20,
34
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "15936988_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "15936988_T14",
"arg2_id": "15936988_T35",
"normalized": []
},
{
"id": "15936988_1",
"type": "INHIBITOR",
"arg1_id": "15936988_T5",
"arg2_id": "15936988_T18",
"normalized": []
},
{
"id": "15936988_2",
"type": "INHIBITOR",
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"arg2_id": "15936988_T19",
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},
{
"id": "15936988_3",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "15936988_T5",
"arg2_id": "15936988_T20",
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},
{
"id": "15936988_4",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "15936988_T5",
"arg2_id": "15936988_T21",
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},
{
"id": "15936988_5",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "15936988_T5",
"arg2_id": "15936988_T22",
"normalized": []
},
{
"id": "15936988_6",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "15936988_T7",
"arg2_id": "15936988_T23",
"normalized": []
},
{
"id": "15936988_7",
"type": "ACTIVATOR",
"arg1_id": "15936988_T7",
"arg2_id": "15936988_T24",
"normalized": []
},
{
"id": "15936988_8",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "15936988_T8",
"arg2_id": "15936988_T25",
"normalized": []
},
{
"id": "15936988_9",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "15936988_T8",
"arg2_id": "15936988_T26",
"normalized": []
},
{
"id": "15936988_10",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "15936988_T10",
"arg2_id": "15936988_T29",
"normalized": []
},
{
"id": "15936988_11",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "15936988_T10",
"arg2_id": "15936988_T30",
"normalized": []
},
{
"id": "15936988_12",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "15936988_T10",
"arg2_id": "15936988_T31",
"normalized": []
},
{
"id": "15936988_13",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "15936988_T10",
"arg2_id": "15936988_T32",
"normalized": []
},
{
"id": "15936988_14",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "15936988_T10",
"arg2_id": "15936988_T33",
"normalized": []
},
{
"id": "15936988_15",
"type": "PRODUCT-OF",
"arg1_id": "15936988_T1",
"arg2_id": "15936988_T34",
"normalized": []
}
] |
15155769 | 15155769 | [
{
"id": "15155769_title",
"type": "title",
"text": [
"Redesign of carnitine acetyltransferase specificity by protein engineering."
],
"offsets": [
[
0,
75
]
]
},
{
"id": "15155769_abstract",
"type": "abstract",
"text": [
"In eukaryotes, L-carnitine is involved in energy metabolism by facilitating beta-oxidation of fatty acids. Carnitine acetyltransferases (CrAT) catalyze the reversible conversion of acetyl-CoA and carnitine to acetylcarnitine and free CoA. To redesign the specificity of rat CrAT toward its substrates, we mutated Met564. The M564G mutated CrAT showed higher activity toward longer chain acyl-CoAs: activity toward myristoyl-CoA was 1250-fold higher than that of the wild-type CrAT, and lower activity toward its natural substrate, acetyl-CoA. Kinetic constants of the mutant CrAT showed modification in favor of longer acyl-CoAs as substrates. In the reverse case, mutation of the orthologous glycine (Gly553) to methionine in carnitine octanoyltransferase (COT) decreased activity toward its natural substrates, medium- and long-chain acyl-CoAs, and increased activity toward short-chain acyl-CoAs. Another CrAT mutant, M564A, was prepared and tested in the same way, with similar results. We conclude that Met564 blocks the entry of medium- and long-chain acyl-CoAs to the catalytic site of CrAT. Three-dimensional models of wild-type and mutated CrAT and COT support this hypothesis. We show for the first time that a single amino acid is able to determine the substrate specificity of CrAT and COT."
],
"offsets": [
[
76,
1378
]
]
}
] | [
{
"id": "15155769_T1",
"type": "CHEMICAL",
"text": [
"acyl-CoAs"
],
"offsets": [
[
1134,
1143
]
],
"normalized": []
},
{
"id": "15155769_T2",
"type": "CHEMICAL",
"text": [
"Carnitine"
],
"offsets": [
[
183,
192
]
],
"normalized": []
},
{
"id": "15155769_T3",
"type": "CHEMICAL",
"text": [
"amino acid"
],
"offsets": [
[
1304,
1314
]
],
"normalized": []
},
{
"id": "15155769_T4",
"type": "CHEMICAL",
"text": [
"L-carnitine"
],
"offsets": [
[
91,
102
]
],
"normalized": []
},
{
"id": "15155769_T5",
"type": "CHEMICAL",
"text": [
"acetyl-CoA"
],
"offsets": [
[
257,
267
]
],
"normalized": []
},
{
"id": "15155769_T6",
"type": "CHEMICAL",
"text": [
"carnitine"
],
"offsets": [
[
272,
281
]
],
"normalized": []
},
{
"id": "15155769_T7",
"type": "CHEMICAL",
"text": [
"acetylcarnitine"
],
"offsets": [
[
285,
300
]
],
"normalized": []
},
{
"id": "15155769_T8",
"type": "CHEMICAL",
"text": [
"acyl-CoAs"
],
"offsets": [
[
463,
472
]
],
"normalized": []
},
{
"id": "15155769_T9",
"type": "CHEMICAL",
"text": [
"myristoyl-CoA"
],
"offsets": [
[
490,
503
]
],
"normalized": []
},
{
"id": "15155769_T10",
"type": "CHEMICAL",
"text": [
"acetyl-CoA"
],
"offsets": [
[
607,
617
]
],
"normalized": []
},
{
"id": "15155769_T11",
"type": "CHEMICAL",
"text": [
"acyl-CoAs"
],
"offsets": [
[
695,
704
]
],
"normalized": []
},
{
"id": "15155769_T12",
"type": "CHEMICAL",
"text": [
"glycine"
],
"offsets": [
[
769,
776
]
],
"normalized": []
},
{
"id": "15155769_T13",
"type": "CHEMICAL",
"text": [
"methionine"
],
"offsets": [
[
789,
799
]
],
"normalized": []
},
{
"id": "15155769_T14",
"type": "CHEMICAL",
"text": [
"carnitine"
],
"offsets": [
[
803,
812
]
],
"normalized": []
},
{
"id": "15155769_T15",
"type": "CHEMICAL",
"text": [
"acyl-CoAs"
],
"offsets": [
[
912,
921
]
],
"normalized": []
},
{
"id": "15155769_T16",
"type": "CHEMICAL",
"text": [
"acyl-CoAs"
],
"offsets": [
[
965,
974
]
],
"normalized": []
},
{
"id": "15155769_T17",
"type": "CHEMICAL",
"text": [
"fatty acids"
],
"offsets": [
[
170,
181
]
],
"normalized": []
},
{
"id": "15155769_T18",
"type": "CHEMICAL",
"text": [
"carnitine"
],
"offsets": [
[
12,
21
]
],
"normalized": []
},
{
"id": "15155769_T19",
"type": "GENE-Y",
"text": [
"Carnitine acetyltransferases"
],
"offsets": [
[
183,
211
]
],
"normalized": []
},
{
"id": "15155769_T20",
"type": "GENE-Y",
"text": [
"CrAT"
],
"offsets": [
[
1169,
1173
]
],
"normalized": []
},
{
"id": "15155769_T21",
"type": "GENE-Y",
"text": [
"CrAT"
],
"offsets": [
[
1225,
1229
]
],
"normalized": []
},
{
"id": "15155769_T22",
"type": "GENE-Y",
"text": [
"COT"
],
"offsets": [
[
1234,
1237
]
],
"normalized": []
},
{
"id": "15155769_T23",
"type": "GENE-Y",
"text": [
"CrAT"
],
"offsets": [
[
1365,
1369
]
],
"normalized": []
},
{
"id": "15155769_T24",
"type": "GENE-Y",
"text": [
"COT"
],
"offsets": [
[
1374,
1377
]
],
"normalized": []
},
{
"id": "15155769_T25",
"type": "GENE-Y",
"text": [
"CrAT"
],
"offsets": [
[
213,
217
]
],
"normalized": []
},
{
"id": "15155769_T26",
"type": "GENE-Y",
"text": [
"rat CrAT"
],
"offsets": [
[
346,
354
]
],
"normalized": []
},
{
"id": "15155769_T27",
"type": "GENE-N",
"text": [
"M564G"
],
"offsets": [
[
401,
406
]
],
"normalized": []
},
{
"id": "15155769_T28",
"type": "GENE-Y",
"text": [
"CrAT"
],
"offsets": [
[
415,
419
]
],
"normalized": []
},
{
"id": "15155769_T29",
"type": "GENE-Y",
"text": [
"CrAT"
],
"offsets": [
[
552,
556
]
],
"normalized": []
},
{
"id": "15155769_T30",
"type": "GENE-Y",
"text": [
"CrAT"
],
"offsets": [
[
651,
655
]
],
"normalized": []
},
{
"id": "15155769_T31",
"type": "GENE-N",
"text": [
"glycine (Gly553) to methionine"
],
"offsets": [
[
769,
799
]
],
"normalized": []
},
{
"id": "15155769_T32",
"type": "GENE-Y",
"text": [
"carnitine octanoyltransferase"
],
"offsets": [
[
803,
832
]
],
"normalized": []
},
{
"id": "15155769_T33",
"type": "GENE-Y",
"text": [
"COT"
],
"offsets": [
[
834,
837
]
],
"normalized": []
},
{
"id": "15155769_T34",
"type": "GENE-Y",
"text": [
"CrAT"
],
"offsets": [
[
984,
988
]
],
"normalized": []
},
{
"id": "15155769_T35",
"type": "GENE-N",
"text": [
"M564A"
],
"offsets": [
[
997,
1002
]
],
"normalized": []
},
{
"id": "15155769_T36",
"type": "GENE-Y",
"text": [
"carnitine acetyltransferase"
],
"offsets": [
[
12,
39
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "15155769_0",
"type": "SUBSTRATE_PRODUCT-OF",
"arg1_id": "15155769_T5",
"arg2_id": "15155769_T19",
"normalized": []
},
{
"id": "15155769_1",
"type": "SUBSTRATE_PRODUCT-OF",
"arg1_id": "15155769_T6",
"arg2_id": "15155769_T19",
"normalized": []
},
{
"id": "15155769_2",
"type": "SUBSTRATE_PRODUCT-OF",
"arg1_id": "15155769_T7",
"arg2_id": "15155769_T19",
"normalized": []
},
{
"id": "15155769_3",
"type": "SUBSTRATE",
"arg1_id": "15155769_T8",
"arg2_id": "15155769_T28",
"normalized": []
},
{
"id": "15155769_4",
"type": "SUBSTRATE",
"arg1_id": "15155769_T9",
"arg2_id": "15155769_T28",
"normalized": []
},
{
"id": "15155769_5",
"type": "SUBSTRATE",
"arg1_id": "15155769_T8",
"arg2_id": "15155769_T27",
"normalized": []
},
{
"id": "15155769_6",
"type": "SUBSTRATE",
"arg1_id": "15155769_T9",
"arg2_id": "15155769_T27",
"normalized": []
},
{
"id": "15155769_7",
"type": "SUBSTRATE",
"arg1_id": "15155769_T9",
"arg2_id": "15155769_T29",
"normalized": []
},
{
"id": "15155769_8",
"type": "SUBSTRATE",
"arg1_id": "15155769_T10",
"arg2_id": "15155769_T29",
"normalized": []
},
{
"id": "15155769_9",
"type": "SUBSTRATE",
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"arg2_id": "15155769_T30",
"normalized": []
},
{
"id": "15155769_10",
"type": "SUBSTRATE",
"arg1_id": "15155769_T15",
"arg2_id": "15155769_T32",
"normalized": []
},
{
"id": "15155769_11",
"type": "SUBSTRATE",
"arg1_id": "15155769_T16",
"arg2_id": "15155769_T32",
"normalized": []
},
{
"id": "15155769_12",
"type": "SUBSTRATE",
"arg1_id": "15155769_T16",
"arg2_id": "15155769_T33",
"normalized": []
},
{
"id": "15155769_13",
"type": "SUBSTRATE",
"arg1_id": "15155769_T15",
"arg2_id": "15155769_T33",
"normalized": []
},
{
"id": "15155769_14",
"type": "SUBSTRATE",
"arg1_id": "15155769_T1",
"arg2_id": "15155769_T20",
"normalized": []
},
{
"id": "15155769_15",
"type": "SUBSTRATE",
"arg1_id": "15155769_T10",
"arg2_id": "15155769_T27",
"normalized": []
},
{
"id": "15155769_16",
"type": "SUBSTRATE",
"arg1_id": "15155769_T10",
"arg2_id": "15155769_T28",
"normalized": []
},
{
"id": "15155769_17",
"type": "PART-OF",
"arg1_id": "15155769_T3",
"arg2_id": "15155769_T23",
"normalized": []
},
{
"id": "15155769_18",
"type": "PART-OF",
"arg1_id": "15155769_T3",
"arg2_id": "15155769_T24",
"normalized": []
}
] |
22080034 | 22080034 | [
{
"id": "22080034_title",
"type": "title",
"text": [
"Nanosilver effects on growth parameters in experimental aflatoxicosis in broiler chickens."
],
"offsets": [
[
0,
90
]
]
},
{
"id": "22080034_abstract",
"type": "abstract",
"text": [
"Aflatoxicosis is a cause of economic losses in broiler production. In this study, the effect of one commercial nanocompound, Nanocid (Nano Nasb Pars Co., Iran) was evaluated in reduction of aflatoxin effects on the growth and performance indices in broiler chickens suffering from experimental aflatoxicosis. For this, a total of 300 one-day-old broiler chicks (Ross strain) were randomly divided into 4 groups with 3 replicates of 15 chicks in each separated pen during the 28-day experiment. Treatment groups including group A: chickens fed basal diet, group B: chickens fed 3 ppm productive aflatoxin in basal diet, group C: chickens fed basal diet plus 2500 ppm Nanocid, and group D: chickens fed 3 ppm productive aflatoxin and 2500 ppm Nanocid, in basal diet. Data on body weight, body weight gain (BWG), feed intake, and feed conversion ratio (FCR) were recorded at weekly intervals. Also cumulative data were assessed. Results showed, although supplement of Nanocid to conventional diet had no effect on performance but addition of Nanocid to diet containing 3 ppm aflatoxin increased significantly the cumulative BWG, cumulative feed consumption and decreased FCR in the last 2 weeks of experimental period. The improvement in these performance indices by supplement of Nanocid to diet containing aflatoxin showed the ability of Nanocid to diminish the inhibitory effects of aflatoxin."
],
"offsets": [
[
91,
1484
]
]
}
] | [
{
"id": "22080034_T1",
"type": "CHEMICAL",
"text": [
"aflatoxin"
],
"offsets": [
[
1163,
1172
]
],
"normalized": []
},
{
"id": "22080034_T2",
"type": "CHEMICAL",
"text": [
"aflatoxin"
],
"offsets": [
[
1396,
1405
]
],
"normalized": []
},
{
"id": "22080034_T3",
"type": "CHEMICAL",
"text": [
"aflatoxin"
],
"offsets": [
[
1474,
1483
]
],
"normalized": []
},
{
"id": "22080034_T4",
"type": "CHEMICAL",
"text": [
"aflatoxin"
],
"offsets": [
[
281,
290
]
],
"normalized": []
},
{
"id": "22080034_T5",
"type": "CHEMICAL",
"text": [
"aflatoxin"
],
"offsets": [
[
685,
694
]
],
"normalized": []
},
{
"id": "22080034_T6",
"type": "CHEMICAL",
"text": [
"aflatoxin"
],
"offsets": [
[
809,
818
]
],
"normalized": []
}
] | [] | [] | [] |
23625750 | 23625750 | [
{
"id": "23625750_title",
"type": "title",
"text": [
"The effects of the adenosine A3 receptor agonist IB-MECA on sodium taurocholate-induced experimental acute pancreatitis."
],
"offsets": [
[
0,
120
]
]
},
{
"id": "23625750_abstract",
"type": "abstract",
"text": [
"The role of adenosine A3 receptors and their distribution in the gastrointestinal tract have been widely investigated. Most of the reports discuss their role in intestinal inflammations. However, the role of adenosine A3 receptor agonist in pancreatitis has not been well established. The aim of this study is (Ed note: Purpose statements should be in present tense) to evaluate the effects of the adenosine A3 receptor agonist on the course of sodium taurocholate-induced experimental acute pancreatitis (EAP). The experiments were performed on 80 male Wistar rats, 58 of which survived, subdivided into 3 groups: C-control rats, I-EAP group, and II-EAP group treated with the adenosine A3 receptor agonist IB-MECA (1-deoxy-1-6[[(3-iodophenyl) methyl]amino]-9H-purin-9-yl)-N-methyl-B-D-ribofuronamide at a dose of 0.75 mg/kg b.w. i.p. at 48, 24, 12 and 1 h before and 1 h after the injection of 5 % sodium taurocholate solution into the biliary-pancreatic duct. Serum for α-amylase and lipase determinations and tissue samples for morphological examinations were collected at 2, 6, and 24 h of the experiment. In the IB-MECA group, α-amylase activity was decreased with statistically high significance compared to group I. The activity of lipase was not significantly different among the experimental groups but higher than in the control group. The administration of IB-MECA attenuated the histological parameters of inflammation as compared to untreated animals. The use of A3 receptor agonist IB-MECA attenuates EAP. Our findings suggest that stimulation of adenosine A3 receptors plays a positive role in the sodium taurocholate-induced EAP in rats."
],
"offsets": [
[
121,
1775
]
]
}
] | [
{
"id": "23625750_T1",
"type": "CHEMICAL",
"text": [
"IB-MECA"
],
"offsets": [
[
1239,
1246
]
],
"normalized": []
},
{
"id": "23625750_T2",
"type": "CHEMICAL",
"text": [
"adenosine"
],
"offsets": [
[
133,
142
]
],
"normalized": []
},
{
"id": "23625750_T3",
"type": "CHEMICAL",
"text": [
"IB-MECA"
],
"offsets": [
[
1490,
1497
]
],
"normalized": []
},
{
"id": "23625750_T4",
"type": "CHEMICAL",
"text": [
"IB-MECA"
],
"offsets": [
[
1618,
1625
]
],
"normalized": []
},
{
"id": "23625750_T5",
"type": "CHEMICAL",
"text": [
"adenosine"
],
"offsets": [
[
1683,
1692
]
],
"normalized": []
},
{
"id": "23625750_T6",
"type": "CHEMICAL",
"text": [
"sodium taurocholate"
],
"offsets": [
[
1735,
1754
]
],
"normalized": []
},
{
"id": "23625750_T7",
"type": "CHEMICAL",
"text": [
"adenosine"
],
"offsets": [
[
329,
338
]
],
"normalized": []
},
{
"id": "23625750_T8",
"type": "CHEMICAL",
"text": [
"adenosine"
],
"offsets": [
[
519,
528
]
],
"normalized": []
},
{
"id": "23625750_T9",
"type": "CHEMICAL",
"text": [
"sodium taurocholate"
],
"offsets": [
[
566,
585
]
],
"normalized": []
},
{
"id": "23625750_T10",
"type": "CHEMICAL",
"text": [
"adenosine"
],
"offsets": [
[
799,
808
]
],
"normalized": []
},
{
"id": "23625750_T11",
"type": "CHEMICAL",
"text": [
"IB-MECA"
],
"offsets": [
[
829,
836
]
],
"normalized": []
},
{
"id": "23625750_T12",
"type": "CHEMICAL",
"text": [
"(1-deoxy-1-6[[(3-iodophenyl) methyl]amino]-9H-purin-9-yl)-N-methyl-B-D-ribofuronamide"
],
"offsets": [
[
837,
922
]
],
"normalized": []
},
{
"id": "23625750_T13",
"type": "CHEMICAL",
"text": [
"sodium taurocholate"
],
"offsets": [
[
1021,
1040
]
],
"normalized": []
},
{
"id": "23625750_T14",
"type": "CHEMICAL",
"text": [
"adenosine"
],
"offsets": [
[
19,
28
]
],
"normalized": []
},
{
"id": "23625750_T15",
"type": "CHEMICAL",
"text": [
"IB-MECA"
],
"offsets": [
[
49,
56
]
],
"normalized": []
},
{
"id": "23625750_T16",
"type": "CHEMICAL",
"text": [
"sodium taurocholate"
],
"offsets": [
[
60,
79
]
],
"normalized": []
},
{
"id": "23625750_T17",
"type": "GENE-N",
"text": [
"α-amylase"
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] |
23305807 | 23305807 | [
{
"id": "23305807_title",
"type": "title",
"text": [
"Prophylactic effect of resveratrol against ethinylestradiol-induced liver cholestasis."
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"Estrogens, and particularly glucuronides such as ethinylestradiol (EE), have been shown to cause cholestasis in animal studies, by reducing bile acid uptake by hepatocytes. The aim of the present article was to investigate anticholestatic activity of resveratrol (RES) against liver cholestasis induced by EE in adult female rats. The daily oral administration of the RES at a concentration of 25 mg/kg body weight for 15 days to rats treated with EE (100 μg/kg body weight for 5 days) resulted in a significant protection against EE-induced decrease in both serum cholesterol and bile acid levels as well as against an increase of serum bilirubin concentration. The treatment also resulted in a significant increase in hepatic superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase activities as well as hepatic protein-bound and nonprotein sulfhydryl groups. RES inhibited serum alkaline phosphatase, alanine aminotransferase, pi-glutathione-S-transferase, gamma-glutamyl transpeptidase, and alpha-glutathione-S-transferase activities, as well as reduced serum tumor necrosis factor-alpha, nitric oxide, and hepatic malondialdehyde as compared to EE-treated rats. The results clearly suggest that RES has a powerful prophylactic action in cholestasis induced by EE. Taken together, RES has potential as a preventive and therapeutic agent for cholestasis and deserves clinical trial in the near future as an adjuvant therapy in women treated with estrogen."
],
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136,
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43,
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1108,
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"id": "23305807_T27",
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835
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837,
859
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861,
882
]
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888,
896
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"id": "23305807_T32",
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995,
1015
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"id": "23305807_T33",
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"alanine aminotransferase"
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1017,
1041
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"id": "23305807_T34",
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1043,
1071
]
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},
{
"id": "23305807_T35",
"type": "GENE-N",
"text": [
"gamma-glutamyl transpeptidase"
],
"offsets": [
[
1073,
1102
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23305807_0",
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{
"id": "23305807_1",
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"arg2_id": "23305807_T27",
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}
] |
23223177 | 23223177 | [
{
"id": "23223177_title",
"type": "title",
"text": [
"Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes."
],
"offsets": [
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0,
140
]
]
},
{
"id": "23223177_abstract",
"type": "abstract",
"text": [
"Diabetic cardiomyopathy is associated with suppression of cardiac autophagy, and activation of AMP-activated protein kinase (AMPK) restores cardiac autophagy and prevents cardiomyopathy in diabetic mice, albeit by an unknown mechanism. We hypothesized that AMPK-induced autophagy ameliorates diabetic cardiomyopathy by inhibiting cardiomyocyte apoptosis and examined the effects of AMPK on the interaction between Beclin1 and Bcl-2, a switch between autophagy and apoptosis, in diabetic mice and high glucose-treated H9c2 cardiac myoblast cells. Exposure of H9c2 cells to high glucose reduced AMPK activity, inhibited Jun NH2-terminal kinase 1 (JNK1)-B-cell lymphoma 2 (Bcl-2) signaling, and promoted Beclin1 binding to Bcl-2. Conversely, activation of AMPK by metformin stimulated JNK1-Bcl-2 signaling and disrupted the Beclin1-Bcl-2 complex. Activation of AMPK, which normalized cardiac autophagy, attenuated high glucose-induced apoptosis in cultured H9c2 cells. This effect was attenuated by inhibition of autophagy. Finally, chronic administration of metformin in diabetic mice restored cardiac autophagy by activating JNK1-Bcl-2 pathways and dissociating Beclin1 and Bcl-2. The induction of autophagy protected against cardiac apoptosis and improved cardiac structure and function in diabetic mice. We concluded that dissociation of Bcl-2 from Beclin1 may be an important mechanism for preventing diabetic cardiomyopathy via AMPK activation that restores autophagy and protects against cardiac apoptosis."
],
"offsets": [
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141,
1651
]
]
}
] | [
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"id": "23223177_T1",
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1197,
1206
]
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642,
649
]
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"id": "23223177_T3",
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718,
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]
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"id": "23223177_T4",
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"NH2"
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763,
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]
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1057,
1064
]
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236,
239
]
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1269
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1270,
1275
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1302,
1309
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1314,
1319
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266,
270
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1491,
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523,
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786,
790
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]
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842,
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861,
866
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894,
898
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933
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"Beclin1"
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962,
969
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"id": "23223177_T30",
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"Bcl-2"
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970,
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"id": "23223177_T31",
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"AMPK"
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999,
1003
]
],
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},
{
"id": "23223177_T32",
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"AMP-activated protein kinase"
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[
236,
264
]
],
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},
{
"id": "23223177_T33",
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"Bcl-2"
],
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[
16,
21
]
],
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},
{
"id": "23223177_T34",
"type": "GENE-Y",
"text": [
"Beclin1"
],
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[
22,
29
]
],
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},
{
"id": "23223177_T35",
"type": "GENE-Y",
"text": [
"AMPK"
],
"offsets": [
[
51,
55
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23223177_0",
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"arg2_id": "23223177_T19",
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},
{
"id": "23223177_1",
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"arg2_id": "23223177_T20",
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},
{
"id": "23223177_2",
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"arg2_id": "23223177_T21",
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},
{
"id": "23223177_3",
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"arg2_id": "23223177_T22",
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},
{
"id": "23223177_4",
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"arg2_id": "23223177_T23",
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},
{
"id": "23223177_5",
"type": "ACTIVATOR",
"arg1_id": "23223177_T1",
"arg2_id": "23223177_T7",
"normalized": []
},
{
"id": "23223177_6",
"type": "ACTIVATOR",
"arg1_id": "23223177_T1",
"arg2_id": "23223177_T8",
"normalized": []
}
] |
23407783 | 23407783 | [
{
"id": "23407783_title",
"type": "title",
"text": [
"The CRF(1) receptor antagonist SSR125543 prevents stress-induced cognitive deficit associated with hippocampal dysfunction: Comparison with paroxetine and D-cycloserine."
],
"offsets": [
[
0,
169
]
]
},
{
"id": "23407783_abstract",
"type": "abstract",
"text": [
"RATIONALE: The selective CRF(1) (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure. Memory disturbances described in post-traumatic stress disorder (PTSD) patients are believed to be associated with changes in neuronal activity, in particular at the level of the hippocampus. OBJECTIVES: The present study aims at investigating whether the effects of SSR125543 (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day), and the partial N-methyl-D-aspartate (NMDA) receptor agonist, D-cycloserine (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD. METHODS: Mice received two unavoidable electric foot-shocks. Then, 1 or 16 days after stress, they were tested for their memory performance using the object recognition test. Neuronal excitability was recorded during the third week post-stress in the CA1 area of the hippocampus. Drugs were administered from day 1 post-stress to the day preceding the electrophysiological study. RESULTS: Application of electric shocks produced cognitive impairment 16, but not 1 day after stress, an effect which was associated with a decrease in hippocampal neuronal excitability. Both stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine. CONCLUSIONS: These findings confirm that the CRF(1) receptor antagonist SSR125543 is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress."
],
"offsets": [
[
170,
2029
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]
}
] | [
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"id": "23407783_T1",
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"SSR125543"
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"id": "23407783_T2",
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"paroxetine"
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1720,
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"id": "23407783_T3",
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"D-cycloserine"
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"id": "23407783_T7",
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"5-HT"
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855,
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"paroxetine"
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"N-methyl-D-aspartate"
],
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923,
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]
],
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},
{
"id": "23407783_T10",
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"NMDA"
],
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945,
949
]
],
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"D-cycloserine"
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"SSR125543"
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262,
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"paroxetine"
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140,
150
]
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"id": "23407783_T14",
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155,
168
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],
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31,
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"CRF(1) receptor"
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],
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},
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"CRF(1) (corticotropin releasing factor type 1) receptor"
],
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195,
250
]
],
"normalized": []
},
{
"id": "23407783_T18",
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"N-methyl-D-aspartate (NMDA) receptor"
],
"offsets": [
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923,
959
]
],
"normalized": []
},
{
"id": "23407783_T19",
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"text": [
"CRF(1) receptor"
],
"offsets": [
[
4,
19
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23407783_0",
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"arg2_id": "23407783_T19",
"normalized": []
},
{
"id": "23407783_1",
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"arg1_id": "23407783_T12",
"arg2_id": "23407783_T17",
"normalized": []
},
{
"id": "23407783_2",
"type": "AGONIST",
"arg1_id": "23407783_T11",
"arg2_id": "23407783_T18",
"normalized": []
},
{
"id": "23407783_3",
"type": "ANTAGONIST",
"arg1_id": "23407783_T4",
"arg2_id": "23407783_T16",
"normalized": []
}
] |
9557255 | 9557255 | [
{
"id": "9557255_title",
"type": "title",
"text": [
"A new concept of drug delivery for acne."
],
"offsets": [
[
0,
40
]
]
},
{
"id": "9557255_abstract",
"type": "abstract",
"text": [
"Adapalene is a stable naphthoic acid derivative that displays a strong retinoid agonist pharmacology. This drug controls cell proliferation and differentiation, and possesses significant anti-inflammatory action. The retinoid action of adapalene are mediated by the ligand-activated gene transcription factors retinoic acid receptors RAR beta and RAR gamma. We describe here how an aqueous gel containing adapalene was selected for the topical treatment of acne."
],
"offsets": [
[
41,
503
]
]
}
] | [
{
"id": "9557255_T1",
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"Adapalene"
],
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[
41,
50
]
],
"normalized": []
},
{
"id": "9557255_T2",
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"text": [
"retinoid"
],
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[
258,
266
]
],
"normalized": []
},
{
"id": "9557255_T3",
"type": "CHEMICAL",
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"naphthoic acid"
],
"offsets": [
[
63,
77
]
],
"normalized": []
},
{
"id": "9557255_T4",
"type": "CHEMICAL",
"text": [
"adapalene"
],
"offsets": [
[
277,
286
]
],
"normalized": []
},
{
"id": "9557255_T5",
"type": "CHEMICAL",
"text": [
"retinoic acid"
],
"offsets": [
[
351,
364
]
],
"normalized": []
},
{
"id": "9557255_T6",
"type": "CHEMICAL",
"text": [
"adapalene"
],
"offsets": [
[
446,
455
]
],
"normalized": []
},
{
"id": "9557255_T7",
"type": "CHEMICAL",
"text": [
"retinoid"
],
"offsets": [
[
112,
120
]
],
"normalized": []
},
{
"id": "9557255_T8",
"type": "GENE-N",
"text": [
"ligand-activated gene transcription factors"
],
"offsets": [
[
307,
350
]
],
"normalized": []
},
{
"id": "9557255_T9",
"type": "GENE-N",
"text": [
"retinoic acid receptors"
],
"offsets": [
[
351,
374
]
],
"normalized": []
},
{
"id": "9557255_T10",
"type": "GENE-Y",
"text": [
"RAR beta"
],
"offsets": [
[
375,
383
]
],
"normalized": []
},
{
"id": "9557255_T11",
"type": "GENE-Y",
"text": [
"RAR gamma"
],
"offsets": [
[
388,
397
]
],
"normalized": []
}
] | [] | [] | [] |
12198239 | 12198239 | [
{
"id": "12198239_title",
"type": "title",
"text": [
"The mineralocorticoid receptor may compensate for the loss of the glucocorticoid receptor at specific stages of mammary gland development."
],
"offsets": [
[
0,
138
]
]
},
{
"id": "12198239_abstract",
"type": "abstract",
"text": [
"To study the role of glucocorticoid receptor (GR) at different stages of mammary gland development, mammary anlage were rescued from GR-/- mice by transplantation into the cleared fat pad of wild-type mice. In virgin mice, GR-/- outgrowths displayed abnormal ductal morphogenesis characterized by distended lumena, multiple layers of luminal epithelial cells in some regions along the ducts, and increased periductal stroma. In contrast, the loss of GR did not result in overt phenotypic changes in mammary gland development during pregnancy, lactation, and involution. Surprisingly, despite the known synergism between glucocorticoids and prolactin in the regulation of milk protein gene expression, whey acidic protein and beta-casein mRNA levels were unaffected in GR-/- transplants as compared with wild-type transplants. That mineralocorticoid receptor (MR) might compensate for the loss of GR was suggested by the detection of MR in the mammary gland at d 1 of lactation. This hypothesis was tested using explant cultures derived from the GR-/- transplants in which the mineralocorticoid fludrocortisone was able to synergistically induce beta-casein gene expression in the presence of prolactin and insulin. These studies suggest that MR may compensate for the absence of GR at some, but not at all stages of mammary gland development."
],
"offsets": [
[
139,
1481
]
]
}
] | [
{
"id": "12198239_T1",
"type": "CHEMICAL",
"text": [
"fludrocortisone"
],
"offsets": [
[
1233,
1248
]
],
"normalized": []
},
{
"id": "12198239_T2",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
1184,
1186
]
],
"normalized": []
},
{
"id": "12198239_T3",
"type": "GENE-Y",
"text": [
"beta-casein"
],
"offsets": [
[
1284,
1295
]
],
"normalized": []
},
{
"id": "12198239_T4",
"type": "GENE-Y",
"text": [
"prolactin"
],
"offsets": [
[
1331,
1340
]
],
"normalized": []
},
{
"id": "12198239_T5",
"type": "GENE-N",
"text": [
"insulin"
],
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[
1345,
1352
]
],
"normalized": []
},
{
"id": "12198239_T6",
"type": "GENE-Y",
"text": [
"MR"
],
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[
1381,
1383
]
],
"normalized": []
},
{
"id": "12198239_T7",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
1418,
1420
]
],
"normalized": []
},
{
"id": "12198239_T8",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
272,
274
]
],
"normalized": []
},
{
"id": "12198239_T9",
"type": "GENE-Y",
"text": [
"glucocorticoid receptor"
],
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[
160,
183
]
],
"normalized": []
},
{
"id": "12198239_T10",
"type": "GENE-Y",
"text": [
"GR"
],
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[
362,
364
]
],
"normalized": []
},
{
"id": "12198239_T11",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
589,
591
]
],
"normalized": []
},
{
"id": "12198239_T12",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
185,
187
]
],
"normalized": []
},
{
"id": "12198239_T13",
"type": "GENE-Y",
"text": [
"whey acidic protein"
],
"offsets": [
[
840,
859
]
],
"normalized": []
},
{
"id": "12198239_T14",
"type": "GENE-Y",
"text": [
"beta-casein"
],
"offsets": [
[
864,
875
]
],
"normalized": []
},
{
"id": "12198239_T15",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
907,
909
]
],
"normalized": []
},
{
"id": "12198239_T16",
"type": "GENE-Y",
"text": [
"mineralocorticoid receptor"
],
"offsets": [
[
970,
996
]
],
"normalized": []
},
{
"id": "12198239_T17",
"type": "GENE-Y",
"text": [
"MR"
],
"offsets": [
[
998,
1000
]
],
"normalized": []
},
{
"id": "12198239_T18",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
1035,
1037
]
],
"normalized": []
},
{
"id": "12198239_T19",
"type": "GENE-Y",
"text": [
"MR"
],
"offsets": [
[
1072,
1074
]
],
"normalized": []
},
{
"id": "12198239_T20",
"type": "GENE-Y",
"text": [
"mineralocorticoid receptor"
],
"offsets": [
[
4,
30
]
],
"normalized": []
},
{
"id": "12198239_T21",
"type": "GENE-Y",
"text": [
"glucocorticoid receptor"
],
"offsets": [
[
66,
89
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12198239_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "12198239_T1",
"arg2_id": "12198239_T3",
"normalized": []
}
] |
17410123 | 17410123 | [
{
"id": "17410123_title",
"type": "title",
"text": [
"Presynaptic alpha-2C adrenoceptor-mediated control of noradrenaline release in humans: genotype- or age-dependent?"
],
"offsets": [
[
0,
114
]
]
},
{
"id": "17410123_abstract",
"type": "abstract",
"text": [
"In vitro alpha-2CDel322-325 adrenoceptor (AR) polymorphism exhibits reduced functional responsiveness. We studied whether this is true also in vivo in humans. We assessed in nine young wild-type (WT) alpha-2C AR subjects (aged 23 years), 10 elder WT alpha-2C AR subjects (aged 63 years), and nine alpha-2CDel AR subjects (aged 28 years) clonidine (1 microg/kg intravenous (i.v.) bolus)-evoked plasma noradrenaline (pNA), heart rate (HR), and blood pressure (BP) changes. Clonidine-evoked pNA decreases were comparable in young WT alpha-2C and in alpha-2CDel AR subjects, but significantly lower (P=0.033) in elder subjects. Similarly, clonidine-evoked HR decreases were significantly larger in young WT alpha-2C and in alpha-2CDel AR subjects than in elder subjects, whereas clonidine-evoked BP decreases were larger in elder subjects. In conclusion, alpha-2CDel AR appears to play only a minor role in presynaptic regulation of NA release and/or to be not hypofunctional in vivo in humans, but functional responsiveness of presynaptic alpha-2 AR declines with ageing."
],
"offsets": [
[
115,
1183
]
]
}
] | [
{
"id": "17410123_T1",
"type": "CHEMICAL",
"text": [
"noradrenaline"
],
"offsets": [
[
515,
528
]
],
"normalized": []
},
{
"id": "17410123_T2",
"type": "CHEMICAL",
"text": [
"Clonidine"
],
"offsets": [
[
586,
595
]
],
"normalized": []
},
{
"id": "17410123_T3",
"type": "CHEMICAL",
"text": [
"clonidine"
],
"offsets": [
[
750,
759
]
],
"normalized": []
},
{
"id": "17410123_T4",
"type": "CHEMICAL",
"text": [
"clonidine"
],
"offsets": [
[
890,
899
]
],
"normalized": []
},
{
"id": "17410123_T5",
"type": "CHEMICAL",
"text": [
"NA"
],
"offsets": [
[
1044,
1046
]
],
"normalized": []
},
{
"id": "17410123_T6",
"type": "CHEMICAL",
"text": [
"noradrenaline"
],
"offsets": [
[
54,
67
]
],
"normalized": []
},
{
"id": "17410123_T7",
"type": "GENE-N",
"text": [
"alpha-2 AR"
],
"offsets": [
[
1151,
1161
]
],
"normalized": []
},
{
"id": "17410123_T8",
"type": "GENE-Y",
"text": [
"alpha-2C AR"
],
"offsets": [
[
315,
326
]
],
"normalized": []
},
{
"id": "17410123_T9",
"type": "GENE-Y",
"text": [
"alpha-2C AR"
],
"offsets": [
[
365,
376
]
],
"normalized": []
},
{
"id": "17410123_T10",
"type": "GENE-Y",
"text": [
"alpha-2CDel AR"
],
"offsets": [
[
412,
426
]
],
"normalized": []
},
{
"id": "17410123_T11",
"type": "GENE-N",
"text": [
"AR"
],
"offsets": [
[
157,
159
]
],
"normalized": []
},
{
"id": "17410123_T12",
"type": "GENE-Y",
"text": [
"alpha-2C"
],
"offsets": [
[
645,
653
]
],
"normalized": []
},
{
"id": "17410123_T13",
"type": "GENE-Y",
"text": [
"alpha-2CDel AR"
],
"offsets": [
[
661,
675
]
],
"normalized": []
},
{
"id": "17410123_T14",
"type": "GENE-Y",
"text": [
"alpha-2C"
],
"offsets": [
[
818,
826
]
],
"normalized": []
},
{
"id": "17410123_T15",
"type": "GENE-Y",
"text": [
"alpha-2CDel AR"
],
"offsets": [
[
834,
848
]
],
"normalized": []
},
{
"id": "17410123_T16",
"type": "GENE-Y",
"text": [
"alpha-2CDel AR"
],
"offsets": [
[
966,
980
]
],
"normalized": []
},
{
"id": "17410123_T17",
"type": "GENE-Y",
"text": [
"alpha-2CDel322-325 adrenoceptor"
],
"offsets": [
[
124,
155
]
],
"normalized": []
},
{
"id": "17410123_T18",
"type": "GENE-Y",
"text": [
"alpha-2C adrenoceptor"
],
"offsets": [
[
12,
33
]
],
"normalized": []
}
] | [] | [] | [] |
16426349 | 16426349 | [
{
"id": "16426349_title",
"type": "title",
"text": [
"The effects of pentoxifylline on the myocardial inflammation and ischemia-reperfusion injury during cardiopulmonary bypass."
],
"offsets": [
[
0,
123
]
]
},
{
"id": "16426349_abstract",
"type": "abstract",
"text": [
"BACKGROUND: Pentoxifylline (Ptx) decreases necessity of cell energy and inflammatory reactions via inhibition of 5'-nucleotidase (5'-NT). The aim of this study is to investigate whether the addition of Ptx into the cardioplegic solutions avoids myocardial inflammatory reactions and ischemia/reperfusion (I/R) injury during extracorpereal circulation. METHODS: Between December 1999 and February 2002, we operated 75 patients with the diagnoses of atrial septal defect (ASD), ventricular septal defect (VSD), valve disease, and coronary disease. The average age of patients was 42.4 and male-female ratio was 1: 1.5. The patients were divided into two groups, which were the study group (n = 40) and the control group (n = 35). We used cold blood cardioplegia mixed with St. Thomas' Hospital II cardioplegic solution for both of the groups. Ptx was added into the cardioplegic solution (500 mg/L) in the study group. Interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrotisis factor-alpha (TNF-alpha) levels in coronary sinus blood samples during cross-clamp time (X-clamp) and after releasing of it and tissue TNF-alpha in the right atrial appendix biopsy material that was taken after X-clamp were studied to compare the both groups. RESULTS: After releasing X-clamp, results of blood TNF-alpha, IL-6, and IL-8 of both groups were statistically significant (p < 0.005). At the pathological examination, we also observed that the amount of tissue TNF-alpha in the control group (66 +/- 17.1) was much higher than the study group (16.6 +/- 5.9, p <0.005). CONCLUSIONS: These results show that Ptx may be added into cardioplegic solution to avoid the myocardial inflammation and I/R injury during open heart surgery."
],
"offsets": [
[
124,
1845
]
]
}
] | [
{
"id": "16426349_T1",
"type": "CHEMICAL",
"text": [
"Pentoxifylline"
],
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[
136,
150
]
],
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},
{
"id": "16426349_T2",
"type": "CHEMICAL",
"text": [
"Ptx"
],
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1723,
1726
]
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{
"id": "16426349_T3",
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"Ptx"
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326,
329
]
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"Ptx"
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152,
155
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"Ptx"
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965,
968
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"text": [
"pentoxifylline"
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[
15,
29
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{
"id": "16426349_T7",
"type": "GENE-Y",
"text": [
"TNF-alpha"
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1241,
1250
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"id": "16426349_T8",
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"text": [
"5'-nucleotidase"
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237,
252
]
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{
"id": "16426349_T9",
"type": "GENE-Y",
"text": [
"TNF-alpha"
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1417,
1426
]
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{
"id": "16426349_T10",
"type": "GENE-Y",
"text": [
"5'-NT"
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254,
259
]
],
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{
"id": "16426349_T11",
"type": "GENE-Y",
"text": [
"IL-6"
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1428,
1432
]
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"id": "16426349_T12",
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"text": [
"IL-8"
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1438,
1442
]
],
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{
"id": "16426349_T13",
"type": "GENE-Y",
"text": [
"TNF-alpha"
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1578,
1587
]
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"id": "16426349_T14",
"type": "GENE-Y",
"text": [
"Interleukin-6"
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1041,
1054
]
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"IL-6"
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1056,
1060
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"text": [
"interleukin-8"
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1063,
1076
]
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"id": "16426349_T17",
"type": "GENE-Y",
"text": [
"IL-8"
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1078,
1082
]
],
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},
{
"id": "16426349_T18",
"type": "GENE-Y",
"text": [
"tumor necrotisis factor-alpha"
],
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1089,
1118
]
],
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},
{
"id": "16426349_T19",
"type": "GENE-Y",
"text": [
"TNF-alpha"
],
"offsets": [
[
1120,
1129
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16426349_0",
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"arg2_id": "16426349_T8",
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},
{
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},
{
"id": "16426349_3",
"type": "INHIBITOR",
"arg1_id": "16426349_T4",
"arg2_id": "16426349_T10",
"normalized": []
}
] |
23537749 | 23537749 | [
{
"id": "23537749_title",
"type": "title",
"text": [
"Combination of essential oils and antibiotics reduce antibiotic resistance in plasmid-conferred multidrug resistant bacteria."
],
"offsets": [
[
0,
125
]
]
},
{
"id": "23537749_abstract",
"type": "abstract",
"text": [
"In this study we investigated the relationship between several selected commercially available essential oils and beta-lactam antibiotics on their antibacterial effect against multidrug resistant bacteria. The antibacterial activity of essential oils and antibiotics was assessed using broth microdilution. The combined effects between essential oils of cinnamon bark, lavender, marjoram, tea tree, peppermint and ampicillin, piperacillin, cefazolin, cefuroxime, carbenicillin, ceftazidime, meropenem, were evaluated by means of the checkerboard method against beta-lactamase-producing Escherichia coli. In the latter assays, fractional inhibitory concentration (FIC) values were calculated to characterize interaction between the combinations. Substantial susceptibility of the bacteria toward natural antibiotics and a considerable reduction in the minimum inhibitory concentrations (MIC) of the antibiotics were noted in some paired combinations of antibiotics and essential oils. Out of 35 antibiotic-essential oil pairs tested, four of them showed synergistic effect (FIC≤0.5) and 31 pairs showed no interaction (FIC>0.5-4.0). The preliminary results obtained highlighted the occurrence of a pronounced synergistic relationship between piperacillin/cinnamon bark oil, piperacillin/lavender oil, piperacillin/peppermint oil as well as meropenem/peppermint oil against two of the three bacteria under study with a FIC index in the range 0.26-0.5. The finding highlighted the potential of peppermint, cinnamon bark and lavender essential oils being as antibiotic resistance modifying agent. Reduced usage of antibiotics could be employed as a treatment strategy to decrease the adverse effects and possibly to reverse the beta-lactam antibiotic resistance."
],
"offsets": [
[
126,
1884
]
]
}
] | [
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"id": "23537749_T1",
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"text": [
"beta-lactam"
],
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[
240,
251
]
],
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"id": "23537749_T2",
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"text": [
"piperacillin"
],
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1367,
1379
]
],
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},
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"id": "23537749_T3",
"type": "CHEMICAL",
"text": [
"piperacillin"
],
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[
1399,
1411
]
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"id": "23537749_T4",
"type": "CHEMICAL",
"text": [
"piperacillin"
],
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[
1426,
1438
]
],
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{
"id": "23537749_T5",
"type": "CHEMICAL",
"text": [
"meropenem"
],
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[
1465,
1474
]
],
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"id": "23537749_T6",
"type": "CHEMICAL",
"text": [
"beta-lactam"
],
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[
1850,
1861
]
],
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"id": "23537749_T7",
"type": "CHEMICAL",
"text": [
"ampicillin"
],
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[
540,
550
]
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},
{
"id": "23537749_T8",
"type": "CHEMICAL",
"text": [
"piperacillin"
],
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[
552,
564
]
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{
"id": "23537749_T9",
"type": "CHEMICAL",
"text": [
"cefazolin"
],
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[
566,
575
]
],
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},
{
"id": "23537749_T10",
"type": "CHEMICAL",
"text": [
"cefuroxime"
],
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[
577,
587
]
],
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},
{
"id": "23537749_T11",
"type": "CHEMICAL",
"text": [
"carbenicillin"
],
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[
589,
602
]
],
"normalized": []
},
{
"id": "23537749_T12",
"type": "CHEMICAL",
"text": [
"ceftazidime"
],
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[
604,
615
]
],
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},
{
"id": "23537749_T13",
"type": "CHEMICAL",
"text": [
"meropenem"
],
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[
617,
626
]
],
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},
{
"id": "23537749_T14",
"type": "GENE-Y",
"text": [
"beta-lactamase"
],
"offsets": [
[
687,
701
]
],
"normalized": []
}
] | [] | [] | [] |
17259377 | 17259377 | [
{
"id": "17259377_title",
"type": "title",
"text": [
"Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy."
],
"offsets": [
[
0,
90
]
]
},
{
"id": "17259377_abstract",
"type": "abstract",
"text": [
"It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-kappaB DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-kappaB, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. Salicylates, in doses administrated in our experiments, inhibited NF-kappaB and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy."
],
"offsets": [
[
91,
2313
]
]
}
] | [
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"id": "17259377_T1",
"type": "CHEMICAL",
"text": [
"aspirin"
],
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[
1184,
1191
]
],
"normalized": []
},
{
"id": "17259377_T2",
"type": "CHEMICAL",
"text": [
"salicylate"
],
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[
1220,
1230
]
],
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},
{
"id": "17259377_T3",
"type": "CHEMICAL",
"text": [
"salicylates"
],
"offsets": [
[
1437,
1448
]
],
"normalized": []
},
{
"id": "17259377_T4",
"type": "CHEMICAL",
"text": [
"Sulfasalazine"
],
"offsets": [
[
1738,
1751
]
],
"normalized": []
},
{
"id": "17259377_T5",
"type": "CHEMICAL",
"text": [
"salicylates"
],
"offsets": [
[
1785,
1796
]
],
"normalized": []
},
{
"id": "17259377_T6",
"type": "CHEMICAL",
"text": [
"nitric oxide"
],
"offsets": [
[
2003,
2015
]
],
"normalized": []
},
{
"id": "17259377_T7",
"type": "CHEMICAL",
"text": [
"Salicylates"
],
"offsets": [
[
2072,
2083
]
],
"normalized": []
},
{
"id": "17259377_T8",
"type": "CHEMICAL",
"text": [
"salicylate"
],
"offsets": [
[
397,
407
]
],
"normalized": []
},
{
"id": "17259377_T9",
"type": "CHEMICAL",
"text": [
"aspirin"
],
"offsets": [
[
421,
428
]
],
"normalized": []
},
{
"id": "17259377_T10",
"type": "CHEMICAL",
"text": [
"sodium salicylate"
],
"offsets": [
[
430,
447
]
],
"normalized": []
},
{
"id": "17259377_T11",
"type": "CHEMICAL",
"text": [
"sulfasalazine"
],
"offsets": [
[
453,
466
]
],
"normalized": []
},
{
"id": "17259377_T12",
"type": "CHEMICAL",
"text": [
"aspirin"
],
"offsets": [
[
128,
135
]
],
"normalized": []
},
{
"id": "17259377_T13",
"type": "CHEMICAL",
"text": [
"salicylate"
],
"offsets": [
[
900,
910
]
],
"normalized": []
},
{
"id": "17259377_T14",
"type": "CHEMICAL",
"text": [
"salicylates"
],
"offsets": [
[
1083,
1094
]
],
"normalized": []
},
{
"id": "17259377_T15",
"type": "CHEMICAL",
"text": [
"Salicylate"
],
"offsets": [
[
0,
10
]
],
"normalized": []
},
{
"id": "17259377_T16",
"type": "GENE-N",
"text": [
"NF-kappaB"
],
"offsets": [
[
1278,
1287
]
],
"normalized": []
},
{
"id": "17259377_T17",
"type": "GENE-Y",
"text": [
"p50"
],
"offsets": [
[
1497,
1500
]
],
"normalized": []
},
{
"id": "17259377_T18",
"type": "GENE-N",
"text": [
"NF-kappaB"
],
"offsets": [
[
1515,
1524
]
],
"normalized": []
},
{
"id": "17259377_T19",
"type": "GENE-Y",
"text": [
"p50"
],
"offsets": [
[
1627,
1630
]
],
"normalized": []
},
{
"id": "17259377_T20",
"type": "GENE-Y",
"text": [
"p65"
],
"offsets": [
[
1635,
1638
]
],
"normalized": []
},
{
"id": "17259377_T21",
"type": "GENE-N",
"text": [
"NF-kappaB"
],
"offsets": [
[
1904,
1913
]
],
"normalized": []
},
{
"id": "17259377_T22",
"type": "GENE-Y",
"text": [
"intracellular adhesion molecule-1"
],
"offsets": [
[
1958,
1991
]
],
"normalized": []
},
{
"id": "17259377_T23",
"type": "GENE-Y",
"text": [
"inducible nitric oxide synthase"
],
"offsets": [
[
1993,
2024
]
],
"normalized": []
},
{
"id": "17259377_T24",
"type": "GENE-Y",
"text": [
"cyclooxygenase-2"
],
"offsets": [
[
2030,
2046
]
],
"normalized": []
},
{
"id": "17259377_T25",
"type": "GENE-N",
"text": [
"NF-kappa"
],
"offsets": [
[
2138,
2146
]
],
"normalized": []
},
{
"id": "17259377_T26",
"type": "GENE-N",
"text": [
"cyclooxygenase"
],
"offsets": [
[
589,
603
]
],
"normalized": []
},
{
"id": "17259377_T27",
"type": "GENE-N",
"text": [
"nuclear factor-kappaB"
],
"offsets": [
[
636,
657
]
],
"normalized": []
},
{
"id": "17259377_T28",
"type": "GENE-N",
"text": [
"NF-kappaB"
],
"offsets": [
[
659,
668
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17259377_0",
"type": "INHIBITOR",
"arg1_id": "17259377_T1",
"arg2_id": "17259377_T16",
"normalized": []
},
{
"id": "17259377_1",
"type": "INHIBITOR",
"arg1_id": "17259377_T2",
"arg2_id": "17259377_T16",
"normalized": []
},
{
"id": "17259377_2",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "17259377_T3",
"arg2_id": "17259377_T17",
"normalized": []
},
{
"id": "17259377_3",
"type": "INHIBITOR",
"arg1_id": "17259377_T3",
"arg2_id": "17259377_T18",
"normalized": []
},
{
"id": "17259377_4",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "17259377_T3",
"arg2_id": "17259377_T19",
"normalized": []
},
{
"id": "17259377_5",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "17259377_T3",
"arg2_id": "17259377_T20",
"normalized": []
},
{
"id": "17259377_6",
"type": "INHIBITOR",
"arg1_id": "17259377_T4",
"arg2_id": "17259377_T21",
"normalized": []
},
{
"id": "17259377_7",
"type": "INHIBITOR",
"arg1_id": "17259377_T5",
"arg2_id": "17259377_T21",
"normalized": []
},
{
"id": "17259377_8",
"type": "INHIBITOR",
"arg1_id": "17259377_T4",
"arg2_id": "17259377_T22",
"normalized": []
},
{
"id": "17259377_9",
"type": "INHIBITOR",
"arg1_id": "17259377_T4",
"arg2_id": "17259377_T23",
"normalized": []
},
{
"id": "17259377_10",
"type": "INHIBITOR",
"arg1_id": "17259377_T4",
"arg2_id": "17259377_T24",
"normalized": []
},
{
"id": "17259377_11",
"type": "INHIBITOR",
"arg1_id": "17259377_T7",
"arg2_id": "17259377_T25",
"normalized": []
}
] |
17006762 | 17006762 | [
{
"id": "17006762_title",
"type": "title",
"text": [
"Kinetic parameters and lactate dehydrogenase isozyme activities support possible lactate utilization by neurons."
],
"offsets": [
[
0,
112
]
]
},
{
"id": "17006762_abstract",
"type": "abstract",
"text": [
"Lactate is potentially a major energy source in brain, particularly following hypoxia/ischemia; however, the regulation of brain lactate metabolism is not well understood. Lactate dehydrogenase (LDH) isozymes in cytosol from primary cultures of neurons and astrocytes, and freshly isolated synaptic terminals (synaptosomes) from adult rat brain were separated by electrophoresis, visualized with an activity-based stain, and quantified. The activity and kinetics of LDH were determined in the same preparations. In synaptosomes, the forward reaction (pyruvate + NADH + H(+ )--> lactate + NAD(+)), which had a V (max) of 1,163 micromol/min/mg protein was 62% of the rate in astrocyte cytoplasm. In contrast, the reverse reaction (lactate + NAD(+ )--> pyruvate + NADH + H(+)), which had a V (max) of 268 micromol/min/mg protein was 237% of the rate in astrocytes. Although the relative distribution was different, all five isozymes of LDH were present in synaptosomes and primary cultures of cortical neurons and astrocytes from rat brain. LDH1 was 14.1% of the isozyme in synaptic terminals, but only 2.6% and 2.4% in neurons and astrocytes, respectively. LDH5 was considerably lower in synaptic terminals than in neurons and astrocytes, representing 20.4%, 37.3% and 34.8% of the isozyme in these preparations, respectively. The distribution of LDH isozymes in primary cultures of cortical neurons does not directly reflect the kinetics of LDH and the capacity for lactate oxidation. However, the kinetics of LDH in brain are consistent with the possible release of lactate by astrocytes and oxidative use of lactate for energy in synaptic terminals."
],
"offsets": [
[
113,
1763
]
]
}
] | [
{
"id": "17006762_T1",
"type": "CHEMICAL",
"text": [
"Lactate"
],
"offsets": [
[
113,
120
]
],
"normalized": []
},
{
"id": "17006762_T2",
"type": "CHEMICAL",
"text": [
"lactate"
],
"offsets": [
[
242,
249
]
],
"normalized": []
},
{
"id": "17006762_T3",
"type": "CHEMICAL",
"text": [
"lactate"
],
"offsets": [
[
1578,
1585
]
],
"normalized": []
},
{
"id": "17006762_T4",
"type": "CHEMICAL",
"text": [
"lactate"
],
"offsets": [
[
1679,
1686
]
],
"normalized": []
},
{
"id": "17006762_T5",
"type": "CHEMICAL",
"text": [
"lactate"
],
"offsets": [
[
1722,
1729
]
],
"normalized": []
},
{
"id": "17006762_T6",
"type": "CHEMICAL",
"text": [
"Lactate"
],
"offsets": [
[
285,
292
]
],
"normalized": []
},
{
"id": "17006762_T7",
"type": "CHEMICAL",
"text": [
"pyruvate"
],
"offsets": [
[
664,
672
]
],
"normalized": []
},
{
"id": "17006762_T8",
"type": "CHEMICAL",
"text": [
"NADH"
],
"offsets": [
[
675,
679
]
],
"normalized": []
},
{
"id": "17006762_T9",
"type": "CHEMICAL",
"text": [
"H(+ )"
],
"offsets": [
[
682,
687
]
],
"normalized": []
},
{
"id": "17006762_T10",
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"lactate"
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"NAD(+)"
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701,
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842,
849
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"NAD(+ )"
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852,
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"NADH"
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874,
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308,
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"LDH"
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582
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"LDH"
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"id": "17006762_T28",
"type": "GENE-N",
"text": [
"lactate dehydrogenase"
],
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23,
44
]
],
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}
] | [] | [] | [
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"arg2_id": "17006762_T28",
"normalized": []
}
] |
19337422 | 19337422 | [
{
"id": "19337422_title",
"type": "title",
"text": [
"Tolvaptan and its potential in the treatment of hyponatremia."
],
"offsets": [
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0,
61
]
]
},
{
"id": "19337422_abstract",
"type": "abstract",
"text": [
"Tolvaptan is a selective arginine vasopressin (AVP) V(2) receptor blocker used to induce free water diuresis in the treatment of euvolemic or hypervolemic hyponatremia. Currently the orally active medication is in the final stages prior to approval by the FDA for outpatient therapy. It appears to be safe and effective at promoting aquaresis and raising serum sodium levels in both short- and long-term studies. Tolvaptan is also effective for treatment of congestive heart failure (CHF) exacerbation, but whether there are long standing beneficial effects on CHF is still controversial. Prolonged use of tolvaptan leads to increased endogenous levels of AVP and perhaps over-stimulation of V(1A) receptors. Theoretically this activation could lead to increased afterload and cardiac myocyte fibrosis, causing progression of CHF. However, after 52 weeks of tolvaptan therapy there was no worsening of left ventricular dilatation. In addition, tolvaptan is metabolized by the CYP3A4 system; thus physicians should be aware of the potential for increased interactions with other medications. Tolvaptan is a breakthrough in the therapy of hyponatremia as it directly combats elevated AVP levels associated with the syndrome of inappropriate secretion of antidiuretic hormone, congestive heart failure, and cirrhosis of the liver."
],
"offsets": [
[
62,
1389
]
]
}
] | [
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"id": "19337422_T1",
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"Tolvaptan"
],
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[
62,
71
]
],
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},
{
"id": "19337422_T2",
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"text": [
"Tolvaptan"
],
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[
1153,
1162
]
],
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},
{
"id": "19337422_T3",
"type": "CHEMICAL",
"text": [
"AVP"
],
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[
1244,
1247
]
],
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},
{
"id": "19337422_T4",
"type": "CHEMICAL",
"text": [
"arginine vasopressin"
],
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[
87,
107
]
],
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},
{
"id": "19337422_T5",
"type": "CHEMICAL",
"text": [
"sodium"
],
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[
423,
429
]
],
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},
{
"id": "19337422_T6",
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"Tolvaptan"
],
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475,
484
]
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{
"id": "19337422_T7",
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"AVP"
],
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109,
112
]
],
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"id": "19337422_T8",
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"tolvaptan"
],
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668,
677
]
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{
"id": "19337422_T9",
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"AVP"
],
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718,
721
]
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"id": "19337422_T10",
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"text": [
"tolvaptan"
],
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920,
929
]
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},
{
"id": "19337422_T11",
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"text": [
"tolvaptan"
],
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1006,
1015
]
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},
{
"id": "19337422_T12",
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"text": [
"Tolvaptan"
],
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[
0,
9
]
],
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},
{
"id": "19337422_T13",
"type": "GENE-Y",
"text": [
"AVP"
],
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1244,
1247
]
],
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},
{
"id": "19337422_T14",
"type": "GENE-Y",
"text": [
"antidiuretic hormone"
],
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1314,
1334
]
],
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},
{
"id": "19337422_T15",
"type": "GENE-Y",
"text": [
"arginine vasopressin (AVP) V(2) receptor"
],
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87,
127
]
],
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},
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"id": "19337422_T16",
"type": "GENE-Y",
"text": [
"AVP"
],
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718,
721
]
],
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},
{
"id": "19337422_T17",
"type": "GENE-Y",
"text": [
"V(1A) receptors"
],
"offsets": [
[
754,
769
]
],
"normalized": []
},
{
"id": "19337422_T18",
"type": "GENE-Y",
"text": [
"CYP3A4"
],
"offsets": [
[
1038,
1044
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "19337422_0",
"type": "INHIBITOR",
"arg1_id": "19337422_T1",
"arg2_id": "19337422_T15",
"normalized": []
},
{
"id": "19337422_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "19337422_T8",
"arg2_id": "19337422_T16",
"normalized": []
},
{
"id": "19337422_2",
"type": "ACTIVATOR",
"arg1_id": "19337422_T8",
"arg2_id": "19337422_T17",
"normalized": []
},
{
"id": "19337422_3",
"type": "SUBSTRATE",
"arg1_id": "19337422_T11",
"arg2_id": "19337422_T18",
"normalized": []
}
] |
16262557 | 16262557 | [
{
"id": "16262557_title",
"type": "title",
"text": [
"The unexpected side effects of new nonsteroidal anti-inflammatory drugs."
],
"offsets": [
[
0,
72
]
]
},
{
"id": "16262557_abstract",
"type": "abstract",
"text": [
"Conventional nonselective NSAIDs are classically associated with a risk of gastrointestinal disorders. These drugs have a broad range of relative selectivity towards the COX family, mainly towards two isoforms of these enzymes: COX-1 and -2. As examples, ketorolac, flurbiprofen, ketoprofen and indomethacin have increased COX-1 selectivity when compared with naproxen and ibuprofen."
],
"offsets": [
[
73,
456
]
]
}
] | [
{
"id": "16262557_T1",
"type": "CHEMICAL",
"text": [
"ketorolac"
],
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[
328,
337
]
],
"normalized": []
},
{
"id": "16262557_T2",
"type": "CHEMICAL",
"text": [
"flurbiprofen"
],
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339,
351
]
],
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},
{
"id": "16262557_T3",
"type": "CHEMICAL",
"text": [
"ketoprofen"
],
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[
353,
363
]
],
"normalized": []
},
{
"id": "16262557_T4",
"type": "CHEMICAL",
"text": [
"indomethacin"
],
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[
368,
380
]
],
"normalized": []
},
{
"id": "16262557_T5",
"type": "CHEMICAL",
"text": [
"naproxen"
],
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[
433,
441
]
],
"normalized": []
},
{
"id": "16262557_T6",
"type": "CHEMICAL",
"text": [
"ibuprofen"
],
"offsets": [
[
446,
455
]
],
"normalized": []
},
{
"id": "16262557_T7",
"type": "GENE-N",
"text": [
"COX"
],
"offsets": [
[
243,
246
]
],
"normalized": []
},
{
"id": "16262557_T8",
"type": "GENE-N",
"text": [
"COX-1 and -2"
],
"offsets": [
[
301,
313
]
],
"normalized": []
},
{
"id": "16262557_T9",
"type": "GENE-Y",
"text": [
"COX-1"
],
"offsets": [
[
396,
401
]
],
"normalized": []
}
] | [] | [] | [] |
15953344 | 15953344 | [
{
"id": "15953344_title",
"type": "title",
"text": [
"Monocarboxylate transporters in the central nervous system: distribution, regulation and function."
],
"offsets": [
[
0,
98
]
]
},
{
"id": "15953344_abstract",
"type": "abstract",
"text": [
"Monocarboxylate transporters (MCTs) are proton-linked membrane carriers involved in the transport of monocarboxylates such as lactate, pyruvate, as well as ketone bodies. They belong to a larger family of transporters composed of 14 members in mammals based on sequence homologies. MCTs are found in various tissues including the brain where three isoforms, MCT1, MCT2 and MCT4, have been described. Each of these isoforms exhibits a distinct regional and cellular distribution in rodent brain. At the cellular level, MCT1 is expressed by endothelial cells of microvessels, by ependymocytes as well as by astrocytes. MCT4 expression appears to be specific for astrocytes. By contrast, the predominant neuronal monocarboxylate transporter is MCT2. Interestingly, part of MCT2 immunoreactivity is located at postsynaptic sites, suggesting a particular role of monocarboxylates and their transporters in synaptic transmission. In addition to variation in expression during development and upon nutritional modifications, new data indicate that MCT expression is regulated at the translational level by neurotransmitters. Understanding how transport of monocarboxylates is regulated could be of particular importance not only for neuroenergetics but also for areas such as functional brain imaging, regulation of food intake and glucose homeostasis, or for central nervous system disorders such as ischaemia and neurodegenerative diseases."
],
"offsets": [
[
99,
1534
]
]
}
] | [
{
"id": "15953344_T1",
"type": "CHEMICAL",
"text": [
"Monocarboxylate"
],
"offsets": [
[
99,
114
]
],
"normalized": []
},
{
"id": "15953344_T2",
"type": "CHEMICAL",
"text": [
"monocarboxylates"
],
"offsets": [
[
200,
216
]
],
"normalized": []
},
{
"id": "15953344_T3",
"type": "CHEMICAL",
"text": [
"monocarboxylates"
],
"offsets": [
[
1248,
1264
]
],
"normalized": []
},
{
"id": "15953344_T4",
"type": "CHEMICAL",
"text": [
"lactate"
],
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[
225,
232
]
],
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},
{
"id": "15953344_T5",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
1424,
1431
]
],
"normalized": []
},
{
"id": "15953344_T6",
"type": "CHEMICAL",
"text": [
"pyruvate"
],
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[
234,
242
]
],
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},
{
"id": "15953344_T7",
"type": "CHEMICAL",
"text": [
"ketone"
],
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[
255,
261
]
],
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},
{
"id": "15953344_T8",
"type": "CHEMICAL",
"text": [
"monocarboxylate"
],
"offsets": [
[
809,
824
]
],
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},
{
"id": "15953344_T9",
"type": "CHEMICAL",
"text": [
"monocarboxylates"
],
"offsets": [
[
957,
973
]
],
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},
{
"id": "15953344_T10",
"type": "CHEMICAL",
"text": [
"Monocarboxylate"
],
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[
0,
15
]
],
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},
{
"id": "15953344_T11",
"type": "GENE-N",
"text": [
"Monocarboxylate transporters"
],
"offsets": [
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99,
127
]
],
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},
{
"id": "15953344_T12",
"type": "GENE-N",
"text": [
"MCT"
],
"offsets": [
[
1140,
1143
]
],
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},
{
"id": "15953344_T13",
"type": "GENE-N",
"text": [
"MCTs"
],
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[
381,
385
]
],
"normalized": []
},
{
"id": "15953344_T14",
"type": "GENE-N",
"text": [
"MCTs"
],
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[
129,
133
]
],
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},
{
"id": "15953344_T15",
"type": "GENE-Y",
"text": [
"MCT1"
],
"offsets": [
[
457,
461
]
],
"normalized": []
},
{
"id": "15953344_T16",
"type": "GENE-Y",
"text": [
"MCT2"
],
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[
463,
467
]
],
"normalized": []
},
{
"id": "15953344_T17",
"type": "GENE-Y",
"text": [
"MCT4"
],
"offsets": [
[
472,
476
]
],
"normalized": []
},
{
"id": "15953344_T18",
"type": "GENE-Y",
"text": [
"MCT1"
],
"offsets": [
[
617,
621
]
],
"normalized": []
},
{
"id": "15953344_T19",
"type": "GENE-Y",
"text": [
"MCT4"
],
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[
716,
720
]
],
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},
{
"id": "15953344_T20",
"type": "GENE-N",
"text": [
"monocarboxylate transporter"
],
"offsets": [
[
809,
836
]
],
"normalized": []
},
{
"id": "15953344_T21",
"type": "GENE-Y",
"text": [
"MCT2"
],
"offsets": [
[
840,
844
]
],
"normalized": []
},
{
"id": "15953344_T22",
"type": "GENE-Y",
"text": [
"MCT2"
],
"offsets": [
[
869,
873
]
],
"normalized": []
},
{
"id": "15953344_T23",
"type": "GENE-N",
"text": [
"Monocarboxylate transporters"
],
"offsets": [
[
0,
28
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "15953344_0",
"type": "SUBSTRATE",
"arg1_id": "15953344_T2",
"arg2_id": "15953344_T11",
"normalized": []
},
{
"id": "15953344_1",
"type": "SUBSTRATE",
"arg1_id": "15953344_T4",
"arg2_id": "15953344_T11",
"normalized": []
},
{
"id": "15953344_2",
"type": "SUBSTRATE",
"arg1_id": "15953344_T6",
"arg2_id": "15953344_T11",
"normalized": []
},
{
"id": "15953344_3",
"type": "SUBSTRATE",
"arg1_id": "15953344_T7",
"arg2_id": "15953344_T11",
"normalized": []
},
{
"id": "15953344_4",
"type": "SUBSTRATE",
"arg1_id": "15953344_T2",
"arg2_id": "15953344_T14",
"normalized": []
},
{
"id": "15953344_5",
"type": "SUBSTRATE",
"arg1_id": "15953344_T4",
"arg2_id": "15953344_T14",
"normalized": []
},
{
"id": "15953344_6",
"type": "SUBSTRATE",
"arg1_id": "15953344_T6",
"arg2_id": "15953344_T14",
"normalized": []
},
{
"id": "15953344_7",
"type": "SUBSTRATE",
"arg1_id": "15953344_T7",
"arg2_id": "15953344_T14",
"normalized": []
},
{
"id": "15953344_8",
"type": "SUBSTRATE",
"arg1_id": "15953344_T9",
"arg2_id": "15953344_T22",
"normalized": []
}
] |
15465654 | 15465654 | [
{
"id": "15465654_title",
"type": "title",
"text": [
"Viability assessment in sandwich-cultured rat hepatocytes after xenobiotic exposure."
],
"offsets": [
[
0,
84
]
]
},
{
"id": "15465654_abstract",
"type": "abstract",
"text": [
"Troglitazone, bosentan and glibenclamide inhibit the bile salt export pump (Bsep) which transports taurocholate into bile. Sandwich-cultured rat hepatocytes maintain functional sodium taurocholate co-transporting polypeptide and Bsep transport proteins, and may be useful to study inhibition of transport by xenobiotics at concentrations below the lowest observable adverse effect level (LOAEL). The purpose of this study was to compare viability assessments determined with the neutral red, lactate dehydrogenase (LDH), alamar blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide assays in sandwich-cultured rat hepatocytes following exposure to xenobiotics known to inhibit Bsep, and to define the LOAEL for these xenobiotics in this system. The neutral red assay was not amenable to use in this model due to crystal formation on the collagen. Troglitazone decreased viability in every assay examined, with a LOAEL approximately 100 microM. Bosentan also decreased viability as measured by the LDH, MTT and propidium iodide assays, with a LOAEL approximately 200 microM; however, a significant decrease in viability was not observed with the alamar blue assay. Glibenclamide did not decrease viability with any assay at the xenobiotic concentrations examined in this study. Based on the results of this study, the LDH or propidium iodide assays would be the methods of choice to assess viability in sandwich-cultured rat hepatocytes after xenobiotic exposure."
],
"offsets": [
[
85,
1587
]
]
}
] | [
{
"id": "15465654_T1",
"type": "CHEMICAL",
"text": [
"Troglitazone"
],
"offsets": [
[
85,
97
]
],
"normalized": []
},
{
"id": "15465654_T2",
"type": "CHEMICAL",
"text": [
"MTT"
],
"offsets": [
[
1127,
1130
]
],
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},
{
"id": "15465654_T3",
"type": "CHEMICAL",
"text": [
"propidium iodide"
],
"offsets": [
[
1135,
1151
]
],
"normalized": []
},
{
"id": "15465654_T4",
"type": "CHEMICAL",
"text": [
"alamar blue"
],
"offsets": [
[
1270,
1281
]
],
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},
{
"id": "15465654_T5",
"type": "CHEMICAL",
"text": [
"Glibenclamide"
],
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[
1289,
1302
]
],
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{
"id": "15465654_T6",
"type": "CHEMICAL",
"text": [
"propidium iodide"
],
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[
1449,
1465
]
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},
{
"id": "15465654_T7",
"type": "CHEMICAL",
"text": [
"bosentan"
],
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[
99,
107
]
],
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},
{
"id": "15465654_T8",
"type": "CHEMICAL",
"text": [
"sodium taurocholate"
],
"offsets": [
[
262,
281
]
],
"normalized": []
},
{
"id": "15465654_T9",
"type": "CHEMICAL",
"text": [
"glibenclamide"
],
"offsets": [
[
112,
125
]
],
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},
{
"id": "15465654_T10",
"type": "CHEMICAL",
"text": [
"lactate"
],
"offsets": [
[
577,
584
]
],
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},
{
"id": "15465654_T11",
"type": "CHEMICAL",
"text": [
"alamar blue"
],
"offsets": [
[
606,
617
]
],
"normalized": []
},
{
"id": "15465654_T12",
"type": "CHEMICAL",
"text": [
"3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide"
],
"offsets": [
[
619,
679
]
],
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},
{
"id": "15465654_T13",
"type": "CHEMICAL",
"text": [
"MTT"
],
"offsets": [
[
681,
684
]
],
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},
{
"id": "15465654_T14",
"type": "CHEMICAL",
"text": [
"propidium iodide"
],
"offsets": [
[
690,
706
]
],
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},
{
"id": "15465654_T15",
"type": "CHEMICAL",
"text": [
"Troglitazone"
],
"offsets": [
[
972,
984
]
],
"normalized": []
},
{
"id": "15465654_T16",
"type": "CHEMICAL",
"text": [
"Bosentan"
],
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[
1069,
1077
]
],
"normalized": []
},
{
"id": "15465654_T17",
"type": "CHEMICAL",
"text": [
"taurocholate"
],
"offsets": [
[
184,
196
]
],
"normalized": []
},
{
"id": "15465654_T18",
"type": "GENE-N",
"text": [
"LDH"
],
"offsets": [
[
1122,
1125
]
],
"normalized": []
},
{
"id": "15465654_T19",
"type": "GENE-N",
"text": [
"LDH"
],
"offsets": [
[
1442,
1445
]
],
"normalized": []
},
{
"id": "15465654_T20",
"type": "GENE-Y",
"text": [
"sodium taurocholate co-transporting polypeptide"
],
"offsets": [
[
262,
309
]
],
"normalized": []
},
{
"id": "15465654_T21",
"type": "GENE-Y",
"text": [
"Bsep"
],
"offsets": [
[
314,
318
]
],
"normalized": []
},
{
"id": "15465654_T22",
"type": "GENE-N",
"text": [
"lactate dehydrogenase"
],
"offsets": [
[
577,
598
]
],
"normalized": []
},
{
"id": "15465654_T23",
"type": "GENE-N",
"text": [
"LDH"
],
"offsets": [
[
600,
603
]
],
"normalized": []
},
{
"id": "15465654_T24",
"type": "GENE-Y",
"text": [
"bile salt export pump"
],
"offsets": [
[
138,
159
]
],
"normalized": []
},
{
"id": "15465654_T25",
"type": "GENE-Y",
"text": [
"Bsep"
],
"offsets": [
[
802,
806
]
],
"normalized": []
},
{
"id": "15465654_T26",
"type": "GENE-Y",
"text": [
"Bsep"
],
"offsets": [
[
161,
165
]
],
"normalized": []
},
{
"id": "15465654_T27",
"type": "GENE-N",
"text": [
"collagen"
],
"offsets": [
[
962,
970
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "15465654_0",
"type": "INHIBITOR",
"arg1_id": "15465654_T1",
"arg2_id": "15465654_T24",
"normalized": []
},
{
"id": "15465654_1",
"type": "INHIBITOR",
"arg1_id": "15465654_T7",
"arg2_id": "15465654_T24",
"normalized": []
},
{
"id": "15465654_2",
"type": "INHIBITOR",
"arg1_id": "15465654_T9",
"arg2_id": "15465654_T24",
"normalized": []
},
{
"id": "15465654_3",
"type": "INHIBITOR",
"arg1_id": "15465654_T1",
"arg2_id": "15465654_T26",
"normalized": []
},
{
"id": "15465654_4",
"type": "INHIBITOR",
"arg1_id": "15465654_T7",
"arg2_id": "15465654_T26",
"normalized": []
},
{
"id": "15465654_5",
"type": "INHIBITOR",
"arg1_id": "15465654_T9",
"arg2_id": "15465654_T26",
"normalized": []
},
{
"id": "15465654_6",
"type": "SUBSTRATE",
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"arg2_id": "15465654_T24",
"normalized": []
},
{
"id": "15465654_7",
"type": "SUBSTRATE",
"arg1_id": "15465654_T17",
"arg2_id": "15465654_T26",
"normalized": []
}
] |
11518758 | 11518758 | [
{
"id": "11518758_title",
"type": "title",
"text": [
"Impaired synthesis of DHA in patients with X-linked retinitis pigmentosa."
],
"offsets": [
[
0,
73
]
]
},
{
"id": "11518758_abstract",
"type": "abstract",
"text": [
"Many patients with X-linked retinitis pigmentosa (XLRP) have lower than normal blood levels of the long-chain polyunsaturated omega3 fatty acid docosahexaenoic acid (DHA; 22:6omega3). This clinical trial was designed to test whether down-regulation of DHA biosynthesis might be responsible for these reduced DHA levels. DHA biosynthesis was assessed in five severely affected patients with XLRP and in five age-matched controls by quantifying conversion of [U-(13)C]alpha-linolenic acid (alpha-LNA) to [(13)C]DHA. Following oral administration of [U-(13)C]alpha-LNA, blood samples were collected at designated intervals for 21 days and isotopic enrichment of all omega3 fatty acids was determined by gas chromatography/mass spectroscopy. Activity of each metabolic step in the conversion of alpha-LNA to DHA was determined by comparison of the ratios of the integrated concentration of (13)C-product to (13)C-precursor in plasma total lipid fractions. The ratio of [(13)C]DHA to [(13)C]18:3omega3 (the entire pathway) and that of [(13)C]20:5omega3 to [(13)C]20:4omega3 (Delta(5)-desaturase) were significantly lower in patients versus controls (P = 0.03 and 0.05, respectively). The estimated biosynthetic rates of [(13)C]20:5omega3, [(13)C]22:5omega3, [(13)C]24:5omega3, [(13)C]24:6omega3, and [(13)C]22:6omega3 were significantly lower in XLRP patients (42%, 43%, 31%, 18%, and 32% of control values, respectively; P < 0.04), supporting down-regulation of Delta(5)-desaturase in XLRP. The disappearance of (13)C-labeled fatty acids from plasma was not greater in XLRP patients compared with controls, suggesting that XLRP was not associated with increased rates of fatty acid oxidation or other routes of catabolism.Thus, despite individual variation among both patients and controls, the data are consistent with a lower rate of Delta(5)-desaturation, suggesting that decreased biosynthesis of DHA may contribute to lower blood levels of DHA in patients with XLRP."
],
"offsets": [
[
74,
2041
]
]
}
] | [
{
"id": "11518758_T1",
"type": "CHEMICAL",
"text": [
"(13)C"
],
"offsets": [
[
1105,
1110
]
],
"normalized": []
},
{
"id": "11518758_T2",
"type": "CHEMICAL",
"text": [
"(13)C"
],
"offsets": [
[
1126,
1131
]
],
"normalized": []
},
{
"id": "11518758_T3",
"type": "CHEMICAL",
"text": [
"(13)C"
],
"offsets": [
[
1290,
1295
]
],
"normalized": []
},
{
"id": "11518758_T4",
"type": "CHEMICAL",
"text": [
"(13)C"
],
"offsets": [
[
1309,
1314
]
],
"normalized": []
},
{
"id": "11518758_T5",
"type": "CHEMICAL",
"text": [
"(13)C"
],
"offsets": [
[
1328,
1333
]
],
"normalized": []
},
{
"id": "11518758_T6",
"type": "CHEMICAL",
"text": [
"(13)C"
],
"offsets": [
[
1347,
1352
]
],
"normalized": []
},
{
"id": "11518758_T7",
"type": "CHEMICAL",
"text": [
"(13)C"
],
"offsets": [
[
1370,
1375
]
],
"normalized": []
},
{
"id": "11518758_T8",
"type": "CHEMICAL",
"text": [
"docosahexaenoic acid"
],
"offsets": [
[
218,
238
]
],
"normalized": []
},
{
"id": "11518758_T9",
"type": "CHEMICAL",
"text": [
"(13)C"
],
"offsets": [
[
1582,
1587
]
],
"normalized": []
},
{
"id": "11518758_T10",
"type": "CHEMICAL",
"text": [
"fatty acids"
],
"offsets": [
[
1596,
1607
]
],
"normalized": []
},
{
"id": "11518758_T11",
"type": "CHEMICAL",
"text": [
"DHA"
],
"offsets": [
[
240,
243
]
],
"normalized": []
},
{
"id": "11518758_T12",
"type": "CHEMICAL",
"text": [
"fatty acid"
],
"offsets": [
[
1741,
1751
]
],
"normalized": []
},
{
"id": "11518758_T13",
"type": "CHEMICAL",
"text": [
"DHA"
],
"offsets": [
[
1971,
1974
]
],
"normalized": []
},
{
"id": "11518758_T14",
"type": "CHEMICAL",
"text": [
"DHA"
],
"offsets": [
[
2015,
2018
]
],
"normalized": []
},
{
"id": "11518758_T15",
"type": "CHEMICAL",
"text": [
"DHA"
],
"offsets": [
[
326,
329
]
],
"normalized": []
},
{
"id": "11518758_T16",
"type": "CHEMICAL",
"text": [
"DHA"
],
"offsets": [
[
382,
385
]
],
"normalized": []
},
{
"id": "11518758_T17",
"type": "CHEMICAL",
"text": [
"DHA"
],
"offsets": [
[
394,
397
]
],
"normalized": []
},
{
"id": "11518758_T18",
"type": "CHEMICAL",
"text": [
"[U-(13)C]alpha-linolenic acid"
],
"offsets": [
[
531,
560
]
],
"normalized": []
},
{
"id": "11518758_T19",
"type": "CHEMICAL",
"text": [
"alpha-LNA"
],
"offsets": [
[
562,
571
]
],
"normalized": []
},
{
"id": "11518758_T20",
"type": "CHEMICAL",
"text": [
"[(13)C]DHA"
],
"offsets": [
[
576,
586
]
],
"normalized": []
},
{
"id": "11518758_T21",
"type": "CHEMICAL",
"text": [
"U-(13)C]alpha-LNA"
],
"offsets": [
[
622,
639
]
],
"normalized": []
},
{
"id": "11518758_T22",
"type": "CHEMICAL",
"text": [
"fatty acids"
],
"offsets": [
[
744,
755
]
],
"normalized": []
},
{
"id": "11518758_T23",
"type": "CHEMICAL",
"text": [
"alpha-LNA"
],
"offsets": [
[
865,
874
]
],
"normalized": []
},
{
"id": "11518758_T24",
"type": "CHEMICAL",
"text": [
"DHA"
],
"offsets": [
[
878,
881
]
],
"normalized": []
},
{
"id": "11518758_T25",
"type": "CHEMICAL",
"text": [
"(13)C"
],
"offsets": [
[
960,
965
]
],
"normalized": []
},
{
"id": "11518758_T26",
"type": "CHEMICAL",
"text": [
"(13)C"
],
"offsets": [
[
977,
982
]
],
"normalized": []
},
{
"id": "11518758_T27",
"type": "CHEMICAL",
"text": [
"[(13)C]DHA"
],
"offsets": [
[
1039,
1049
]
],
"normalized": []
},
{
"id": "11518758_T28",
"type": "CHEMICAL",
"text": [
"(13)C"
],
"offsets": [
[
1054,
1059
]
],
"normalized": []
},
{
"id": "11518758_T29",
"type": "GENE-Y",
"text": [
"Delta(5)-desaturase"
],
"offsets": [
[
1532,
1551
]
],
"normalized": []
}
] | [] | [] | [] |
12545144 | 12545144 | [
{
"id": "12545144_title",
"type": "title",
"text": [
"Effects of age and sex on the disposition of retigabine."
],
"offsets": [
[
0,
56
]
]
},
{
"id": "12545144_abstract",
"type": "abstract",
"text": [
"BACKGROUND: The novel antiepileptic drug retigabine is the first selective M-current potassium channel opener for KCNQ2/3 and KCNQ3/5 channels. Retigabine undergoes phase II metabolism (N-glucuronidation, acetylation) exclusively and renal excretion. OBJECTIVE: Our objective was to evaluate the effects of age and sex on the pharmacokinetics of retigabine. METHODS: Healthy young (age range, 18-40 years) and elderly (age range, 66-81 years) white subjects (12 men and 12 women in each group) received a single 200-mg oral dose of retigabine. After dosing, blood was collected over a 72-hour period to determine plasma concentrations of retigabine and its acetylated metabolite, AWD21-360. Pharmacokinetics was compared for age group and sex by ANOVA. RESULTS: In young men, retigabine was rapidly absorbed, with the maximum concentration occurring within 2 hours, and was eliminated with an apparent clearance of 0.67 L x h(-1) x kg(-1) and a mean terminal half-life of 8.5 hours. Subjects were similarly exposed to AWD21-360. Compared with young men, young women had higher retigabine maximum concentration (56%) and exposure (20%) but similar clearance (0.68 L x h(-1) x kg(-1)); these differences were related to differences in body weight. Although maximum concentration was similar in elderly subjects, retigabine elimination was slower (30% lower apparent clearance normalized for weight), resulting in higher exposure (42%) and a longer half-life (30%). Because phase II metabolism is scarcely affected by age, these differences may be related to the known decline of renal function with age. CONCLUSIONS: Although there are no substantial sex-related differences in the disposition of retigabine, a relevant decrease in clearance resulting in higher exposure occurs in elderly patients. The results suggest that decline of renal function with age may account for some of the observed changes."
],
"offsets": [
[
57,
1959
]
]
}
] | [
{
"id": "12545144_T1",
"type": "CHEMICAL",
"text": [
"AWD21-360"
],
"offsets": [
[
1075,
1084
]
],
"normalized": []
},
{
"id": "12545144_T2",
"type": "CHEMICAL",
"text": [
"retigabine"
],
"offsets": [
[
1134,
1144
]
],
"normalized": []
},
{
"id": "12545144_T3",
"type": "CHEMICAL",
"text": [
"retigabine"
],
"offsets": [
[
1367,
1377
]
],
"normalized": []
},
{
"id": "12545144_T4",
"type": "CHEMICAL",
"text": [
"Retigabine"
],
"offsets": [
[
201,
211
]
],
"normalized": []
},
{
"id": "12545144_T5",
"type": "CHEMICAL",
"text": [
"retigabine"
],
"offsets": [
[
1752,
1762
]
],
"normalized": []
},
{
"id": "12545144_T6",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
243,
244
]
],
"normalized": []
},
{
"id": "12545144_T7",
"type": "CHEMICAL",
"text": [
"retigabine"
],
"offsets": [
[
403,
413
]
],
"normalized": []
},
{
"id": "12545144_T8",
"type": "CHEMICAL",
"text": [
"retigabine"
],
"offsets": [
[
98,
108
]
],
"normalized": []
},
{
"id": "12545144_T9",
"type": "CHEMICAL",
"text": [
"retigabine"
],
"offsets": [
[
589,
599
]
],
"normalized": []
},
{
"id": "12545144_T10",
"type": "CHEMICAL",
"text": [
"retigabine"
],
"offsets": [
[
695,
705
]
],
"normalized": []
},
{
"id": "12545144_T11",
"type": "CHEMICAL",
"text": [
"AWD21-360"
],
"offsets": [
[
737,
746
]
],
"normalized": []
},
{
"id": "12545144_T12",
"type": "CHEMICAL",
"text": [
"retigabine"
],
"offsets": [
[
833,
843
]
],
"normalized": []
},
{
"id": "12545144_T13",
"type": "CHEMICAL",
"text": [
"potassium"
],
"offsets": [
[
142,
151
]
],
"normalized": []
},
{
"id": "12545144_T14",
"type": "CHEMICAL",
"text": [
"retigabine"
],
"offsets": [
[
45,
55
]
],
"normalized": []
},
{
"id": "12545144_T15",
"type": "GENE-N",
"text": [
"KCNQ2/3"
],
"offsets": [
[
171,
178
]
],
"normalized": []
},
{
"id": "12545144_T16",
"type": "GENE-N",
"text": [
"KCNQ3/5"
],
"offsets": [
[
183,
190
]
],
"normalized": []
},
{
"id": "12545144_T17",
"type": "GENE-N",
"text": [
"M-current potassium channel"
],
"offsets": [
[
132,
159
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12545144_0",
"type": "ACTIVATOR",
"arg1_id": "12545144_T8",
"arg2_id": "12545144_T17",
"normalized": []
}
] |
16547010 | 16547010 | [
{
"id": "16547010_title",
"type": "title",
"text": [
"Structural and functional characterization of HQL-79, an orally selective inhibitor of human hematopoietic prostaglandin D synthase."
],
"offsets": [
[
0,
132
]
]
},
{
"id": "16547010_abstract",
"type": "abstract",
"text": [
"We determined the crystal structure of human hematopoietic prostaglandin (PG) D synthase (H-PGDS) as the quaternary complex with glutathione (GSH), Mg2+, and an inhibitor, HQL-79, having anti-inflammatory activities in vivo, at a 1.45-A resolution. In the quaternary complex, HQL-79 was found to reside within the catalytic cleft between Trp104 and GSH. HQL-79 was stabilized by interaction of a phenyl ring of its diphenyl group with Trp104 and by its piperidine group with GSH and Arg14 through water molecules, which form a network with hydrogen bonding and salt bridges linked to Mg2+. HQL-79 inhibited human H-PGDS competitively against the substrate PGH2 and non-competitively against GSH with Ki of 5 and 3 microm, respectively. Surface plasmon resonance analysis revealed that HQL-79 bound to H-PGDS with an affinity that was 12-fold higher in the presence of GSH and Mg2+ (Kd, 0.8 microm) than in their absence. Mutational studies revealed that Arg14 was important for the Mg2+-mediated increase in the binding affinity of H-PGDS for HQL-79, and that Trp104, Lys112, and Lys198 were important for maintaining the HQL-binding pocket. HQL-79 selectively inhibited PGD2 production by H-PGDS-expressing human megakaryocytes and rat mastocytoma cells with an IC50 value of about 100 microm but only marginally affected the production of other prostanoids, suggesting the tight functional engagement between H-PGDS and cyclooxygenase. Orally administered HQL-79 (30 mg/kg body weight) inhibited antigen-induced production of PGD2, without affecting the production of PGE2 and PGF2alpha, and ameliorated airway inflammation in wild-type and human H-PGDS-overexpressing mice. Knowledge about this structure of quaternary complex is useful for understanding the inhibitory mechanism of HQL-79 and should accelerate the structure-based development of novel anti-inflammatory drugs that inhibit PGD2 production specifically."
],
"offsets": [
[
133,
2055
]
]
}
] | [
{
"id": "16547010_T1",
"type": "CHEMICAL",
"text": [
"HQL-79"
],
"offsets": [
[
1176,
1182
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{
"id": "16547010_T2",
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"text": [
"HQL-79"
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1275,
1281
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{
"id": "16547010_T3",
"type": "CHEMICAL",
"text": [
"glutathione"
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262,
273
]
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{
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"prostanoids"
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1480,
1491
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"GSH"
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275,
278
]
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"id": "16547010_T6",
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1591,
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281,
285
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305,
311
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409,
415
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"phenyl"
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529,
535
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548,
556
]
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{
"id": "16547010_T13",
"type": "CHEMICAL",
"text": [
"piperidine"
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586,
596
]
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{
"id": "16547010_T14",
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"GSH"
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608,
611
]
],
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},
{
"id": "16547010_T15",
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"text": [
"hydrogen"
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673,
681
]
],
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},
{
"id": "16547010_T16",
"type": "CHEMICAL",
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"Mg2+"
],
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717,
721
]
],
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{
"id": "16547010_T17",
"type": "CHEMICAL",
"text": [
"HQL-79"
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723,
729
]
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},
{
"id": "16547010_T18",
"type": "CHEMICAL",
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"prostaglandin (PG) D"
],
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192,
212
]
],
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},
{
"id": "16547010_T19",
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"GSH"
],
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824,
827
]
],
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},
{
"id": "16547010_T20",
"type": "CHEMICAL",
"text": [
"HQL-79"
],
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918,
924
]
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{
"id": "16547010_T21",
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"GSH"
],
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1001,
1004
]
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},
{
"id": "16547010_T22",
"type": "CHEMICAL",
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"Mg2+"
],
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1009,
1013
]
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},
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"id": "16547010_T23",
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"Mg2+"
],
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1115,
1119
]
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{
"id": "16547010_T24",
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"prostaglandin D"
],
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107,
122
]
],
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},
{
"id": "16547010_T25",
"type": "CHEMICAL",
"text": [
"HQL-79"
],
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46,
52
]
],
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},
{
"id": "16547010_T26",
"type": "GENE-Y",
"text": [
"H-PGDS"
],
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[
1165,
1171
]
],
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},
{
"id": "16547010_T27",
"type": "GENE-Y",
"text": [
"H-PGDS"
],
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1323,
1329
]
],
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},
{
"id": "16547010_T28",
"type": "GENE-Y",
"text": [
"H-PGDS"
],
"offsets": [
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1544,
1550
]
],
"normalized": []
},
{
"id": "16547010_T29",
"type": "GENE-N",
"text": [
"cyclooxygenase"
],
"offsets": [
[
1555,
1569
]
],
"normalized": []
},
{
"id": "16547010_T30",
"type": "GENE-Y",
"text": [
"human H-PGDS"
],
"offsets": [
[
1776,
1788
]
],
"normalized": []
},
{
"id": "16547010_T31",
"type": "GENE-Y",
"text": [
"human hematopoietic prostaglandin (PG) D synthase"
],
"offsets": [
[
172,
221
]
],
"normalized": []
},
{
"id": "16547010_T32",
"type": "GENE-Y",
"text": [
"human H-PGDS"
],
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[
740,
752
]
],
"normalized": []
},
{
"id": "16547010_T33",
"type": "GENE-Y",
"text": [
"H-PGDS"
],
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[
934,
940
]
],
"normalized": []
},
{
"id": "16547010_T34",
"type": "GENE-Y",
"text": [
"H-PGDS"
],
"offsets": [
[
223,
229
]
],
"normalized": []
},
{
"id": "16547010_T35",
"type": "GENE-Y",
"text": [
"human hematopoietic prostaglandin D synthase"
],
"offsets": [
[
87,
131
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16547010_0",
"type": "INHIBITOR",
"arg1_id": "16547010_T25",
"arg2_id": "16547010_T35",
"normalized": []
},
{
"id": "16547010_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "16547010_T3",
"arg2_id": "16547010_T31",
"normalized": []
},
{
"id": "16547010_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "16547010_T3",
"arg2_id": "16547010_T34",
"normalized": []
},
{
"id": "16547010_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "16547010_T5",
"arg2_id": "16547010_T31",
"normalized": []
},
{
"id": "16547010_4",
"type": "DIRECT-REGULATOR",
"arg1_id": "16547010_T5",
"arg2_id": "16547010_T34",
"normalized": []
},
{
"id": "16547010_5",
"type": "DIRECT-REGULATOR",
"arg1_id": "16547010_T7",
"arg2_id": "16547010_T31",
"normalized": []
},
{
"id": "16547010_6",
"type": "DIRECT-REGULATOR",
"arg1_id": "16547010_T7",
"arg2_id": "16547010_T34",
"normalized": []
},
{
"id": "16547010_7",
"type": "INHIBITOR",
"arg1_id": "16547010_T8",
"arg2_id": "16547010_T31",
"normalized": []
},
{
"id": "16547010_8",
"type": "INHIBITOR",
"arg1_id": "16547010_T8",
"arg2_id": "16547010_T34",
"normalized": []
},
{
"id": "16547010_9",
"type": "DIRECT-REGULATOR",
"arg1_id": "16547010_T8",
"arg2_id": "16547010_T31",
"normalized": []
},
{
"id": "16547010_10",
"type": "DIRECT-REGULATOR",
"arg1_id": "16547010_T8",
"arg2_id": "16547010_T34",
"normalized": []
},
{
"id": "16547010_11",
"type": "INHIBITOR",
"arg1_id": "16547010_T17",
"arg2_id": "16547010_T32",
"normalized": []
},
{
"id": "16547010_12",
"type": "DIRECT-REGULATOR",
"arg1_id": "16547010_T20",
"arg2_id": "16547010_T33",
"normalized": []
},
{
"id": "16547010_13",
"type": "DIRECT-REGULATOR",
"arg1_id": "16547010_T1",
"arg2_id": "16547010_T26",
"normalized": []
},
{
"id": "16547010_14",
"type": "INHIBITOR",
"arg1_id": "16547010_T2",
"arg2_id": "16547010_T27",
"normalized": []
},
{
"id": "16547010_15",
"type": "PRODUCT-OF",
"arg1_id": "16547010_T4",
"arg2_id": "16547010_T27",
"normalized": []
},
{
"id": "16547010_16",
"type": "INHIBITOR",
"arg1_id": "16547010_T6",
"arg2_id": "16547010_T30",
"normalized": []
}
] |
22815312 | 22815312 | [
{
"id": "22815312_title",
"type": "title",
"text": [
"Quantitative prediction of CYP2B6 induction by estradiol during pregnancy: potential explanation for increased methadone clearance during pregnancy."
],
"offsets": [
[
0,
148
]
]
},
{
"id": "22815312_abstract",
"type": "abstract",
"text": [
"There is considerable evidence that pregnancy changes the disposition of drugs in an enzyme- and gestational stage-specific manner. On the basis of probe drug studies, the activity of CYP3A4 and CYP2D6 increases and CYP1A2 decreases during human pregnancy. However, no studies of CYP2B6 activity during human pregnancy have been conducted. In rodent models and in HepG2 cells, CYP2B enzymes have been shown to be regulated by estradiol. Because estradiol concentrations increase by ∼50-fold during human pregnancy, it was hypothesized that the increasing estradiol concentrations during human pregnancy would result in induction of CYP2B6 activity. Hepatocytes from three female donors were treated with estradiol, and the EC(50) and E(max) were measured for CYP2B6 mRNA and bupropion hydroxylation activity. The measured values were used to predict the magnitude of CYP2B6 induction during human pregnancy. At 100 nM total estradiol, a concentration achievable during the third trimester of pregnancy, CYP2B6 activity was predicted to increase by 1.5-3-fold, based on increased CYP2B6 activity and mRNA. When the E(max) and EC(50) values were compared with those for carbamazepine and rifampin, estradiol was found to be as potent an inducer of CYP2B6 as rifampin and carbamazepine. These data suggest that, during human pregnancy, the increasing estradiol concentrations will result in increased clearance of drugs that have CYP2B6-mediated clearance pathways. This could in part explain the observed increase in methadone clearance during pregnancy."
],
"offsets": [
[
149,
1701
]
]
}
] | [
{
"id": "22815312_T1",
"type": "CHEMICAL",
"text": [
"carbamazepine"
],
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[
1317,
1330
]
],
"normalized": []
},
{
"id": "22815312_T2",
"type": "CHEMICAL",
"text": [
"rifampin"
],
"offsets": [
[
1335,
1343
]
],
"normalized": []
},
{
"id": "22815312_T3",
"type": "CHEMICAL",
"text": [
"estradiol"
],
"offsets": [
[
1345,
1354
]
],
"normalized": []
},
{
"id": "22815312_T4",
"type": "CHEMICAL",
"text": [
"rifampin"
],
"offsets": [
[
1405,
1413
]
],
"normalized": []
},
{
"id": "22815312_T5",
"type": "CHEMICAL",
"text": [
"carbamazepine"
],
"offsets": [
[
1418,
1431
]
],
"normalized": []
},
{
"id": "22815312_T6",
"type": "CHEMICAL",
"text": [
"estradiol"
],
"offsets": [
[
1497,
1506
]
],
"normalized": []
},
{
"id": "22815312_T7",
"type": "CHEMICAL",
"text": [
"methadone"
],
"offsets": [
[
1664,
1673
]
],
"normalized": []
},
{
"id": "22815312_T8",
"type": "CHEMICAL",
"text": [
"estradiol"
],
"offsets": [
[
575,
584
]
],
"normalized": []
},
{
"id": "22815312_T9",
"type": "CHEMICAL",
"text": [
"estradiol"
],
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[
594,
603
]
],
"normalized": []
},
{
"id": "22815312_T10",
"type": "CHEMICAL",
"text": [
"estradiol"
],
"offsets": [
[
704,
713
]
],
"normalized": []
},
{
"id": "22815312_T11",
"type": "CHEMICAL",
"text": [
"estradiol"
],
"offsets": [
[
853,
862
]
],
"normalized": []
},
{
"id": "22815312_T12",
"type": "CHEMICAL",
"text": [
"bupropion"
],
"offsets": [
[
924,
933
]
],
"normalized": []
},
{
"id": "22815312_T13",
"type": "CHEMICAL",
"text": [
"estradiol"
],
"offsets": [
[
1073,
1082
]
],
"normalized": []
},
{
"id": "22815312_T14",
"type": "CHEMICAL",
"text": [
"methadone"
],
"offsets": [
[
111,
120
]
],
"normalized": []
},
{
"id": "22815312_T15",
"type": "CHEMICAL",
"text": [
"estradiol"
],
"offsets": [
[
47,
56
]
],
"normalized": []
},
{
"id": "22815312_T16",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
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[
1152,
1158
]
],
"normalized": []
},
{
"id": "22815312_T17",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
1228,
1234
]
],
"normalized": []
},
{
"id": "22815312_T18",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
1395,
1401
]
],
"normalized": []
},
{
"id": "22815312_T19",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
1576,
1582
]
],
"normalized": []
},
{
"id": "22815312_T20",
"type": "GENE-Y",
"text": [
"CYP3A4"
],
"offsets": [
[
333,
339
]
],
"normalized": []
},
{
"id": "22815312_T21",
"type": "GENE-Y",
"text": [
"CYP2D6"
],
"offsets": [
[
344,
350
]
],
"normalized": []
},
{
"id": "22815312_T22",
"type": "GENE-Y",
"text": [
"CYP1A2"
],
"offsets": [
[
365,
371
]
],
"normalized": []
},
{
"id": "22815312_T23",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
429,
435
]
],
"normalized": []
},
{
"id": "22815312_T24",
"type": "GENE-N",
"text": [
"CYP2B"
],
"offsets": [
[
526,
531
]
],
"normalized": []
},
{
"id": "22815312_T25",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
781,
787
]
],
"normalized": []
},
{
"id": "22815312_T26",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
908,
914
]
],
"normalized": []
},
{
"id": "22815312_T27",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
1016,
1022
]
],
"normalized": []
},
{
"id": "22815312_T28",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
27,
33
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "22815312_0",
"type": "ACTIVATOR",
"arg1_id": "22815312_T10",
"arg2_id": "22815312_T25",
"normalized": []
},
{
"id": "22815312_1",
"type": "ACTIVATOR",
"arg1_id": "22815312_T13",
"arg2_id": "22815312_T16",
"normalized": []
},
{
"id": "22815312_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "22815312_T13",
"arg2_id": "22815312_T17",
"normalized": []
},
{
"id": "22815312_3",
"type": "ACTIVATOR",
"arg1_id": "22815312_T13",
"arg2_id": "22815312_T17",
"normalized": []
},
{
"id": "22815312_4",
"type": "ACTIVATOR",
"arg1_id": "22815312_T3",
"arg2_id": "22815312_T18",
"normalized": []
},
{
"id": "22815312_5",
"type": "ACTIVATOR",
"arg1_id": "22815312_T4",
"arg2_id": "22815312_T18",
"normalized": []
},
{
"id": "22815312_6",
"type": "ACTIVATOR",
"arg1_id": "22815312_T5",
"arg2_id": "22815312_T18",
"normalized": []
}
] |
23583910 | 23583910 | [
{
"id": "23583910_title",
"type": "title",
"text": [
"Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors."
],
"offsets": [
[
0,
108
]
]
},
{
"id": "23583910_abstract",
"type": "abstract",
"text": [
"A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line."
],
"offsets": [
[
109,
664
]
]
}
] | [
{
"id": "23583910_T1",
"type": "CHEMICAL",
"text": [
"aminopropylindenes"
],
"offsets": [
[
121,
139
]
],
"normalized": []
},
{
"id": "23583910_T2",
"type": "CHEMICAL",
"text": [
"2,3-oxidosqualen"
],
"offsets": [
[
261,
277
]
],
"normalized": []
},
{
"id": "23583910_T3",
"type": "CHEMICAL",
"text": [
"lanosterol"
],
"offsets": [
[
281,
291
]
],
"normalized": []
},
{
"id": "23583910_T4",
"type": "CHEMICAL",
"text": [
"Grundmann's ketone"
],
"offsets": [
[
310,
328
]
],
"normalized": []
},
{
"id": "23583910_T5",
"type": "CHEMICAL",
"text": [
"N,N-dimethylaminopropyl"
],
"offsets": [
[
456,
479
]
],
"normalized": []
},
{
"id": "23583910_T6",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
618,
629
]
],
"normalized": []
},
{
"id": "23583910_T7",
"type": "CHEMICAL",
"text": [
"oxidosqualene"
],
"offsets": [
[
206,
219
]
],
"normalized": []
},
{
"id": "23583910_T8",
"type": "CHEMICAL",
"text": [
"Aminopropylindenes"
],
"offsets": [
[
0,
18
]
],
"normalized": []
},
{
"id": "23583910_T9",
"type": "CHEMICAL",
"text": [
"Grundmann's ketone"
],
"offsets": [
[
32,
50
]
],
"normalized": []
},
{
"id": "23583910_T10",
"type": "GENE-Y",
"text": [
"OSC"
],
"offsets": [
[
232,
235
]
],
"normalized": []
},
{
"id": "23583910_T11",
"type": "GENE-N",
"text": [
"OSCs"
],
"offsets": [
[
343,
347
]
],
"normalized": []
},
{
"id": "23583910_T12",
"type": "GENE-Y",
"text": [
"Trypanosoma cruzi OSC"
],
"offsets": [
[
522,
543
]
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230
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"oxidosqualene cyclase"
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75,
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] |
23608737 | 23608737 | [
{
"id": "23608737_title",
"type": "title",
"text": [
"Estradiol replacement enhances cocaine-stimulated locomotion in female C57BL/6 mice through estrogen receptor alpha."
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0,
116
]
]
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{
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"type": "abstract",
"text": [
"Psychostimulant effects are enhanced by ovarian hormones in women and female rodents. Estradiol increases behavioral responses to psychostimulants in women and female rats, although the underlying mechanism is unknown. This study utilized mice to investigate the time frame and receptor mediation of estradiol's enhancement of cocaine-induced behavior as mice enable parallel use of genetic, surgical and pharmacological methods. The spontaneous behavior of Sham and Ovariectomized (Ovx) female wildtype (WT) mice was determined during habituation to a novel environment and after cocaine administration. Ovx mice were replaced with vehicle (sesame oil) or 17β-estradiol (E2) for 2 days or 30 min prior to a cocaine challenge to investigate the time course of E2's effects. To examine receptor mediation of estradiol effects, Ovx mice replaced for 2 days with either the ERα-selective agonist PPT or the ERβ-selective agonist DPN were compared to Sham mice, and mice lacking either ERα (αERKO) or ERβ (βERKO) were compared to WT littermates. Ovx mice exhibited fewer ambulations during habituation than Sham females. Cocaine-induced increases in behavioral ratings were greater in Sham than in Ovx mice. Two days but not 30 min of E2 replacement in Ovx mice increased cocaine responses to Sham levels. PPT replacement also increased the cocaine response relative to vehicle- or DPN- treated Ovx mice. αERKO mice displayed modestly attenuated behavioral responses to novelty and cocaine compared to αWT littermates, but no behavioral differences were found between βERKO and βWT mice. These results suggest that E2 enhances cocaine-stimulated locomotion in mice predominantly through ERα."
],
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117,
1804
]
]
}
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"id": "23608737_T1",
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1234,
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1385,
1392
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1419,
1422
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"cocaine"
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1595,
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]
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1740,
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417,
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]
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444,
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]
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"id": "23608737_T10",
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698,
705
]
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774,
787
]
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825,
832
]
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924,
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]
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203,
212
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1010,
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1043,
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0,
9
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31,
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92,
100
]
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1119,
1122
]
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1518,
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1681,
1684
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1800,
1803
]
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"id": "23608737_T24",
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988,
991
]
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},
{
"id": "23608737_T25",
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1021,
1024
]
],
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},
{
"id": "23608737_T26",
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1099,
1102
]
],
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},
{
"id": "23608737_T27",
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1104,
1107
]
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},
{
"id": "23608737_T28",
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1114,
1117
]
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},
{
"id": "23608737_T29",
"type": "GENE-Y",
"text": [
"estrogen receptor alpha"
],
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[
92,
115
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23608737_0",
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"arg2_id": "23608737_T24",
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},
{
"id": "23608737_1",
"type": "AGONIST",
"arg1_id": "23608737_T16",
"arg2_id": "23608737_T25",
"normalized": []
}
] |
16722247 | 16722247 | [
{
"id": "16722247_title",
"type": "title",
"text": [
"The norepinephrine transporter in physiology and disease."
],
"offsets": [
[
0,
57
]
]
},
{
"id": "16722247_abstract",
"type": "abstract",
"text": [
"The norepinephrine transporter (NET) terminates noradrenergic signalling by rapid re-uptake of neuronally released norepinephrine (NE) into presynaptic terminals. NET exerts a fine regulated control over NE-mediated behavioural and physiological effects including mood, depression, feeding behaviour, cognition, regulation of blood pressure and heart rate. NET is a target of several drugs which are therapeutically used in the treatment or diagnosis of disorders among which depression, attention-deficit hyperactivity disorder and feeding disturbances are the most common. Individual genetic variations in the gene encoding the human NET (hNET), located at chromosome 16q12.2, may contribute to the pathogenesis of those diseases. An increasing number of studies concerning the identification of single nucleotide polymorphisms in the hNET gene and their potential association with disease as well as the functional investigation of naturally occurring or induced amino acid variations in hNET have contributed to a better understanding of NET function, regulation and genetic contribution to disorders. This review will reflect the current knowledge in the field of NET from its initial discovery until now."
],
"offsets": [
[
58,
1268
]
]
}
] | [
{
"id": "16722247_T1",
"type": "CHEMICAL",
"text": [
"norepinephrine"
],
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[
173,
187
]
],
"normalized": []
},
{
"id": "16722247_T2",
"type": "CHEMICAL",
"text": [
"NE"
],
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189,
191
]
],
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},
{
"id": "16722247_T3",
"type": "CHEMICAL",
"text": [
"NE"
],
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[
262,
264
]
],
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},
{
"id": "16722247_T4",
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"text": [
"norepinephrine"
],
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[
62,
76
]
],
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},
{
"id": "16722247_T5",
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"text": [
"nucleotide"
],
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863,
873
]
],
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},
{
"id": "16722247_T6",
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"amino acid"
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1024,
1034
]
],
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},
{
"id": "16722247_T7",
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"norepinephrine"
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4,
18
]
],
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},
{
"id": "16722247_T8",
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1100,
1103
]
],
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},
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"id": "16722247_T9",
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"NET"
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1227,
1230
]
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},
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"id": "16722247_T10",
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221,
224
]
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},
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"id": "16722247_T11",
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90,
93
]
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"id": "16722247_T12",
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"NET"
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415,
418
]
],
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},
{
"id": "16722247_T13",
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"norepinephrine transporter"
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62,
88
]
],
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},
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"id": "16722247_T14",
"type": "GENE-Y",
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"human NET"
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688,
697
]
],
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},
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"id": "16722247_T15",
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"hNET"
],
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699,
703
]
],
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},
{
"id": "16722247_T16",
"type": "GENE-Y",
"text": [
"hNET"
],
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895,
899
]
],
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},
{
"id": "16722247_T17",
"type": "GENE-Y",
"text": [
"hNET"
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1049,
1053
]
],
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},
{
"id": "16722247_T18",
"type": "GENE-Y",
"text": [
"norepinephrine transporter"
],
"offsets": [
[
4,
30
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16722247_0",
"type": "SUBSTRATE",
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"arg2_id": "16722247_T13",
"normalized": []
},
{
"id": "16722247_1",
"type": "SUBSTRATE",
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"arg2_id": "16722247_T13",
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},
{
"id": "16722247_2",
"type": "SUBSTRATE",
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"arg2_id": "16722247_T10",
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},
{
"id": "16722247_3",
"type": "PART-OF",
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"arg2_id": "16722247_T16",
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},
{
"id": "16722247_4",
"type": "PART-OF",
"arg1_id": "16722247_T6",
"arg2_id": "16722247_T17",
"normalized": []
}
] |
9040115 | 9040115 | [
{
"id": "9040115_title",
"type": "title",
"text": [
"Endogenous opioid systems and alcohol addiction."
],
"offsets": [
[
0,
48
]
]
},
{
"id": "9040115_abstract",
"type": "abstract",
"text": [
"Alcohol exerts numerous pharmacological effects through its interaction with various neurotransmitters and neuromodulators. Among the latter, the endogenous opioids play a key role in the rewarding (addictive) properties of ethanol. Three types of opioid receptors (mu, delta and kappa) represent the respective targets of the major opioid peptides (beta-endorphin, enkephalins and dynorphins, respectively). The rewarding (reinforcing) properties of mu- and delta-receptor ligands are brought by activation of the mesolimbic dopamine system which ascends from the ventral tegmentum of the midbrain (VTA) to rostral structures; of these, the nucleus accumbens (NAC) is of particular importance in drug addiction. In contrast, dysphoria results from activation of kappa-receptors. The neurochemical manifestations of these opposing effects are, respectively, increases and decreases in dopamine release in the NAC. Several lines of evidence indicate that alcohol interferes with endogenous opioid mechanisms which are closely linked with dopamine transmission in the mesolimbic pathway. The view that condensation products of dopamine and alcohol-derived aldehyde (tetrahydroisoquinolines) play a role remains controversial. There is, however, much information on the direct (acute and chronic) effects of alcohol on the binding properties of opioid receptors, as well as modulation of opioid peptide synthesis and secretion (e.g. a suggested increase in beta-endorphin release). In view of the reinforcing properties of alcohol, it is relevant to consider behavioural studies involving alcohol self-administration in rodents and primates. Low doses of morphine have been found to increase, and higher doses of the opiate to decrease, alcohol consumption. Conversely, opioid antagonists such as naloxone and naltrexone (which bind to non-selectively opioid receptors) have been shown to decrease alcohol consumption under various experimental conditions. Similar results have been reported when selective mu- or delta-receptor antagonists are administered. Results obtained in genetic models of high preference for alcohol also support the view that alcohol intake depends on the activity of the endogenous opioid reward system and that alcohol consumption may serve to compensate for inherent deficits in this system. One hypothetical model proposes that reward results from activation of mu-opioid receptors in the VTA and/or delta-receptor in the NAC; both these nuclei are targets of endogenous beta-endorphin. It is suggested that alcohol interferes with this reward pathway either directly or indirectly. The available experimental data accord well with those obtained from clinical studies which opioid antagonists have been used to prevent relapse in alcoholics. Conceptual considerations concerning communalities between various forms of addictions are also discussed in this review."
],
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49,
2940
]
]
}
] | [
{
"id": "9040115_T1",
"type": "CHEMICAL",
"text": [
"Alcohol"
],
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49,
56
]
],
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},
{
"id": "9040115_T2",
"type": "CHEMICAL",
"text": [
"dopamine"
],
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1086,
1094
]
],
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},
{
"id": "9040115_T3",
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"text": [
"dopamine"
],
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1174,
1182
]
],
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},
{
"id": "9040115_T4",
"type": "CHEMICAL",
"text": [
"alcohol"
],
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[
1187,
1194
]
],
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},
{
"id": "9040115_T5",
"type": "CHEMICAL",
"text": [
"aldehyde"
],
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[
1203,
1211
]
],
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},
{
"id": "9040115_T6",
"type": "CHEMICAL",
"text": [
"tetrahydroisoquinolines"
],
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[
1213,
1236
]
],
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},
{
"id": "9040115_T7",
"type": "CHEMICAL",
"text": [
"alcohol"
],
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[
1354,
1361
]
],
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},
{
"id": "9040115_T8",
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"alcohol"
],
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[
1569,
1576
]
],
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},
{
"id": "9040115_T9",
"type": "CHEMICAL",
"text": [
"alcohol"
],
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[
1635,
1642
]
],
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},
{
"id": "9040115_T10",
"type": "CHEMICAL",
"text": [
"alcohol"
],
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[
1783,
1790
]
],
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},
{
"id": "9040115_T11",
"type": "CHEMICAL",
"text": [
"naloxone"
],
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[
1843,
1851
]
],
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},
{
"id": "9040115_T12",
"type": "CHEMICAL",
"text": [
"naltrexone"
],
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[
1856,
1866
]
],
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},
{
"id": "9040115_T13",
"type": "CHEMICAL",
"text": [
"alcohol"
],
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[
1944,
1951
]
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},
{
"id": "9040115_T14",
"type": "CHEMICAL",
"text": [
"alcohol"
],
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2163,
2170
]
],
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},
{
"id": "9040115_T15",
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"text": [
"alcohol"
],
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[
2285,
2292
]
],
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},
{
"id": "9040115_T16",
"type": "CHEMICAL",
"text": [
"ethanol"
],
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[
273,
280
]
],
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},
{
"id": "9040115_T17",
"type": "CHEMICAL",
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"alcohol"
],
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2584,
2591
]
],
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},
{
"id": "9040115_T18",
"type": "CHEMICAL",
"text": [
"enkephalins"
],
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[
415,
426
]
],
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},
{
"id": "9040115_T19",
"type": "CHEMICAL",
"text": [
"dopamine"
],
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[
934,
942
]
],
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},
{
"id": "9040115_T20",
"type": "CHEMICAL",
"text": [
"alcohol"
],
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1003,
1010
]
],
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},
{
"id": "9040115_T21",
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"text": [
"alcohol"
],
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[
30,
37
]
],
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},
{
"id": "9040115_T22",
"type": "GENE-N",
"text": [
"opioid receptors"
],
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[
1391,
1407
]
],
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},
{
"id": "9040115_T23",
"type": "GENE-N",
"text": [
"opioid peptide"
],
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[
1434,
1448
]
],
"normalized": []
},
{
"id": "9040115_T24",
"type": "GENE-Y",
"text": [
"beta-endorphin"
],
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1503,
1517
]
],
"normalized": []
},
{
"id": "9040115_T25",
"type": "GENE-N",
"text": [
"opioid receptors"
],
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[
1898,
1914
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],
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},
{
"id": "9040115_T26",
"type": "GENE-N",
"text": [
"mu- or delta-receptor"
],
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[
2053,
2074
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],
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{
"id": "9040115_T27",
"type": "GENE-Y",
"text": [
"mu-opioid receptors"
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[
2438,
2457
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],
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"id": "9040115_T28",
"type": "GENE-Y",
"text": [
"delta-receptor"
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[
2476,
2490
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"id": "9040115_T29",
"type": "GENE-N",
"text": [
"opioid receptors (mu, delta and kappa)"
],
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297,
335
]
],
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{
"id": "9040115_T30",
"type": "GENE-Y",
"text": [
"beta-endorphin"
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[
2547,
2561
]
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},
{
"id": "9040115_T31",
"type": "GENE-N",
"text": [
"opioid peptides"
],
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382,
397
]
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"id": "9040115_T32",
"type": "GENE-Y",
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"beta-endorphin"
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[
399,
413
]
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},
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"id": "9040115_T33",
"type": "GENE-N",
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"enkephalins"
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415,
426
]
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},
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"id": "9040115_T34",
"type": "GENE-Y",
"text": [
"dynorphins"
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431,
441
]
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"id": "9040115_T35",
"type": "GENE-N",
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"mu- and delta-receptor"
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[
500,
522
]
],
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{
"id": "9040115_T36",
"type": "GENE-N",
"text": [
"kappa-receptors"
],
"offsets": [
[
812,
827
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "9040115_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "9040115_T7",
"arg2_id": "9040115_T22",
"normalized": []
},
{
"id": "9040115_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "9040115_T7",
"arg2_id": "9040115_T24",
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},
{
"id": "9040115_2",
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},
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},
{
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},
{
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"normalized": []
}
] |
2362440 | 2362440 | [
{
"id": "2362440_title",
"type": "title",
"text": [
"Affinity alkylation of human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase by 2 alpha-bromoacetoxyprogesterone: evidence for separate dehydrogenase and isomerase sites on one protein."
],
"offsets": [
[
0,
223
]
]
},
{
"id": "2362440_abstract",
"type": "abstract",
"text": [
"We have copurified human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase, which synthesize progesterone from pregnenolone and androstenedione from fetal dehydroepiandrosterone sulfate, from microsomes as a homogeneous protein based on electrophoretic and NH2-terminal sequencing data. The affinity alkylator, 2 alpha-bromoacetoxyprogesterone, simultaneously inactivates the pregnene and androstene dehydrogenase activities as well as the C21 and C19 isomerase activities in a time-dependent, irreversible manner following first order kinetics. At four concentrations (50/1-20/1 steroid/enzyme M ratios), the alkylator inactivates the dehydrogenase activity (t1/2 = 1.5-3.7 min) 2-fold faster than the isomerase activity. Pregnenolone and dehydroepiandrosterone protect the dehydrogenase activity, while 5-pregnene-3,20-dione, progesterone, and androstenedione protect isomerase activity from inactivation. The protection studies and competitive kinetics of inhibition demonstrate that the affinity alkylator is active site-directed. Kitz and Wilson analyses show that 2 alpha-bromoacetoxyprogesterone inactivates the dehydrogenase activity by a bimolecular mechanism (k3' = 160.9 l/mol.s), while the alkylator inactivates isomerase by a unimolecular mechanism (Ki = 0.14 mM, k3 = 0.013 s-1). Pregnenolone completely protects the dehydrogenase activity but does not slow the rate of isomerase inactivation by 2 alpha-bromoacetoxyprogesterone at all. NADH completely protects both activities from inactivation by the alkylator, while NAD+ protects neither. From Dixon analysis, NADH competitively inhibits NAD+ reduction by dehydrogenase activity. Mixed cofactor studies show that isomerase binds NAD+ and NADH at a common site. Therefore, NADH must not protect either activity by simply binding at the cofactor site. We postulate that NADH binding as an allosteric activator of isomerase protects both the dehydrogenase and isomerase activities from affinity alkylation by inducing a conformational change in the enzyme protein. The human placental enzyme appears to express the pregnene and androstene dehydrogenase activities at one site and the C21 and C19 isomerase activities at a second site on the same protein."
],
"offsets": [
[
224,
2479
]
]
}
] | [
{
"id": "2362440_T1",
"type": "CHEMICAL",
"text": [
"2 alpha-bromoacetoxyprogesterone"
],
"offsets": [
[
1330,
1362
]
],
"normalized": []
},
{
"id": "2362440_T2",
"type": "CHEMICAL",
"text": [
"progesterone"
],
"offsets": [
[
353,
365
]
],
"normalized": []
},
{
"id": "2362440_T3",
"type": "CHEMICAL",
"text": [
"Pregnenolone"
],
"offsets": [
[
1554,
1566
]
],
"normalized": []
},
{
"id": "2362440_T4",
"type": "CHEMICAL",
"text": [
"2 alpha-bromoacetoxyprogesterone"
],
"offsets": [
[
1670,
1702
]
],
"normalized": []
},
{
"id": "2362440_T5",
"type": "CHEMICAL",
"text": [
"pregnenolone"
],
"offsets": [
[
371,
383
]
],
"normalized": []
},
{
"id": "2362440_T6",
"type": "CHEMICAL",
"text": [
"NADH"
],
"offsets": [
[
1711,
1715
]
],
"normalized": []
},
{
"id": "2362440_T7",
"type": "CHEMICAL",
"text": [
"NAD+"
],
"offsets": [
[
1794,
1798
]
],
"normalized": []
},
{
"id": "2362440_T8",
"type": "CHEMICAL",
"text": [
"NADH"
],
"offsets": [
[
1838,
1842
]
],
"normalized": []
},
{
"id": "2362440_T9",
"type": "CHEMICAL",
"text": [
"androstenedione"
],
"offsets": [
[
388,
403
]
],
"normalized": []
},
{
"id": "2362440_T10",
"type": "CHEMICAL",
"text": [
"NAD+"
],
"offsets": [
[
1866,
1870
]
],
"normalized": []
},
{
"id": "2362440_T11",
"type": "CHEMICAL",
"text": [
"NAD+"
],
"offsets": [
[
1957,
1961
]
],
"normalized": []
},
{
"id": "2362440_T12",
"type": "CHEMICAL",
"text": [
"NADH"
],
"offsets": [
[
1966,
1970
]
],
"normalized": []
},
{
"id": "2362440_T13",
"type": "CHEMICAL",
"text": [
"NADH"
],
"offsets": [
[
2000,
2004
]
],
"normalized": []
},
{
"id": "2362440_T14",
"type": "CHEMICAL",
"text": [
"NADH"
],
"offsets": [
[
2096,
2100
]
],
"normalized": []
},
{
"id": "2362440_T15",
"type": "CHEMICAL",
"text": [
"dehydroepiandrosterone sulfate"
],
"offsets": [
[
415,
445
]
],
"normalized": []
},
{
"id": "2362440_T16",
"type": "CHEMICAL",
"text": [
"pregnene"
],
"offsets": [
[
2340,
2348
]
],
"normalized": []
},
{
"id": "2362440_T17",
"type": "CHEMICAL",
"text": [
"androstene"
],
"offsets": [
[
2353,
2363
]
],
"normalized": []
},
{
"id": "2362440_T18",
"type": "CHEMICAL",
"text": [
"NH2"
],
"offsets": [
[
517,
520
]
],
"normalized": []
},
{
"id": "2362440_T19",
"type": "CHEMICAL",
"text": [
"2 alpha-bromoacetoxyprogesterone"
],
"offsets": [
[
571,
603
]
],
"normalized": []
},
{
"id": "2362440_T20",
"type": "CHEMICAL",
"text": [
"3 beta-hydroxy-5-ene-steroid"
],
"offsets": [
[
259,
287
]
],
"normalized": []
},
{
"id": "2362440_T21",
"type": "CHEMICAL",
"text": [
"pregnene"
],
"offsets": [
[
636,
644
]
],
"normalized": []
},
{
"id": "2362440_T22",
"type": "CHEMICAL",
"text": [
"androstene"
],
"offsets": [
[
649,
659
]
],
"normalized": []
},
{
"id": "2362440_T23",
"type": "CHEMICAL",
"text": [
"steroid"
],
"offsets": [
[
840,
847
]
],
"normalized": []
},
{
"id": "2362440_T24",
"type": "CHEMICAL",
"text": [
"Pregnenolone"
],
"offsets": [
[
983,
995
]
],
"normalized": []
},
{
"id": "2362440_T25",
"type": "CHEMICAL",
"text": [
"dehydroepiandrosterone"
],
"offsets": [
[
1000,
1022
]
],
"normalized": []
},
{
"id": "2362440_T26",
"type": "CHEMICAL",
"text": [
"steroid"
],
"offsets": [
[
306,
313
]
],
"normalized": []
},
{
"id": "2362440_T27",
"type": "CHEMICAL",
"text": [
"5-pregnene-3,20-dione"
],
"offsets": [
[
1065,
1086
]
],
"normalized": []
},
{
"id": "2362440_T28",
"type": "CHEMICAL",
"text": [
"progesterone"
],
"offsets": [
[
1088,
1100
]
],
"normalized": []
},
{
"id": "2362440_T29",
"type": "CHEMICAL",
"text": [
"androstenedione"
],
"offsets": [
[
1106,
1121
]
],
"normalized": []
},
{
"id": "2362440_T30",
"type": "CHEMICAL",
"text": [
"2 alpha-bromoacetoxyprogesterone"
],
"offsets": [
[
118,
150
]
],
"normalized": []
},
{
"id": "2362440_T31",
"type": "CHEMICAL",
"text": [
"3 beta-hydroxy-5-ene-steroid"
],
"offsets": [
[
39,
67
]
],
"normalized": []
},
{
"id": "2362440_T32",
"type": "CHEMICAL",
"text": [
"steroid"
],
"offsets": [
[
86,
93
]
],
"normalized": []
},
{
"id": "2362440_T33",
"type": "GENE-N",
"text": [
"dehydrogenase"
],
"offsets": [
[
1379,
1392
]
],
"normalized": []
},
{
"id": "2362440_T34",
"type": "GENE-N",
"text": [
"dehydrogenase"
],
"offsets": [
[
1591,
1604
]
],
"normalized": []
},
{
"id": "2362440_T35",
"type": "GENE-N",
"text": [
"dehydrogenase"
],
"offsets": [
[
1884,
1897
]
],
"normalized": []
},
{
"id": "2362440_T36",
"type": "GENE-N",
"text": [
"dehydrogenase"
],
"offsets": [
[
2167,
2180
]
],
"normalized": []
},
{
"id": "2362440_T37",
"type": "GENE-Y",
"text": [
"human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase"
],
"offsets": [
[
243,
301
]
],
"normalized": []
},
{
"id": "2362440_T38",
"type": "GENE-N",
"text": [
"pregnene and androstene dehydrogenase"
],
"offsets": [
[
2340,
2377
]
],
"normalized": []
},
{
"id": "2362440_T39",
"type": "GENE-N",
"text": [
"pregnene and androstene dehydrogenase"
],
"offsets": [
[
636,
673
]
],
"normalized": []
},
{
"id": "2362440_T40",
"type": "GENE-N",
"text": [
"dehydrogenase"
],
"offsets": [
[
896,
909
]
],
"normalized": []
},
{
"id": "2362440_T41",
"type": "GENE-N",
"text": [
"dehydrogenase"
],
"offsets": [
[
1035,
1048
]
],
"normalized": []
},
{
"id": "2362440_T42",
"type": "GENE-N",
"text": [
"steroid 5----4-ene-isomerase"
],
"offsets": [
[
306,
334
]
],
"normalized": []
},
{
"id": "2362440_T43",
"type": "GENE-N",
"text": [
"dehydrogenase"
],
"offsets": [
[
174,
187
]
],
"normalized": []
},
{
"id": "2362440_T44",
"type": "GENE-Y",
"text": [
"human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase"
],
"offsets": [
[
23,
81
]
],
"normalized": []
},
{
"id": "2362440_T45",
"type": "GENE-N",
"text": [
"steroid 5----4-ene-isomerase"
],
"offsets": [
[
86,
114
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "2362440_0",
"type": "PRODUCT-OF",
"arg1_id": "2362440_T2",
"arg2_id": "2362440_T37",
"normalized": []
},
{
"id": "2362440_1",
"type": "PRODUCT-OF",
"arg1_id": "2362440_T2",
"arg2_id": "2362440_T42",
"normalized": []
},
{
"id": "2362440_2",
"type": "SUBSTRATE",
"arg1_id": "2362440_T5",
"arg2_id": "2362440_T37",
"normalized": []
},
{
"id": "2362440_3",
"type": "SUBSTRATE",
"arg1_id": "2362440_T5",
"arg2_id": "2362440_T42",
"normalized": []
},
{
"id": "2362440_4",
"type": "PRODUCT-OF",
"arg1_id": "2362440_T9",
"arg2_id": "2362440_T37",
"normalized": []
},
{
"id": "2362440_5",
"type": "PRODUCT-OF",
"arg1_id": "2362440_T9",
"arg2_id": "2362440_T42",
"normalized": []
},
{
"id": "2362440_6",
"type": "SUBSTRATE",
"arg1_id": "2362440_T15",
"arg2_id": "2362440_T37",
"normalized": []
},
{
"id": "2362440_7",
"type": "SUBSTRATE",
"arg1_id": "2362440_T15",
"arg2_id": "2362440_T42",
"normalized": []
},
{
"id": "2362440_8",
"type": "PART-OF",
"arg1_id": "2362440_T18",
"arg2_id": "2362440_T37",
"normalized": []
},
{
"id": "2362440_9",
"type": "PART-OF",
"arg1_id": "2362440_T18",
"arg2_id": "2362440_T42",
"normalized": []
},
{
"id": "2362440_10",
"type": "ACTIVATOR",
"arg1_id": "2362440_T24",
"arg2_id": "2362440_T41",
"normalized": []
},
{
"id": "2362440_11",
"type": "ACTIVATOR",
"arg1_id": "2362440_T25",
"arg2_id": "2362440_T41",
"normalized": []
},
{
"id": "2362440_12",
"type": "INHIBITOR",
"arg1_id": "2362440_T1",
"arg2_id": "2362440_T33",
"normalized": []
},
{
"id": "2362440_13",
"type": "ACTIVATOR",
"arg1_id": "2362440_T3",
"arg2_id": "2362440_T34",
"normalized": []
},
{
"id": "2362440_14",
"type": "ACTIVATOR",
"arg1_id": "2362440_T14",
"arg2_id": "2362440_T36",
"normalized": []
},
{
"id": "2362440_15",
"type": "INHIBITOR",
"arg1_id": "2362440_T8",
"arg2_id": "2362440_T35",
"normalized": []
},
{
"id": "2362440_16",
"type": "SUBSTRATE",
"arg1_id": "2362440_T10",
"arg2_id": "2362440_T35",
"normalized": []
},
{
"id": "2362440_17",
"type": "INHIBITOR",
"arg1_id": "2362440_T23",
"arg2_id": "2362440_T40",
"normalized": []
}
] |
23314308 | 23314308 | [
{
"id": "23314308_title",
"type": "title",
"text": [
"Electrical field stimulation (EFS)-induced relaxations turn into contractions upon removal of extracellular calcium in rat mesenteric artery."
],
"offsets": [
[
0,
141
]
]
},
{
"id": "23314308_abstract",
"type": "abstract",
"text": [
"In the present study, we aimed to examine the effect of blockade of L-type Ca(2+) channels (LTCC) and in addition the removal of extracellular Ca(2+), on EFS-induced relaxations in rings of rat mesenteric artery. EFS applied to the tissues precontracted with phenylephrine caused relaxations which were markedly inhibited by nifedipine (10(-7)M) and tetraethylammonium (TEA) (1mM). Addition of LTCC opener BAY K 8644 (10(-7)M) failed to enhance the relaxations. Upon removal of Ca(2+), EFS with the same stimulation parameters produced frequency-dependent transient contractions. Tetrodotoxin (10(-6)M), capsaicin (10(-5)M) and removal of endothelium did not alter these contractions suggesting that they were not neural in origin and endothelium-derived contracting factors were unlikely to be involved. However, they were increased by nearly 40% in response to BAY K 8644 (10(-7)M) and were inhibited by nifedipine (10(-7)M), indicating that activation of the LTCCs was essential. Inositol triphosphate (InsP3) receptor antagonist 2-APB (10(-4)M) significantly reduced, and high concentration of caffeine (20mM) almost totally suppressed the contractions. These results suggest that in the absence of extracellular Ca(2+) EFS through membrane depolarization, evokes the opening of the LTCCs which subsequently leads to the release of Ca(2+) from internal stores via InsP3 receptors, a phenomenon known as Ca(2+) channel-induced Ca(2+) release (CCICR), to trigger vasoconstriction. That activation of LTCCs causes arterial relaxation or contraction depending on the Ca(2+) status apparently exemplifies how the same messenger fulfils opposing physiological functions in a given cell."
],
"offsets": [
[
142,
1826
]
]
}
] | [
{
"id": "23314308_T1",
"type": "CHEMICAL",
"text": [
"2-APB"
],
"offsets": [
[
1175,
1180
]
],
"normalized": []
},
{
"id": "23314308_T2",
"type": "CHEMICAL",
"text": [
"caffeine"
],
"offsets": [
[
1240,
1248
]
],
"normalized": []
},
{
"id": "23314308_T3",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
1359,
1365
]
],
"normalized": []
},
{
"id": "23314308_T4",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
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[
1478,
1484
]
],
"normalized": []
},
{
"id": "23314308_T5",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
1549,
1555
]
],
"normalized": []
},
{
"id": "23314308_T6",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
1572,
1578
]
],
"normalized": []
},
{
"id": "23314308_T7",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
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[
285,
291
]
],
"normalized": []
},
{
"id": "23314308_T8",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
1709,
1715
]
],
"normalized": []
},
{
"id": "23314308_T9",
"type": "CHEMICAL",
"text": [
"phenylephrine"
],
"offsets": [
[
401,
414
]
],
"normalized": []
},
{
"id": "23314308_T10",
"type": "CHEMICAL",
"text": [
"nifedipine"
],
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467,
477
]
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},
{
"id": "23314308_T11",
"type": "CHEMICAL",
"text": [
"tetraethylammonium"
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492,
510
]
],
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},
{
"id": "23314308_T12",
"type": "CHEMICAL",
"text": [
"TEA"
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512,
515
]
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{
"id": "23314308_T13",
"type": "CHEMICAL",
"text": [
"BAY K 8644"
],
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[
548,
558
]
],
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},
{
"id": "23314308_T14",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
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[
620,
626
]
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},
{
"id": "23314308_T15",
"type": "CHEMICAL",
"text": [
"Tetrodotoxin"
],
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722,
734
]
],
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},
{
"id": "23314308_T16",
"type": "CHEMICAL",
"text": [
"capsaicin"
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746,
755
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{
"id": "23314308_T17",
"type": "CHEMICAL",
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"Ca(2+)"
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217,
223
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{
"id": "23314308_T18",
"type": "CHEMICAL",
"text": [
"BAY K 8644"
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1005,
1015
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{
"id": "23314308_T19",
"type": "CHEMICAL",
"text": [
"nifedipine"
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{
"id": "23314308_T20",
"type": "CHEMICAL",
"text": [
"Inositol triphosphate"
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1125,
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]
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{
"id": "23314308_T21",
"type": "CHEMICAL",
"text": [
"calcium"
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108,
115
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"id": "23314308_T22",
"type": "GENE-N",
"text": [
"LTCCs"
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1429,
1434
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"id": "23314308_T23",
"type": "GENE-N",
"text": [
"InsP3 receptors"
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1510,
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"id": "23314308_T24",
"type": "GENE-N",
"text": [
"Ca(2+) channel"
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"id": "23314308_T25",
"type": "GENE-N",
"text": [
"LTCCs"
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1644,
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]
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"id": "23314308_T26",
"type": "GENE-N",
"text": [
"LTCC"
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536,
540
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"id": "23314308_T27",
"type": "GENE-N",
"text": [
"L-type Ca(2+) channels"
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210,
232
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"id": "23314308_T28",
"type": "GENE-N",
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"LTCC"
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238
]
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"id": "23314308_T29",
"type": "GENE-N",
"text": [
"LTCCs"
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1104,
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"id": "23314308_T30",
"type": "GENE-N",
"text": [
"Inositol triphosphate (InsP3) receptor"
],
"offsets": [
[
1125,
1163
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23314308_0",
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"arg2_id": "23314308_T26",
"normalized": []
},
{
"id": "23314308_1",
"type": "ACTIVATOR",
"arg1_id": "23314308_T18",
"arg2_id": "23314308_T29",
"normalized": []
},
{
"id": "23314308_2",
"type": "INHIBITOR",
"arg1_id": "23314308_T19",
"arg2_id": "23314308_T29",
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},
{
"id": "23314308_3",
"type": "ANTAGONIST",
"arg1_id": "23314308_T1",
"arg2_id": "23314308_T30",
"normalized": []
},
{
"id": "23314308_4",
"type": "SUBSTRATE",
"arg1_id": "23314308_T4",
"arg2_id": "23314308_T22",
"normalized": []
},
{
"id": "23314308_5",
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},
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"type": "SUBSTRATE",
"arg1_id": "23314308_T8",
"arg2_id": "23314308_T25",
"normalized": []
}
] |
23541928 | 23541928 | [
{
"id": "23541928_title",
"type": "title",
"text": [
"Osteochondral tissue regeneration using a bilayered composite hydrogel with modulating dual growth factor release kinetics in a rabbit model."
],
"offsets": [
[
0,
141
]
]
},
{
"id": "23541928_abstract",
"type": "abstract",
"text": [
"Biodegradable oligo(poly(ethylene glycol) fumarate) (OPF) composite hydrogels have been investigated for the delivery of growth factors (GFs) with the aid of gelatin microparticles (GMPs) and stem cell populations for osteochondral tissue regeneration. In this study, a bilayered OPF composite hydrogel that mimics the distinctive hierarchical structure of native osteochondral tissue was utilized to investigate the effect of transforming growth factor-β3 (TGF-β3) with varying release kinetics and/or insulin-like growth factor-1 (IGF-1) on osteochondral tissue regeneration in a rabbit full-thickness osteochondral defect model. The four groups investigated included (i) a blank control (no GFs), (ii) GMP-loaded IGF-1 alone, (iii) GMP-loaded IGF-1 and gel-loaded TGF-β3, and (iv) GMP-loaded IGF-1 and GMP-loaded TGF-β3 in OPF composite hydrogels. The results of an in vitro release study demonstrated that TGF-β3 release kinetics could be modulated by the GF incorporation method. At 12weeks post-implantation, the quality of tissue repair in both chondral and subchondral layers was analyzed based on quantitative histological scoring. All groups incorporating GFs resulted in a significant improvement in cartilage morphology compared to the control. Single delivery of IGF-1 showed higher scores in subchondral bone morphology as well as chondrocyte and glycosaminoglycan amount in adjacent cartilage tissue when compared to a dual delivery of IGF-1 and TGF-β3, independent of the TGF-β3 release kinetics. The results suggest that although the dual delivery of TGF-β3 and IGF-1 may not synergistically enhance the quality of engineered tissue, the delivery of IGF-1 alone from bilayered composite hydrogels positively affects osteochondral tissue repair and holds promise for osteochondral tissue engineering applications."
],
"offsets": [
[
142,
1971
]
]
}
] | [
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"id": "23541928_T1",
"type": "CHEMICAL",
"text": [
"oligo(poly(ethylene glycol) fumarate)"
],
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[
156,
193
]
],
"normalized": []
},
{
"id": "23541928_T2",
"type": "CHEMICAL",
"text": [
"OPF"
],
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[
422,
425
]
],
"normalized": []
},
{
"id": "23541928_T3",
"type": "CHEMICAL",
"text": [
"OPF"
],
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195,
198
]
],
"normalized": []
},
{
"id": "23541928_T4",
"type": "CHEMICAL",
"text": [
"OPF"
],
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968,
971
]
],
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},
{
"id": "23541928_T5",
"type": "GENE-Y",
"text": [
"IGF-1"
],
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[
1418,
1423
]
],
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},
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"id": "23541928_T6",
"type": "GENE-Y",
"text": [
"IGF-1"
],
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[
1593,
1598
]
],
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},
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"id": "23541928_T7",
"type": "GENE-Y",
"text": [
"TGF-β3"
],
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[
1603,
1609
]
],
"normalized": []
},
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"id": "23541928_T8",
"type": "GENE-Y",
"text": [
"TGF-β3"
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[
1630,
1636
]
],
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},
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"id": "23541928_T9",
"type": "GENE-Y",
"text": [
"TGF-β3"
],
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[
1710,
1716
]
],
"normalized": []
},
{
"id": "23541928_T10",
"type": "GENE-Y",
"text": [
"IGF-1"
],
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[
1721,
1726
]
],
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},
{
"id": "23541928_T11",
"type": "GENE-Y",
"text": [
"IGF-1"
],
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[
1809,
1814
]
],
"normalized": []
},
{
"id": "23541928_T12",
"type": "GENE-Y",
"text": [
"transforming growth factor-β3"
],
"offsets": [
[
569,
598
]
],
"normalized": []
},
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"id": "23541928_T13",
"type": "GENE-Y",
"text": [
"TGF-β3"
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[
600,
606
]
],
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},
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"id": "23541928_T14",
"type": "GENE-Y",
"text": [
"insulin-like growth factor-1"
],
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[
645,
673
]
],
"normalized": []
},
{
"id": "23541928_T15",
"type": "GENE-Y",
"text": [
"IGF-1"
],
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[
675,
680
]
],
"normalized": []
},
{
"id": "23541928_T16",
"type": "GENE-Y",
"text": [
"IGF-1"
],
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[
858,
863
]
],
"normalized": []
},
{
"id": "23541928_T17",
"type": "GENE-Y",
"text": [
"IGF-1"
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[
888,
893
]
],
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},
{
"id": "23541928_T18",
"type": "GENE-Y",
"text": [
"TGF-β3"
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[
909,
915
]
],
"normalized": []
},
{
"id": "23541928_T19",
"type": "GENE-Y",
"text": [
"IGF-1"
],
"offsets": [
[
937,
942
]
],
"normalized": []
},
{
"id": "23541928_T20",
"type": "GENE-Y",
"text": [
"TGF-β3"
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"offsets": [
[
958,
964
]
],
"normalized": []
},
{
"id": "23541928_T21",
"type": "GENE-Y",
"text": [
"TGF-β3"
],
"offsets": [
[
1052,
1058
]
],
"normalized": []
}
] | [] | [] | [] |
23352650 | 23352650 | [
{
"id": "23352650_title",
"type": "title",
"text": [
"Point-to-point ligand-receptor interactions across the subunit interface modulate the induction and stabilization of conformational states of alpha7 nAChR by benzylidene anabaseines."
],
"offsets": [
[
0,
182
]
]
},
{
"id": "23352650_abstract",
"type": "abstract",
"text": [
"The homomeric α7 nicotinic acetylcholine receptor is a well-studied therapeutic target, though its characteristically rapid desensitization complicates the development of drugs with specific agonist effects. Moreover, some experimental compounds such as GTS-21 (2,4diMeOBA), a derivative of the α7-selective partial agonist benzylidene anabaseine (BA), produce a prolonged residual desensitization (RD) in which the receptor remains non-activatable long after the drug has been removed from extracellular solution. In contrast, the desensitization caused by GTS-21's dihydroxy metabolite (2,4diOHBA) is relatively short-lived. RD is hypothetically due to stable binding of the ligand to the receptor in its desensitized state. We can attribute the reduction in RD to a single BA hydroxyl group on the 4' benzylidene position. Computational prediction derived from homology modeling showed the serine36 (S36) residue of α7 as a reasonable candidate for point-to-point interaction between BA compounds and the receptor. Through evaluating the activity of BA and simple derivatives on wild-type and mutant α7 receptors, it was observed that the drug-receptor pairs which were capable of hydrogen bonding at residue 36 exhibited significantly less stable desensitization. Further experiments involving the type II positive allosteric modulator (PAM) PNU-120596 showed that the various BA compounds' preference to induce either a PAM-sensitive (D(s)) or PAM-insensitive (D(i)) desensitized state is concentration dependent and suggested that both states are destabilized by S36 H-bonding. These results indicate that the fine-tuning of agonists for specific interaction with S36 can facilitate the development of therapeutics with targeted effects on ion channel desensitization properties and conformational state stability."
],
"offsets": [
[
183,
2003
]
]
}
] | [
{
"id": "23352650_T1",
"type": "CHEMICAL",
"text": [
"hydrogen"
],
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[
1367,
1375
]
],
"normalized": []
},
{
"id": "23352650_T2",
"type": "CHEMICAL",
"text": [
"PNU-120596"
],
"offsets": [
[
1529,
1539
]
],
"normalized": []
},
{
"id": "23352650_T3",
"type": "CHEMICAL",
"text": [
"H"
],
"offsets": [
[
1756,
1757
]
],
"normalized": []
},
{
"id": "23352650_T4",
"type": "CHEMICAL",
"text": [
"GTS-21"
],
"offsets": [
[
437,
443
]
],
"normalized": []
},
{
"id": "23352650_T5",
"type": "CHEMICAL",
"text": [
"2,4diMeOBA"
],
"offsets": [
[
445,
455
]
],
"normalized": []
},
{
"id": "23352650_T6",
"type": "CHEMICAL",
"text": [
"acetylcholine"
],
"offsets": [
[
210,
223
]
],
"normalized": []
},
{
"id": "23352650_T7",
"type": "CHEMICAL",
"text": [
"benzylidene anabaseine"
],
"offsets": [
[
507,
529
]
],
"normalized": []
},
{
"id": "23352650_T8",
"type": "CHEMICAL",
"text": [
"GTS-21"
],
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[
741,
747
]
],
"normalized": []
},
{
"id": "23352650_T9",
"type": "CHEMICAL",
"text": [
"dihydroxy"
],
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[
750,
759
]
],
"normalized": []
},
{
"id": "23352650_T10",
"type": "CHEMICAL",
"text": [
"2,4diOHBA"
],
"offsets": [
[
772,
781
]
],
"normalized": []
},
{
"id": "23352650_T11",
"type": "CHEMICAL",
"text": [
"hydroxyl"
],
"offsets": [
[
962,
970
]
],
"normalized": []
},
{
"id": "23352650_T12",
"type": "CHEMICAL",
"text": [
"benzylidene"
],
"offsets": [
[
987,
998
]
],
"normalized": []
},
{
"id": "23352650_T13",
"type": "CHEMICAL",
"text": [
"serine"
],
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[
1076,
1082
]
],
"normalized": []
},
{
"id": "23352650_T14",
"type": "CHEMICAL",
"text": [
"benzylidene anabaseines"
],
"offsets": [
[
158,
181
]
],
"normalized": []
},
{
"id": "23352650_T15",
"type": "GENE-Y",
"text": [
"α7 receptors"
],
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[
1286,
1298
]
],
"normalized": []
},
{
"id": "23352650_T16",
"type": "GENE-Y",
"text": [
"α7 nicotinic acetylcholine receptor"
],
"offsets": [
[
197,
232
]
],
"normalized": []
},
{
"id": "23352650_T17",
"type": "GENE-Y",
"text": [
"α7"
],
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[
478,
480
]
],
"normalized": []
},
{
"id": "23352650_T18",
"type": "GENE-Y",
"text": [
"α7"
],
"offsets": [
[
1102,
1104
]
],
"normalized": []
},
{
"id": "23352650_T19",
"type": "GENE-Y",
"text": [
"alpha7 nAChR"
],
"offsets": [
[
142,
154
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23352650_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "23352650_T14",
"arg2_id": "23352650_T19",
"normalized": []
},
{
"id": "23352650_1",
"type": "AGONIST",
"arg1_id": "23352650_T7",
"arg2_id": "23352650_T17",
"normalized": []
},
{
"id": "23352650_2",
"type": "PART-OF",
"arg1_id": "23352650_T13",
"arg2_id": "23352650_T18",
"normalized": []
},
{
"id": "23352650_3",
"type": "AGONIST",
"arg1_id": "23352650_T4",
"arg2_id": "23352650_T17",
"normalized": []
},
{
"id": "23352650_4",
"type": "AGONIST",
"arg1_id": "23352650_T5",
"arg2_id": "23352650_T17",
"normalized": []
}
] |
23484434 | 23484434 | [
{
"id": "23484434_title",
"type": "title",
"text": [
"Progress and Developments in Tau Aggregation Inhibitors for Alzheimer Disease."
],
"offsets": [
[
0,
78
]
]
},
{
"id": "23484434_abstract",
"type": "abstract",
"text": [
"Pharmacological approaches directed toward Alzheimer disease are diversifying in parallel with a growing number of promising targets. Investigations on the microtubule-associated protein tau yielded innovative targets backed by recent findings about the central role of tau in numerous neurodegenerative diseases. In this review, we summarize the recent evolution in the development of nonpeptidic small molecules tau aggregation inhibitors (TAGIs) and their advancement toward clinical trials. The compounds are classified according to their chemical structures, providing correlative insights into their pharmacology. Overall, shared structure-activity traits are emerging, as well as specific binding modes related to their ability to engage in hydrogen bonding. Medicinal chemistry efforts on TAGIs together with encouraging in vivo data argue for successful translation to the clinic."
],
"offsets": [
[
79,
968
]
]
}
] | [
{
"id": "23484434_T1",
"type": "CHEMICAL",
"text": [
"hydrogen"
],
"offsets": [
[
827,
835
]
],
"normalized": []
},
{
"id": "23484434_T2",
"type": "GENE-Y",
"text": [
"tau"
],
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[
266,
269
]
],
"normalized": []
},
{
"id": "23484434_T3",
"type": "GENE-Y",
"text": [
"tau"
],
"offsets": [
[
349,
352
]
],
"normalized": []
},
{
"id": "23484434_T4",
"type": "GENE-Y",
"text": [
"tau"
],
"offsets": [
[
493,
496
]
],
"normalized": []
},
{
"id": "23484434_T5",
"type": "GENE-Y",
"text": [
"Tau"
],
"offsets": [
[
29,
32
]
],
"normalized": []
}
] | [] | [] | [] |
16899342 | 16899342 | [
{
"id": "16899342_title",
"type": "title",
"text": [
"The P/Q-type voltage-dependent calcium channel as pharmacological target in spinocerebellar ataxia type 6: gabapentin and pregabalin may be of therapeutic benefit."
],
"offsets": [
[
0,
163
]
]
},
{
"id": "16899342_abstract",
"type": "abstract",
"text": [
"Voltage-dependent calcium channels (VDCCs) are heteromultimeric complexes that mediate calcium influx into cells in response to changes in membrane potential. The alpha1A subunit, encoded by the CACNA1A gene, is the pore-forming subunit specific to the neuronal P/Q-type VDCCs. These are implicated in fast excitatory and inhibitory neurotransmission. Their highest levels of expression are found in the Purkinje cell layer of the cerebellum, and in the hippocampus. Spinocerebellar ataxia type 6 (SCA 6) is an autosomal dominant cerebellar degeneration that shares neuropathological findings with late-onset cortical cerebellar atrophy (CCA). It is caused by an abnormal expansion of a trinucleotide (CAG) repeat in exon 47 of CACNA1A, on chromosome 19p13. This translates into a polyglutamine (polyQ) tract of prolonged length in the carboxyl terminal of the alpha1A subunit. Heterologous expression of mutated alpha1A subunits results in increased channel inactivation in electrophysiological tests. No treatment is known to improve SCA 6 at present, as none of the available drugs is able to reverse alpha1A dysregulation, nor disturbed protein aggregation, transport and localization in this disease. The drugs gabapentin and pregabalin interact with the alpha2delta subunit of the P/Q-type VDCCs. Gabapentin and pregabalin slow the rate of inactivation in recombinant P/Q-type VDCCs, expressed in Xenopus oocytes. These drugs improve ataxia in cases of CCA, olivopontocerebellar atrophy and ataxia-telangiectasia. On the basis of the neuropathological identity of SCA 6 with CCA, and given the capacity of gabapentin and pregabalin to decrease P/Q-type VDCCs inactivation, in this paper the authors put forward the hypothesis that the administration of gabapentin and pregabalin might prove beneficial in SCA 6 as the ataxia caused by this disease would be expected to improve. The authors hope that researchers working with this illness will be inspired and encouraged to undertake the appropriate clinical and experimental work."
],
"offsets": [
[
164,
2200
]
]
}
] | [
{
"id": "16899342_T1",
"type": "CHEMICAL",
"text": [
"gabapentin"
],
"offsets": [
[
1380,
1390
]
],
"normalized": []
},
{
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] |
23566515 | 23566515 | [
{
"id": "23566515_title",
"type": "title",
"text": [
"Synthesis and structure-activity relationships of 2-amino-3-carboxy-4-phenylthiophenes as novel atypical protein kinase C inhibitors."
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0,
133
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]
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{
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"type": "abstract",
"text": [
"Recent evidence suggests atypical protein kinase C (aPKC) isoforms are required for both TNF- and VEGF-induced breakdown of the blood-retinal barrier (BRB) and endothelial permeability to 70kDa dextran or albumin. A chemical library screen revealed a series of novel small molecule phenylthiophene based inhibitors of aPKC isoforms that effectively block permeability in cell culture and in vivo. In an effort to further elucidate the structural requirements of this series of inhibitors, we detail in this study a structure-activity relationship (SAR) built on screening hit 1, which expands on our initial pharmacophore model. The biological activity of our analogues was evaluated in models of bona fide aPKC-dependent signaling including NFκB driven-gene transcription as a marker for an inflammatory response and VEGF/TNF-induced vascular endothelial permeability. The EC50 for the most efficacious inhibitors (6, 32) was in the low nanomolar range in these two cellular assays. Our study demonstrates the key structural elements that confer inhibitory activity and highlights the requirement for electron-donating moieties off the C-4 aryl moiety of the 2-amino-3-carboxy-4-phenylthiophene backbone. These studies suggest that this class has potential for further development into small molecule aPKC inhibitors with therapeutic efficacy in a host of diseases involving increased vascular permeability and inflammation."
],
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]
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232,
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96,
121
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],
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}
] | [] | [] | [
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"normalized": []
}
] |
22902307 | 22902307 | [
{
"id": "22902307_title",
"type": "title",
"text": [
"A human hemi-cornea model for eye irritation testing: quality control of production, reliability and predictive capacity."
],
"offsets": [
[
0,
121
]
]
},
{
"id": "22902307_abstract",
"type": "abstract",
"text": [
"We have developed a 3-dimensional human hemi-cornea which comprises an immortalized epithelial cell line and keratocytes embedded in a collagen stroma. In the present study, we have used MTT reduction of the whole tissue to clarify whether the production of this complex 3-D-model is transferable into other laboratories and whether these tissues can be constructed reproducibly. Our results demonstrate the reproducible production of the hemi-cornea model according to standard operation procedures using 15 independent batches of reconstructed hemi-cornea models in two independent laboratories each. Furthermore, the hemi-cornea tissues have been treated with 20 chemicals of different eye-irritating potential under blind conditions to assess the performance and limitations of our test system comparing three different prediction models. The most suitable prediction model revealed an overall in vitro-in vivo concordance of 80% and 70% in the participating laboratories, respectively, and an inter-laboratory concordance of 80%. Sensitivity of the test was 77% and specificity was between 57% and 86% to discriminate classified from non-classified chemicals. We conclude that additional physiologically relevant endpoints in both epithelium and stroma have to be developed for the reliable prediction of all GHS classes of eye irritation in one stand alone test system."
],
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122,
1497
]
]
}
] | [
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]
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"text": [
"collagen"
],
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[
257,
265
]
],
"normalized": []
}
] | [] | [] | [] |
17705025 | 17705025 | [
{
"id": "17705025_title",
"type": "title",
"text": [
"High frequency of missense mutations in glycogen storage disease type VI."
],
"offsets": [
[
0,
73
]
]
},
{
"id": "17705025_abstract",
"type": "abstract",
"text": [
"Deficiency of liver glycogen phosphorylase in glycogen storage disease (GSD) type VI results in a reduced ability to mobilize glucose from glycogen. Six mutations of the PYGL gene, which encodes the liver isoform of the enzyme, have been identified in the literature. We have characterized eight patients from seven families with GSD type VI and identified 11 novel PYGL gene defects. The majority of the mutations were missense, resulting in the substitution of highly conserved residues. These could be grouped into those that were predicted to affect substrate binding (p.V456M, p.E673K, p.S675L, p.S675T), pyridoxal phosphate binding (p.R491C, p.K681T), or activation of glycogen phosphorylase (p.Q13P) or that had an unknown effect (p.N632I and p.D634H). Two mutations were predicted to result in null alleles, p.R399X and [c.1964_1969inv6;c.1969+1_+4delGTAC]. Only 7 of the 23 (30%) reported PYGL alleles carry nonsense, splice site or frameshift mutations compared to 68-80% of affected alleles of the highly homologous muscle glycogen phosphorylase gene, PYGM, that underlie McArdle disease. There was heterogeneity in the clinical symptoms observed in affected individuals. These varied from hepatomegaly and subclinical hypoglycaemia, to severe hepatomegaly with recurrent severe hypoglycaemia and postprandial lactic acidosis. We conclude that deficiency of liver glycogen phosphorylase is predominantly the result of missense mutations affecting enzyme activity. There are no common mutations and the severity of clinical symptoms varies significantly."
],
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[
74,
1638
]
]
}
] | [
{
"id": "17705025_T1",
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]
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"id": "17705025_T2",
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"pyridoxal phosphate"
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684,
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]
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"id": "17705025_T3",
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"muscle glycogen phosphorylase"
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1101,
1130
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},
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"id": "17705025_T4",
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"PYGM"
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1137,
1141
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1443,
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]
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88,
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"R491C"
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715,
720
]
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"id": "17705025_T14",
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]
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},
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"id": "17705025_T16",
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"N632I"
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814,
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},
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"type": "GENE-N",
"text": [
"R399X"
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892,
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},
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"id": "17705025_T19",
"type": "GENE-Y",
"text": [
"PYGL"
],
"offsets": [
[
972,
976
]
],
"normalized": []
}
] | [] | [] | [] |
10768100 | 10768100 | [
{
"id": "10768100_title",
"type": "title",
"text": [
"Troglitazone reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes."
],
"offsets": [
[
0,
109
]
]
},
{
"id": "10768100_abstract",
"type": "abstract",
"text": [
"AIMS/HYPOTHESIS: Increased plasma plasminogen activator inhibitor-1 (PAI-1) concentrations are characteristic for subjects with insulin resistance and could contribute to the increased cardiovascular risk in this state. In this study, we investigated the effect of troglitazone, a ligand of the nuclear receptor peroxisome proliferator activated receptor-gamma, on PAI-1 expression and secretion in human adipocytes. METHODS: We used two models: in vitro differentiated subcutaneous and omental adipocytes cultured under serum-free conditions and isolated subcutaneous and omental fat cells kept in suspension culture. Plasminogen activator inhibitor-1 protein was measured by ELISA, PAI-1 mRNA by a semiquantitative RT-PCR technique. RESULTS: Exposure of in vitro differentiated subcutaneous adipocytes from young normal-weight females to 1 microgram/ml troglitazone for 72 h caused a reduction of both PAI-1 secretion (by 29 +/- 5%; p < 0.01) and PAI-1 mRNA expression (by 26 +/- 3%; p < 0.05). In cultures from severely obese subjects, troglitazone induced a decrease of PAI-1 antigen secretion from newly differentiated omental adipocytes by 49 +/- 8% (p < 0.01) and from subcutaneous adipocytes by 30 +/- 7% (p < 0.05). Exposure of freshly isolated subcutaneous and omental adipocytes in suspension culture to troglitazone induced a similar reduction of PAI-1 concentration in the culture medium (by 35 +/- 11%, p < 0.05, and 33 +/- 8%, p < 0.05 compared with control, respectively). CONCLUSION/INTERPRETATION: This study provides evidence that troglitazone reduces PAI-1 production in human adipocytes, probably at the transcriptional level. This observation could point to a new beneficial effect of troglitazone, particularly in obese subjects, which could be associated with a reduced cardiovascular risk."
],
"offsets": [
[
110,
1924
]
]
}
] | [
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0,
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1184,
1189
]
],
"normalized": []
},
{
"id": "10768100_T9",
"type": "GENE-Y",
"text": [
"insulin"
],
"offsets": [
[
238,
245
]
],
"normalized": []
},
{
"id": "10768100_T10",
"type": "GENE-Y",
"text": [
"PAI-1"
],
"offsets": [
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1469,
1474
]
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{
"id": "10768100_T11",
"type": "GENE-Y",
"text": [
"PAI-1"
],
"offsets": [
[
1681,
1686
]
],
"normalized": []
},
{
"id": "10768100_T12",
"type": "GENE-Y",
"text": [
"plasma plasminogen activator inhibitor-1"
],
"offsets": [
[
137,
177
]
],
"normalized": []
},
{
"id": "10768100_T13",
"type": "GENE-N",
"text": [
"nuclear receptor"
],
"offsets": [
[
405,
421
]
],
"normalized": []
},
{
"id": "10768100_T14",
"type": "GENE-Y",
"text": [
"peroxisome proliferator activated receptor-gamma"
],
"offsets": [
[
422,
470
]
],
"normalized": []
},
{
"id": "10768100_T15",
"type": "GENE-Y",
"text": [
"PAI-1"
],
"offsets": [
[
475,
480
]
],
"normalized": []
},
{
"id": "10768100_T16",
"type": "GENE-Y",
"text": [
"Plasminogen activator inhibitor-1"
],
"offsets": [
[
729,
762
]
],
"normalized": []
},
{
"id": "10768100_T17",
"type": "GENE-Y",
"text": [
"PAI-1"
],
"offsets": [
[
794,
799
]
],
"normalized": []
},
{
"id": "10768100_T18",
"type": "GENE-Y",
"text": [
"PAI-1"
],
"offsets": [
[
179,
184
]
],
"normalized": []
},
{
"id": "10768100_T19",
"type": "GENE-Y",
"text": [
"PAI-1"
],
"offsets": [
[
1014,
1019
]
],
"normalized": []
},
{
"id": "10768100_T20",
"type": "GENE-Y",
"text": [
"PAI-1"
],
"offsets": [
[
1059,
1064
]
],
"normalized": []
},
{
"id": "10768100_T21",
"type": "GENE-Y",
"text": [
"plasminogen activator inhibitor-1"
],
"offsets": [
[
21,
54
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "10768100_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "10768100_T7",
"arg2_id": "10768100_T21",
"normalized": []
},
{
"id": "10768100_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "10768100_T5",
"arg2_id": "10768100_T13",
"normalized": []
},
{
"id": "10768100_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "10768100_T5",
"arg2_id": "10768100_T14",
"normalized": []
},
{
"id": "10768100_3",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "10768100_T6",
"arg2_id": "10768100_T19",
"normalized": []
},
{
"id": "10768100_4",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "10768100_T6",
"arg2_id": "10768100_T20",
"normalized": []
},
{
"id": "10768100_5",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "10768100_T1",
"arg2_id": "10768100_T8",
"normalized": []
},
{
"id": "10768100_6",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "10768100_T2",
"arg2_id": "10768100_T10",
"normalized": []
},
{
"id": "10768100_7",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "10768100_T3",
"arg2_id": "10768100_T11",
"normalized": []
}
] |
8741039 | 8741039 | [
{
"id": "8741039_title",
"type": "title",
"text": [
"Atypical vitamin B12-unresponsive methylmalonic aciduria in sibship with severe progressive encephalomyelopathy: a new genetic disease?"
],
"offsets": [
[
0,
135
]
]
},
{
"id": "8741039_abstract",
"type": "abstract",
"text": [
"UNLABELLED: We report on two siblings, a girl of 7 years and a boy of 2 years, who presented in infancy with hypotonia, athetoid movements, myopathy and severe developmental delay. The progressive clinical course was characterized by ophthalmoplegia, pyramidal tract signs, loss of visual contact and failure to thrive. The older sister died at the age of 7 years. The younger brother followed an almost identical clinical course. MRI of the brain revealed bilateral hypodensities and atrophy of the putamen. Neurophysiological investigations were consistent with peripheral neuropathy. Investigations for neurometabolic disorders in urine, plasma and CSF of both patients revealed a consistent increase of methylmalonic acid in urine, plasma and CSF as well as borderline low free GABA in CSF. Except for an inconstant elevation of lactate in the boy, metabolic acidosis, hypoglycaemia, episodic ketoacidosis, or hyperammonaemia, the usual concomitants of organoacidopathies, were absent in both children. Homocystinuria was excluded. Methylmalonic aciduria did not respond to antibiotic treatment, vitamin B12 therapy nor dietary protein restriction. Incorporation of [14C]propionate into protein in cultured fibroblasts was pathologically but inconsistently decreased. Both patients' cell lines showed only minimal response to hydroxocobalamin and normal methylmalonyl-CoA mutase activity. CONCLUSION: Even though the definitive underlying enzymatic defect in this sibship remains obscure our results suggest a new genetic disorder. This report illustrates that hitherto undescribed metabolic disorders remain to be elucidated even in long investigated areas of intermediary metabolism such as methylmalonic aciduria."
],
"offsets": [
[
136,
1856
]
]
}
] | [
{
"id": "8741039_T1",
"type": "CHEMICAL",
"text": [
"vitamin B12"
],
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[
1236,
1247
]
],
"normalized": []
},
{
"id": "8741039_T2",
"type": "CHEMICAL",
"text": [
"[14C]propionate"
],
"offsets": [
[
1306,
1321
]
],
"normalized": []
},
{
"id": "8741039_T3",
"type": "CHEMICAL",
"text": [
"hydroxocobalamin"
],
"offsets": [
[
1466,
1482
]
],
"normalized": []
},
{
"id": "8741039_T4",
"type": "CHEMICAL",
"text": [
"methylmalonyl-CoA"
],
"offsets": [
[
1494,
1511
]
],
"normalized": []
},
{
"id": "8741039_T5",
"type": "CHEMICAL",
"text": [
"methylmalonic acid"
],
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[
843,
861
]
],
"normalized": []
},
{
"id": "8741039_T6",
"type": "CHEMICAL",
"text": [
"lactate"
],
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[
969,
976
]
],
"normalized": []
},
{
"id": "8741039_T7",
"type": "CHEMICAL",
"text": [
"vitamin B12"
],
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[
9,
20
]
],
"normalized": []
},
{
"id": "8741039_T8",
"type": "GENE-Y",
"text": [
"methylmalonyl-CoA mutase"
],
"offsets": [
[
1494,
1518
]
],
"normalized": []
}
] | [] | [] | [] |
23000249 | 23000249 | [
{
"id": "23000249_title",
"type": "title",
"text": [
"Snake venom metalloproteinases."
],
"offsets": [
[
0,
31
]
]
},
{
"id": "23000249_abstract",
"type": "abstract",
"text": [
"Recent proteomic analyses of snake venoms show that metalloproteinases represent major components in most of the Crotalid and Viperid venoms. In this chapter we discuss the multiple activities of the SVMPs. In addition to hemorrhagic activity, members of the SVMP family also have fibrin(ogen)olytic activity, act as prothrombin activators, activate blood coagulation factor X, possess apoptotic activity, inhibit platelet aggregation, are pro-inflammatory and inactivate blood serine proteinase inhibitors. Clearly the SVMPs have multiple functions in addition to their well-known hemorrhagic activity. The realization that there are structural variations in the SVMPs and the early studies that led to their classification represents an important event in our understanding of the structural forms of the SVMPs. The SVMPs were subdivided into the P-I, P-II and P-III protein classes. The noticeable characteristic that distinguished the different classes was their size (molecular weight) differences and domain structure: Class I (P-I), the small SVMPs, have molecular masses of 20-30 kDa, contain only a pro domain and the proteinase domain; Class II (P-II), the medium size SVMPs, molecular masses of 30-60 kDa, contain the pro domain, proteinase domain and disintegrin domain; Class III (P-III), the large SVMPs, have molecular masses of 60-100 kDa, contain pro, proteinase, disintegrin-like and cysteine-rich domain structure. Another significant advance in the SVMP field was the characterization of the crystal structure of the first P-I class SVMP. The structures of other P-I SVMPs soon followed and the structures of P-III SVMPs have also been determined. The active site of the metalloproteinase domain has a consensus HEXXHXXGXXHD sequence and a Met-turn. The \"Met-turn\" structure contains a conserved Met residue that forms a hydrophobic basement for the three zinc-binding histidines in the consensus sequence."
],
"offsets": [
[
32,
1958
]
]
}
] | [
{
"id": "23000249_T1",
"type": "CHEMICAL",
"text": [
"cysteine"
],
"offsets": [
[
1434,
1442
]
],
"normalized": []
},
{
"id": "23000249_T2",
"type": "CHEMICAL",
"text": [
"Met"
],
"offsets": [
[
1792,
1795
]
],
"normalized": []
},
{
"id": "23000249_T3",
"type": "CHEMICAL",
"text": [
"Met"
],
"offsets": [
[
1807,
1810
]
],
"normalized": []
},
{
"id": "23000249_T4",
"type": "CHEMICAL",
"text": [
"Met"
],
"offsets": [
[
1848,
1851
]
],
"normalized": []
},
{
"id": "23000249_T5",
"type": "CHEMICAL",
"text": [
"zinc"
],
"offsets": [
[
1908,
1912
]
],
"normalized": []
},
{
"id": "23000249_T6",
"type": "CHEMICAL",
"text": [
"histidines"
],
"offsets": [
[
1921,
1931
]
],
"normalized": []
},
{
"id": "23000249_T7",
"type": "GENE-N",
"text": [
"SVMPs"
],
"offsets": [
[
1082,
1087
]
],
"normalized": []
},
{
"id": "23000249_T8",
"type": "GENE-N",
"text": [
"pro domain"
],
"offsets": [
[
1140,
1150
]
],
"normalized": []
},
{
"id": "23000249_T9",
"type": "GENE-N",
"text": [
"proteinase domain"
],
"offsets": [
[
1159,
1176
]
],
"normalized": []
},
{
"id": "23000249_T10",
"type": "GENE-N",
"text": [
"SVMPs"
],
"offsets": [
[
1211,
1216
]
],
"normalized": []
},
{
"id": "23000249_T11",
"type": "GENE-N",
"text": [
"pro domain"
],
"offsets": [
[
1261,
1271
]
],
"normalized": []
},
{
"id": "23000249_T12",
"type": "GENE-N",
"text": [
"proteinase domain"
],
"offsets": [
[
1273,
1290
]
],
"normalized": []
},
{
"id": "23000249_T13",
"type": "GENE-N",
"text": [
"disintegrin domain"
],
"offsets": [
[
1295,
1313
]
],
"normalized": []
},
{
"id": "23000249_T14",
"type": "GENE-N",
"text": [
"SVMPs"
],
"offsets": [
[
1344,
1349
]
],
"normalized": []
},
{
"id": "23000249_T15",
"type": "GENE-N",
"text": [
"pro"
],
"offsets": [
[
1396,
1399
]
],
"normalized": []
},
{
"id": "23000249_T16",
"type": "GENE-N",
"text": [
"proteinase"
],
"offsets": [
[
1401,
1411
]
],
"normalized": []
},
{
"id": "23000249_T17",
"type": "GENE-N",
"text": [
"disintegrin-like"
],
"offsets": [
[
1413,
1429
]
],
"normalized": []
},
{
"id": "23000249_T18",
"type": "GENE-N",
"text": [
"cysteine-rich domain"
],
"offsets": [
[
1434,
1454
]
],
"normalized": []
},
{
"id": "23000249_T19",
"type": "GENE-N",
"text": [
"SVMP"
],
"offsets": [
[
1501,
1505
]
],
"normalized": []
},
{
"id": "23000249_T20",
"type": "GENE-N",
"text": [
"P-I class SVMP"
],
"offsets": [
[
1575,
1589
]
],
"normalized": []
},
{
"id": "23000249_T21",
"type": "GENE-N",
"text": [
"P-I SVMPs"
],
"offsets": [
[
1615,
1624
]
],
"normalized": []
},
{
"id": "23000249_T22",
"type": "GENE-N",
"text": [
"P-III SVMPs"
],
"offsets": [
[
1661,
1672
]
],
"normalized": []
},
{
"id": "23000249_T23",
"type": "GENE-N",
"text": [
"metalloproteinase domain"
],
"offsets": [
[
1723,
1747
]
],
"normalized": []
},
{
"id": "23000249_T24",
"type": "GENE-N",
"text": [
"HEXXHXXGXXHD"
],
"offsets": [
[
1764,
1776
]
],
"normalized": []
},
{
"id": "23000249_T25",
"type": "GENE-N",
"text": [
"SVMPs"
],
"offsets": [
[
232,
237
]
],
"normalized": []
},
{
"id": "23000249_T26",
"type": "GENE-N",
"text": [
"SVMP"
],
"offsets": [
[
291,
295
]
],
"normalized": []
},
{
"id": "23000249_T27",
"type": "GENE-Y",
"text": [
"prothrombin"
],
"offsets": [
[
349,
360
]
],
"normalized": []
},
{
"id": "23000249_T28",
"type": "GENE-Y",
"text": [
"coagulation factor X"
],
"offsets": [
[
388,
408
]
],
"normalized": []
},
{
"id": "23000249_T29",
"type": "GENE-N",
"text": [
"serine proteinase"
],
"offsets": [
[
510,
527
]
],
"normalized": []
},
{
"id": "23000249_T30",
"type": "GENE-N",
"text": [
"SVMPs"
],
"offsets": [
[
552,
557
]
],
"normalized": []
},
{
"id": "23000249_T31",
"type": "GENE-N",
"text": [
"metalloproteinases"
],
"offsets": [
[
84,
102
]
],
"normalized": []
},
{
"id": "23000249_T32",
"type": "GENE-N",
"text": [
"SVMPs"
],
"offsets": [
[
696,
701
]
],
"normalized": []
},
{
"id": "23000249_T33",
"type": "GENE-N",
"text": [
"SVMPs"
],
"offsets": [
[
839,
844
]
],
"normalized": []
},
{
"id": "23000249_T34",
"type": "GENE-N",
"text": [
"SVMPs"
],
"offsets": [
[
850,
855
]
],
"normalized": []
},
{
"id": "23000249_T35",
"type": "GENE-N",
"text": [
"Snake venom metalloproteinases"
],
"offsets": [
[
0,
30
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23000249_0",
"type": "PART-OF",
"arg1_id": "23000249_T2",
"arg2_id": "23000249_T23",
"normalized": []
}
] |
17475673 | 17475673 | [
{
"id": "17475673_title",
"type": "title",
"text": [
"Underexpression of the Na+-dependent neutral amino acid transporter ASCT2 in the spontaneously hypertensive rat kidney."
],
"offsets": [
[
0,
119
]
]
},
{
"id": "17475673_abstract",
"type": "abstract",
"text": [
"This study examined the inward transport of l-[(14)C]alanine, an ASCT2 preferential substrate, in monolayers of immortalized renal proximal tubular epithelial (PTE) cells from Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. The expression of ASCT2 in WKY and SHR PTE cells and kidney cortices from WKY and SHR was also evaluated. l-[(14)C]alanine uptake was highly dependent on extracellular Na(+). Replacement of NaCl by LiCl or choline chloride abolished transport activity in SHR and WKY PTE cells. In the presence of the system L inhibitor BCH, Na(+)-dependent l-alanine uptake in WKY and SHR PTE cells was inhibited by alanine, serine, and cysteine, which is consistent with amino acid transport through ASCT2. The saturable component of Na(+)-dependent l-alanine transport under V(max) conditions in SHR PTE cells was one-half of that in WKY PTE cells, with similar K(m) values. Differences in magnitude of Na(+)-dependent l-alanine uptake through ASCT2 between WKY and SHR PTE cells correlated positively with differences in ASCT2 protein expression, this being more abundant in WKY PTE cells. Abundance of ASCT2 transcript and protein in kidney cortices of SHR rats was also lower than that in normotensive WKY rats. In conclusion, immortalized SHR and WKY PTE cells take up l-alanine mainly through a high-affinity Na(+)-dependent amino acid transporter, with functional features of ASCT2 transport. The activity and expression of the ASCT2 transporter were considerably lower in the SHR cells."
],
"offsets": [
[
120,
1637
]
]
}
] | [
{
"id": "17475673_T1",
"type": "CHEMICAL",
"text": [
"l-alanine"
],
"offsets": [
[
1417,
1426
]
],
"normalized": []
},
{
"id": "17475673_T2",
"type": "CHEMICAL",
"text": [
"Na(+)"
],
"offsets": [
[
1458,
1463
]
],
"normalized": []
},
{
"id": "17475673_T3",
"type": "CHEMICAL",
"text": [
"amino acid"
],
"offsets": [
[
1474,
1484
]
],
"normalized": []
},
{
"id": "17475673_T4",
"type": "CHEMICAL",
"text": [
"l-[(14)C]alanine"
],
"offsets": [
[
464,
480
]
],
"normalized": []
},
{
"id": "17475673_T5",
"type": "CHEMICAL",
"text": [
"Na(+)"
],
"offsets": [
[
526,
531
]
],
"normalized": []
},
{
"id": "17475673_T6",
"type": "CHEMICAL",
"text": [
"NaCl"
],
"offsets": [
[
548,
552
]
],
"normalized": []
},
{
"id": "17475673_T7",
"type": "CHEMICAL",
"text": [
"LiCl"
],
"offsets": [
[
556,
560
]
],
"normalized": []
},
{
"id": "17475673_T8",
"type": "CHEMICAL",
"text": [
"choline chloride"
],
"offsets": [
[
564,
580
]
],
"normalized": []
},
{
"id": "17475673_T9",
"type": "CHEMICAL",
"text": [
"l-[(14)C]alanine"
],
"offsets": [
[
164,
180
]
],
"normalized": []
},
{
"id": "17475673_T10",
"type": "CHEMICAL",
"text": [
"Na(+)"
],
"offsets": [
[
683,
688
]
],
"normalized": []
},
{
"id": "17475673_T11",
"type": "CHEMICAL",
"text": [
"l-alanine"
],
"offsets": [
[
699,
708
]
],
"normalized": []
},
{
"id": "17475673_T12",
"type": "CHEMICAL",
"text": [
"alanine"
],
"offsets": [
[
758,
765
]
],
"normalized": []
},
{
"id": "17475673_T13",
"type": "CHEMICAL",
"text": [
"serine"
],
"offsets": [
[
767,
773
]
],
"normalized": []
},
{
"id": "17475673_T14",
"type": "CHEMICAL",
"text": [
"cysteine"
],
"offsets": [
[
779,
787
]
],
"normalized": []
},
{
"id": "17475673_T15",
"type": "CHEMICAL",
"text": [
"amino acid"
],
"offsets": [
[
814,
824
]
],
"normalized": []
},
{
"id": "17475673_T16",
"type": "CHEMICAL",
"text": [
"Na(+)"
],
"offsets": [
[
877,
882
]
],
"normalized": []
},
{
"id": "17475673_T17",
"type": "CHEMICAL",
"text": [
"l-alanine"
],
"offsets": [
[
893,
902
]
],
"normalized": []
},
{
"id": "17475673_T18",
"type": "CHEMICAL",
"text": [
"Na(+)"
],
"offsets": [
[
1047,
1052
]
],
"normalized": []
},
{
"id": "17475673_T19",
"type": "CHEMICAL",
"text": [
"l-alanine"
],
"offsets": [
[
1063,
1072
]
],
"normalized": []
},
{
"id": "17475673_T20",
"type": "CHEMICAL",
"text": [
"Na+"
],
"offsets": [
[
23,
26
]
],
"normalized": []
},
{
"id": "17475673_T21",
"type": "CHEMICAL",
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45,
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1248,
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23,
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]
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"ASCT2"
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68,
73
]
],
"normalized": []
}
] | [] | [] | [
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}
] |
12504781 | 12504781 | [
{
"id": "12504781_title",
"type": "title",
"text": [
"In vitro effect of sanguinarine alkaloid on binding of [3H]candesartan to the human angiotensin AT1 receptor."
],
"offsets": [
[
0,
109
]
]
},
{
"id": "12504781_abstract",
"type": "abstract",
"text": [
"The type of interaction of 5-methyl-2,3,7,8-bis(methylenedioxy)benzo[c]phenanthridinium (sanguinarine), an alkaloid isolated from the root of Bocconia frutescens L., with the human angiotensin AT(1) receptor was evaluated in both intact cells and membrane binding of [3H](2-ethoxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H-benzimidazoline-7 -carboxylic acid) ([3H]candesartan). The results indicate that the inhibition of [3H]candesartan binding by sanguinarine is independent of cell viability, since the alkaloid inhibited at a similar extent radioligand binding on both intact Chinese hamster ovary (CHO) cells transfected with the human angiotensin AT(1) receptor (hAT(1)) and their cell membranes (K(i)=0.14 and 1.10 microM, respectively). The unsuccessful recovery of [3H]candesartan binding after washing sanguinarine off the cells suggested a nearly irreversible or slow reversible interaction. Saturation binding studies showed a substantial reduction of the B(max) without affecting the K(d). In addition, the presence of 2-n-butyl-4chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]i midazole (losartan) could not prevent sanguinarine inhibition of [3H]candesartan binding neither. The present findings indicate that sanguinarine interacts with the receptor in a slow, nearly irreversible and noncompetitive manner."
],
"offsets": [
[
110,
1463
]
]
}
] | [
{
"id": "12504781_T1",
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"text": [
"2-n-butyl-4chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]i midazole"
],
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1150,
1240
]
],
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},
{
"id": "12504781_T2",
"type": "CHEMICAL",
"text": [
"losartan"
],
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[
1242,
1250
]
],
"normalized": []
},
{
"id": "12504781_T3",
"type": "CHEMICAL",
"text": [
"sanguinarine"
],
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[
1270,
1282
]
],
"normalized": []
},
{
"id": "12504781_T4",
"type": "CHEMICAL",
"text": [
"[3H]candesartan"
],
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1297,
1312
]
],
"normalized": []
},
{
"id": "12504781_T5",
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"text": [
"sanguinarine"
],
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[
1365,
1377
]
],
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},
{
"id": "12504781_T6",
"type": "CHEMICAL",
"text": [
"angiotensin"
],
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291,
302
]
],
"normalized": []
},
{
"id": "12504781_T7",
"type": "CHEMICAL",
"text": [
"[3H](2-ethoxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H-benzimidazoline-7 -carboxylic acid)"
],
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377,
476
]
],
"normalized": []
},
{
"id": "12504781_T8",
"type": "CHEMICAL",
"text": [
"5-methyl-2,3,7,8-bis(methylenedioxy)benzo[c]phenanthridinium"
],
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137,
197
]
],
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},
{
"id": "12504781_T9",
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"text": [
"[3H]candesartan"
],
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478,
493
]
],
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},
{
"id": "12504781_T10",
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"[3H]candesartan"
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540,
555
]
],
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},
{
"id": "12504781_T11",
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],
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567,
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]
],
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},
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"id": "12504781_T12",
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"angiotensin"
],
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759,
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]
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},
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892,
907
]
],
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},
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"id": "12504781_T14",
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],
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930,
942
]
],
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},
{
"id": "12504781_T15",
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"text": [
"sanguinarine"
],
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199,
211
]
],
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},
{
"id": "12504781_T16",
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"text": [
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],
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19,
31
]
],
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},
{
"id": "12504781_T17",
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"text": [
"[3H]candesartan"
],
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55,
70
]
],
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},
{
"id": "12504781_T18",
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"text": [
"angiotensin"
],
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84,
95
]
],
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},
{
"id": "12504781_T19",
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285,
317
]
],
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},
{
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753,
785
]
],
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},
{
"id": "12504781_T21",
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"text": [
"hAT(1)"
],
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787,
793
]
],
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},
{
"id": "12504781_T22",
"type": "GENE-Y",
"text": [
"human angiotensin AT1 receptor"
],
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78,
108
]
],
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}
] | [] | [] | [
{
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"arg2_id": "12504781_T22",
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},
{
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},
{
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},
{
"id": "12504781_3",
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"arg2_id": "12504781_T20",
"normalized": []
},
{
"id": "12504781_4",
"type": "INHIBITOR",
"arg1_id": "12504781_T11",
"arg2_id": "12504781_T21",
"normalized": []
}
] |
23583259 | 23583259 | [
{
"id": "23583259_title",
"type": "title",
"text": [
"Agonism of human pregnane X receptor by rilpivirine and etravirine: Comparison with first generation non-nucleoside reverse transcriptase inhibitors."
],
"offsets": [
[
0,
149
]
]
},
{
"id": "23583259_abstract",
"type": "abstract",
"text": [
"Rilpivirine and etravirine are second generation non-nucleoside reverse transcriptase inhibitors approved recently by the United States Food and Drug Administration for the treatment of human immunodeficiency virus-1 infection. Pregnane X receptor (PXR) is a member of the superfamily of nuclear receptors that regulate the expression of various genes controlling diverse biological functions. The present study investigated the effects of rilpivirine and etravirine on the activity of human PXR (hPXR), including the mode of activation, and compared them to those of efavirenz, nevirapine, and delavirdine, which are first generation non-nucleoside reverse transcriptase inhibitors. In transiently transfected HepG2 cells, rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, activated human, mouse, and rat PXR. Results from mechanistic studies indicated that rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, bound to the ligand-binding domain of hPXR, as assessed by a transactivation assay and by a competitive ligand-binding assay using time-resolved fluorescence resonance energy transfer; triggered nuclear translocation of a green fluorescence protein-tagged hPXR, as visualized by confocal imaging; and recruited steroid receptor coactivator-1 (SRC-1), SRC-2, and SRC-3 to hPXR, as demonstrated by mammalian two-hybrid assays. Rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, increased hPXR target gene (CYP3A4) expression in primary cultures of human hepatocytes. In summary, select non-nucleoside reverse transcriptase inhibitors activated human and rodent PXR. Rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, were identified as agonists of hPXR, as assessed in mechanistic experiments, and inducers of CYP3A4, as determined in primary cultures of human hepatocytes."
],
"offsets": [
[
150,
2028
]
]
}
] | [
{
"id": "23583259_T1",
"type": "CHEMICAL",
"text": [
"Rilpivirine"
],
"offsets": [
[
150,
161
]
],
"normalized": []
},
{
"id": "23583259_T2",
"type": "CHEMICAL",
"text": [
"steroid"
],
"offsets": [
[
1420,
1427
]
],
"normalized": []
},
{
"id": "23583259_T3",
"type": "CHEMICAL",
"text": [
"Rilpivirine"
],
"offsets": [
[
1534,
1545
]
],
"normalized": []
},
{
"id": "23583259_T4",
"type": "CHEMICAL",
"text": [
"etravirine"
],
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[
1547,
1557
]
],
"normalized": []
},
{
"id": "23583259_T5",
"type": "CHEMICAL",
"text": [
"efavirenz"
],
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[
1563,
1572
]
],
"normalized": []
},
{
"id": "23583259_T6",
"type": "CHEMICAL",
"text": [
"nevirapine"
],
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[
1582,
1592
]
],
"normalized": []
},
{
"id": "23583259_T7",
"type": "CHEMICAL",
"text": [
"delavirdine"
],
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[
1596,
1607
]
],
"normalized": []
},
{
"id": "23583259_T8",
"type": "CHEMICAL",
"text": [
"nucleoside"
],
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1721,
1731
]
],
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},
{
"id": "23583259_T9",
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"text": [
"etravirine"
],
"offsets": [
[
166,
176
]
],
"normalized": []
},
{
"id": "23583259_T10",
"type": "CHEMICAL",
"text": [
"Rilpivirine"
],
"offsets": [
[
1797,
1808
]
],
"normalized": []
},
{
"id": "23583259_T11",
"type": "CHEMICAL",
"text": [
"etravirine"
],
"offsets": [
[
1810,
1820
]
],
"normalized": []
},
{
"id": "23583259_T12",
"type": "CHEMICAL",
"text": [
"efavirenz"
],
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[
1826,
1835
]
],
"normalized": []
},
{
"id": "23583259_T13",
"type": "CHEMICAL",
"text": [
"nevirapine"
],
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[
1845,
1855
]
],
"normalized": []
},
{
"id": "23583259_T14",
"type": "CHEMICAL",
"text": [
"delavirdine"
],
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[
1859,
1870
]
],
"normalized": []
},
{
"id": "23583259_T15",
"type": "CHEMICAL",
"text": [
"Pregnane"
],
"offsets": [
[
378,
386
]
],
"normalized": []
},
{
"id": "23583259_T16",
"type": "CHEMICAL",
"text": [
"rilpivirine"
],
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[
590,
601
]
],
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},
{
"id": "23583259_T17",
"type": "CHEMICAL",
"text": [
"etravirine"
],
"offsets": [
[
606,
616
]
],
"normalized": []
},
{
"id": "23583259_T18",
"type": "CHEMICAL",
"text": [
"nucleoside"
],
"offsets": [
[
203,
213
]
],
"normalized": []
},
{
"id": "23583259_T19",
"type": "CHEMICAL",
"text": [
"efavirenz"
],
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[
718,
727
]
],
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},
{
"id": "23583259_T20",
"type": "CHEMICAL",
"text": [
"nevirapine"
],
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[
729,
739
]
],
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},
{
"id": "23583259_T21",
"type": "CHEMICAL",
"text": [
"delavirdine"
],
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[
745,
756
]
],
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},
{
"id": "23583259_T22",
"type": "CHEMICAL",
"text": [
"nucleoside"
],
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[
789,
799
]
],
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},
{
"id": "23583259_T23",
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"text": [
"rilpivirine"
],
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[
874,
885
]
],
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},
{
"id": "23583259_T24",
"type": "CHEMICAL",
"text": [
"etravirine"
],
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[
887,
897
]
],
"normalized": []
},
{
"id": "23583259_T25",
"type": "CHEMICAL",
"text": [
"efavirenz"
],
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[
903,
912
]
],
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},
{
"id": "23583259_T26",
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"text": [
"nevirapine"
],
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[
922,
932
]
],
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},
{
"id": "23583259_T27",
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"text": [
"delavirdine"
],
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[
936,
947
]
],
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},
{
"id": "23583259_T28",
"type": "CHEMICAL",
"text": [
"rilpivirine"
],
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[
1034,
1045
]
],
"normalized": []
},
{
"id": "23583259_T29",
"type": "CHEMICAL",
"text": [
"etravirine"
],
"offsets": [
[
1047,
1057
]
],
"normalized": []
},
{
"id": "23583259_T30",
"type": "CHEMICAL",
"text": [
"efavirenz"
],
"offsets": [
[
1063,
1072
]
],
"normalized": []
},
{
"id": "23583259_T31",
"type": "CHEMICAL",
"text": [
"nevirapine"
],
"offsets": [
[
1082,
1092
]
],
"normalized": []
},
{
"id": "23583259_T32",
"type": "CHEMICAL",
"text": [
"delavirdine"
],
"offsets": [
[
1096,
1107
]
],
"normalized": []
},
{
"id": "23583259_T33",
"type": "CHEMICAL",
"text": [
"nucleoside"
],
"offsets": [
[
105,
115
]
],
"normalized": []
},
{
"id": "23583259_T34",
"type": "CHEMICAL",
"text": [
"pregnane"
],
"offsets": [
[
17,
25
]
],
"normalized": []
},
{
"id": "23583259_T35",
"type": "CHEMICAL",
"text": [
"rilpivirine"
],
"offsets": [
[
40,
51
]
],
"normalized": []
},
{
"id": "23583259_T36",
"type": "CHEMICAL",
"text": [
"etravirine"
],
"offsets": [
[
56,
66
]
],
"normalized": []
},
{
"id": "23583259_T37",
"type": "GENE-Y",
"text": [
"hPXR"
],
"offsets": [
[
1365,
1369
]
],
"normalized": []
},
{
"id": "23583259_T38",
"type": "GENE-Y",
"text": [
"steroid receptor coactivator-1"
],
"offsets": [
[
1420,
1450
]
],
"normalized": []
},
{
"id": "23583259_T39",
"type": "GENE-Y",
"text": [
"SRC-1"
],
"offsets": [
[
1452,
1457
]
],
"normalized": []
},
{
"id": "23583259_T40",
"type": "GENE-Y",
"text": [
"SRC-2"
],
"offsets": [
[
1460,
1465
]
],
"normalized": []
},
{
"id": "23583259_T41",
"type": "GENE-Y",
"text": [
"SRC-3"
],
"offsets": [
[
1471,
1476
]
],
"normalized": []
},
{
"id": "23583259_T42",
"type": "GENE-Y",
"text": [
"hPXR"
],
"offsets": [
[
1480,
1484
]
],
"normalized": []
},
{
"id": "23583259_T43",
"type": "GENE-Y",
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399,
402
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{
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438,
455
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{
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636,
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{
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{
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116,
137
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}
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"arg2_id": "23583259_T42",
"normalized": []
}
] |
23234271 | 23234271 | [
{
"id": "23234271_title",
"type": "title",
"text": [
"Design and synthesis of diazatricyclodecane agonists of the G-protein-coupled receptor 119."
],
"offsets": [
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0,
91
]
]
},
{
"id": "23234271_abstract",
"type": "abstract",
"text": [
"A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1∼3,7∼]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Löffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the \"agonist conformation\" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules."
],
"offsets": [
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92,
1068
]
]
}
] | [
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288,
302
]
],
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},
{
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],
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131,
168
]
],
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},
{
"id": "23234271_T3",
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],
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559,
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]
],
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"id": "23234271_T4",
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610,
619
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637,
650
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24,
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104,
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"G-protein-coupled receptor 119"
],
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60,
90
]
],
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}
] | [] | [] | [
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}
] |
8469910 | 8469910 | [
{
"id": "8469910_title",
"type": "title",
"text": [
"Inhibitors of the arachidonic acid metabolism attenuate the thyroliberin (TRH) stimulated prolactin production without modifying the production of inositolphosphates in GH4C1 pituitary cells."
],
"offsets": [
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0,
191
]
]
},
{
"id": "8469910_abstract",
"type": "abstract",
"text": [
"Some arachidonic acid metabolites might be among the intracellular signalling substances that regulate hormone release. We report that the phospholipase A2 and diacylglycerol lipase inhibitor quinacrine (1-10 mumol l-1) inhibited the thyroliberin stimulated prolactin (rPRL) production in a dose-dependent way in a rat pituitary tumour cell line (GH4Cl cells). The lipoxygenase inhibitor nafazatrom (5-50 mumol-1) also dose-dependently inhibited the thyroliberin stimulated rPRL production, while the cyclo-oxygenase inhibitor indomethacin had no such effect on rPRL production. The inhibitors of the arachidonic acid metabolism (quinacrine, ETYA and nafazatrom) had no effect on the accumulation of inositolpolyphosphates indicating that the arachidonic acid metabolites are not involved in the regulation of the phospholipase C activity."
],
"offsets": [
[
192,
1031
]
]
}
] | [
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],
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352,
366
]
],
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},
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384,
394
]
],
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},
{
"id": "8469910_T3",
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426,
438
]
],
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},
{
"id": "8469910_T4",
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580,
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]
],
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},
{
"id": "8469910_T5",
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],
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642,
654
]
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"id": "8469910_T6",
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197,
213
]
],
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"id": "8469910_T7",
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719,
731
]
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"id": "8469910_T8",
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793,
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822,
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"ETYA"
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834,
838
]
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[
843,
853
]
],
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[
892,
914
]
],
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"id": "8469910_T13",
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935,
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],
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"id": "8469910_T14",
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"text": [
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],
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[
147,
165
]
],
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{
"id": "8469910_T15",
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"arachidonic acid"
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[
18,
34
]
],
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"id": "8469910_T16",
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"thyroliberin"
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[
60,
72
]
],
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"id": "8469910_T17",
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"TRH"
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74,
77
]
],
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},
{
"id": "8469910_T18",
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"text": [
"phospholipase A2"
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[
331,
347
]
],
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},
{
"id": "8469910_T19",
"type": "GENE-N",
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"diacylglycerol lipase"
],
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[
352,
373
]
],
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},
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"id": "8469910_T20",
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"thyroliberin"
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426,
438
]
],
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},
{
"id": "8469910_T21",
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"prolactin"
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[
450,
459
]
],
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},
{
"id": "8469910_T22",
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"rPRL"
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461,
465
]
],
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},
{
"id": "8469910_T23",
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"lipoxygenase"
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557,
569
]
],
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},
{
"id": "8469910_T24",
"type": "GENE-Y",
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"thyroliberin"
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[
642,
654
]
],
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},
{
"id": "8469910_T25",
"type": "GENE-Y",
"text": [
"rPRL"
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[
666,
670
]
],
"normalized": []
},
{
"id": "8469910_T26",
"type": "GENE-N",
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"cyclo-oxygenase"
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[
693,
708
]
],
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},
{
"id": "8469910_T27",
"type": "GENE-Y",
"text": [
"rPRL"
],
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[
754,
758
]
],
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},
{
"id": "8469910_T28",
"type": "GENE-N",
"text": [
"phospholipase C"
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[
1006,
1021
]
],
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},
{
"id": "8469910_T29",
"type": "GENE-Y",
"text": [
"thyroliberin"
],
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[
60,
72
]
],
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},
{
"id": "8469910_T30",
"type": "GENE-Y",
"text": [
"TRH"
],
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[
74,
77
]
],
"normalized": []
},
{
"id": "8469910_T31",
"type": "GENE-Y",
"text": [
"prolactin"
],
"offsets": [
[
90,
99
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "8469910_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "8469910_T16",
"arg2_id": "8469910_T31",
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},
{
"id": "8469910_1",
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},
{
"id": "8469910_2",
"type": "INHIBITOR",
"arg1_id": "8469910_T2",
"arg2_id": "8469910_T18",
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},
{
"id": "8469910_3",
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},
{
"id": "8469910_4",
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"arg2_id": "8469910_T20",
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},
{
"id": "8469910_5",
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"arg2_id": "8469910_T21",
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},
{
"id": "8469910_6",
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"arg2_id": "8469910_T22",
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},
{
"id": "8469910_7",
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"arg2_id": "8469910_T23",
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},
{
"id": "8469910_8",
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"arg2_id": "8469910_T24",
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},
{
"id": "8469910_9",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "8469910_T4",
"arg2_id": "8469910_T25",
"normalized": []
},
{
"id": "8469910_10",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "8469910_T2",
"arg2_id": "8469910_T21",
"normalized": []
},
{
"id": "8469910_11",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "8469910_T2",
"arg2_id": "8469910_T22",
"normalized": []
},
{
"id": "8469910_12",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "8469910_T5",
"arg2_id": "8469910_T25",
"normalized": []
},
{
"id": "8469910_13",
"type": "INHIBITOR",
"arg1_id": "8469910_T7",
"arg2_id": "8469910_T26",
"normalized": []
}
] |
10411647 | 10411647 | [
{
"id": "10411647_title",
"type": "title",
"text": [
"Tyrosine hydroxylase binds tetrahydrobiopterin cofactor with negative cooperativity, as shown by kinetic analyses and surface plasmon resonance detection."
],
"offsets": [
[
0,
154
]
]
},
{
"id": "10411647_abstract",
"type": "abstract",
"text": [
"Kinetic studies of tetrameric recombinant human tyrosine hydroxylase isoform 1 (hTH1) have revealed properties so far not reported for this enzyme. Firstly, with the natural cofactor (6R)-Lerythro-5,6,7, 8-tetrahydrobiopterin (H4biopterin) a time-dependent change (burst) in enzyme activity was observed, with a half-time of about 20 s for the kinetic transient. Secondly, nonhyperbolic saturation behaviour was found for H4biopterin with a pronounced negative cooperativity (0.39 < h < 0.58; [S]0.5 = 24 +/- 4 microM). On phosphorylation of Ser40 by protein kinase A, the affinity for H4biopterin increased ([S]0.5 = 11 +/- 2 microM) and the negative cooperativity was amplified (h = 0.27 +/- 0.03). The dimeric C-terminal deletion mutant (Delta473-528) of hTH1 also showed negative cooperativity of H4biopterin binding (h = 0.4). Cooperativity was not observed with the cofactor analogues 6-methyl-5,6,7,8-tetrahydropterin (h = 0.9 +/- 0.1; Km = 62.7 +/- 5.7 microM) and 3-methyl-5,6,7, 8-tetrahydropterin (H43-methyl-pterin)(h = 1.0 +/- 0.1; Km = 687 +/- 50 microM). In the presence of 1 mM H43-methyl-pterin, used as a competitive cofactor analogue to BH4, hyperbolic saturation curves were also found for H4biopterin (h = 1.0), thus confirming the genuine nature of the kinetic negative cooperativity. This cooperativity was confirmed by real-time biospecific interaction analysis by surface plasmon resonance detection. The equilibrium binding of H4biopterin to the immobilized iron-free apoenzyme results in a saturable positive resonance unit (DeltaRU) response with negative cooperativity (h = 0.52-0.56). Infrared spectroscopic studies revealed a reduced thermal stability both of the apo-and the holo-hTH1 on binding of H4biopterin and Lerythro-dihydrobiopterin (H2biopterin). Moreover, the ligand-bound forms of the enzyme also showed a decreased resistance to limited tryptic proteolysis. These findings indicate that the binding of H4biopterin at the active site induces a destabilizing conformational change in the enzyme which could be related to the observed negative cooperativity. Thus, our studies provide new insight into the regulation of TH by the concentration of H4biopterin which may have significant implications for the physiological regulation of catecholamine biosynthesis in neuroendocrine cells."
],
"offsets": [
[
155,
2482
]
]
}
] | [
{
"id": "10411647_T1",
"type": "CHEMICAL",
"text": [
"H43-methyl-pterin"
],
"offsets": [
[
1164,
1181
]
],
"normalized": []
},
{
"id": "10411647_T2",
"type": "CHEMICAL",
"text": [
"H43-methyl-pterin"
],
"offsets": [
[
1249,
1266
]
],
"normalized": []
},
{
"id": "10411647_T3",
"type": "CHEMICAL",
"text": [
"H4biopterin"
],
"offsets": [
[
1365,
1376
]
],
"normalized": []
},
{
"id": "10411647_T4",
"type": "CHEMICAL",
"text": [
"H4biopterin"
],
"offsets": [
[
1608,
1619
]
],
"normalized": []
},
{
"id": "10411647_T5",
"type": "CHEMICAL",
"text": [
"H4biopterin"
],
"offsets": [
[
1886,
1897
]
],
"normalized": []
},
{
"id": "10411647_T6",
"type": "CHEMICAL",
"text": [
"Lerythro-dihydrobiopterin"
],
"offsets": [
[
1902,
1927
]
],
"normalized": []
},
{
"id": "10411647_T7",
"type": "CHEMICAL",
"text": [
"H2biopterin"
],
"offsets": [
[
1929,
1940
]
],
"normalized": []
},
{
"id": "10411647_T8",
"type": "CHEMICAL",
"text": [
"(6R)-Lerythro-5,6,7, 8-tetrahydrobiopterin"
],
"offsets": [
[
338,
380
]
],
"normalized": []
},
{
"id": "10411647_T9",
"type": "CHEMICAL",
"text": [
"H4biopterin"
],
"offsets": [
[
2101,
2112
]
],
"normalized": []
},
{
"id": "10411647_T10",
"type": "CHEMICAL",
"text": [
"H4biopterin"
],
"offsets": [
[
2343,
2354
]
],
"normalized": []
},
{
"id": "10411647_T11",
"type": "CHEMICAL",
"text": [
"H4biopterin"
],
"offsets": [
[
382,
393
]
],
"normalized": []
},
{
"id": "10411647_T12",
"type": "CHEMICAL",
"text": [
"catecholamine"
],
"offsets": [
[
2431,
2444
]
],
"normalized": []
},
{
"id": "10411647_T13",
"type": "CHEMICAL",
"text": [
"H4biopterin"
],
"offsets": [
[
577,
588
]
],
"normalized": []
},
{
"id": "10411647_T14",
"type": "CHEMICAL",
"text": [
"tyrosine"
],
"offsets": [
[
203,
211
]
],
"normalized": []
},
{
"id": "10411647_T15",
"type": "CHEMICAL",
"text": [
"Ser40"
],
"offsets": [
[
697,
702
]
],
"normalized": []
},
{
"id": "10411647_T16",
"type": "CHEMICAL",
"text": [
"H4biopterin"
],
"offsets": [
[
741,
752
]
],
"normalized": []
},
{
"id": "10411647_T17",
"type": "CHEMICAL",
"text": [
"C"
],
"offsets": [
[
868,
869
]
],
"normalized": []
},
{
"id": "10411647_T18",
"type": "CHEMICAL",
"text": [
"H4biopterin"
],
"offsets": [
[
956,
967
]
],
"normalized": []
},
{
"id": "10411647_T19",
"type": "CHEMICAL",
"text": [
"6-methyl-5,6,7,8-tetrahydropterin"
],
"offsets": [
[
1046,
1079
]
],
"normalized": []
},
{
"id": "10411647_T20",
"type": "CHEMICAL",
"text": [
"3-methyl-5,6,7, 8-tetrahydropterin"
],
"offsets": [
[
1128,
1162
]
],
"normalized": []
},
{
"id": "10411647_T21",
"type": "CHEMICAL",
"text": [
"Tyrosine"
],
"offsets": [
[
0,
8
]
],
"normalized": []
},
{
"id": "10411647_T22",
"type": "CHEMICAL",
"text": [
"tetrahydrobiopterin"
],
"offsets": [
[
27,
46
]
],
"normalized": []
},
{
"id": "10411647_T23",
"type": "GENE-Y",
"text": [
"hTH1"
],
"offsets": [
[
1867,
1871
]
],
"normalized": []
},
{
"id": "10411647_T24",
"type": "GENE-Y",
"text": [
"TH"
],
"offsets": [
[
2316,
2318
]
],
"normalized": []
},
{
"id": "10411647_T25",
"type": "GENE-Y",
"text": [
"human tyrosine hydroxylase isoform 1"
],
"offsets": [
[
197,
233
]
],
"normalized": []
},
{
"id": "10411647_T26",
"type": "GENE-N",
"text": [
"protein kinase A"
],
"offsets": [
[
706,
722
]
],
"normalized": []
},
{
"id": "10411647_T27",
"type": "GENE-Y",
"text": [
"hTH1"
],
"offsets": [
[
913,
917
]
],
"normalized": []
},
{
"id": "10411647_T28",
"type": "GENE-Y",
"text": [
"hTH1"
],
"offsets": [
[
235,
239
]
],
"normalized": []
},
{
"id": "10411647_T29",
"type": "GENE-Y",
"text": [
"Tyrosine hydroxylase"
],
"offsets": [
[
0,
20
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "10411647_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "10411647_T22",
"arg2_id": "10411647_T29",
"normalized": []
},
{
"id": "10411647_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "10411647_T16",
"arg2_id": "10411647_T26",
"normalized": []
},
{
"id": "10411647_2",
"type": "PART-OF",
"arg1_id": "10411647_T17",
"arg2_id": "10411647_T27",
"normalized": []
},
{
"id": "10411647_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "10411647_T5",
"arg2_id": "10411647_T23",
"normalized": []
},
{
"id": "10411647_4",
"type": "DIRECT-REGULATOR",
"arg1_id": "10411647_T6",
"arg2_id": "10411647_T23",
"normalized": []
},
{
"id": "10411647_5",
"type": "DIRECT-REGULATOR",
"arg1_id": "10411647_T7",
"arg2_id": "10411647_T23",
"normalized": []
},
{
"id": "10411647_6",
"type": "SUBSTRATE",
"arg1_id": "10411647_T15",
"arg2_id": "10411647_T26",
"normalized": []
}
] |
23149657 | 23149657 | [
{
"id": "23149657_title",
"type": "title",
"text": [
"Short duration of diabetes and disuse of sulfonylurea have any association with insulin cessation of the patients with type 2 diabetes in a clinical setting in Japan (JDDM 30)."
],
"offsets": [
[
0,
176
]
]
},
{
"id": "23149657_abstract",
"type": "abstract",
"text": [
"Insulin therapy is often required to achieve good glycemic control for the patients with type 2 diabetes mellitus (T2DM), while protraction of glycemic control without insulin therapy may be preferable for patients. To determine the characteristics of and therapeutic regimen in outpatients with T2DM who were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan by a case-control study. The present study was performed on 928 patients with T2DM who started insulin therapy in 2007. Data regarding age, sex, body mass index, duration of diabetes, HbA1c, postprandial plasma glucose, plasma fasting C-peptide immunoreactivity and treatment modality were compared between patients who were able to stop insulin therapy and those who continued with insulin. Of the 928 patients, 37 had stopped insulin therapy within 1 year. In the patients who stopped insulin therapy, the duration of diabetes was significantly shorter and the daily insulin dosage at initiation and the prevalence of sulfonylurea pretreatment significantly lower compared with patients who continued on insulin. In conclusion, almost 4% of T2DM patients were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan. Shorter duration of diabetes and disuse of sulfonylureas prior to insulin may associate with stopping insulin therapy as a near-normoglycemic remission in outpatients with T2DM in Japan."
],
"offsets": [
[
177,
1654
]
]
}
] | [
{
"id": "23149657_T1",
"type": "CHEMICAL",
"text": [
"sulfonylurea"
],
"offsets": [
[
1216,
1228
]
],
"normalized": []
},
{
"id": "23149657_T2",
"type": "CHEMICAL",
"text": [
"sulfonylureas"
],
"offsets": [
[
1511,
1524
]
],
"normalized": []
},
{
"id": "23149657_T3",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
807,
814
]
],
"normalized": []
},
{
"id": "23149657_T4",
"type": "CHEMICAL",
"text": [
"sulfonylurea"
],
"offsets": [
[
41,
53
]
],
"normalized": []
},
{
"id": "23149657_T5",
"type": "GENE-N",
"text": [
"Insulin"
],
"offsets": [
[
177,
184
]
],
"normalized": []
},
{
"id": "23149657_T6",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1302,
1309
]
],
"normalized": []
},
{
"id": "23149657_T7",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1371,
1378
]
],
"normalized": []
},
{
"id": "23149657_T8",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1570,
1577
]
],
"normalized": []
},
{
"id": "23149657_T9",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
345,
352
]
],
"normalized": []
},
{
"id": "23149657_T10",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
500,
507
]
],
"normalized": []
},
{
"id": "23149657_T11",
"type": "GENE-N",
"text": [
"HbA1c"
],
"offsets": [
[
780,
785
]
],
"normalized": []
},
{
"id": "23149657_T12",
"type": "GENE-N",
"text": [
"C-peptide"
],
"offsets": [
[
831,
840
]
],
"normalized": []
},
{
"id": "23149657_T13",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
934,
941
]
],
"normalized": []
},
{
"id": "23149657_T14",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
979,
986
]
],
"normalized": []
},
{
"id": "23149657_T15",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1024,
1031
]
],
"normalized": []
},
{
"id": "23149657_T16",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1083,
1090
]
],
"normalized": []
},
{
"id": "23149657_T17",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
1165,
1172
]
],
"normalized": []
},
{
"id": "23149657_T18",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
80,
87
]
],
"normalized": []
}
] | [] | [] | [] |
23214926 | 23214926 | [
{
"id": "23214926_title",
"type": "title",
"text": [
"Total synthesis of AMF-26, an antitumor agent for inhibition of the Golgi system, targeting ADP-ribosylation factor 1."
],
"offsets": [
[
0,
118
]
]
},
{
"id": "23214926_abstract",
"type": "abstract",
"text": [
"An effective method for the total synthesis of 1 (AMF-26), a potentially promising new anticancer drug that disrupts the Golgi system by inhibiting the ADP-ribosylation factor 1 (Arf1) activation, has been developed for the first time. The construction of the chiral linear precursor (a key to the synthesis) was achieved by the asymmetric aldol reaction followed by the computer-assisted predictive stereoselective intramolecular Diels-Alder reaction. The global antitumor activity of the totally synthetic 1 against a variety of human cancer cells was assessed using a panel of 39 human cancer cell lines (JFCR39), and it was shown that the synthetic 1 strongly inhibited the growth of several cancer cell lines at concentrations of less than 0.04 μM. Biological assays of novel derivatives, 26 and 31, which have different side-chains at the C-4 positions in the Δ¹,²-octalin backbone, disclosed the importance of the suitable structure of the side-chain containing conjugated multidouble bonds."
],
"offsets": [
[
119,
1117
]
]
}
] | [
{
"id": "23214926_T1",
"type": "CHEMICAL",
"text": [
"ADP"
],
"offsets": [
[
271,
274
]
],
"normalized": []
},
{
"id": "23214926_T2",
"type": "CHEMICAL",
"text": [
"AMF-26"
],
"offsets": [
[
169,
175
]
],
"normalized": []
},
{
"id": "23214926_T3",
"type": "CHEMICAL",
"text": [
"Δ¹,²-octalin"
],
"offsets": [
[
985,
997
]
],
"normalized": []
},
{
"id": "23214926_T4",
"type": "CHEMICAL",
"text": [
"AMF-26"
],
"offsets": [
[
19,
25
]
],
"normalized": []
},
{
"id": "23214926_T5",
"type": "CHEMICAL",
"text": [
"ADP"
],
"offsets": [
[
92,
95
]
],
"normalized": []
},
{
"id": "23214926_T6",
"type": "GENE-Y",
"text": [
"ADP-ribosylation factor 1"
],
"offsets": [
[
271,
296
]
],
"normalized": []
},
{
"id": "23214926_T7",
"type": "GENE-Y",
"text": [
"Arf1"
],
"offsets": [
[
298,
302
]
],
"normalized": []
},
{
"id": "23214926_T8",
"type": "GENE-Y",
"text": [
"ADP-ribosylation factor 1"
],
"offsets": [
[
92,
117
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23214926_0",
"type": "INHIBITOR",
"arg1_id": "23214926_T2",
"arg2_id": "23214926_T6",
"normalized": []
},
{
"id": "23214926_1",
"type": "INHIBITOR",
"arg1_id": "23214926_T2",
"arg2_id": "23214926_T7",
"normalized": []
}
] |
23537574 | 23537574 | [
{
"id": "23537574_title",
"type": "title",
"text": [
"Amino acids as co-amorphous stabilizers for poorly water soluble drugs - Part 1: Preparation, stability and dissolution enhancement."
],
"offsets": [
[
0,
132
]
]
},
{
"id": "23537574_abstract",
"type": "abstract",
"text": [
"Poor aqueous solubility of an active pharmaceutical ingredient (API) is one of the most pressing problems in pharmaceutical research and development because up to 90% of new API candidates under development are poorly water soluble. These drugs usually have a low and variable oral bioavailability, and therefore an unsatisfactory therapeutic effect. One of the most promising approaches to increase dissolution rate and solubility of these drugs is the conversion of a crystalline form of the drug into its respective amorphous form, usually by incorporation into hydrophilic polymers, forming glass solutions. However, this strategy only led to a small number of marketed products usually because of inadequate physical stability of the drug (crystallization). In this study, we investigated a fundamentally different approach to stabilize the amorphous form of drugs, namely the use of amino acids as small molecular weight excipients that form specific molecular interactions with the drug resulting in co-amorphous forms. The two poorly water soluble drugs carbamazepine and indomethacin were combined with amino acids from the binding sites of the biological receptors of these drugs. Mixtures of drug and the amino acids arginine, phenylalanine, tryptophan and tyrosine were prepared by vibrational ball milling. Solid-state characterization with X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) revealed that the various blends could be prepared as homogeneous, single phase co-amorphous formulations indicated by the appearance of an amorphous halo in the XRPD diffractograms and a single glass transition temperature (Tg) in the DSC measurements. In addition, the Tgs of the co-amorphous mixtures were significantly increased over those of the individual drugs. The drugs remained chemically stable during the milling process and the co-amorphous formulations were generally physically stable over at least 6months at 40°C under dry conditions. The dissolution rate of all co-amorphous drug-amino acid mixtures was significantly increased over that of the respective crystalline and amorphous pure drugs. Amino acids thus appear as promising excipients to solve challenges connected with the stability and dissolution of amorphous drugs."
],
"offsets": [
[
133,
2407
]
]
}
] | [
{
"id": "23537574_T1",
"type": "CHEMICAL",
"text": [
"carbamazepine"
],
"offsets": [
[
1195,
1208
]
],
"normalized": []
},
{
"id": "23537574_T2",
"type": "CHEMICAL",
"text": [
"indomethacin"
],
"offsets": [
[
1213,
1225
]
],
"normalized": []
},
{
"id": "23537574_T3",
"type": "CHEMICAL",
"text": [
"amino acids"
],
"offsets": [
[
1245,
1256
]
],
"normalized": []
},
{
"id": "23537574_T4",
"type": "CHEMICAL",
"text": [
"amino acids"
],
"offsets": [
[
1349,
1360
]
],
"normalized": []
},
{
"id": "23537574_T5",
"type": "CHEMICAL",
"text": [
"arginine"
],
"offsets": [
[
1361,
1369
]
],
"normalized": []
},
{
"id": "23537574_T6",
"type": "CHEMICAL",
"text": [
"phenylalanine"
],
"offsets": [
[
1371,
1384
]
],
"normalized": []
},
{
"id": "23537574_T7",
"type": "CHEMICAL",
"text": [
"tryptophan"
],
"offsets": [
[
1386,
1396
]
],
"normalized": []
},
{
"id": "23537574_T8",
"type": "CHEMICAL",
"text": [
"tyrosine"
],
"offsets": [
[
1401,
1409
]
],
"normalized": []
},
{
"id": "23537574_T9",
"type": "CHEMICAL",
"text": [
"amino acid"
],
"offsets": [
[
2161,
2171
]
],
"normalized": []
},
{
"id": "23537574_T10",
"type": "CHEMICAL",
"text": [
"Amino acids"
],
"offsets": [
[
2275,
2286
]
],
"normalized": []
},
{
"id": "23537574_T11",
"type": "CHEMICAL",
"text": [
"amino acids"
],
"offsets": [
[
1022,
1033
]
],
"normalized": []
},
{
"id": "23537574_T12",
"type": "CHEMICAL",
"text": [
"Amino acids"
],
"offsets": [
[
0,
11
]
],
"normalized": []
}
] | [] | [] | [] |
23252711 | 23252711 | [
{
"id": "23252711_title",
"type": "title",
"text": [
"Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity."
],
"offsets": [
[
0,
165
]
]
},
{
"id": "23252711_abstract",
"type": "abstract",
"text": [
"Cyclin-dependent kinase 9/cyclin T, the protein kinase heterodimer that constitutes positive transcription elongation factor b, is a well-validated target for treatment of several diseases, including cancer and cardiac hypertrophy. In order to aid inhibitor design and rationalize the basis for CDK9 selectivity, we have studied the CDK-binding properties of six different members of a 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series that bind to both CDK9/cyclin T and CDK2/cyclin A. We find that for a given CDK, the melting temperature of a CDK/cyclin/inhibitor complex correlates well with inhibitor potency, suggesting that differential scanning fluorimetry (DSF) is a useful orthogonal measure of inhibitory activity for this series. We have used DSF to demonstrate that the binding of these compounds is independent of the presence or absence of the C-terminal tail region of CDK9, unlike the binding of the CDK9-selective inhibitor 5,6-dichlorobenzimidazone-1-β-d-ribofuranoside (DRB). Finally, on the basis of 11 cocrystal structures bound to CDK9/cyclin T or CDK2/cyclin A, we conclude that selective inhibition of CDK9/cyclin T by members of the 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series results from the relative malleability of the CDK9 active site rather than from the formation of specific polar contacts."
],
"offsets": [
[
166,
1526
]
]
}
] | [
{
"id": "23252711_T1",
"type": "CHEMICAL",
"text": [
"DRB"
],
"offsets": [
[
1171,
1174
]
],
"normalized": []
},
{
"id": "23252711_T2",
"type": "CHEMICAL",
"text": [
"4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile"
],
"offsets": [
[
1340,
1397
]
],
"normalized": []
},
{
"id": "23252711_T3",
"type": "CHEMICAL",
"text": [
"4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile"
],
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[
552,
609
]
],
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"id": "23252711_T4",
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"text": [
"C"
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[
1040,
1041
]
],
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},
{
"id": "23252711_T5",
"type": "CHEMICAL",
"text": [
"5,6-dichlorobenzimidazone-1-β-d-ribofuranoside"
],
"offsets": [
[
1123,
1169
]
],
"normalized": []
},
{
"id": "23252711_T6",
"type": "CHEMICAL",
"text": [
"4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile"
],
"offsets": [
[
49,
106
]
],
"normalized": []
},
{
"id": "23252711_T7",
"type": "GENE-Y",
"text": [
"Cyclin-dependent kinase 9"
],
"offsets": [
[
166,
191
]
],
"normalized": []
},
{
"id": "23252711_T8",
"type": "GENE-Y",
"text": [
"CDK9"
],
"offsets": [
[
1235,
1239
]
],
"normalized": []
},
{
"id": "23252711_T9",
"type": "GENE-Y",
"text": [
"cyclin T"
],
"offsets": [
[
1240,
1248
]
],
"normalized": []
},
{
"id": "23252711_T10",
"type": "GENE-Y",
"text": [
"CDK2"
],
"offsets": [
[
1252,
1256
]
],
"normalized": []
},
{
"id": "23252711_T11",
"type": "GENE-Y",
"text": [
"cyclin A"
],
"offsets": [
[
1257,
1265
]
],
"normalized": []
},
{
"id": "23252711_T12",
"type": "GENE-Y",
"text": [
"CDK9"
],
"offsets": [
[
1308,
1312
]
],
"normalized": []
},
{
"id": "23252711_T13",
"type": "GENE-Y",
"text": [
"cyclin T"
],
"offsets": [
[
1313,
1321
]
],
"normalized": []
},
{
"id": "23252711_T14",
"type": "GENE-Y",
"text": [
"CDK9"
],
"offsets": [
[
1451,
1455
]
],
"normalized": []
},
{
"id": "23252711_T15",
"type": "GENE-Y",
"text": [
"cyclin T"
],
"offsets": [
[
192,
200
]
],
"normalized": []
},
{
"id": "23252711_T16",
"type": "GENE-Y",
"text": [
"CDK9"
],
"offsets": [
[
461,
465
]
],
"normalized": []
},
{
"id": "23252711_T17",
"type": "GENE-N",
"text": [
"CDK"
],
"offsets": [
[
499,
502
]
],
"normalized": []
},
{
"id": "23252711_T18",
"type": "GENE-N",
"text": [
"protein kinase"
],
"offsets": [
[
206,
220
]
],
"normalized": []
},
{
"id": "23252711_T19",
"type": "GENE-Y",
"text": [
"CDK9"
],
"offsets": [
[
635,
639
]
],
"normalized": []
},
{
"id": "23252711_T20",
"type": "GENE-Y",
"text": [
"cyclin T"
],
"offsets": [
[
640,
648
]
],
"normalized": []
},
{
"id": "23252711_T21",
"type": "GENE-Y",
"text": [
"CDK2"
],
"offsets": [
[
653,
657
]
],
"normalized": []
},
{
"id": "23252711_T22",
"type": "GENE-Y",
"text": [
"cyclin A"
],
"offsets": [
[
658,
666
]
],
"normalized": []
},
{
"id": "23252711_T23",
"type": "GENE-N",
"text": [
"CDK"
],
"offsets": [
[
693,
696
]
],
"normalized": []
},
{
"id": "23252711_T24",
"type": "GENE-N",
"text": [
"CDK"
],
"offsets": [
[
727,
730
]
],
"normalized": []
},
{
"id": "23252711_T25",
"type": "GENE-N",
"text": [
"cyclin"
],
"offsets": [
[
731,
737
]
],
"normalized": []
},
{
"id": "23252711_T26",
"type": "GENE-Y",
"text": [
"positive transcription elongation factor b"
],
"offsets": [
[
250,
292
]
],
"normalized": []
},
{
"id": "23252711_T27",
"type": "GENE-N",
"text": [
"C-terminal tail region"
],
"offsets": [
[
1040,
1062
]
],
"normalized": []
},
{
"id": "23252711_T28",
"type": "GENE-Y",
"text": [
"CDK9"
],
"offsets": [
[
1066,
1070
]
],
"normalized": []
},
{
"id": "23252711_T29",
"type": "GENE-Y",
"text": [
"CDK9"
],
"offsets": [
[
1098,
1102
]
],
"normalized": []
},
{
"id": "23252711_T30",
"type": "GENE-Y",
"text": [
"CDK9"
],
"offsets": [
[
107,
111
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23252711_0",
"type": "INHIBITOR",
"arg1_id": "23252711_T6",
"arg2_id": "23252711_T30",
"normalized": []
},
{
"id": "23252711_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "23252711_T3",
"arg2_id": "23252711_T17",
"normalized": []
},
{
"id": "23252711_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "23252711_T3",
"arg2_id": "23252711_T19",
"normalized": []
},
{
"id": "23252711_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "23252711_T3",
"arg2_id": "23252711_T20",
"normalized": []
},
{
"id": "23252711_4",
"type": "DIRECT-REGULATOR",
"arg1_id": "23252711_T3",
"arg2_id": "23252711_T21",
"normalized": []
},
{
"id": "23252711_5",
"type": "DIRECT-REGULATOR",
"arg1_id": "23252711_T3",
"arg2_id": "23252711_T22",
"normalized": []
},
{
"id": "23252711_6",
"type": "PART-OF",
"arg1_id": "23252711_T4",
"arg2_id": "23252711_T28",
"normalized": []
},
{
"id": "23252711_7",
"type": "INHIBITOR",
"arg1_id": "23252711_T5",
"arg2_id": "23252711_T29",
"normalized": []
},
{
"id": "23252711_8",
"type": "INHIBITOR",
"arg1_id": "23252711_T1",
"arg2_id": "23252711_T29",
"normalized": []
},
{
"id": "23252711_9",
"type": "DIRECT-REGULATOR",
"arg1_id": "23252711_T5",
"arg2_id": "23252711_T29",
"normalized": []
},
{
"id": "23252711_10",
"type": "DIRECT-REGULATOR",
"arg1_id": "23252711_T1",
"arg2_id": "23252711_T29",
"normalized": []
},
{
"id": "23252711_11",
"type": "INHIBITOR",
"arg1_id": "23252711_T2",
"arg2_id": "23252711_T12",
"normalized": []
},
{
"id": "23252711_12",
"type": "INHIBITOR",
"arg1_id": "23252711_T2",
"arg2_id": "23252711_T13",
"normalized": []
},
{
"id": "23252711_13",
"type": "DIRECT-REGULATOR",
"arg1_id": "23252711_T2",
"arg2_id": "23252711_T14",
"normalized": []
}
] |
16199241 | 16199241 | [
{
"id": "16199241_title",
"type": "title",
"text": [
"Duloxetine hydrochloride: a new dual-acting medication for the treatment of major depressive disorder."
],
"offsets": [
[
0,
102
]
]
},
{
"id": "16199241_abstract",
"type": "abstract",
"text": [
"BACKGROUND: Duloxetine hydrochloride has recently been approved by the US Food and Drug Administration for the treatment of major depressive disorder (MDD). Duloxetine is a potent inhibitor of serotonin and norepinephrine reuptake, with weak effects on dopamine reuptake. OBJECTIVE: This article reviews the literature on duloxetine with regard to its pharmacodynamics, pharmacokinetics, clinical efficacy, and tolerability. METHODS: A comprehensive search of MEDLINE was performed using the terms duloxetine, Cymbalta, and major depressive disorder, with no restriction on year. The Eli Lilly and Company clinical trial registry, and abstracts and posters from recent American Psychiatric Association meetings were also reviewed. RESULTS: Duloxetine exhibits linear, dose-dependent pharmacokinetics across the approved oral dosage range of 40 to 60 mg/d. No dose adjustment appears to be needed based on age. Duloxetine has shown efficacy in reducing depressive symptoms compared with placebo, and duloxetine recipients have shown significant improvements in global functioning compared with placebo (both, P < 0.05). Response and remission rates have been comparable to or greater than those seen with fluoxetine or paroxetine. Duloxetine is generally well tolerated, with nausea, dry mouth, and fatigue being the most common treatment-emergent adverse effects. Cardiovascular adverse effects do not appear to result in sustained blood pressure elevations, QTc-interval prolongation, or other electrocardiographic changes. CONCLUSIONS: Based on the available evidence, duloxetine is a well-tolerated and effective treatment for MDD in adults. Randomized head-to-head comparisons against established antidepressants are needed to determine the relative safety and efficacy of duloxetine."
],
"offsets": [
[
103,
1891
]
]
}
] | [
{
"id": "16199241_T1",
"type": "CHEMICAL",
"text": [
"fluoxetine"
],
"offsets": [
[
1307,
1317
]
],
"normalized": []
},
{
"id": "16199241_T2",
"type": "CHEMICAL",
"text": [
"paroxetine"
],
"offsets": [
[
1321,
1331
]
],
"normalized": []
},
{
"id": "16199241_T3",
"type": "CHEMICAL",
"text": [
"Duloxetine"
],
"offsets": [
[
1333,
1343
]
],
"normalized": []
},
{
"id": "16199241_T4",
"type": "CHEMICAL",
"text": [
"Duloxetine hydrochloride"
],
"offsets": [
[
115,
139
]
],
"normalized": []
},
{
"id": "16199241_T5",
"type": "CHEMICAL",
"text": [
"duloxetine"
],
"offsets": [
[
1674,
1684
]
],
"normalized": []
},
{
"id": "16199241_T6",
"type": "CHEMICAL",
"text": [
"Duloxetine"
],
"offsets": [
[
260,
270
]
],
"normalized": []
},
{
"id": "16199241_T7",
"type": "CHEMICAL",
"text": [
"duloxetine"
],
"offsets": [
[
1880,
1890
]
],
"normalized": []
},
{
"id": "16199241_T8",
"type": "CHEMICAL",
"text": [
"serotonin"
],
"offsets": [
[
296,
305
]
],
"normalized": []
},
{
"id": "16199241_T9",
"type": "CHEMICAL",
"text": [
"norepinephrine"
],
"offsets": [
[
310,
324
]
],
"normalized": []
},
{
"id": "16199241_T10",
"type": "CHEMICAL",
"text": [
"dopamine"
],
"offsets": [
[
356,
364
]
],
"normalized": []
},
{
"id": "16199241_T11",
"type": "CHEMICAL",
"text": [
"duloxetine"
],
"offsets": [
[
425,
435
]
],
"normalized": []
},
{
"id": "16199241_T12",
"type": "CHEMICAL",
"text": [
"duloxetine"
],
"offsets": [
[
601,
611
]
],
"normalized": []
},
{
"id": "16199241_T13",
"type": "CHEMICAL",
"text": [
"Cymbalta"
],
"offsets": [
[
613,
621
]
],
"normalized": []
},
{
"id": "16199241_T14",
"type": "CHEMICAL",
"text": [
"Duloxetine"
],
"offsets": [
[
843,
853
]
],
"normalized": []
},
{
"id": "16199241_T15",
"type": "CHEMICAL",
"text": [
"Duloxetine"
],
"offsets": [
[
1013,
1023
]
],
"normalized": []
},
{
"id": "16199241_T16",
"type": "CHEMICAL",
"text": [
"Duloxetine hydrochloride"
],
"offsets": [
[
0,
24
]
],
"normalized": []
}
] | [] | [] | [] |
11401111 | 11401111 | [
{
"id": "11401111_title",
"type": "title",
"text": [
"Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group."
],
"offsets": [
[
0,
221
]
]
},
{
"id": "11401111_abstract",
"type": "abstract",
"text": [
"OBJECTIVES: We sought to assess plasma concentrations of the amino (N)-terminal portion of pro-brain natriuretic peptide (N-BNP) and adrenomedullin for prediction of adverse outcomes and responses to treatment in 297 patients with ischemic left ventricular (LV) dysfunction who were randomly assigned to receive carvedilol or placebo. BACKGROUND: Although neurohormonal status has known prognostic significance in heart failure, the predictive power of either N-BNP or adrenomedullin in chronic ischemic LV dysfunction has not been previously reported. METHODS: Plasma N-BNP and adrenomedullin were measured in 297 patients with chronic ischemic (LV) dysfunction before randomization to carvedilol or placebo, added to established treatment with a converting enzyme inhibitor and loop diuretic (with or without digoxin). The patients' clinical outcomes, induding mortality and heart failure events, were recorded for 18 months. RESULTS: Above-median N-BNP and adrenomedullin levels conferred increased risks (all p < 0.001) of mortality (risk ratios [95% confidence intervals]: 4.67 [2-10.9] and 3.92 [1.76-8.7], respectively) and hospital admission with heart failure (4.7 [2.2-10.3] and 2.4 [1.3-4.5], respectively). Both of these predicted death or heart failure independent of age, New York Heart Association functional class, LV ejection fraction, previous myocardial infarction or previous admission with heart failure. Carvedilol reduced the risk of death or heart failure in patients with above-median levels of N-BNP or adrenomedullin, or both, to rates not significantly different from those observed in patients with levels below the median value. CONCLUSIONS: In patients with established ischemic LV dysfunction, plasma N-BNP and adrenomedullin are independent predictors of mortality and heart failure. Carvedilol reduced mortality and heart failure in patients with higher pre-treatment plasma N-BNP and adrenomedullin."
],
"offsets": [
[
222,
2156
]
]
}
] | [
{
"id": "11401111_T1",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
344,
345
]
],
"normalized": []
},
{
"id": "11401111_T2",
"type": "CHEMICAL",
"text": [
"Carvedilol"
],
"offsets": [
[
1648,
1658
]
],
"normalized": []
},
{
"id": "11401111_T3",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
1742,
1743
]
],
"normalized": []
},
{
"id": "11401111_T4",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
1955,
1956
]
],
"normalized": []
},
{
"id": "11401111_T5",
"type": "CHEMICAL",
"text": [
"Carvedilol"
],
"offsets": [
[
2039,
2049
]
],
"normalized": []
},
{
"id": "11401111_T6",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
2131,
2132
]
],
"normalized": []
},
{
"id": "11401111_T7",
"type": "CHEMICAL",
"text": [
"carvedilol"
],
"offsets": [
[
534,
544
]
],
"normalized": []
},
{
"id": "11401111_T8",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
682,
683
]
],
"normalized": []
},
{
"id": "11401111_T9",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
791,
792
]
],
"normalized": []
},
{
"id": "11401111_T10",
"type": "CHEMICAL",
"text": [
"amino"
],
"offsets": [
[
283,
288
]
],
"normalized": []
},
{
"id": "11401111_T11",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
290,
291
]
],
"normalized": []
},
{
"id": "11401111_T12",
"type": "CHEMICAL",
"text": [
"carvedilol"
],
"offsets": [
[
909,
919
]
],
"normalized": []
},
{
"id": "11401111_T13",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
1172,
1173
]
],
"normalized": []
},
{
"id": "11401111_T14",
"type": "CHEMICAL",
"text": [
"carvedilol"
],
"offsets": [
[
118,
128
]
],
"normalized": []
},
{
"id": "11401111_T15",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
7,
8
]
],
"normalized": []
},
{
"id": "11401111_T16",
"type": "GENE-Y",
"text": [
"N-BNP"
],
"offsets": [
[
344,
349
]
],
"normalized": []
},
{
"id": "11401111_T17",
"type": "GENE-Y",
"text": [
"adrenomedullin"
],
"offsets": [
[
355,
369
]
],
"normalized": []
},
{
"id": "11401111_T18",
"type": "GENE-Y",
"text": [
"N-BNP"
],
"offsets": [
[
1742,
1747
]
],
"normalized": []
},
{
"id": "11401111_T19",
"type": "GENE-Y",
"text": [
"adrenomedullin"
],
"offsets": [
[
1751,
1765
]
],
"normalized": []
},
{
"id": "11401111_T20",
"type": "GENE-Y",
"text": [
"N-BNP"
],
"offsets": [
[
1955,
1960
]
],
"normalized": []
},
{
"id": "11401111_T21",
"type": "GENE-Y",
"text": [
"adrenomedullin"
],
"offsets": [
[
1965,
1979
]
],
"normalized": []
},
{
"id": "11401111_T22",
"type": "GENE-Y",
"text": [
"N-BNP"
],
"offsets": [
[
2131,
2136
]
],
"normalized": []
},
{
"id": "11401111_T23",
"type": "GENE-Y",
"text": [
"adrenomedullin"
],
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]
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"id": "11401111_T24",
"type": "GENE-Y",
"text": [
"N-BNP"
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682,
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]
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"id": "11401111_T25",
"type": "GENE-Y",
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"adrenomedullin"
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691,
705
]
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"id": "11401111_T26",
"type": "GENE-Y",
"text": [
"N-BNP"
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791,
796
]
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"id": "11401111_T27",
"type": "GENE-Y",
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"adrenomedullin"
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801,
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"amino (N)-terminal portion of pro-brain natriuretic peptide"
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283,
342
]
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"type": "GENE-Y",
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"N-BNP"
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1172,
1177
]
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"id": "11401111_T30",
"type": "GENE-Y",
"text": [
"adrenomedullin"
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1182,
1196
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"adrenomedullin"
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52,
66
]
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"id": "11401111_T32",
"type": "GENE-Y",
"text": [
"N-terminal pro-brain natriuretic peptide"
],
"offsets": [
[
7,
47
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "11401111_0",
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"arg2_id": "11401111_T18",
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},
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"id": "11401111_1",
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},
{
"id": "11401111_2",
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"arg2_id": "11401111_T22",
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},
{
"id": "11401111_3",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "11401111_T5",
"arg2_id": "11401111_T23",
"normalized": []
}
] |
23402744 | 23402744 | [
{
"id": "23402744_title",
"type": "title",
"text": [
"Sexually dimorphic behavior after developmental exposure to characterize endocrine-mediated effects of different non-dioxin-like PCBs in rats."
],
"offsets": [
[
0,
142
]
]
},
{
"id": "23402744_abstract",
"type": "abstract",
"text": [
"Many chemicals are known to exhibit endocrine activity and affect reproductive functions in vertebrates and invertebrates. Endocrine effects include influences on sexual differentiation of the brain during development and reproductive and non-reproductive behavior in adult offspring. We previously demonstrated that developmental exposure to a mixture of polychlorinated biphenyls (PCBs) which was reconstituted according to the congener pattern found in human breast milk caused feminization of sweet preference as a sexually dimorphic behavior in adult male rats, following decreases in aromatase activity in the brain of newborn male pups. This result may be due to dioxin-like or non-dioxin-like (NDL) PCBs and their respective effects on steroid hormones. The aim of the present experiments was to determine if exposure to highly purified NDL-PCBs (to remove Ah receptor active contaminants) also results in alteration of sweet preference. Pregnant rats were orally exposed to PCB52 (6 dose groups, total dose of 0-3000mg/kg body weight) or PCB180 (6 dose groups, total dose of 0-1000mg/kg body weight). In a further experiment rat dams were treated with equimolar doses of PCB74 or PCB95 (total dose, 760μmol/kg body weight, corresponding to 229mg/kg or 248mg/kg body weight of PCB74 and PCB95, respectively). Adult male and female offspring were given a choice between a bottle of saccharin solution (0.25%) and a bottle of tap water on five consecutive days. Control females consumed approximately twice as much sweetened solution compared with control males, thus, demonstrating sexual dimorphism of this behavior. Only non-significant reduction of sweet preference was found at the top dose level in female offspring after exposure to PCB52. Female offspring exposed to PCB180 exhibited signs of supernormal behavior as illustrated by increased saccharin consumption at intermediate dose levels. Decreased sweet preference was observed in females after developmental PCB74, whereas males were unaffected. Only PCB95 increased saccharin consumption in exposed males, leading to decreased sexual dimorphism of this behavior and behavioral feminization. The results demonstrate that different NDL-PCBs exhibit differential effects on sexually dimorphic behavior and that feminization occurs after removal of Ah receptor active contaminants. Comparison with data from the literature reveals little evidence for a relation to anti-androgenic activity of the studied NDL-PCBs."
],
"offsets": [
[
143,
2624
]
]
}
] | [
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"id": "23402744_T1",
"type": "CHEMICAL",
"text": [
"PCB180"
],
"offsets": [
[
1190,
1196
]
],
"normalized": []
},
{
"id": "23402744_T2",
"type": "CHEMICAL",
"text": [
"PCB74"
],
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[
1323,
1328
]
],
"normalized": []
},
{
"id": "23402744_T3",
"type": "CHEMICAL",
"text": [
"PCB95"
],
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[
1332,
1337
]
],
"normalized": []
},
{
"id": "23402744_T4",
"type": "CHEMICAL",
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"PCB74"
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[
1428,
1433
]
],
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},
{
"id": "23402744_T5",
"type": "CHEMICAL",
"text": [
"PCB95"
],
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[
1438,
1443
]
],
"normalized": []
},
{
"id": "23402744_T6",
"type": "CHEMICAL",
"text": [
"saccharin"
],
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[
1532,
1541
]
],
"normalized": []
},
{
"id": "23402744_T7",
"type": "CHEMICAL",
"text": [
"PCB52"
],
"offsets": [
[
1889,
1894
]
],
"normalized": []
},
{
"id": "23402744_T8",
"type": "CHEMICAL",
"text": [
"PCB180"
],
"offsets": [
[
1924,
1930
]
],
"normalized": []
},
{
"id": "23402744_T9",
"type": "CHEMICAL",
"text": [
"saccharin"
],
"offsets": [
[
1999,
2008
]
],
"normalized": []
},
{
"id": "23402744_T10",
"type": "CHEMICAL",
"text": [
"PCB74"
],
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[
2121,
2126
]
],
"normalized": []
},
{
"id": "23402744_T11",
"type": "CHEMICAL",
"text": [
"PCB95"
],
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[
2164,
2169
]
],
"normalized": []
},
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"id": "23402744_T12",
"type": "CHEMICAL",
"text": [
"saccharin"
],
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[
2180,
2189
]
],
"normalized": []
},
{
"id": "23402744_T13",
"type": "CHEMICAL",
"text": [
"PCBs"
],
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2348,
2352
]
],
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},
{
"id": "23402744_T14",
"type": "CHEMICAL",
"text": [
"PCBs"
],
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[
2619,
2623
]
],
"normalized": []
},
{
"id": "23402744_T15",
"type": "CHEMICAL",
"text": [
"polychlorinated biphenyls"
],
"offsets": [
[
499,
524
]
],
"normalized": []
},
{
"id": "23402744_T16",
"type": "CHEMICAL",
"text": [
"PCBs"
],
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526,
530
]
],
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},
{
"id": "23402744_T17",
"type": "CHEMICAL",
"text": [
"dioxin"
],
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[
813,
819
]
],
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},
{
"id": "23402744_T18",
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"dioxin"
],
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832,
838
]
],
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},
{
"id": "23402744_T19",
"type": "CHEMICAL",
"text": [
"PCBs"
],
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850,
854
]
],
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},
{
"id": "23402744_T20",
"type": "CHEMICAL",
"text": [
"steroid"
],
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887,
894
]
],
"normalized": []
},
{
"id": "23402744_T21",
"type": "CHEMICAL",
"text": [
"PCBs"
],
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992,
996
]
],
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},
{
"id": "23402744_T22",
"type": "CHEMICAL",
"text": [
"PCB52"
],
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[
1126,
1131
]
],
"normalized": []
},
{
"id": "23402744_T23",
"type": "CHEMICAL",
"text": [
"dioxin"
],
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[
117,
123
]
],
"normalized": []
},
{
"id": "23402744_T24",
"type": "CHEMICAL",
"text": [
"PCBs"
],
"offsets": [
[
129,
133
]
],
"normalized": []
},
{
"id": "23402744_T25",
"type": "GENE-Y",
"text": [
"Ah receptor"
],
"offsets": [
[
2459,
2470
]
],
"normalized": []
},
{
"id": "23402744_T26",
"type": "GENE-Y",
"text": [
"aromatase"
],
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733,
742
]
],
"normalized": []
},
{
"id": "23402744_T27",
"type": "GENE-Y",
"text": [
"Ah receptor"
],
"offsets": [
[
1008,
1019
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23402744_0",
"type": "INHIBITOR",
"arg1_id": "23402744_T15",
"arg2_id": "23402744_T26",
"normalized": []
},
{
"id": "23402744_1",
"type": "INHIBITOR",
"arg1_id": "23402744_T16",
"arg2_id": "23402744_T26",
"normalized": []
}
] |
1318989 | 1318989 | [
{
"id": "1318989_title",
"type": "title",
"text": [
"Further characterization of alpha N-acetyl beta-endorphin-(1-31) regulatory activity, I: Effect on opioid- and alpha 2-mediated supraspinal antinociception in mice."
],
"offsets": [
[
0,
164
]
]
},
{
"id": "1318989_abstract",
"type": "abstract",
"text": [
"Picomol doses of the acetylated derivative of beta-endorphin-(1-31), injected intracerebroventricularly (icv) in mice, reduced the analgesic activity of morphine, etorphine and beta-endorphin-(1-31), while the efficiency of DAGO and DADLE in producing analgesia was enhanced. The effects of the delta agonists DPDPE and [D-Ala2]-Deltorphin II were not altered by this treatment. After alpha N-acetyl beta-endorphin-(1-31) injection, morphine antagonized the analgesia of DAGO. The regulatory effect of alpha N-acetyl beta-endorphin-(1-31) was exhibited when giving the peptide both before (up to 24 h) and after the opioids. Naloxone did not prevent or reverse that modulatory activity; moreover, pretreatment with the acetylated peptide did not change the pA2 value displayed by the antagonist at the mu receptor. The antinociceptive activity of the alpha 2-adrenoceptor agonist clonidine was also increased in mice treated with alpha N-acetyl beta-endorphin-(1-31). The reducing activity of alpha N-acetyl beta-endorphin-(1-31) upon morphine- and beta-endorphin-induced analgesia was not exhibited in mice undergoing treatment with pertussis toxin or N-ethylmaleimide, agents known to impair the function of Gi/Go transducer proteins. However, the enhancing activity displayed by this peptide upon DAGO- DADLE and clonidine-evoked antinociception was still manifested. These results confirm and strengthen the idea of alpha N-acetyl beta-endorphin-(1-31) acting as a non-competitive regulator of mu opioid- and alpha 2-adrenoceptor-mediated supraspinal antinociception. A neural substrate acted on by both receptors (likely Gi/Go transducer proteins) appears to be involved in the effects of that neuropeptide."
],
"offsets": [
[
165,
1877
]
]
}
] | [
{
"id": "1318989_T1",
"type": "CHEMICAL",
"text": [
"morphine"
],
"offsets": [
[
1200,
1208
]
],
"normalized": []
},
{
"id": "1318989_T2",
"type": "CHEMICAL",
"text": [
"N-ethylmaleimide"
],
"offsets": [
[
1318,
1334
]
],
"normalized": []
},
{
"id": "1318989_T3",
"type": "CHEMICAL",
"text": [
"DAGO"
],
"offsets": [
[
1465,
1469
]
],
"normalized": []
},
{
"id": "1318989_T4",
"type": "CHEMICAL",
"text": [
"DADLE"
],
"offsets": [
[
1471,
1476
]
],
"normalized": []
},
{
"id": "1318989_T5",
"type": "CHEMICAL",
"text": [
"clonidine"
],
"offsets": [
[
1481,
1490
]
],
"normalized": []
},
{
"id": "1318989_T6",
"type": "CHEMICAL",
"text": [
"N-acetyl"
],
"offsets": [
[
1591,
1599
]
],
"normalized": []
},
{
"id": "1318989_T7",
"type": "CHEMICAL",
"text": [
"morphine"
],
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[
318,
326
]
],
"normalized": []
},
{
"id": "1318989_T8",
"type": "CHEMICAL",
"text": [
"etorphine"
],
"offsets": [
[
328,
337
]
],
"normalized": []
},
{
"id": "1318989_T9",
"type": "CHEMICAL",
"text": [
"DAGO"
],
"offsets": [
[
389,
393
]
],
"normalized": []
},
{
"id": "1318989_T10",
"type": "CHEMICAL",
"text": [
"DADLE"
],
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[
398,
403
]
],
"normalized": []
},
{
"id": "1318989_T11",
"type": "CHEMICAL",
"text": [
"DPDPE"
],
"offsets": [
[
475,
480
]
],
"normalized": []
},
{
"id": "1318989_T12",
"type": "CHEMICAL",
"text": [
"[D-Ala2]-Deltorphin II"
],
"offsets": [
[
485,
507
]
],
"normalized": []
},
{
"id": "1318989_T13",
"type": "CHEMICAL",
"text": [
"N-acetyl"
],
"offsets": [
[
556,
564
]
],
"normalized": []
},
{
"id": "1318989_T14",
"type": "CHEMICAL",
"text": [
"morphine"
],
"offsets": [
[
598,
606
]
],
"normalized": []
},
{
"id": "1318989_T15",
"type": "CHEMICAL",
"text": [
"DAGO"
],
"offsets": [
[
636,
640
]
],
"normalized": []
},
{
"id": "1318989_T16",
"type": "CHEMICAL",
"text": [
"N-acetyl"
],
"offsets": [
[
673,
681
]
],
"normalized": []
},
{
"id": "1318989_T17",
"type": "CHEMICAL",
"text": [
"Naloxone"
],
"offsets": [
[
790,
798
]
],
"normalized": []
},
{
"id": "1318989_T18",
"type": "CHEMICAL",
"text": [
"clonidine"
],
"offsets": [
[
1045,
1054
]
],
"normalized": []
},
{
"id": "1318989_T19",
"type": "CHEMICAL",
"text": [
"N-acetyl"
],
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[
1101,
1109
]
],
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},
{
"id": "1318989_T20",
"type": "CHEMICAL",
"text": [
"N-acetyl"
],
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[
1164,
1172
]
],
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},
{
"id": "1318989_T21",
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"text": [
"N-acetyl"
],
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34,
42
]
],
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},
{
"id": "1318989_T22",
"type": "GENE-N",
"text": [
"Gi"
],
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[
1375,
1377
]
],
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},
{
"id": "1318989_T23",
"type": "GENE-N",
"text": [
"Go"
],
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[
1378,
1380
]
],
"normalized": []
},
{
"id": "1318989_T24",
"type": "GENE-Y",
"text": [
"mu opioid"
],
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[
1663,
1672
]
],
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},
{
"id": "1318989_T25",
"type": "GENE-N",
"text": [
"alpha 2-adrenoceptor"
],
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[
1678,
1698
]
],
"normalized": []
},
{
"id": "1318989_T26",
"type": "GENE-N",
"text": [
"Gi"
],
"offsets": [
[
1791,
1793
]
],
"normalized": []
},
{
"id": "1318989_T27",
"type": "GENE-N",
"text": [
"Go"
],
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[
1794,
1796
]
],
"normalized": []
},
{
"id": "1318989_T28",
"type": "GENE-Y",
"text": [
"mu receptor"
],
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[
967,
978
]
],
"normalized": []
},
{
"id": "1318989_T29",
"type": "GENE-N",
"text": [
"alpha 2-adrenoceptor"
],
"offsets": [
[
1016,
1036
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "1318989_0",
"type": "AGONIST",
"arg1_id": "1318989_T18",
"arg2_id": "1318989_T29",
"normalized": []
},
{
"id": "1318989_1",
"type": "ANTAGONIST",
"arg1_id": "1318989_T17",
"arg2_id": "1318989_T28",
"normalized": []
}
] |
22935038 | 22935038 | [
{
"id": "22935038_title",
"type": "title",
"text": [
"Postpartum corticosterone administration reduces dendritic complexity and increases the density of mushroom spines of hippocampal CA3 arbours in dams."
],
"offsets": [
[
0,
150
]
]
},
{
"id": "22935038_abstract",
"type": "abstract",
"text": [
"Postpartum depression (PPD) affects approximately 15% of mothers after giving birth. A complete understanding of depression during the postpartum period has yet to be established, although disruptions in the hypothalamic-pituitary-adrenal axis and stress during the postpartum may be involved. To model these components in rats, we administered high corticosterone (CORT) postpartum, which increases immobility in the forced swim test (FST), and reduces maternal care, body weight and hippocampal cell proliferation in dams. The hippocampus is altered in response to chronic stress, exposure to high glucocorticoids and in major depression in humans. In the present study, we examined whether high CORT reduced dendritic complexity and spines in the CA3 region of the hippocampus. Additionally, housing complexity was manipulated so that dams and litters were housed either with tubes (complex) or without tubes (impoverished) to investigate the consequences of new animal care regulations. Dams received 40 mg/kg/day of CORT or oil starting on day 2 postpartum for 23 days. Maternal behaviours were assessed on postpartum days 2-8 and dams were tested using the FST on days 21 and 22. Dams were killed on day 24 and brains were processed for Golgi impregnation. Pyramidal cells in the CA3 subfield were traced using a camera lucida and analysed for branch points and dendritic complexity, as well as spine density and type on both basal and apical arbours. As previously established, high CORT postpartum reduced maternal care and increased immobility in the FST, which is a measure of depressive-like behaviour. High CORT postpartum reduced the complexity of basal arbours and increased mushroom spines on both apical and basal dendrites. Housing complexity had no effect on spines of CA3 pyramidal cells but modest effects on cell morphology. These data show that chronic high CORT in postpartum females alters hippocampal morphology and may provide insight regarding the neurobiological consequences of high stress or CORT during the postpartum period, as well as be relevant for postpartum stress or depression."
],
"offsets": [
[
151,
2267
]
]
}
] | [
{
"id": "22935038_T1",
"type": "CHEMICAL",
"text": [
"CORT"
],
"offsets": [
[
1172,
1176
]
],
"normalized": []
},
{
"id": "22935038_T2",
"type": "CHEMICAL",
"text": [
"CORT"
],
"offsets": [
[
1641,
1645
]
],
"normalized": []
},
{
"id": "22935038_T3",
"type": "CHEMICAL",
"text": [
"CORT"
],
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[
1770,
1774
]
],
"normalized": []
},
{
"id": "22935038_T4",
"type": "CHEMICAL",
"text": [
"CORT"
],
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[
2031,
2035
]
],
"normalized": []
},
{
"id": "22935038_T5",
"type": "CHEMICAL",
"text": [
"CORT"
],
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[
2173,
2177
]
],
"normalized": []
},
{
"id": "22935038_T6",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
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[
501,
515
]
],
"normalized": []
},
{
"id": "22935038_T7",
"type": "CHEMICAL",
"text": [
"CORT"
],
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[
517,
521
]
],
"normalized": []
},
{
"id": "22935038_T8",
"type": "CHEMICAL",
"text": [
"CORT"
],
"offsets": [
[
849,
853
]
],
"normalized": []
},
{
"id": "22935038_T9",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
"offsets": [
[
11,
25
]
],
"normalized": []
}
] | [] | [] | [] |
16396637 | 16396637 | [
{
"id": "16396637_title",
"type": "title",
"text": [
"Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine-homocysteine S-methyltransferase."
],
"offsets": [
[
0,
155
]
]
},
{
"id": "16396637_abstract",
"type": "abstract",
"text": [
"We have previously reported a positive correlation between the expression of BHMT (betaine-homocysteine S-methyltransferase) and ApoB (apolipoprotein B) in rat hepatoma McA (McArdle RH-7777) cells [Sowden, Collins, Smith, Garrow, Sparks and Sparks (1999) Biochem. J. 341, 639-645]. To examine whether a similar relationship occurs in vivo, hepatic BHMT expression was induced by feeding rats a Met (L-methionine)-restricted betaine-containing diet, and parameters of ApoB metabolism were evaluated. There were no generalized metabolic abnormalities associated with Met restriction for 7 days, as evidenced by control levels of serum glucose, ketones, alanine aminotransferase and L-homocysteine levels. Betaine plus the Met restriction resulted in lower serum insulin and non-esterified fatty acid levels. Betaine plus Met restriction induced hepatic BHMT 4-fold and ApoB mRNA 3-fold compared with Met restriction alone. No changes in percentage of edited ApoB mRNA were observed on the test diets. An increase in liver ApoB mRNA correlated with an 82% and 46% increase in ApoB and triacylglycerol production respectively using in vivo Triton WR 1339. Increased secretion of VLDL (very-low-density lipoprotein) with Met restriction plus betaine was associated with a 45% reduction in liver triacylglycerol compared with control. Nuclear run-off assays established that transcription of both bhmt and apob genes was also increased in Met-restricted plus betaine diets. No change in ApoB mRNA stability was detected in BHMT-transfected McA cells. Hepatic ApoB and BHMT mRNA levels were also increased by 1.8- and 3-fold respectively by betaine supplementation of Met-replete diets. Since dietary betaine increased ApoB mRNA, VLDL ApoB and triacylglycerol production and decreased hepatic triacylglycerol, results suggest that induction of apob transcription may provide a potential mechanism for mobilizing hepatic triacylglycerol by increasing ApoB available for VLDL assembly and secretion."
],
"offsets": [
[
156,
2146
]
]
}
] | [
{
"id": "16396637_T1",
"type": "CHEMICAL",
"text": [
"S"
],
"offsets": [
[
260,
261
]
],
"normalized": []
},
{
"id": "16396637_T2",
"type": "CHEMICAL",
"text": [
"triacylglycerol"
],
"offsets": [
[
1238,
1253
]
],
"normalized": []
},
{
"id": "16396637_T3",
"type": "CHEMICAL",
"text": [
"Triton WR 1339"
],
"offsets": [
[
1292,
1306
]
],
"normalized": []
},
{
"id": "16396637_T4",
"type": "CHEMICAL",
"text": [
"Met"
],
"offsets": [
[
1372,
1375
]
],
"normalized": []
},
{
"id": "16396637_T5",
"type": "CHEMICAL",
"text": [
"betaine"
],
"offsets": [
[
1393,
1400
]
],
"normalized": []
},
{
"id": "16396637_T6",
"type": "CHEMICAL",
"text": [
"triacylglycerol"
],
"offsets": [
[
1446,
1461
]
],
"normalized": []
},
{
"id": "16396637_T7",
"type": "CHEMICAL",
"text": [
"Met"
],
"offsets": [
[
1589,
1592
]
],
"normalized": []
},
{
"id": "16396637_T8",
"type": "CHEMICAL",
"text": [
"betaine"
],
"offsets": [
[
1609,
1616
]
],
"normalized": []
},
{
"id": "16396637_T9",
"type": "CHEMICAL",
"text": [
"betaine"
],
"offsets": [
[
1790,
1797
]
],
"normalized": []
},
{
"id": "16396637_T10",
"type": "CHEMICAL",
"text": [
"Met"
],
"offsets": [
[
1817,
1820
]
],
"normalized": []
},
{
"id": "16396637_T11",
"type": "CHEMICAL",
"text": [
"betaine"
],
"offsets": [
[
1850,
1857
]
],
"normalized": []
},
{
"id": "16396637_T12",
"type": "CHEMICAL",
"text": [
"triacylglycerol"
],
"offsets": [
[
1893,
1908
]
],
"normalized": []
},
{
"id": "16396637_T13",
"type": "CHEMICAL",
"text": [
"triacylglycerol"
],
"offsets": [
[
1942,
1957
]
],
"normalized": []
},
{
"id": "16396637_T14",
"type": "CHEMICAL",
"text": [
"triacylglycerol"
],
"offsets": [
[
2069,
2084
]
],
"normalized": []
},
{
"id": "16396637_T15",
"type": "CHEMICAL",
"text": [
"Met"
],
"offsets": [
[
550,
553
]
],
"normalized": []
},
{
"id": "16396637_T16",
"type": "CHEMICAL",
"text": [
"L-methionine"
],
"offsets": [
[
555,
567
]
],
"normalized": []
},
{
"id": "16396637_T17",
"type": "CHEMICAL",
"text": [
"betaine"
],
"offsets": [
[
580,
587
]
],
"normalized": []
},
{
"id": "16396637_T18",
"type": "CHEMICAL",
"text": [
"Met"
],
"offsets": [
[
721,
724
]
],
"normalized": []
},
{
"id": "16396637_T19",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
789,
796
]
],
"normalized": []
},
{
"id": "16396637_T20",
"type": "CHEMICAL",
"text": [
"ketones"
],
"offsets": [
[
798,
805
]
],
"normalized": []
},
{
"id": "16396637_T21",
"type": "CHEMICAL",
"text": [
"alanine"
],
"offsets": [
[
807,
814
]
],
"normalized": []
},
{
"id": "16396637_T22",
"type": "CHEMICAL",
"text": [
"L-homocysteine"
],
"offsets": [
[
836,
850
]
],
"normalized": []
},
{
"id": "16396637_T23",
"type": "CHEMICAL",
"text": [
"Betaine"
],
"offsets": [
[
859,
866
]
],
"normalized": []
},
{
"id": "16396637_T24",
"type": "CHEMICAL",
"text": [
"Met"
],
"offsets": [
[
876,
879
]
],
"normalized": []
},
{
"id": "16396637_T25",
"type": "CHEMICAL",
"text": [
"fatty acid"
],
"offsets": [
[
943,
953
]
],
"normalized": []
},
{
"id": "16396637_T26",
"type": "CHEMICAL",
"text": [
"Betaine"
],
"offsets": [
[
962,
969
]
],
"normalized": []
},
{
"id": "16396637_T27",
"type": "CHEMICAL",
"text": [
"Met"
],
"offsets": [
[
975,
978
]
],
"normalized": []
},
{
"id": "16396637_T28",
"type": "CHEMICAL",
"text": [
"betaine"
],
"offsets": [
[
239,
246
]
],
"normalized": []
},
{
"id": "16396637_T29",
"type": "CHEMICAL",
"text": [
"Met"
],
"offsets": [
[
1054,
1057
]
],
"normalized": []
},
{
"id": "16396637_T30",
"type": "CHEMICAL",
"text": [
"homocysteine"
],
"offsets": [
[
247,
259
]
],
"normalized": []
},
{
"id": "16396637_T31",
"type": "CHEMICAL",
"text": [
"betaine"
],
"offsets": [
[
114,
121
]
],
"normalized": []
},
{
"id": "16396637_T32",
"type": "CHEMICAL",
"text": [
"homocysteine"
],
"offsets": [
[
122,
134
]
],
"normalized": []
},
{
"id": "16396637_T33",
"type": "CHEMICAL",
"text": [
"S"
],
"offsets": [
[
135,
136
]
],
"normalized": []
},
{
"id": "16396637_T34",
"type": "GENE-Y",
"text": [
"ApoB"
],
"offsets": [
[
1176,
1180
]
],
"normalized": []
},
{
"id": "16396637_T35",
"type": "GENE-Y",
"text": [
"ApoB"
],
"offsets": [
[
1229,
1233
]
],
"normalized": []
},
{
"id": "16396637_T36",
"type": "GENE-N",
"text": [
"VLDL"
],
"offsets": [
[
1331,
1335
]
],
"normalized": []
},
{
"id": "16396637_T37",
"type": "GENE-N",
"text": [
"very-low-density lipoprotein"
],
"offsets": [
[
1337,
1365
]
],
"normalized": []
},
{
"id": "16396637_T38",
"type": "GENE-Y",
"text": [
"ApoB"
],
"offsets": [
[
285,
289
]
],
"normalized": []
},
{
"id": "16396637_T39",
"type": "GENE-Y",
"text": [
"apolipoprotein B"
],
"offsets": [
[
291,
307
]
],
"normalized": []
},
{
"id": "16396637_T40",
"type": "GENE-Y",
"text": [
"bhmt"
],
"offsets": [
[
1547,
1551
]
],
"normalized": []
},
{
"id": "16396637_T41",
"type": "GENE-Y",
"text": [
"apob"
],
"offsets": [
[
1556,
1560
]
],
"normalized": []
},
{
"id": "16396637_T42",
"type": "GENE-Y",
"text": [
"ApoB"
],
"offsets": [
[
1637,
1641
]
],
"normalized": []
},
{
"id": "16396637_T43",
"type": "GENE-Y",
"text": [
"BHMT"
],
"offsets": [
[
1673,
1677
]
],
"normalized": []
},
{
"id": "16396637_T44",
"type": "GENE-Y",
"text": [
"ApoB"
],
"offsets": [
[
1709,
1713
]
],
"normalized": []
},
{
"id": "16396637_T45",
"type": "GENE-Y",
"text": [
"BHMT"
],
"offsets": [
[
1718,
1722
]
],
"normalized": []
},
{
"id": "16396637_T46",
"type": "GENE-Y",
"text": [
"ApoB"
],
"offsets": [
[
1868,
1872
]
],
"normalized": []
},
{
"id": "16396637_T47",
"type": "GENE-N",
"text": [
"VLDL"
],
"offsets": [
[
1879,
1883
]
],
"normalized": []
},
{
"id": "16396637_T48",
"type": "GENE-Y",
"text": [
"ApoB"
],
"offsets": [
[
1884,
1888
]
],
"normalized": []
},
{
"id": "16396637_T49",
"type": "GENE-Y",
"text": [
"apob"
],
"offsets": [
[
1993,
1997
]
],
"normalized": []
},
{
"id": "16396637_T50",
"type": "GENE-Y",
"text": [
"ApoB"
],
"offsets": [
[
2099,
2103
]
],
"normalized": []
},
{
"id": "16396637_T51",
"type": "GENE-N",
"text": [
"VLDL"
],
"offsets": [
[
2118,
2122
]
],
"normalized": []
},
{
"id": "16396637_T52",
"type": "GENE-Y",
"text": [
"BHMT"
],
"offsets": [
[
504,
508
]
],
"normalized": []
},
{
"id": "16396637_T53",
"type": "GENE-Y",
"text": [
"ApoB"
],
"offsets": [
[
623,
627
]
],
"normalized": []
},
{
"id": "16396637_T54",
"type": "GENE-N",
"text": [
"alanine aminotransferase"
],
"offsets": [
[
807,
831
]
],
"normalized": []
},
{
"id": "16396637_T55",
"type": "GENE-N",
"text": [
"insulin"
],
"offsets": [
[
916,
923
]
],
"normalized": []
},
{
"id": "16396637_T56",
"type": "GENE-Y",
"text": [
"BHMT"
],
"offsets": [
[
233,
237
]
],
"normalized": []
},
{
"id": "16396637_T57",
"type": "GENE-Y",
"text": [
"betaine-homocysteine S-methyltransferase"
],
"offsets": [
[
239,
279
]
],
"normalized": []
},
{
"id": "16396637_T58",
"type": "GENE-Y",
"text": [
"BHMT"
],
"offsets": [
[
1007,
1011
]
],
"normalized": []
},
{
"id": "16396637_T59",
"type": "GENE-Y",
"text": [
"ApoB"
],
"offsets": [
[
1023,
1027
]
],
"normalized": []
},
{
"id": "16396637_T60",
"type": "GENE-Y",
"text": [
"ApoB"
],
"offsets": [
[
1112,
1116
]
],
"normalized": []
},
{
"id": "16396637_T61",
"type": "GENE-Y",
"text": [
"betaine-homocysteine S-methyltransferase"
],
"offsets": [
[
114,
154
]
],
"normalized": []
},
{
"id": "16396637_T62",
"type": "GENE-Y",
"text": [
"apolipoprotein B"
],
"offsets": [
[
41,
57
]
],
"normalized": []
},
{
"id": "16396637_T63",
"type": "GENE-N",
"text": [
"very-low-density lipoprotein"
],
"offsets": [
[
8,
36
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16396637_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "16396637_T11",
"arg2_id": "16396637_T46",
"normalized": []
},
{
"id": "16396637_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "16396637_T3",
"arg2_id": "16396637_T34",
"normalized": []
},
{
"id": "16396637_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "16396637_T3",
"arg2_id": "16396637_T35",
"normalized": []
},
{
"id": "16396637_3",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "16396637_T9",
"arg2_id": "16396637_T44",
"normalized": []
},
{
"id": "16396637_4",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "16396637_T9",
"arg2_id": "16396637_T45",
"normalized": []
},
{
"id": "16396637_5",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "16396637_T10",
"arg2_id": "16396637_T44",
"normalized": []
},
{
"id": "16396637_6",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "16396637_T10",
"arg2_id": "16396637_T45",
"normalized": []
},
{
"id": "16396637_7",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "16396637_T11",
"arg2_id": "16396637_T47",
"normalized": []
},
{
"id": "16396637_8",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "16396637_T11",
"arg2_id": "16396637_T48",
"normalized": []
}
] |
23100159 | 23100159 | [
{
"id": "23100159_title",
"type": "title",
"text": [
"Enhanced carcinogenicity by coexposure to arsenic and iron and a novel remediation system for the elements in well drinking water."
],
"offsets": [
[
0,
130
]
]
},
{
"id": "23100159_abstract",
"type": "abstract",
"text": [
"Various carcinomas including skin cancer are explosively increasing in arsenicosis patients who drink arsenic-polluted well water, especially in Bangladesh. Although well drinking water in the cancer-prone areas contains various elements, very little is known about the effects of elements except arsenic on carcinogenicity. In order to clarify the carcinogenic effects of coexposure to arsenic and iron, anchorage-independent growth and invasion in human untransformed HaCaT and transformed A431 keratinocytes were examined. Since the mean ratio of arsenic and iron in well water was 1:10 in cancer-prone areas of Bangladesh, effects of 1 μM arsenic and 10 μM iron were investigated. Iron synergistically promoted arsenic-mediated anchorage-independent growth in untransformed and transformed keratinocytes. Iron additionally increased invasion in both types of keratinocytes. Activities of c-SRC and ERK that regulate anchorage-independent growth and invasion were synergistically enhanced in both types of keratinocytes. Our results suggest that iron promotes arsenic-mediated transformation of untransformed keratinocytes and progression of transformed keratinocytes. We then developed a low-cost and high-performance adsorbent composed of a hydrotalcite-like compound for arsenic and iron. The adsorbent rapidly reduced concentrations of both elements from well drinking water in cancer-prone areas of Bangladesh to levels less than those in WHO health-based guidelines for drinking water. Thus, we not only demonstrated for the first time increased carcinogenicity by coexposure to arsenic and iron but also proposed a novel remediation system for well drinking water."
],
"offsets": [
[
131,
1805
]
]
}
] | [
{
"id": "23100159_T1",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
233,
240
]
],
"normalized": []
},
{
"id": "23100159_T2",
"type": "CHEMICAL",
"text": [
"iron"
],
"offsets": [
[
1180,
1184
]
],
"normalized": []
},
{
"id": "23100159_T3",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1194,
1201
]
],
"normalized": []
},
{
"id": "23100159_T4",
"type": "CHEMICAL",
"text": [
"hydrotalcite"
],
"offsets": [
[
1377,
1389
]
],
"normalized": []
},
{
"id": "23100159_T5",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1408,
1415
]
],
"normalized": []
},
{
"id": "23100159_T6",
"type": "CHEMICAL",
"text": [
"iron"
],
"offsets": [
[
1420,
1424
]
],
"normalized": []
},
{
"id": "23100159_T7",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
1719,
1726
]
],
"normalized": []
},
{
"id": "23100159_T8",
"type": "CHEMICAL",
"text": [
"iron"
],
"offsets": [
[
1731,
1735
]
],
"normalized": []
},
{
"id": "23100159_T9",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
428,
435
]
],
"normalized": []
},
{
"id": "23100159_T10",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
518,
525
]
],
"normalized": []
},
{
"id": "23100159_T11",
"type": "CHEMICAL",
"text": [
"iron"
],
"offsets": [
[
530,
534
]
],
"normalized": []
},
{
"id": "23100159_T12",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
681,
688
]
],
"normalized": []
},
{
"id": "23100159_T13",
"type": "CHEMICAL",
"text": [
"iron"
],
"offsets": [
[
693,
697
]
],
"normalized": []
},
{
"id": "23100159_T14",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
774,
781
]
],
"normalized": []
},
{
"id": "23100159_T15",
"type": "CHEMICAL",
"text": [
"iron"
],
"offsets": [
[
792,
796
]
],
"normalized": []
},
{
"id": "23100159_T16",
"type": "CHEMICAL",
"text": [
"Iron"
],
"offsets": [
[
816,
820
]
],
"normalized": []
},
{
"id": "23100159_T17",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
846,
853
]
],
"normalized": []
},
{
"id": "23100159_T18",
"type": "CHEMICAL",
"text": [
"Iron"
],
"offsets": [
[
940,
944
]
],
"normalized": []
},
{
"id": "23100159_T19",
"type": "CHEMICAL",
"text": [
"arsenic"
],
"offsets": [
[
42,
49
]
],
"normalized": []
},
{
"id": "23100159_T20",
"type": "CHEMICAL",
"text": [
"iron"
],
"offsets": [
[
54,
58
]
],
"normalized": []
},
{
"id": "23100159_T21",
"type": "GENE-Y",
"text": [
"c-SRC"
],
"offsets": [
[
1023,
1028
]
],
"normalized": []
},
{
"id": "23100159_T22",
"type": "GENE-N",
"text": [
"ERK"
],
"offsets": [
[
1033,
1036
]
],
"normalized": []
}
] | [] | [] | [] |
16982784 | 16982784 | [
{
"id": "16982784_title",
"type": "title",
"text": [
"Role of Asp104 in the SHV beta-lactamase."
],
"offsets": [
[
0,
41
]
]
},
{
"id": "16982784_abstract",
"type": "abstract",
"text": [
"Among the TEM-type extended-spectrum beta-lactamases (ESBLs), an amino acid change at Ambler position 104 (Glu to Lys) results in increased resistance to ceftazidime and cefotaxime when found with other substitutions (e.g., Gly238Ser and Arg164Ser). To examine the role of Asp104 in SHV beta-lactamases, site saturation mutagenesis was performed. Our goal was to investigate the properties of amino acid residues at this position that affect resistance to penicillins and oxyimino-cephalosporins. Unexpectedly, 58% of amino acid variants at position 104 in SHV expressed in Escherichia coli DH10B resulted in beta-lactamases with lowered resistance to ampicillin. In contrast, increased resistance to cefotaxime was demonstrated only for the Asp104Arg and Asp104Lys beta-lactamases. When all 19 substitutions were introduced into the SHV-2 (Gly238Ser) ESBL, the most significant increases in cefotaxime and ceftazidime resistance were noted for both the doubly substituted Asp104Lys Gly238Ser and the doubly substituted Asp104Arg Gly238Ser beta-lactamases. Correspondingly, the overall catalytic efficiency (kcat/Km) of hydrolysis for cefotaxime was increased from 0.60 +/- 0.07 microM(-1) s(-1) (mean +/- standard deviation) for Gly238Ser to 1.70 +/- 0.01 microM(-1) s(-1) for the Asp104Lys and Gly238Ser beta-lactamase (threefold increase). We also showed that (i) k3 was the rate-limiting step for the hydrolysis of cefotaxime by Asp104Lys, (ii) the Km for cefotaxime of the doubly substituted Asp104Lys Gly238Ser variant approached that of the Gly238Ser beta-lactamase as pH increased, and (iii) Lys at position 104 functions in an energetically additive manner with the Gly238Ser substitution to enhance catalysis of cephalothin. Based on this analysis, we propose that the amino acid at Ambler position 104 in SHV-1 beta-lactamase plays a major role in substrate binding and recognition of oxyimino-cephalosporins and influences the interactions of Tyr105 with penicillins."
],
"offsets": [
[
42,
2021
]
]
}
] | [
{
"id": "16982784_T1",
"type": "CHEMICAL",
"text": [
"Glu"
],
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[
149,
152
]
],
"normalized": []
},
{
"id": "16982784_T2",
"type": "CHEMICAL",
"text": [
"cefotaxime"
],
"offsets": [
[
1177,
1187
]
],
"normalized": []
},
{
"id": "16982784_T3",
"type": "CHEMICAL",
"text": [
"Lys"
],
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[
156,
159
]
],
"normalized": []
},
{
"id": "16982784_T4",
"type": "CHEMICAL",
"text": [
"cefotaxime"
],
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[
1461,
1471
]
],
"normalized": []
},
{
"id": "16982784_T5",
"type": "CHEMICAL",
"text": [
"cefotaxime"
],
"offsets": [
[
1502,
1512
]
],
"normalized": []
},
{
"id": "16982784_T6",
"type": "CHEMICAL",
"text": [
"ceftazidime"
],
"offsets": [
[
196,
207
]
],
"normalized": []
},
{
"id": "16982784_T7",
"type": "CHEMICAL",
"text": [
"cefotaxime"
],
"offsets": [
[
212,
222
]
],
"normalized": []
},
{
"id": "16982784_T8",
"type": "CHEMICAL",
"text": [
"cephalothin"
],
"offsets": [
[
1764,
1775
]
],
"normalized": []
},
{
"id": "16982784_T9",
"type": "CHEMICAL",
"text": [
"amino acid"
],
"offsets": [
[
1821,
1831
]
],
"normalized": []
},
{
"id": "16982784_T10",
"type": "CHEMICAL",
"text": [
"oxyimino-cephalosporins"
],
"offsets": [
[
1938,
1961
]
],
"normalized": []
},
{
"id": "16982784_T11",
"type": "CHEMICAL",
"text": [
"penicillins"
],
"offsets": [
[
2009,
2020
]
],
"normalized": []
},
{
"id": "16982784_T12",
"type": "CHEMICAL",
"text": [
"amino acid"
],
"offsets": [
[
435,
445
]
],
"normalized": []
},
{
"id": "16982784_T13",
"type": "CHEMICAL",
"text": [
"penicillins"
],
"offsets": [
[
498,
509
]
],
"normalized": []
},
{
"id": "16982784_T14",
"type": "CHEMICAL",
"text": [
"oxyimino-cephalosporins"
],
"offsets": [
[
514,
537
]
],
"normalized": []
},
{
"id": "16982784_T15",
"type": "CHEMICAL",
"text": [
"amino acid"
],
"offsets": [
[
560,
570
]
],
"normalized": []
},
{
"id": "16982784_T16",
"type": "CHEMICAL",
"text": [
"ampicillin"
],
"offsets": [
[
694,
704
]
],
"normalized": []
},
{
"id": "16982784_T17",
"type": "CHEMICAL",
"text": [
"amino acid"
],
"offsets": [
[
107,
117
]
],
"normalized": []
},
{
"id": "16982784_T18",
"type": "CHEMICAL",
"text": [
"cefotaxime"
],
"offsets": [
[
743,
753
]
],
"normalized": []
},
{
"id": "16982784_T19",
"type": "CHEMICAL",
"text": [
"cefotaxime"
],
"offsets": [
[
934,
944
]
],
"normalized": []
},
{
"id": "16982784_T20",
"type": "CHEMICAL",
"text": [
"ceftazidime"
],
"offsets": [
[
949,
960
]
],
"normalized": []
},
{
"id": "16982784_T21",
"type": "GENE-N",
"text": [
"Asp104Arg"
],
"offsets": [
[
1062,
1071
]
],
"normalized": []
},
{
"id": "16982784_T22",
"type": "GENE-N",
"text": [
"Gly238Ser"
],
"offsets": [
[
1072,
1081
]
],
"normalized": []
},
{
"id": "16982784_T23",
"type": "GENE-N",
"text": [
"beta-lactamases"
],
"offsets": [
[
1082,
1097
]
],
"normalized": []
},
{
"id": "16982784_T24",
"type": "GENE-N",
"text": [
"TEM-type extended-spectrum beta-lactamases"
],
"offsets": [
[
52,
94
]
],
"normalized": []
},
{
"id": "16982784_T25",
"type": "GENE-N",
"text": [
"Glu to Lys"
],
"offsets": [
[
149,
159
]
],
"normalized": []
},
{
"id": "16982784_T26",
"type": "GENE-N",
"text": [
"Gly238Ser"
],
"offsets": [
[
1272,
1281
]
],
"normalized": []
},
{
"id": "16982784_T27",
"type": "GENE-N",
"text": [
"Asp104Lys"
],
"offsets": [
[
1324,
1333
]
],
"normalized": []
},
{
"id": "16982784_T28",
"type": "GENE-N",
"text": [
"Gly238Ser"
],
"offsets": [
[
1338,
1347
]
],
"normalized": []
},
{
"id": "16982784_T29",
"type": "GENE-N",
"text": [
"beta-lactamase"
],
"offsets": [
[
1348,
1362
]
],
"normalized": []
},
{
"id": "16982784_T30",
"type": "GENE-N",
"text": [
"Asp104Lys"
],
"offsets": [
[
1475,
1484
]
],
"normalized": []
},
{
"id": "16982784_T31",
"type": "GENE-N",
"text": [
"Asp104Lys"
],
"offsets": [
[
1539,
1548
]
],
"normalized": []
},
{
"id": "16982784_T32",
"type": "GENE-N",
"text": [
"Gly238Ser"
],
"offsets": [
[
1549,
1558
]
],
"normalized": []
},
{
"id": "16982784_T33",
"type": "GENE-N",
"text": [
"Gly238Ser"
],
"offsets": [
[
1590,
1599
]
],
"normalized": []
},
{
"id": "16982784_T34",
"type": "GENE-N",
"text": [
"beta-lactamase"
],
"offsets": [
[
1600,
1614
]
],
"normalized": []
},
{
"id": "16982784_T35",
"type": "GENE-N",
"text": [
"Gly238Ser"
],
"offsets": [
[
1717,
1726
]
],
"normalized": []
},
{
"id": "16982784_T36",
"type": "GENE-Y",
"text": [
"SHV-1 beta-lactamase"
],
"offsets": [
[
1858,
1878
]
],
"normalized": []
},
{
"id": "16982784_T37",
"type": "GENE-N",
"text": [
"Gly238Ser"
],
"offsets": [
[
266,
275
]
],
"normalized": []
},
{
"id": "16982784_T38",
"type": "GENE-N",
"text": [
"Arg164Ser"
],
"offsets": [
[
280,
289
]
],
"normalized": []
},
{
"id": "16982784_T39",
"type": "GENE-N",
"text": [
"SHV beta-lactamases"
],
"offsets": [
[
325,
344
]
],
"normalized": []
},
{
"id": "16982784_T40",
"type": "GENE-N",
"text": [
"ESBLs"
],
"offsets": [
[
96,
101
]
],
"normalized": []
},
{
"id": "16982784_T41",
"type": "GENE-N",
"text": [
"SHV"
],
"offsets": [
[
599,
602
]
],
"normalized": []
},
{
"id": "16982784_T42",
"type": "GENE-N",
"text": [
"beta-lactamases"
],
"offsets": [
[
651,
666
]
],
"normalized": []
},
{
"id": "16982784_T43",
"type": "GENE-N",
"text": [
"Asp104Arg"
],
"offsets": [
[
784,
793
]
],
"normalized": []
},
{
"id": "16982784_T44",
"type": "GENE-N",
"text": [
"Asp104Lys"
],
"offsets": [
[
798,
807
]
],
"normalized": []
},
{
"id": "16982784_T45",
"type": "GENE-N",
"text": [
"beta-lactamases"
],
"offsets": [
[
808,
823
]
],
"normalized": []
},
{
"id": "16982784_T46",
"type": "GENE-Y",
"text": [
"SHV-2"
],
"offsets": [
[
876,
881
]
],
"normalized": []
},
{
"id": "16982784_T47",
"type": "GENE-N",
"text": [
"Gly238Ser"
],
"offsets": [
[
883,
892
]
],
"normalized": []
},
{
"id": "16982784_T48",
"type": "GENE-N",
"text": [
"ESBL"
],
"offsets": [
[
894,
898
]
],
"normalized": []
},
{
"id": "16982784_T49",
"type": "GENE-N",
"text": [
"Asp104Lys"
],
"offsets": [
[
1015,
1024
]
],
"normalized": []
},
{
"id": "16982784_T50",
"type": "GENE-N",
"text": [
"Gly238Ser"
],
"offsets": [
[
1025,
1034
]
],
"normalized": []
},
{
"id": "16982784_T51",
"type": "GENE-N",
"text": [
"SHV beta-lactamase"
],
"offsets": [
[
22,
40
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16982784_0",
"type": "PART-OF",
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"arg2_id": "16982784_T24",
"normalized": []
},
{
"id": "16982784_1",
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"arg2_id": "16982784_T40",
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},
{
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},
{
"id": "16982784_3",
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"arg2_id": "16982784_T40",
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},
{
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},
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},
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"id": "16982784_8",
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"normalized": []
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"id": "16982784_10",
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"arg1_id": "16982784_T2",
"arg2_id": "16982784_T29",
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},
{
"id": "16982784_11",
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"arg2_id": "16982784_T30",
"normalized": []
},
{
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"type": "SUBSTRATE",
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"arg2_id": "16982784_T31",
"normalized": []
},
{
"id": "16982784_13",
"type": "SUBSTRATE",
"arg1_id": "16982784_T5",
"arg2_id": "16982784_T32",
"normalized": []
},
{
"id": "16982784_14",
"type": "SUBSTRATE",
"arg1_id": "16982784_T5",
"arg2_id": "16982784_T33",
"normalized": []
},
{
"id": "16982784_15",
"type": "SUBSTRATE",
"arg1_id": "16982784_T5",
"arg2_id": "16982784_T34",
"normalized": []
},
{
"id": "16982784_16",
"type": "SUBSTRATE",
"arg1_id": "16982784_T8",
"arg2_id": "16982784_T35",
"normalized": []
},
{
"id": "16982784_17",
"type": "PART-OF",
"arg1_id": "16982784_T9",
"arg2_id": "16982784_T36",
"normalized": []
},
{
"id": "16982784_18",
"type": "DIRECT-REGULATOR",
"arg1_id": "16982784_T10",
"arg2_id": "16982784_T36",
"normalized": []
},
{
"id": "16982784_19",
"type": "DIRECT-REGULATOR",
"arg1_id": "16982784_T11",
"arg2_id": "16982784_T36",
"normalized": []
}
] |
23022324 | 23022324 | [
{
"id": "23022324_title",
"type": "title",
"text": [
"Inhibition of neurite outgrowth and alteration of cytoskeletal gene expression by sodium arsenite."
],
"offsets": [
[
0,
98
]
]
},
{
"id": "23022324_abstract",
"type": "abstract",
"text": [
"Arsenic compounds that are often found in drinking water increase the risk of developmental brain disorders. In this study, we performed live imaging analyses of Neuro-2a cells expressing SCAT3, a caspase-3 cleavage peptide sequence linking two fluorescent proteins; enhanced cyan fluorescence protein (ECFP) and Venus, to determine whether sodium arsenite (NaAsO(2); 0, 1, 5, or 10 μM) affects both neurite outgrowth and/or induces apoptosis with the same doses and in the same cell cultures. We observed that the area ratio of neurite to cell body in SCAT3-expressing cells was significantly reduced by 5 and 10 μM NaAsO(2), but not by 1 μM, although the emission ratio of ECFP to Venus, an endpoint of caspase-3 activity, was not changed. However, cytological assay using apoptotic and necrotic markers resulted in that apoptosis, but not necrosis, was significantly induced in Neuro-2a cells when NaAsO(2) exposure continued after the significant effects of NaAsO(2) on neurite outgrowth were found by live imaging. These results suggested that neurite outgrowth was suppressed by NaAsO(2) prior to NaAsO(2)-induced apoptosis. Next, we examined the effects of NaAsO(2) on cytoskeletal gene expression in Neuro-2a cells. NaAsO(2) increased the mRNA levels of the light and medium subunits of neurofilament and decreased the mRNA levels of tau and tubulin in a dose-dependent manner; no significant effect was found in the mRNA levels of the heavy subunit of neurofilament, microtubule-associated protein 2, or actin. The changes in cytoskeletal gene expression are likely responsible for the inhibitory effects of NaAsO(2) on neurite outgrowth."
],
"offsets": [
[
99,
1746
]
]
}
] | [
{
"id": "23022324_T1",
"type": "CHEMICAL",
"text": [
"Arsenic"
],
"offsets": [
[
99,
106
]
],
"normalized": []
},
{
"id": "23022324_T2",
"type": "CHEMICAL",
"text": [
"NaAsO(2)"
],
"offsets": [
[
1184,
1192
]
],
"normalized": []
},
{
"id": "23022324_T3",
"type": "CHEMICAL",
"text": [
"NaAsO(2)"
],
"offsets": [
[
1202,
1210
]
],
"normalized": []
},
{
"id": "23022324_T4",
"type": "CHEMICAL",
"text": [
"NaAsO(2)"
],
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[
1263,
1271
]
],
"normalized": []
},
{
"id": "23022324_T5",
"type": "CHEMICAL",
"text": [
"NaAsO(2)"
],
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[
1323,
1331
]
],
"normalized": []
},
{
"id": "23022324_T6",
"type": "CHEMICAL",
"text": [
"NaAsO(2)"
],
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[
1716,
1724
]
],
"normalized": []
},
{
"id": "23022324_T7",
"type": "CHEMICAL",
"text": [
"sodium arsenite"
],
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[
440,
455
]
],
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},
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"id": "23022324_T8",
"type": "CHEMICAL",
"text": [
"NaAsO(2)"
],
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457,
465
]
],
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},
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"id": "23022324_T9",
"type": "CHEMICAL",
"text": [
"NaAsO(2)"
],
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716,
724
]
],
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},
{
"id": "23022324_T10",
"type": "CHEMICAL",
"text": [
"NaAsO(2)"
],
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[
1000,
1008
]
],
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},
{
"id": "23022324_T11",
"type": "CHEMICAL",
"text": [
"NaAsO(2)"
],
"offsets": [
[
1061,
1069
]
],
"normalized": []
},
{
"id": "23022324_T12",
"type": "CHEMICAL",
"text": [
"sodium arsenite"
],
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[
82,
97
]
],
"normalized": []
},
{
"id": "23022324_T13",
"type": "GENE-N",
"text": [
"light and medium subunits of neurofilament"
],
"offsets": [
[
1365,
1407
]
],
"normalized": []
},
{
"id": "23022324_T14",
"type": "GENE-Y",
"text": [
"tau"
],
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[
1441,
1444
]
],
"normalized": []
},
{
"id": "23022324_T15",
"type": "GENE-N",
"text": [
"tubulin"
],
"offsets": [
[
1449,
1456
]
],
"normalized": []
},
{
"id": "23022324_T16",
"type": "GENE-Y",
"text": [
"heavy subunit of neurofilament"
],
"offsets": [
[
1543,
1573
]
],
"normalized": []
},
{
"id": "23022324_T17",
"type": "GENE-Y",
"text": [
"microtubule-associated protein 2"
],
"offsets": [
[
1575,
1607
]
],
"normalized": []
},
{
"id": "23022324_T18",
"type": "GENE-N",
"text": [
"actin"
],
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1612,
1617
]
],
"normalized": []
},
{
"id": "23022324_T19",
"type": "GENE-Y",
"text": [
"caspase-3"
],
"offsets": [
[
296,
305
]
],
"normalized": []
},
{
"id": "23022324_T20",
"type": "GENE-Y",
"text": [
"caspase-3"
],
"offsets": [
[
804,
813
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23022324_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23022324_T5",
"arg2_id": "23022324_T13",
"normalized": []
},
{
"id": "23022324_1",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23022324_T5",
"arg2_id": "23022324_T14",
"normalized": []
},
{
"id": "23022324_2",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23022324_T5",
"arg2_id": "23022324_T15",
"normalized": []
}
] |
8032658 | 8032658 | [
{
"id": "8032658_title",
"type": "title",
"text": [
"Further characterization of 5-hydroxytryptamine receptors (putative 5-HT2B) in rat stomach fundus longitudinal muscle."
],
"offsets": [
[
0,
118
]
]
},
{
"id": "8032658_abstract",
"type": "abstract",
"text": [
"1. The present study was undertaken to isolate and characterize pharmacologically homogeneous populations of 5-hydroxytryptamine (5-HT) receptors from a possible mixed receptor population mediating concentration of the longitudinal muscle of rat stomach fundus. Our aim was to extend the pharmacological characterization of the 5-HT2B receptor which is reported to be expressed in this preparation. 2. To minimize spontaneous activity and any influence of circular muscle on the contractile response, narrow (1-1.5 x 20 mm) segments of mucosa-denuded longitudinal muscle were used. Under these conditions, blockade of monoamine oxidase with pargyline (100 microM for 15 min) caused a leftward displacement of concentration-effect curves for both 5-methoxytryptamine (5-MeO-T) and tryptamine. Neither pargyline nor a number of uptake inhibitors affected responses to 5-HT. 3. In pargyline pretreated preparations, the order of potency of a number of tryptamine analogues was as follows: 5-MeO-T > or = alpha-Me-5-HT > or = 5-HT > 5-carboxamidotryptamine (5-CT) > tryptamine > 2-Me-5-HT. In addition several ligands known to act as agonists at either 5-HT2A or 5-HT2C receptors including 1-m-chlorophenylpiperazine (m-CPP), Ru 24969, MK 212 and SCH 23390 were also agonists in rat fundus whilst sumatriptan, renzapride and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) were very weak or inactive. With the exception of 2-Me-5-HT and m-CPP, most agonists produced monophasic concentration-effect curves consistent with an interaction at a single site. High concentrations of 2-Me-5-HT evoked relaxations which were blocked by phentolamine (1 MicroM) suggesting an interaction with alpha-adrenoceptors. m-CPP often evoked biphasic concentration-effect curves with a second contractile phase which was insensitive to yohimbine at concentrations higher than required for antagonism of responses to 5-HT.4. LY 53857, methiothepin, methysergide, ritanserin and ICI 170809 were potent but non-surmountable antagonists of 5-HT in rat fundus. In contrast, several ligands behaved as surmountable antagonists with the following order of potency: rauwolscine >yohimbine = mesulergine > mianserin = SB 204070 >WY 26703 > SB 200646> pirenpirone> renzapride. DAU 6285, granisetron, spiperone, ketanserin,phentolamine and GR 127935 did not affect responses to 5-HT at concentrations up to 1 pM. The agonist and concentration independent profile of antagonism supported a single site interaction for both agonists and antagonists.5. We conclude that despite small differences concerning the enantiomeric selectivity and affinity of rauwolscine and yohimbine, the close pharmacological identity of 5-HT receptors in rat stomach fundus and the recently cloned 5-HT2B receptor is maintained. SB 200646, which demonstrates some selectivity for 5-HT receptors in rat stomach fundus, should provide a useful ligand for confirmation of this view and allow discrimination of 5-HT2B function both in vitro and in vivo."
],
"offsets": [
[
119,
3116
]
]
}
] | [
{
"id": "8032658_T1",
"type": "CHEMICAL",
"text": [
"alpha-Me-5-HT"
],
"offsets": [
[
1120,
1133
]
],
"normalized": []
},
{
"id": "8032658_T2",
"type": "CHEMICAL",
"text": [
"5-HT"
],
"offsets": [
[
1141,
1145
]
],
"normalized": []
},
{
"id": "8032658_T3",
"type": "CHEMICAL",
"text": [
"5-carboxamidotryptamine"
],
"offsets": [
[
1148,
1171
]
],
"normalized": []
},
{
"id": "8032658_T4",
"type": "CHEMICAL",
"text": [
"5-CT"
],
"offsets": [
[
1173,
1177
]
],
"normalized": []
},
{
"id": "8032658_T5",
"type": "CHEMICAL",
"text": [
"tryptamine"
],
"offsets": [
[
1181,
1191
]
],
"normalized": []
},
{
"id": "8032658_T6",
"type": "CHEMICAL",
"text": [
"2-Me-5-HT"
],
"offsets": [
[
1194,
1203
]
],
"normalized": []
},
{
"id": "8032658_T7",
"type": "CHEMICAL",
"text": [
"5-hydroxytryptamine"
],
"offsets": [
[
228,
247
]
],
"normalized": []
},
{
"id": "8032658_T8",
"type": "CHEMICAL",
"text": [
"1-m-chlorophenylpiperazine"
],
"offsets": [
[
1305,
1331
]
],
"normalized": []
},
{
"id": "8032658_T9",
"type": "CHEMICAL",
"text": [
"m-CPP"
],
"offsets": [
[
1333,
1338
]
],
"normalized": []
},
{
"id": "8032658_T10",
"type": "CHEMICAL",
"text": [
"Ru 24969"
],
"offsets": [
[
1341,
1349
]
],
"normalized": []
},
{
"id": "8032658_T11",
"type": "CHEMICAL",
"text": [
"MK 212"
],
"offsets": [
[
1351,
1357
]
],
"normalized": []
},
{
"id": "8032658_T12",
"type": "CHEMICAL",
"text": [
"SCH 23390"
],
"offsets": [
[
1362,
1371
]
],
"normalized": []
},
{
"id": "8032658_T13",
"type": "CHEMICAL",
"text": [
"sumatriptan"
],
"offsets": [
[
1412,
1423
]
],
"normalized": []
},
{
"id": "8032658_T14",
"type": "CHEMICAL",
"text": [
"5-HT"
],
"offsets": [
[
249,
253
]
],
"normalized": []
},
{
"id": "8032658_T15",
"type": "CHEMICAL",
"text": [
"renzapride"
],
"offsets": [
[
1425,
1435
]
],
"normalized": []
},
{
"id": "8032658_T16",
"type": "CHEMICAL",
"text": [
"8-hydroxy-2-(di-n-propylamino) tetralin"
],
"offsets": [
[
1440,
1479
]
],
"normalized": []
},
{
"id": "8032658_T17",
"type": "CHEMICAL",
"text": [
"8-OH-DPAT"
],
"offsets": [
[
1481,
1490
]
],
"normalized": []
},
{
"id": "8032658_T18",
"type": "CHEMICAL",
"text": [
"2-Me-5-HT"
],
"offsets": [
[
1542,
1551
]
],
"normalized": []
},
{
"id": "8032658_T19",
"type": "CHEMICAL",
"text": [
"m-CPP"
],
"offsets": [
[
1556,
1561
]
],
"normalized": []
},
{
"id": "8032658_T20",
"type": "CHEMICAL",
"text": [
"yohimbine"
],
"offsets": [
[
1937,
1946
]
],
"normalized": []
},
{
"id": "8032658_T21",
"type": "CHEMICAL",
"text": [
"5-HT"
],
"offsets": [
[
2017,
2021
]
],
"normalized": []
},
{
"id": "8032658_T22",
"type": "CHEMICAL",
"text": [
"LY 53857"
],
"offsets": [
[
2025,
2033
]
],
"normalized": []
},
{
"id": "8032658_T23",
"type": "CHEMICAL",
"text": [
"methiothepin"
],
"offsets": [
[
2035,
2047
]
],
"normalized": []
},
{
"id": "8032658_T24",
"type": "CHEMICAL",
"text": [
"methysergide"
],
"offsets": [
[
2049,
2061
]
],
"normalized": []
},
{
"id": "8032658_T25",
"type": "CHEMICAL",
"text": [
"ritanserin"
],
"offsets": [
[
2063,
2073
]
],
"normalized": []
},
{
"id": "8032658_T26",
"type": "CHEMICAL",
"text": [
"ICI 170809"
],
"offsets": [
[
2078,
2088
]
],
"normalized": []
},
{
"id": "8032658_T27",
"type": "CHEMICAL",
"text": [
"5-HT"
],
"offsets": [
[
2137,
2141
]
],
"normalized": []
},
{
"id": "8032658_T28",
"type": "CHEMICAL",
"text": [
"rauwolscine"
],
"offsets": [
[
2259,
2270
]
],
"normalized": []
},
{
"id": "8032658_T29",
"type": "CHEMICAL",
"text": [
"yohimbine"
],
"offsets": [
[
2272,
2281
]
],
"normalized": []
},
{
"id": "8032658_T30",
"type": "CHEMICAL",
"text": [
"mesulergine"
],
"offsets": [
[
2284,
2295
]
],
"normalized": []
},
{
"id": "8032658_T31",
"type": "CHEMICAL",
"text": [
"mianserin"
],
"offsets": [
[
2298,
2307
]
],
"normalized": []
},
{
"id": "8032658_T32",
"type": "CHEMICAL",
"text": [
"SB 204070"
],
"offsets": [
[
2310,
2319
]
],
"normalized": []
},
{
"id": "8032658_T33",
"type": "CHEMICAL",
"text": [
"WY 26703"
],
"offsets": [
[
2321,
2329
]
],
"normalized": []
},
{
"id": "8032658_T34",
"type": "CHEMICAL",
"text": [
"SB 200646"
],
"offsets": [
[
2332,
2341
]
],
"normalized": []
},
{
"id": "8032658_T35",
"type": "CHEMICAL",
"text": [
"pirenpirone"
],
"offsets": [
[
2343,
2354
]
],
"normalized": []
},
{
"id": "8032658_T36",
"type": "CHEMICAL",
"text": [
"renzapride"
],
"offsets": [
[
2356,
2366
]
],
"normalized": []
},
{
"id": "8032658_T37",
"type": "CHEMICAL",
"text": [
"DAU 6285"
],
"offsets": [
[
2368,
2376
]
],
"normalized": []
},
{
"id": "8032658_T38",
"type": "CHEMICAL",
"text": [
"granisetron"
],
"offsets": [
[
2378,
2389
]
],
"normalized": []
},
{
"id": "8032658_T39",
"type": "CHEMICAL",
"text": [
"spiperone"
],
"offsets": [
[
2391,
2400
]
],
"normalized": []
},
{
"id": "8032658_T40",
"type": "CHEMICAL",
"text": [
"ketanserin"
],
"offsets": [
[
2402,
2412
]
],
"normalized": []
},
{
"id": "8032658_T41",
"type": "CHEMICAL",
"text": [
"phentolamine"
],
"offsets": [
[
2413,
2425
]
],
"normalized": []
},
{
"id": "8032658_T42",
"type": "CHEMICAL",
"text": [
"GR 127935"
],
"offsets": [
[
2430,
2439
]
],
"normalized": []
},
{
"id": "8032658_T43",
"type": "CHEMICAL",
"text": [
"5-HT"
],
"offsets": [
[
2468,
2472
]
],
"normalized": []
},
{
"id": "8032658_T44",
"type": "CHEMICAL",
"text": [
"rauwolscine"
],
"offsets": [
[
2739,
2750
]
],
"normalized": []
},
{
"id": "8032658_T45",
"type": "CHEMICAL",
"text": [
"yohimbine"
],
"offsets": [
[
2755,
2764
]
],
"normalized": []
},
{
"id": "8032658_T46",
"type": "CHEMICAL",
"text": [
"5-HT"
],
"offsets": [
[
2804,
2808
]
],
"normalized": []
},
{
"id": "8032658_T47",
"type": "CHEMICAL",
"text": [
"SB 200646"
],
"offsets": [
[
2896,
2905
]
],
"normalized": []
},
{
"id": "8032658_T48",
"type": "CHEMICAL",
"text": [
"5-HT"
],
"offsets": [
[
2947,
2951
]
],
"normalized": []
},
{
"id": "8032658_T49",
"type": "CHEMICAL",
"text": [
"monoamine"
],
"offsets": [
[
737,
746
]
],
"normalized": []
},
{
"id": "8032658_T50",
"type": "CHEMICAL",
"text": [
"pargyline"
],
"offsets": [
[
760,
769
]
],
"normalized": []
},
{
"id": "8032658_T51",
"type": "CHEMICAL",
"text": [
"5-methoxytryptamine"
],
"offsets": [
[
865,
884
]
],
"normalized": []
},
{
"id": "8032658_T52",
"type": "CHEMICAL",
"text": [
"5-MeO-T"
],
"offsets": [
[
886,
893
]
],
"normalized": []
},
{
"id": "8032658_T53",
"type": "CHEMICAL",
"text": [
"tryptamine"
],
"offsets": [
[
899,
909
]
],
"normalized": []
},
{
"id": "8032658_T54",
"type": "CHEMICAL",
"text": [
"pargyline"
],
"offsets": [
[
919,
928
]
],
"normalized": []
},
{
"id": "8032658_T55",
"type": "CHEMICAL",
"text": [
"5-HT"
],
"offsets": [
[
985,
989
]
],
"normalized": []
},
{
"id": "8032658_T56",
"type": "CHEMICAL",
"text": [
"pargyline"
],
"offsets": [
[
997,
1006
]
],
"normalized": []
},
{
"id": "8032658_T57",
"type": "CHEMICAL",
"text": [
"tryptamine"
],
"offsets": [
[
1068,
1078
]
],
"normalized": []
},
{
"id": "8032658_T58",
"type": "CHEMICAL",
"text": [
"5-MeO-T"
],
"offsets": [
[
1105,
1112
]
],
"normalized": []
},
{
"id": "8032658_T59",
"type": "CHEMICAL",
"text": [
"5-hydroxytryptamine"
],
"offsets": [
[
28,
47
]
],
"normalized": []
},
{
"id": "8032658_T60",
"type": "GENE-N",
"text": [
"5-hydroxytryptamine (5-HT) receptors"
],
"offsets": [
[
228,
264
]
],
"normalized": []
},
{
"id": "8032658_T61",
"type": "GENE-Y",
"text": [
"5-HT2A"
],
"offsets": [
[
1268,
1274
]
],
"normalized": []
},
{
"id": "8032658_T62",
"type": "GENE-Y",
"text": [
"5-HT2C"
],
"offsets": [
[
1278,
1284
]
],
"normalized": []
},
{
"id": "8032658_T63",
"type": "GENE-N",
"text": [
"alpha-adrenoceptors"
],
"offsets": [
[
1803,
1822
]
],
"normalized": []
},
{
"id": "8032658_T64",
"type": "GENE-N",
"text": [
"5-HT receptors"
],
"offsets": [
[
2804,
2818
]
],
"normalized": []
},
{
"id": "8032658_T65",
"type": "GENE-Y",
"text": [
"5-HT2B"
],
"offsets": [
[
2865,
2871
]
],
"normalized": []
},
{
"id": "8032658_T66",
"type": "GENE-N",
"text": [
"5-HT receptors"
],
"offsets": [
[
2947,
2961
]
],
"normalized": []
},
{
"id": "8032658_T67",
"type": "GENE-Y",
"text": [
"5-HT2B"
],
"offsets": [
[
3074,
3080
]
],
"normalized": []
},
{
"id": "8032658_T68",
"type": "GENE-Y",
"text": [
"5-HT2B"
],
"offsets": [
[
447,
453
]
],
"normalized": []
},
{
"id": "8032658_T69",
"type": "GENE-N",
"text": [
"monoamine oxidase"
],
"offsets": [
[
737,
754
]
],
"normalized": []
},
{
"id": "8032658_T70",
"type": "GENE-N",
"text": [
"5-hydroxytryptamine receptors"
],
"offsets": [
[
28,
57
]
],
"normalized": []
},
{
"id": "8032658_T71",
"type": "GENE-Y",
"text": [
"5-HT2B"
],
"offsets": [
[
68,
74
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "8032658_0",
"type": "INHIBITOR",
"arg1_id": "8032658_T50",
"arg2_id": "8032658_T69",
"normalized": []
},
{
"id": "8032658_1",
"type": "AGONIST",
"arg1_id": "8032658_T8",
"arg2_id": "8032658_T61",
"normalized": []
},
{
"id": "8032658_2",
"type": "AGONIST",
"arg1_id": "8032658_T8",
"arg2_id": "8032658_T62",
"normalized": []
},
{
"id": "8032658_3",
"type": "AGONIST",
"arg1_id": "8032658_T9",
"arg2_id": "8032658_T61",
"normalized": []
},
{
"id": "8032658_4",
"type": "AGONIST",
"arg1_id": "8032658_T9",
"arg2_id": "8032658_T62",
"normalized": []
},
{
"id": "8032658_5",
"type": "AGONIST",
"arg1_id": "8032658_T10",
"arg2_id": "8032658_T61",
"normalized": []
},
{
"id": "8032658_6",
"type": "AGONIST",
"arg1_id": "8032658_T10",
"arg2_id": "8032658_T62",
"normalized": []
},
{
"id": "8032658_7",
"type": "AGONIST",
"arg1_id": "8032658_T11",
"arg2_id": "8032658_T61",
"normalized": []
},
{
"id": "8032658_8",
"type": "AGONIST",
"arg1_id": "8032658_T11",
"arg2_id": "8032658_T62",
"normalized": []
},
{
"id": "8032658_9",
"type": "AGONIST",
"arg1_id": "8032658_T12",
"arg2_id": "8032658_T61",
"normalized": []
},
{
"id": "8032658_10",
"type": "AGONIST",
"arg1_id": "8032658_T12",
"arg2_id": "8032658_T62",
"normalized": []
}
] |
10805052 | 10805052 | [
{
"id": "10805052_title",
"type": "title",
"text": [
"Comparison of the AT1-receptor blocker, candesartan cilexetil, and the ACE inhibitor, lisinopril, in fixed combination with low dose hydrochlorothiazide in hypertensive patients."
],
"offsets": [
[
0,
178
]
]
},
{
"id": "10805052_abstract",
"type": "abstract",
"text": [
"AIM: To compare candesartan cilexetil and lisinopril in fixed combination with hydrochlorothiazide with respect to antihypertensive efficacy and tolerability. METHODS: This was a double-blind (double-dummy), randomised, parallel group comparison in patients with a mean sitting diastolic blood pressure 95-115 mm Hg on prior antihypertensive monotherapy. Treatments were candesartan cilexetil/hydrochlorothiazide 8/12.5 mg once daily (n = 237) and lisinopril/hydrochlorothiazide 10/12.5 mg once daily (n = 116) for 26 weeks. The primary efficacy variable was change in trough sitting diastolic blood pressure. RESULTS: Changes in mean sitting diastolic blood pressure did not differ significantly between the groups (mean difference 0.5 mm Hg; 95% confidence interval -1.6, 2.7, P = 0.20). No significant differences between the groups was found for other haemodynamic variables (sitting systolic blood pressure, standing blood pressure, sitting/erect heart rate, and proportion of responders and controlled patients). Both drugs were well tolerated but the proportion of patients with at least one adverse event was significantly greater in the lisinopril group (80% vs 69%, P = 0.020). The proportion of patients spontaneously reporting cough (23.1% vs 4.6%) and discontinuing therapy due to adverse events (12.0% vs 5.9%) was also higher in the lisinopril group compared with the candesartan cilexetil group. CONCLUSIONS: The fixed combinations of candesartan cilexetil and hydrochlorothiazide 8/12.5 mg and lisinopril and hydrochlorothiazide 10/12.5 mg once daily are equally effective as antihypertensive agents. The fixed combination containing candesartan cilexetil is better tolerated than that containing lisinopril."
],
"offsets": [
[
179,
1904
]
]
}
] | [
{
"id": "10805052_T1",
"type": "CHEMICAL",
"text": [
"lisinopril"
],
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[
1325,
1335
]
],
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},
{
"id": "10805052_T2",
"type": "CHEMICAL",
"text": [
"lisinopril"
],
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1527,
1537
]
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{
"id": "10805052_T3",
"type": "CHEMICAL",
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"candesartan cilexetil"
],
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1562,
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]
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{
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"candesartan cilexetil"
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1630,
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{
"id": "10805052_T5",
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"hydrochlorothiazide"
],
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1656,
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]
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"id": "10805052_T6",
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"lisinopril"
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"hydrochlorothiazide"
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"candesartan cilexetil"
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195,
216
]
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{
"id": "10805052_T9",
"type": "CHEMICAL",
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"candesartan cilexetil"
],
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1830,
1851
]
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{
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"lisinopril"
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1903
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"id": "10805052_T11",
"type": "CHEMICAL",
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"candesartan cilexetil"
],
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550,
571
]
],
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{
"id": "10805052_T12",
"type": "CHEMICAL",
"text": [
"hydrochlorothiazide"
],
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[
572,
591
]
],
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{
"id": "10805052_T13",
"type": "CHEMICAL",
"text": [
"lisinopril"
],
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[
221,
231
]
],
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},
{
"id": "10805052_T14",
"type": "CHEMICAL",
"text": [
"lisinopril"
],
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[
627,
637
]
],
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},
{
"id": "10805052_T15",
"type": "CHEMICAL",
"text": [
"hydrochlorothiazide"
],
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[
638,
657
]
],
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},
{
"id": "10805052_T16",
"type": "CHEMICAL",
"text": [
"hydrochlorothiazide"
],
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[
258,
277
]
],
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{
"id": "10805052_T17",
"type": "CHEMICAL",
"text": [
"hydrochlorothiazide"
],
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[
133,
152
]
],
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},
{
"id": "10805052_T18",
"type": "CHEMICAL",
"text": [
"candesartan cilexetil"
],
"offsets": [
[
40,
61
]
],
"normalized": []
},
{
"id": "10805052_T19",
"type": "CHEMICAL",
"text": [
"lisinopril"
],
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[
86,
96
]
],
"normalized": []
},
{
"id": "10805052_T20",
"type": "GENE-Y",
"text": [
"AT1-receptor"
],
"offsets": [
[
18,
30
]
],
"normalized": []
},
{
"id": "10805052_T21",
"type": "GENE-Y",
"text": [
"ACE"
],
"offsets": [
[
71,
74
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "10805052_0",
"type": "INHIBITOR",
"arg1_id": "10805052_T18",
"arg2_id": "10805052_T20",
"normalized": []
},
{
"id": "10805052_1",
"type": "INHIBITOR",
"arg1_id": "10805052_T19",
"arg2_id": "10805052_T21",
"normalized": []
}
] |
23474645 | 23474645 | [
{
"id": "23474645_title",
"type": "title",
"text": [
"Inverted CdSe/CdS/ZnS quantum dot light emitting devices with titanium dioxide as an electron-injection contact."
],
"offsets": [
[
0,
112
]
]
},
{
"id": "23474645_abstract",
"type": "abstract",
"text": [
"We demonstrated the fabrication of inverted CdSe/CdS/ZnS quantum dot light emitting devices (QD-LEDs) using titanium dioxide (TiO2) as an electron-injection layer and investigated the operating mechanism by utilizing different hole-transport materials, 4,4-N,N-dicarbazole-biphenyl (CBP) and 4,4',4''-tris(carbazol-9-yl)-triphenylamine (TCTA). A more efficient device with CBP as the hole-transport layer (HTL) was obtained compared with the TCTA based device. The peak efficiency of 6.70 cd A(-1) for the CBP based device was found to be about 74.5% higher than the TCTA based device (3.84 cd A(-1)). The studies on the time-resolved photoluminescence spectra of the QD-HTL composite structures showed that the energy transfer (ET) efficiencies from the two HTLs to the QD layer were similar and the charge separation between QDs and HTLs could be neglected. The enhancement in the performance of the CBP based device was attributed to the more efficient hole-injection from CBP to QDs."
],
"offsets": [
[
113,
1100
]
]
}
] | [
{
"id": "23474645_T1",
"type": "CHEMICAL",
"text": [
"titanium dioxide"
],
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[
221,
237
]
],
"normalized": []
},
{
"id": "23474645_T2",
"type": "CHEMICAL",
"text": [
"TiO2"
],
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[
239,
243
]
],
"normalized": []
},
{
"id": "23474645_T3",
"type": "CHEMICAL",
"text": [
"4,4-N,N-dicarbazole-biphenyl"
],
"offsets": [
[
366,
394
]
],
"normalized": []
},
{
"id": "23474645_T4",
"type": "CHEMICAL",
"text": [
"CBP"
],
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[
396,
399
]
],
"normalized": []
},
{
"id": "23474645_T5",
"type": "CHEMICAL",
"text": [
"4,4',4''-tris(carbazol-9-yl)-triphenylamine"
],
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[
405,
448
]
],
"normalized": []
},
{
"id": "23474645_T6",
"type": "CHEMICAL",
"text": [
"TCTA"
],
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[
450,
454
]
],
"normalized": []
},
{
"id": "23474645_T7",
"type": "CHEMICAL",
"text": [
"TCTA"
],
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[
555,
559
]
],
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},
{
"id": "23474645_T8",
"type": "CHEMICAL",
"text": [
"CdSe"
],
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[
157,
161
]
],
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},
{
"id": "23474645_T9",
"type": "CHEMICAL",
"text": [
"CdS"
],
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[
162,
165
]
],
"normalized": []
},
{
"id": "23474645_T10",
"type": "CHEMICAL",
"text": [
"ZnS"
],
"offsets": [
[
166,
169
]
],
"normalized": []
},
{
"id": "23474645_T11",
"type": "CHEMICAL",
"text": [
"TCTA"
],
"offsets": [
[
680,
684
]
],
"normalized": []
},
{
"id": "23474645_T12",
"type": "CHEMICAL",
"text": [
"CdS"
],
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[
14,
17
]
],
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},
{
"id": "23474645_T13",
"type": "CHEMICAL",
"text": [
"ZnS"
],
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[
18,
21
]
],
"normalized": []
},
{
"id": "23474645_T14",
"type": "CHEMICAL",
"text": [
"titanium dioxide"
],
"offsets": [
[
62,
78
]
],
"normalized": []
},
{
"id": "23474645_T15",
"type": "CHEMICAL",
"text": [
"CdSe"
],
"offsets": [
[
9,
13
]
],
"normalized": []
}
] | [] | [] | [] |
23245513 | 23245513 | [
{
"id": "23245513_title",
"type": "title",
"text": [
"A dimeric form of N-methoxycarbonyl-2-amino-1,8-naphthyridine bound to the A-A mismatch in the CAG/CAG base triad in dsRNA."
],
"offsets": [
[
0,
123
]
]
},
{
"id": "23245513_abstract",
"type": "abstract",
"text": [
"A dimeric form of N-methoxycarbonyl-2-amino-1,8-naphthyridine (MCND) connected at the C2 position with a three-atom linker was examined for the binding to mismatches in double stranded RNA. Despite the fully complementary hydrogen bonding groups to guanine, MCND did not bind to guanine-guanine mismatch but did to adenine-adenine mismatch. The base pairs flanking the mismatch had weak effect on the binding, with showing the strongest binding to the A-A mismatch in the CAG/CAG sequence. The A-A mismatch in the GAC/GAC sequence was a poor substrate for the MCND binding. A monomeric derivative of MCND and another derivative lacking a methylcarbamate group showed negligilble binding to the A-A mismatch and the sequence selectivity. These results are important clues for the better molecular design of RNA binding small molecules."
],
"offsets": [
[
124,
958
]
]
}
] | [
{
"id": "23245513_T1",
"type": "CHEMICAL",
"text": [
"N-methoxycarbonyl-2-amino-1,8-naphthyridine"
],
"offsets": [
[
142,
185
]
],
"normalized": []
},
{
"id": "23245513_T2",
"type": "CHEMICAL",
"text": [
"hydrogen"
],
"offsets": [
[
346,
354
]
],
"normalized": []
},
{
"id": "23245513_T3",
"type": "CHEMICAL",
"text": [
"guanine"
],
"offsets": [
[
373,
380
]
],
"normalized": []
},
{
"id": "23245513_T4",
"type": "CHEMICAL",
"text": [
"MCND"
],
"offsets": [
[
382,
386
]
],
"normalized": []
},
{
"id": "23245513_T5",
"type": "CHEMICAL",
"text": [
"guanine"
],
"offsets": [
[
403,
410
]
],
"normalized": []
},
{
"id": "23245513_T6",
"type": "CHEMICAL",
"text": [
"guanine"
],
"offsets": [
[
411,
418
]
],
"normalized": []
},
{
"id": "23245513_T7",
"type": "CHEMICAL",
"text": [
"adenine"
],
"offsets": [
[
439,
446
]
],
"normalized": []
},
{
"id": "23245513_T8",
"type": "CHEMICAL",
"text": [
"adenine"
],
"offsets": [
[
447,
454
]
],
"normalized": []
},
{
"id": "23245513_T9",
"type": "CHEMICAL",
"text": [
"MCND"
],
"offsets": [
[
684,
688
]
],
"normalized": []
},
{
"id": "23245513_T10",
"type": "CHEMICAL",
"text": [
"MCND"
],
"offsets": [
[
724,
728
]
],
"normalized": []
},
{
"id": "23245513_T11",
"type": "CHEMICAL",
"text": [
"MCND"
],
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[
187,
191
]
],
"normalized": []
},
{
"id": "23245513_T12",
"type": "CHEMICAL",
"text": [
"methylcarbamate"
],
"offsets": [
[
762,
777
]
],
"normalized": []
},
{
"id": "23245513_T13",
"type": "CHEMICAL",
"text": [
"N-methoxycarbonyl-2-amino-1,8-naphthyridine"
],
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[
18,
61
]
],
"normalized": []
},
{
"id": "23245513_T14",
"type": "GENE-N",
"text": [
"CAG"
],
"offsets": [
[
596,
599
]
],
"normalized": []
},
{
"id": "23245513_T15",
"type": "GENE-N",
"text": [
"CAG"
],
"offsets": [
[
600,
603
]
],
"normalized": []
},
{
"id": "23245513_T16",
"type": "GENE-N",
"text": [
"GAC"
],
"offsets": [
[
638,
641
]
],
"normalized": []
},
{
"id": "23245513_T17",
"type": "GENE-N",
"text": [
"GAC"
],
"offsets": [
[
642,
645
]
],
"normalized": []
},
{
"id": "23245513_T18",
"type": "GENE-N",
"text": [
"CAG"
],
"offsets": [
[
95,
98
]
],
"normalized": []
},
{
"id": "23245513_T19",
"type": "GENE-N",
"text": [
"CAG"
],
"offsets": [
[
99,
102
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23245513_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "23245513_T13",
"arg2_id": "23245513_T18",
"normalized": []
},
{
"id": "23245513_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "23245513_T13",
"arg2_id": "23245513_T19",
"normalized": []
},
{
"id": "23245513_2",
"type": "SUBSTRATE",
"arg1_id": "23245513_T9",
"arg2_id": "23245513_T16",
"normalized": []
},
{
"id": "23245513_3",
"type": "SUBSTRATE",
"arg1_id": "23245513_T9",
"arg2_id": "23245513_T17",
"normalized": []
}
] |
11716850 | 11716850 | [
{
"id": "11716850_title",
"type": "title",
"text": [
"The effects of mitiglinide (KAD-1229), a new anti-diabetic drug, on ATP-sensitive K+ channels and insulin secretion: comparison with the sulfonylureas and nateglinide."
],
"offsets": [
[
0,
167
]
]
},
{
"id": "11716850_abstract",
"type": "abstract",
"text": [
"Mitiglinide (KAD-1229), a new anti-diabetic drug, is thought to stimulate insulin secretion by closing the ATP-sensitive K+ (K(ATP)) channels in pancreatic beta-cells. However, its selectivity for the various K(ATP) channels is not known. In this study, we examined the effects of mitiglinide on various cloned K(ATP) channels (Kir6.2/SUR1, Kir6.2/SUR2A, and Kir6.2/SUR2B) reconstituted in COS-1 cells, and compared them to another meglitinide-related compound, nateglinide. Patch-clamp analysis using inside-out recording configuration showed that mitiglinide inhibits the Kir6.2/SUR1 channel currents in a dose-dependent manner (IC50 value, 100 nM) but does not significantly inhibit either Kir6.2/SUR2A or Kir6.2/SUR2B channel currents even at high doses (more than 10 microM). Nateglinide inhibits Kir6.2/SUR1 and Kir6.2/SUR2B channels at 100 nM, and inhibits Kir6.2/SUR2A channels at high concentrations (1 microM). Binding experiments on mitiglinide, nateglinide, and repaglinide to SUR1 expressed in COS-1 cells revealed that they inhibit the binding of [3H]glibenclamide to SUR1 (IC50 values: mitiglinide, 280 nM; nateglinide, 8 microM; repaglinide, 1.6 microM), suggesting that they all share a glibenclamide binding site. The insulin responses to glucose, mitiglinide, tolbutamide, and glibenclamide in MIN6 cells after chronic mitiglinide, nateglinide, or repaglinide treatment were comparable to those after chronic tolbutamide and glibenclamide treatment. These results indicate that, similar to the sulfonylureas, mitiglinide is highly specific to the Kir6.2/SUR1 complex, i.e., the pancreatic beta-cell K(ATP) channel, and suggest that mitiglinide may be a clinically useful anti-diabetic drug."
],
"offsets": [
[
168,
1877
]
]
}
] | [
{
"id": "11716850_T1",
"type": "CHEMICAL",
"text": [
"Mitiglinide"
],
"offsets": [
[
168,
179
]
],
"normalized": []
},
{
"id": "11716850_T2",
"type": "CHEMICAL",
"text": [
"[3H]glibenclamide"
],
"offsets": [
[
1229,
1246
]
],
"normalized": []
},
{
"id": "11716850_T3",
"type": "CHEMICAL",
"text": [
"ATP"
],
"offsets": [
[
275,
278
]
],
"normalized": []
},
{
"id": "11716850_T4",
"type": "CHEMICAL",
"text": [
"mitiglinide"
],
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[
1269,
1280
]
],
"normalized": []
},
{
"id": "11716850_T5",
"type": "CHEMICAL",
"text": [
"nateglinide"
],
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[
1290,
1301
]
],
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},
{
"id": "11716850_T6",
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"text": [
"repaglinide"
],
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[
1313,
1324
]
],
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},
{
"id": "11716850_T7",
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"text": [
"glibenclamide"
],
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[
1372,
1385
]
],
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},
{
"id": "11716850_T8",
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"K+"
],
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[
289,
291
]
],
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},
{
"id": "11716850_T9",
"type": "CHEMICAL",
"text": [
"K"
],
"offsets": [
[
293,
294
]
],
"normalized": []
},
{
"id": "11716850_T10",
"type": "CHEMICAL",
"text": [
"glucose"
],
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[
1425,
1432
]
],
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},
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"id": "11716850_T11",
"type": "CHEMICAL",
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"mitiglinide"
],
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[
1434,
1445
]
],
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},
{
"id": "11716850_T12",
"type": "CHEMICAL",
"text": [
"ATP"
],
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[
295,
298
]
],
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},
{
"id": "11716850_T13",
"type": "CHEMICAL",
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"tolbutamide"
],
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[
1447,
1458
]
],
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},
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"id": "11716850_T14",
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"text": [
"glibenclamide"
],
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[
1464,
1477
]
],
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},
{
"id": "11716850_T15",
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"text": [
"KAD-1229"
],
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[
181,
189
]
],
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},
{
"id": "11716850_T16",
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"mitiglinide"
],
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[
1506,
1517
]
],
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},
{
"id": "11716850_T17",
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"nateglinide"
],
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[
1519,
1530
]
],
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},
{
"id": "11716850_T18",
"type": "CHEMICAL",
"text": [
"repaglinide"
],
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[
1535,
1546
]
],
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},
{
"id": "11716850_T19",
"type": "CHEMICAL",
"text": [
"tolbutamide"
],
"offsets": [
[
1596,
1607
]
],
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},
{
"id": "11716850_T20",
"type": "CHEMICAL",
"text": [
"glibenclamide"
],
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[
1612,
1625
]
],
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},
{
"id": "11716850_T21",
"type": "CHEMICAL",
"text": [
"sulfonylureas"
],
"offsets": [
[
1681,
1694
]
],
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},
{
"id": "11716850_T22",
"type": "CHEMICAL",
"text": [
"mitiglinide"
],
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[
1696,
1707
]
],
"normalized": []
},
{
"id": "11716850_T23",
"type": "CHEMICAL",
"text": [
"K"
],
"offsets": [
[
1786,
1787
]
],
"normalized": []
},
{
"id": "11716850_T24",
"type": "CHEMICAL",
"text": [
"ATP"
],
"offsets": [
[
1788,
1791
]
],
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},
{
"id": "11716850_T25",
"type": "CHEMICAL",
"text": [
"mitiglinide"
],
"offsets": [
[
1819,
1830
]
],
"normalized": []
},
{
"id": "11716850_T26",
"type": "CHEMICAL",
"text": [
"K"
],
"offsets": [
[
377,
378
]
],
"normalized": []
},
{
"id": "11716850_T27",
"type": "CHEMICAL",
"text": [
"ATP"
],
"offsets": [
[
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15894928 | 15894928 | [
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"GTC to GAC"
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"V561D"
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"PDGFRA"
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48,
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]
],
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}
] | [] | [] | [] |
15066664 | 15066664 | [
{
"id": "15066664_title",
"type": "title",
"text": [
"Block of human NaV1.5 sodium channels by novel alpha-hydroxyphenylamide analogues of phenytoin."
],
"offsets": [
[
0,
95
]
]
},
{
"id": "15066664_abstract",
"type": "abstract",
"text": [
"Voltage-gated sodium (Na) channels are a critical component of electrically excitable cells. Phenytoin (diphenylhydantoin, DPH) is an established sodium channel blocker and is a useful anticonvulsant and class 1b antiarrhythmic, and has been effectively used in the treatment of neuropathic pain. In this study, we have synthesized novel alpha-hydroxyphenylamide analogues of diphenylhydantoin and examined their ability to inhibit human Na(V)1.5 sodium channels expressed in Chinese Hamster Ovary (CHO-K1) cells. Phenyl ring substitutions were examined including para-methyl, para-fluoro, para-chloro, ortho-chloro and meta-chloro. We have found that phenyl ring substitutions with electron withdrawing properties resulted in compounds with greater activity. In comparison to diphenylhydantoin, the novel chloro-substituted alpha-hydroxyphenylamide compounds produced as much as a 20-fold greater tonic and frequency-dependent blockade of Na(V)1.5 channels with an IC(50) value of 14.5 microM. In addition, the chloro-substitutions have position specific state dependent blocking properties. The ortho-, meta- and para-chloro substitutions have an 8-, 13- and 3-fold increased affinity for the inactivated state, respectively. Molecular modeling suggests that these differences in affinity are due to a direct interaction with the receptor. Comparing models of diphenylhydantoin to the novel alpha-hydroxyphenlyamide compound suggests that the increased activity may be due to an optimized phenyl ring position and increased molecular volume. This information may be useful in the development of more potent sodium channel blockers."
],
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96,
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]
]
}
] | [
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"id": "15066664_T1",
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"chloro"
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]
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"id": "15066664_T2",
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"diphenylhydantoin"
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]
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"id": "15066664_T3",
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]
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"id": "15066664_T4",
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"DPH"
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219,
222
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"alpha-hydroxyphenlyamide"
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"sodium"
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110,
116
]
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"sodium"
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242,
248
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"sodium"
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"id": "15066664_T11",
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"Na"
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118,
120
]
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"alpha-hydroxyphenylamide"
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458
]
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"diphenylhydantoin"
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472,
489
]
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"id": "15066664_T14",
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"text": [
"sodium"
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543,
549
]
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"Phenyl"
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610,
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]
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"para-methyl"
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660,
671
]
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"para-fluoro"
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673,
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]
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"para-chloro"
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686,
697
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699,
711
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716,
727
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"phenyl"
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873,
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"id": "15066664_T23",
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902,
908
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"id": "15066664_T24",
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945
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"id": "15066664_T25",
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"Phenytoin"
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189,
198
]
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"id": "15066664_T26",
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"sodium"
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22,
28
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"alpha-hydroxyphenylamide"
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47,
71
]
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"id": "15066664_T28",
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"text": [
"phenytoin"
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85,
94
]
],
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},
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"id": "15066664_T29",
"type": "GENE-N",
"text": [
"Voltage-gated sodium (Na) channels"
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96,
130
]
],
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},
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"id": "15066664_T30",
"type": "GENE-N",
"text": [
"sodium channel"
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242,
256
]
],
"normalized": []
},
{
"id": "15066664_T31",
"type": "GENE-N",
"text": [
"sodium channel"
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[
1705,
1719
]
],
"normalized": []
},
{
"id": "15066664_T32",
"type": "GENE-Y",
"text": [
"human Na(V)1.5"
],
"offsets": [
[
528,
542
]
],
"normalized": []
},
{
"id": "15066664_T33",
"type": "GENE-N",
"text": [
"sodium channels"
],
"offsets": [
[
543,
558
]
],
"normalized": []
},
{
"id": "15066664_T34",
"type": "GENE-Y",
"text": [
"Na(V)1.5"
],
"offsets": [
[
1036,
1044
]
],
"normalized": []
},
{
"id": "15066664_T35",
"type": "GENE-N",
"text": [
"sodium channels"
],
"offsets": [
[
22,
37
]
],
"normalized": []
},
{
"id": "15066664_T36",
"type": "GENE-Y",
"text": [
"human NaV1.5"
],
"offsets": [
[
9,
21
]
],
"normalized": []
}
] | [] | [] | [
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"id": "15066664_1",
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},
{
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},
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"id": "15066664_12",
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"arg2_id": "15066664_T34",
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},
{
"id": "15066664_13",
"type": "INHIBITOR",
"arg1_id": "15066664_T24",
"arg2_id": "15066664_T34",
"normalized": []
}
] |
23267840 | 23267840 | [
{
"id": "23267840_title",
"type": "title",
"text": [
"NMDA and AMPA receptor mediated excitotoxicity in cerebral cortex of streptozotocin induced diabetic rat: ameliorating effects of curcumin."
],
"offsets": [
[
0,
139
]
]
},
{
"id": "23267840_abstract",
"type": "abstract",
"text": [
"Functional activity of neurotransmitter receptor and their sensitivity to regulation are altered in DM. We evaluated the neuroprotective effect of curcumin in glutamate mediated excitotoxicity in cerebral cortex of streptozotocin induced diabetic rats. Gene expression studies in diabetic rats showed a down regulation of glutamate decarboxylase mRNA leading to accumulation of glutamate. Radioreceptor binding assays showed a significant increase in α-amino-3-hydroxy-5-methyl-4-isoxazole propionate and N-methyl-D-aspartate receptors density which was confirmed by immunohistochemical studies. Decreased glutathione peroxidases gene expression indicates enhanced oxidative stress in diabetic rats. This leads to decreased expression of glutamate aspartate transporter, which in turn reduces glutamate transport. All these events lead to excitotoxic neuronal death in the cerebral cortex, which was confirmed by the increased expression of caspase 3, caspase 8 and BCL2-associated X protein. Curcumin and insulin treatment reversed these altered parameters to near control. We establish, a novel therapeutic role of curcumin by reducing the glutamate mediated excitotoxicity in cerebral cortex of diabetes through modulating the altered neurochemical parameters."
],
"offsets": [
[
140,
1403
]
]
}
] | [
{
"id": "23267840_T1",
"type": "CHEMICAL",
"text": [
"curcumin"
],
"offsets": [
[
1257,
1265
]
],
"normalized": []
},
{
"id": "23267840_T2",
"type": "CHEMICAL",
"text": [
"glutamate"
],
"offsets": [
[
1282,
1291
]
],
"normalized": []
},
{
"id": "23267840_T3",
"type": "CHEMICAL",
"text": [
"curcumin"
],
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[
287,
295
]
],
"normalized": []
},
{
"id": "23267840_T4",
"type": "CHEMICAL",
"text": [
"glutamate"
],
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[
299,
308
]
],
"normalized": []
},
{
"id": "23267840_T5",
"type": "CHEMICAL",
"text": [
"streptozotocin"
],
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[
355,
369
]
],
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"id": "23267840_T6",
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"glutamate"
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462,
471
]
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"id": "23267840_T7",
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"glutamate"
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518,
527
]
],
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},
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"id": "23267840_T8",
"type": "CHEMICAL",
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],
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591,
640
]
],
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},
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"id": "23267840_T9",
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"N-methyl-D-aspartate"
],
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645,
665
]
],
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},
{
"id": "23267840_T10",
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"text": [
"glutathione"
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746,
757
]
],
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},
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"id": "23267840_T11",
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"text": [
"glutamate"
],
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878,
887
]
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},
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"id": "23267840_T12",
"type": "CHEMICAL",
"text": [
"aspartate"
],
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[
888,
897
]
],
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},
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"id": "23267840_T13",
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"glutamate"
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933,
942
]
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},
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"id": "23267840_T14",
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"Curcumin"
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1133,
1141
]
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},
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"id": "23267840_T15",
"type": "CHEMICAL",
"text": [
"NMDA"
],
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0,
4
]
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},
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"id": "23267840_T16",
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130,
138
]
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"id": "23267840_T17",
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69,
83
]
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},
{
"id": "23267840_T18",
"type": "CHEMICAL",
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"AMPA"
],
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[
9,
13
]
],
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},
{
"id": "23267840_T19",
"type": "GENE-Y",
"text": [
"insulin"
],
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1146,
1153
]
],
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},
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"id": "23267840_T20",
"type": "GENE-N",
"text": [
"neurotransmitter receptor"
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163,
188
]
],
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},
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"id": "23267840_T21",
"type": "GENE-Y",
"text": [
"glutamate decarboxylase"
],
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[
462,
485
]
],
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},
{
"id": "23267840_T22",
"type": "GENE-N",
"text": [
"α-amino-3-hydroxy-5-methyl-4-isoxazole propionate and N-methyl-D-aspartate receptors"
],
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[
591,
675
]
],
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},
{
"id": "23267840_T23",
"type": "GENE-N",
"text": [
"glutathione peroxidases"
],
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[
746,
769
]
],
"normalized": []
},
{
"id": "23267840_T24",
"type": "GENE-Y",
"text": [
"glutamate aspartate transporter"
],
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[
878,
909
]
],
"normalized": []
},
{
"id": "23267840_T25",
"type": "GENE-Y",
"text": [
"caspase 3"
],
"offsets": [
[
1081,
1090
]
],
"normalized": []
},
{
"id": "23267840_T26",
"type": "GENE-Y",
"text": [
"caspase 8"
],
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[
1092,
1101
]
],
"normalized": []
},
{
"id": "23267840_T27",
"type": "GENE-Y",
"text": [
"BCL2-associated X protein"
],
"offsets": [
[
1106,
1131
]
],
"normalized": []
},
{
"id": "23267840_T28",
"type": "GENE-N",
"text": [
"NMDA and AMPA receptor"
],
"offsets": [
[
0,
22
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23267840_0",
"type": "SUBSTRATE",
"arg1_id": "23267840_T13",
"arg2_id": "23267840_T24",
"normalized": []
}
] |
15572277 | 15572277 | [
{
"id": "15572277_title",
"type": "title",
"text": [
"Adenosine A1 receptors and the anticonvulsant potential of drugs effective in the model of 3-nitropropionic acid-induced seizures in mice."
],
"offsets": [
[
0,
138
]
]
},
{
"id": "15572277_abstract",
"type": "abstract",
"text": [
"The role of adenosine A1 receptors in the activity of drugs and substances protecting against seizures evoked by mitochondrial toxin, 3-nitropropionic acid (3-NPA) was studied in mice. Non-selective A1/A2 adenosine receptor antagonist, aminophylline and selective A1 adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) diminished the anticonvulsive effects of diazepam, phenobarbital, valproate and gabapentin. In contrast, A1/A2 adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline (8pSPT) not penetrating via blood-brain barrier was ineffective. Aminophylline and DPCPX but not 8pSPT also reversed the protective action of A1/A2 adenosine receptor agonist, 2-chloroadenosine (2-CADO) and selective A1 adenosine receptor agonist, R-N6-phenylisopropyloadenosine (R-PIA), against 3-NPA-evoked convulsions. Obtained results suggest that the central adenosine A1 receptor stimulation may play a role in the anticonvulsive potential of diazepam, phenobarbital, valproate and gabapentin in a novel model of 3-NPA-evoked seizures. Moreover, concomitant application of aminophylline with these drugs may reduce their clinical antiepileptic efficacy, especially among patients suffering from seizures related to the disturbances of mitochondrial respiratory chain."
],
"offsets": [
[
139,
1425
]
]
}
] | [
{
"id": "15572277_T1",
"type": "CHEMICAL",
"text": [
"gabapentin"
],
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[
1140,
1150
]
],
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},
{
"id": "15572277_T2",
"type": "CHEMICAL",
"text": [
"3-NPA"
],
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[
1171,
1176
]
],
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},
{
"id": "15572277_T3",
"type": "CHEMICAL",
"text": [
"aminophylline"
],
"offsets": [
[
1231,
1244
]
],
"normalized": []
},
{
"id": "15572277_T4",
"type": "CHEMICAL",
"text": [
"adenosine"
],
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[
151,
160
]
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"id": "15572277_T5",
"type": "CHEMICAL",
"text": [
"3-nitropropionic acid"
],
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[
273,
294
]
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},
{
"id": "15572277_T6",
"type": "CHEMICAL",
"text": [
"3-NPA"
],
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[
296,
301
]
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{
"id": "15572277_T7",
"type": "CHEMICAL",
"text": [
"adenosine"
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[
344,
353
]
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{
"id": "15572277_T8",
"type": "CHEMICAL",
"text": [
"aminophylline"
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[
375,
388
]
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{
"id": "15572277_T9",
"type": "CHEMICAL",
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"adenosine"
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[
406,
415
]
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{
"id": "15572277_T10",
"type": "CHEMICAL",
"text": [
"8-cyclopentyl-1,3-dipropylxanthine"
],
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[
437,
471
]
],
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},
{
"id": "15572277_T11",
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"DPCPX"
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[
473,
478
]
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{
"id": "15572277_T12",
"type": "CHEMICAL",
"text": [
"diazepam"
],
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521,
529
]
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{
"id": "15572277_T13",
"type": "CHEMICAL",
"text": [
"phenobarbital"
],
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[
531,
544
]
],
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},
{
"id": "15572277_T14",
"type": "CHEMICAL",
"text": [
"valproate"
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[
546,
555
]
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},
{
"id": "15572277_T15",
"type": "CHEMICAL",
"text": [
"gabapentin"
],
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[
560,
570
]
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},
{
"id": "15572277_T16",
"type": "CHEMICAL",
"text": [
"adenosine"
],
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[
591,
600
]
],
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},
{
"id": "15572277_T17",
"type": "CHEMICAL",
"text": [
"8-(p-sulfophenyl)theophylline"
],
"offsets": [
[
622,
651
]
],
"normalized": []
},
{
"id": "15572277_T18",
"type": "CHEMICAL",
"text": [
"8pSPT"
],
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[
653,
658
]
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},
{
"id": "15572277_T19",
"type": "CHEMICAL",
"text": [
"Aminophylline"
],
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[
717,
730
]
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},
{
"id": "15572277_T20",
"type": "CHEMICAL",
"text": [
"DPCPX"
],
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[
735,
740
]
],
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},
{
"id": "15572277_T21",
"type": "CHEMICAL",
"text": [
"8pSPT"
],
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[
749,
754
]
],
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},
{
"id": "15572277_T22",
"type": "CHEMICAL",
"text": [
"adenosine"
],
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[
800,
809
]
],
"normalized": []
},
{
"id": "15572277_T23",
"type": "CHEMICAL",
"text": [
"2-chloroadenosine"
],
"offsets": [
[
828,
845
]
],
"normalized": []
},
{
"id": "15572277_T24",
"type": "CHEMICAL",
"text": [
"2-CADO"
],
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[
847,
853
]
],
"normalized": []
},
{
"id": "15572277_T25",
"type": "CHEMICAL",
"text": [
"adenosine"
],
"offsets": [
[
872,
881
]
],
"normalized": []
},
{
"id": "15572277_T26",
"type": "CHEMICAL",
"text": [
"R-N6-phenylisopropyloadenosine"
],
"offsets": [
[
900,
930
]
],
"normalized": []
},
{
"id": "15572277_T27",
"type": "CHEMICAL",
"text": [
"R-PIA"
],
"offsets": [
[
932,
937
]
],
"normalized": []
},
{
"id": "15572277_T28",
"type": "CHEMICAL",
"text": [
"3-NPA"
],
"offsets": [
[
948,
953
]
],
"normalized": []
},
{
"id": "15572277_T29",
"type": "CHEMICAL",
"text": [
"adenosine"
],
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[
1016,
1025
]
],
"normalized": []
},
{
"id": "15572277_T30",
"type": "CHEMICAL",
"text": [
"diazepam"
],
"offsets": [
[
1101,
1109
]
],
"normalized": []
},
{
"id": "15572277_T31",
"type": "CHEMICAL",
"text": [
"phenobarbital"
],
"offsets": [
[
1111,
1124
]
],
"normalized": []
},
{
"id": "15572277_T32",
"type": "CHEMICAL",
"text": [
"valproate"
],
"offsets": [
[
1126,
1135
]
],
"normalized": []
},
{
"id": "15572277_T33",
"type": "CHEMICAL",
"text": [
"Adenosine"
],
"offsets": [
[
0,
9
]
],
"normalized": []
},
{
"id": "15572277_T34",
"type": "CHEMICAL",
"text": [
"3-nitropropionic acid"
],
"offsets": [
[
91,
112
]
],
"normalized": []
},
{
"id": "15572277_T35",
"type": "GENE-Y",
"text": [
"adenosine A1 receptors"
],
"offsets": [
[
151,
173
]
],
"normalized": []
},
{
"id": "15572277_T36",
"type": "GENE-N",
"text": [
"mitochondrial respiratory chain"
],
"offsets": [
[
1393,
1424
]
],
"normalized": []
},
{
"id": "15572277_T37",
"type": "GENE-N",
"text": [
"A1/A2 adenosine receptor"
],
"offsets": [
[
338,
362
]
],
"normalized": []
},
{
"id": "15572277_T38",
"type": "GENE-Y",
"text": [
"A1 adenosine receptor"
],
"offsets": [
[
403,
424
]
],
"normalized": []
},
{
"id": "15572277_T39",
"type": "GENE-N",
"text": [
"A1/A2 adenosine receptor"
],
"offsets": [
[
585,
609
]
],
"normalized": []
},
{
"id": "15572277_T40",
"type": "GENE-N",
"text": [
"A1/A2 adenosine receptor"
],
"offsets": [
[
794,
818
]
],
"normalized": []
},
{
"id": "15572277_T41",
"type": "GENE-Y",
"text": [
"A1 adenosine receptor"
],
"offsets": [
[
869,
890
]
],
"normalized": []
},
{
"id": "15572277_T42",
"type": "GENE-Y",
"text": [
"adenosine A1 receptor"
],
"offsets": [
[
1016,
1037
]
],
"normalized": []
},
{
"id": "15572277_T43",
"type": "GENE-Y",
"text": [
"Adenosine A1 receptors"
],
"offsets": [
[
0,
22
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "15572277_0",
"type": "ANTAGONIST",
"arg1_id": "15572277_T10",
"arg2_id": "15572277_T38",
"normalized": []
},
{
"id": "15572277_1",
"type": "ANTAGONIST",
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"arg2_id": "15572277_T38",
"normalized": []
},
{
"id": "15572277_2",
"type": "AGONIST",
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"arg2_id": "15572277_T41",
"normalized": []
},
{
"id": "15572277_3",
"type": "AGONIST",
"arg1_id": "15572277_T27",
"arg2_id": "15572277_T41",
"normalized": []
}
] |
23567956 | 23567956 | [
{
"id": "23567956_title",
"type": "title",
"text": [
"Analysis of the antioxidant properties of differently substituted 2- and 3-indolyl carbohydrazides and related derivatives."
],
"offsets": [
[
0,
123
]
]
},
{
"id": "23567956_abstract",
"type": "abstract",
"text": [
"Herein, we report the antioxidant properties of some selected substituted 2-indolyl carbohydrazides (JL34, JL40, JL71, JL87, JL317, JL432, JL436), the substituted 3-indolyl carbohydrazide JL344, 3-(3-hydrazinylpropyl)-1H-indole (JL72) and 3-(1H-indol-3-yl)propanehydrazide (JL418), throughout the assessment of their antioxidative potential using different antioxidant assays such as DPPH, lipid peroxidation in the APPH, or the DMSO method. We conclude that these compounds are convenient templates for the design of useful drugs in to treat Alzheimer's disease (AD), a pathology characterized by extensive oxidative stress and inflammation, thus essentially affected by reactive oxygen species (ROS). Most of them are potent hydroxyl radical scavengers and inhibit in vitro lipid peroxidation. Compounds JL40 and JL432 presenting higher lipoxygenase inhibitory activity among the tested derivatives, were found to present a promising anti-inflammatory in vivo result, as well as antioxidant and LOX inhibitory profile. These results in combination to their known AChE/BuChE inhibitory activities led us to propose these indolyl carbohydrazides as new multifunctional compounds against AD."
],
"offsets": [
[
124,
1314
]
]
}
] | [
{
"id": "23567956_T1",
"type": "CHEMICAL",
"text": [
"JL34"
],
"offsets": [
[
225,
229
]
],
"normalized": []
},
{
"id": "23567956_T2",
"type": "CHEMICAL",
"text": [
"JL40"
],
"offsets": [
[
231,
235
]
],
"normalized": []
},
{
"id": "23567956_T3",
"type": "CHEMICAL",
"text": [
"indolyl carbohydrazides"
],
"offsets": [
[
1246,
1269
]
],
"normalized": []
},
{
"id": "23567956_T4",
"type": "CHEMICAL",
"text": [
"JL71"
],
"offsets": [
[
237,
241
]
],
"normalized": []
},
{
"id": "23567956_T5",
"type": "CHEMICAL",
"text": [
"JL87"
],
"offsets": [
[
243,
247
]
],
"normalized": []
},
{
"id": "23567956_T6",
"type": "CHEMICAL",
"text": [
"JL317"
],
"offsets": [
[
249,
254
]
],
"normalized": []
},
{
"id": "23567956_T7",
"type": "CHEMICAL",
"text": [
"JL432"
],
"offsets": [
[
256,
261
]
],
"normalized": []
},
{
"id": "23567956_T8",
"type": "CHEMICAL",
"text": [
"JL436"
],
"offsets": [
[
263,
268
]
],
"normalized": []
},
{
"id": "23567956_T9",
"type": "CHEMICAL",
"text": [
"3-indolyl carbohydrazide"
],
"offsets": [
[
287,
311
]
],
"normalized": []
},
{
"id": "23567956_T10",
"type": "CHEMICAL",
"text": [
"JL344"
],
"offsets": [
[
312,
317
]
],
"normalized": []
},
{
"id": "23567956_T11",
"type": "CHEMICAL",
"text": [
"3-(3-hydrazinylpropyl)-1H-indole"
],
"offsets": [
[
319,
351
]
],
"normalized": []
},
{
"id": "23567956_T12",
"type": "CHEMICAL",
"text": [
"JL72"
],
"offsets": [
[
353,
357
]
],
"normalized": []
},
{
"id": "23567956_T13",
"type": "CHEMICAL",
"text": [
"3-(1H-indol-3-yl)propanehydrazide"
],
"offsets": [
[
363,
396
]
],
"normalized": []
},
{
"id": "23567956_T14",
"type": "CHEMICAL",
"text": [
"JL418"
],
"offsets": [
[
398,
403
]
],
"normalized": []
},
{
"id": "23567956_T15",
"type": "CHEMICAL",
"text": [
"DPPH"
],
"offsets": [
[
508,
512
]
],
"normalized": []
},
{
"id": "23567956_T16",
"type": "CHEMICAL",
"text": [
"DMSO"
],
"offsets": [
[
553,
557
]
],
"normalized": []
},
{
"id": "23567956_T17",
"type": "CHEMICAL",
"text": [
"oxygen"
],
"offsets": [
[
805,
811
]
],
"normalized": []
},
{
"id": "23567956_T18",
"type": "CHEMICAL",
"text": [
"hydroxyl"
],
"offsets": [
[
851,
859
]
],
"normalized": []
},
{
"id": "23567956_T19",
"type": "CHEMICAL",
"text": [
"2-indolyl carbohydrazides"
],
"offsets": [
[
198,
223
]
],
"normalized": []
},
{
"id": "23567956_T20",
"type": "CHEMICAL",
"text": [
"JL40"
],
"offsets": [
[
930,
934
]
],
"normalized": []
},
{
"id": "23567956_T21",
"type": "CHEMICAL",
"text": [
"JL432"
],
"offsets": [
[
939,
944
]
],
"normalized": []
},
{
"id": "23567956_T22",
"type": "CHEMICAL",
"text": [
"2- and 3-indolyl carbohydrazides"
],
"offsets": [
[
66,
98
]
],
"normalized": []
},
{
"id": "23567956_T23",
"type": "GENE-Y",
"text": [
"AChE"
],
"offsets": [
[
1189,
1193
]
],
"normalized": []
},
{
"id": "23567956_T24",
"type": "GENE-Y",
"text": [
"BuChE"
],
"offsets": [
[
1194,
1199
]
],
"normalized": []
},
{
"id": "23567956_T25",
"type": "GENE-N",
"text": [
"lipoxygenase"
],
"offsets": [
[
963,
975
]
],
"normalized": []
},
{
"id": "23567956_T26",
"type": "GENE-N",
"text": [
"LOX"
],
"offsets": [
[
1121,
1124
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23567956_0",
"type": "INHIBITOR",
"arg1_id": "23567956_T20",
"arg2_id": "23567956_T25",
"normalized": []
},
{
"id": "23567956_1",
"type": "INHIBITOR",
"arg1_id": "23567956_T21",
"arg2_id": "23567956_T25",
"normalized": []
},
{
"id": "23567956_2",
"type": "INHIBITOR",
"arg1_id": "23567956_T20",
"arg2_id": "23567956_T26",
"normalized": []
},
{
"id": "23567956_3",
"type": "INHIBITOR",
"arg1_id": "23567956_T21",
"arg2_id": "23567956_T26",
"normalized": []
},
{
"id": "23567956_4",
"type": "INHIBITOR",
"arg1_id": "23567956_T3",
"arg2_id": "23567956_T23",
"normalized": []
},
{
"id": "23567956_5",
"type": "INHIBITOR",
"arg1_id": "23567956_T3",
"arg2_id": "23567956_T24",
"normalized": []
}
] |
10443304 | 10443304 | [
{
"id": "10443304_title",
"type": "title",
"text": [
"[Brugada syndrome]."
],
"offsets": [
[
0,
19
]
]
},
{
"id": "10443304_abstract",
"type": "abstract",
"text": [
"In 1992 we described a new syndrome consisting of syncopal episodes and/or sudden death in patients with a structurally normal heart and a characteristic electrocardiogram displaying a pattern resembling right bundle branch block with an ST segment elevation in leads V1 to V3. In 1998 it was described that the disease is genetically determined with an autosomal dominant pattern of transmission. Three different mutations have been identified. All three mutations affect the structure and the function of the sodium channel SCN5A. Two mutations result in total loss of function of the sodium channel. The other mutation results in acceleration of the recovery of the sodium channel from inactivation. The disease causes 4 to 10 sudden deaths per 10,000 inhabitants per year in areas like Thailand and Laos. Up to 50% of the yearly sudden deaths in patients with a normal heart might be caused by this syndrome. The diagnosis is easily made by means of the electrocardiogram (ECG). The presence of concealed and intermittent forms, however, makes the diagnosis difficult in some patients. The ECG can be modulated by changes in autonomic balance and the administration of antiarrhythmic drugs. Beta-adrenergic stimulation normalises the ECG, while i.v. ajmaline, flecainide or procainamide accentuate the ST segment elevation and are capable of unmasking concealed and intermittent forms of the disease. The prognosis is poor for patients who do not receive an implantable cardioverter-defibrillator. Antiarrhythmic drugs like amiodarone or beta-blockers do not prevent sudden death in symptomatic or asymptomatic individuals."
],
"offsets": [
[
20,
1647
]
]
}
] | [
{
"id": "10443304_T1",
"type": "CHEMICAL",
"text": [
"ajmaline"
],
"offsets": [
[
1274,
1282
]
],
"normalized": []
},
{
"id": "10443304_T2",
"type": "CHEMICAL",
"text": [
"flecainide"
],
"offsets": [
[
1284,
1294
]
],
"normalized": []
},
{
"id": "10443304_T3",
"type": "CHEMICAL",
"text": [
"procainamide"
],
"offsets": [
[
1298,
1310
]
],
"normalized": []
},
{
"id": "10443304_T4",
"type": "CHEMICAL",
"text": [
"amiodarone"
],
"offsets": [
[
1548,
1558
]
],
"normalized": []
},
{
"id": "10443304_T5",
"type": "CHEMICAL",
"text": [
"sodium"
],
"offsets": [
[
531,
537
]
],
"normalized": []
},
{
"id": "10443304_T6",
"type": "CHEMICAL",
"text": [
"sodium"
],
"offsets": [
[
607,
613
]
],
"normalized": []
},
{
"id": "10443304_T7",
"type": "CHEMICAL",
"text": [
"sodium"
],
"offsets": [
[
689,
695
]
],
"normalized": []
},
{
"id": "10443304_T8",
"type": "GENE-N",
"text": [
"sodium channel"
],
"offsets": [
[
531,
545
]
],
"normalized": []
},
{
"id": "10443304_T9",
"type": "GENE-Y",
"text": [
"SCN5A"
],
"offsets": [
[
546,
551
]
],
"normalized": []
},
{
"id": "10443304_T10",
"type": "GENE-N",
"text": [
"sodium channel"
],
"offsets": [
[
607,
621
]
],
"normalized": []
},
{
"id": "10443304_T11",
"type": "GENE-N",
"text": [
"sodium channel"
],
"offsets": [
[
689,
703
]
],
"normalized": []
}
] | [] | [] | [] |
23219525 | 23219525 | [
{
"id": "23219525_title",
"type": "title",
"text": [
"Influence of sildenafil and tadalafil on the enzyme- and transporter-inducing effects of bosentan and ambrisentan in LS180 cells."
],
"offsets": [
[
0,
129
]
]
},
{
"id": "23219525_abstract",
"type": "abstract",
"text": [
"The combinations of the endothelin-1 receptor antagonists bosentan or ambrisentan with the phosphodiesterase 5 inhibitors sildenafil or tadalafil are current standard therapies of advanced pulmonary arterial hypertension. However, these drugs have a number of drug interactions. Changes of bosentan pharmacokinetics by sildenafil are attributed to reduced hepatic uptake as a consequence of inhibition of organic anion transporting polypeptides. We therefore tested in vitro the hypothesis that sildenafil and tadalafil reduce the enzyme- and transporter-inducing effects of bosentan or ambrisentan by preventing cellular access. Although intracellular concentrations of bosentan and ambrisentan (measured by high pressure liquid chromatography coupled with tandem mass-spectrometry) after four days of incubation of LS180 cells were lower when sildenafil or tadalafil were present, quantification of mRNA expression in these cells by real-time reverse transcription polymerase chain reaction revealed that bosentan and ambrisentan-mediated induction was stable or even increased in combination with sildenafil or tadalafil. For the drug transporter P-glycoprotein this was confirmed at the protein and functional level with highly significant correlations between P-gp mRNA, protein, and function. Moreover, using a reporter gene assay in LS180 cells, our study demonstrates for the first time that tadalafil is a potent, ambrisentan a weak, and sildenafil no activator of pregnane X receptor. In conclusion, our study demonstrates that although sildenafil and tadalafil indeed reduce intracellular concentrations of bosentan and ambrisentan in LS180 cells, they do not mitigate the inducing effects of these endothelin-1 receptor antagonists."
],
"offsets": [
[
130,
1874
]
]
}
] | [
{
"id": "23219525_T1",
"type": "CHEMICAL",
"text": [
"bosentan"
],
"offsets": [
[
1137,
1145
]
],
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1604,
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1748,
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420,
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449,
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705,
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"bosentan"
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188,
196
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"ambrisentan"
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717,
728
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801,
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814,
825
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200,
211
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985
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989,
998
]
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"id": "23219525_T27",
"type": "CHEMICAL",
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],
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102,
113
]
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"id": "23219525_T28",
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13,
23
]
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89,
97
]
],
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},
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"id": "23219525_T30",
"type": "GENE-N",
"text": [
"P-glycoprotein"
],
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1280,
1294
]
],
"normalized": []
},
{
"id": "23219525_T31",
"type": "GENE-N",
"text": [
"P-gp"
],
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1395,
1399
]
],
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},
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"id": "23219525_T32",
"type": "GENE-Y",
"text": [
"pregnane X receptor"
],
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1604,
1623
]
],
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},
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"id": "23219525_T33",
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1840,
1861
]
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},
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"endothelin-1 receptor"
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154,
175
]
],
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},
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"id": "23219525_T35",
"type": "GENE-N",
"text": [
"organic anion transporting polypeptides"
],
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535,
574
]
],
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},
{
"id": "23219525_T36",
"type": "GENE-Y",
"text": [
"phosphodiesterase 5"
],
"offsets": [
[
221,
240
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23219525_0",
"type": "ANTAGONIST",
"arg1_id": "23219525_T20",
"arg2_id": "23219525_T34",
"normalized": []
},
{
"id": "23219525_1",
"type": "ANTAGONIST",
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},
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"id": "23219525_2",
"type": "INHIBITOR",
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},
{
"id": "23219525_3",
"type": "INHIBITOR",
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},
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"id": "23219525_4",
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},
{
"id": "23219525_5",
"type": "ACTIVATOR",
"arg1_id": "23219525_T7",
"arg2_id": "23219525_T32",
"normalized": []
}
] |
12783542 | 12783542 | [
{
"id": "12783542_title",
"type": "title",
"text": [
"Incorporation of trifluoroisoleucine into proteins in vivo."
],
"offsets": [
[
0,
59
]
]
},
{
"id": "12783542_abstract",
"type": "abstract",
"text": [
"Two fluorinated derivatives of isoleucine: d,l-2-amino-3-trifluoromethyl pentanoic acid (3TFI, 2) and d,l-2-amino-5,5,5-trifluoro-3-methyl pentanoic acid (5TFI, 3) were prepared. 5TFI was incorporated into a model target protein, murine dihydrofolate reductase (mDHFR), in an isoleucine auxotrophic Escherichia coli host strain suspended in 5TFI-supplemented minimal medium depleted of isoleucine. Incorporation of 5TFI was confirmed by tryptic peptide analysis and matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) of the protein product. Amino acid analysis showed that more than 93% of the encoded isoleucine residues were replaced by 5TFI. Measurement of the rate of activation of 5TFI by the E. coli isoleucyl-tRNA synthetase (IleRS) yielded a specificity constant (k(cat)/K(m)) 134-fold lower than that for isoleucine. 5TFI was successfully introduced into the cytokine murine interleukin-2 (mIL-2) at the encoded isoleucine positions. The concentration of fluorinated protein that elicits 50% of the maximal proliferative response is 3.87 ng/mL, about 30% higher than that of wild-type mIL-2 (EC(50) = 2.70 ng/mL). The maximal responses are equivalent for the fluorinated and wild-type cytokines, indicating that fluorinated proteins can fold into stable and functional structures. 3TFI yielded no evidence for in vivo incorporation into recombinant proteins, and no evidence for activation by IleRS in vitro."
],
"offsets": [
[
60,
1499
]
]
}
] | [
{
"id": "12783542_T1",
"type": "CHEMICAL",
"text": [
"d,l-2-amino-5,5,5-trifluoro-3-methyl pentanoic acid"
],
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[
162,
213
]
],
"normalized": []
},
{
"id": "12783542_T2",
"type": "CHEMICAL",
"text": [
"3TFI"
],
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[
1372,
1376
]
],
"normalized": []
},
{
"id": "12783542_T3",
"type": "CHEMICAL",
"text": [
"5TFI"
],
"offsets": [
[
215,
219
]
],
"normalized": []
},
{
"id": "12783542_T4",
"type": "CHEMICAL",
"text": [
"5TFI"
],
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[
239,
243
]
],
"normalized": []
},
{
"id": "12783542_T5",
"type": "CHEMICAL",
"text": [
"dihydrofolate"
],
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[
297,
310
]
],
"normalized": []
},
{
"id": "12783542_T6",
"type": "CHEMICAL",
"text": [
"isoleucine"
],
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[
336,
346
]
],
"normalized": []
},
{
"id": "12783542_T7",
"type": "CHEMICAL",
"text": [
"isoleucine"
],
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[
91,
101
]
],
"normalized": []
},
{
"id": "12783542_T8",
"type": "CHEMICAL",
"text": [
"5TFI"
],
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[
401,
405
]
],
"normalized": []
},
{
"id": "12783542_T9",
"type": "CHEMICAL",
"text": [
"isoleucine"
],
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[
446,
456
]
],
"normalized": []
},
{
"id": "12783542_T10",
"type": "CHEMICAL",
"text": [
"5TFI"
],
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[
475,
479
]
],
"normalized": []
},
{
"id": "12783542_T11",
"type": "CHEMICAL",
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"d,l-2-amino-3-trifluoromethyl pentanoic acid"
],
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[
103,
147
]
],
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},
{
"id": "12783542_T12",
"type": "CHEMICAL",
"text": [
"Amino acid"
],
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[
623,
633
]
],
"normalized": []
},
{
"id": "12783542_T13",
"type": "CHEMICAL",
"text": [
"isoleucine"
],
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[
684,
694
]
],
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},
{
"id": "12783542_T14",
"type": "CHEMICAL",
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"5TFI"
],
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[
721,
725
]
],
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},
{
"id": "12783542_T15",
"type": "CHEMICAL",
"text": [
"5TFI"
],
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[
768,
772
]
],
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},
{
"id": "12783542_T16",
"type": "CHEMICAL",
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"isoleucyl"
],
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[
788,
797
]
],
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},
{
"id": "12783542_T17",
"type": "CHEMICAL",
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"isoleucine"
],
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[
896,
906
]
],
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},
{
"id": "12783542_T18",
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"5TFI"
],
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[
908,
912
]
],
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},
{
"id": "12783542_T19",
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"3TFI"
],
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[
149,
153
]
],
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},
{
"id": "12783542_T20",
"type": "CHEMICAL",
"text": [
"isoleucine"
],
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[
1003,
1013
]
],
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},
{
"id": "12783542_T21",
"type": "CHEMICAL",
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"trifluoroisoleucine"
],
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[
17,
36
]
],
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},
{
"id": "12783542_T22",
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"mIL-2"
],
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[
1176,
1181
]
],
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},
{
"id": "12783542_T23",
"type": "GENE-N",
"text": [
"cytokines"
],
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[
1276,
1285
]
],
"normalized": []
},
{
"id": "12783542_T24",
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"IleRS"
],
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[
1484,
1489
]
],
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},
{
"id": "12783542_T25",
"type": "GENE-Y",
"text": [
"murine dihydrofolate reductase"
],
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[
290,
320
]
],
"normalized": []
},
{
"id": "12783542_T26",
"type": "GENE-Y",
"text": [
"mDHFR"
],
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[
322,
327
]
],
"normalized": []
},
{
"id": "12783542_T27",
"type": "GENE-Y",
"text": [
"E. coli isoleucyl-tRNA synthetase"
],
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[
780,
813
]
],
"normalized": []
},
{
"id": "12783542_T28",
"type": "GENE-Y",
"text": [
"IleRS"
],
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[
815,
820
]
],
"normalized": []
},
{
"id": "12783542_T29",
"type": "GENE-N",
"text": [
"cytokine"
],
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[
950,
958
]
],
"normalized": []
},
{
"id": "12783542_T30",
"type": "GENE-Y",
"text": [
"murine interleukin-2"
],
"offsets": [
[
959,
979
]
],
"normalized": []
},
{
"id": "12783542_T31",
"type": "GENE-Y",
"text": [
"mIL-2"
],
"offsets": [
[
981,
986
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12783542_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "12783542_T4",
"arg2_id": "12783542_T25",
"normalized": []
},
{
"id": "12783542_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "12783542_T4",
"arg2_id": "12783542_T26",
"normalized": []
}
] |
23284082 | 23284082 | [
{
"id": "23284082_title",
"type": "title",
"text": [
"Amide hydrolysis of a novel chemical series of microsomal prostaglandin E synthase-1 inhibitors induces kidney toxicity in the rat."
],
"offsets": [
[
0,
131
]
]
},
{
"id": "23284082_abstract",
"type": "abstract",
"text": [
"A novel microsomal prostaglandin E synthase 1 (mPGES-1) inhibitor induced kidney injury at exposures representing less than 4 times the anticipated efficacious exposure in man during a 7-day toxicity study in rats. The findings consisted mainly of tubular lesions and the presence of crystalline material and increases in plasma urea and creatinine. In vitro and in vivo metabolic profiling generated a working hypothesis that a bis-sulfonamide metabolite (determined M1) formed by amide hydrolysis caused this toxicity. To test this hypothesis, rats were subjected to a 7-day study and were administered the suspected metabolite and two low-potency mPGES-1 inhibitor analogs, where amide hydrolysis was undetectable in rat hepatocyte experiments. The results suggested that compounds with a reduced propensity to undergo amide hydrolysis, thus having less ability to form M1, reduced the risk of inducing kidney toxicity. Rats treated with M1 alone showed no histopathologic change in the kidney, which was likely related to underexposure to M1. To circumvent rat kidney toxicity, we identified a potent mPGES-1 inhibitor with a low propensity for amide hydrolysis and superior rat pharmacokinetic properties. A subsequent 14-day rat toxicity study showed that this compound was associated with kidney toxicity at 42, but not 21, times the anticipated efficacious exposure in humans. In conclusion, by including metabolic profiling and exploratory rat toxicity studies, a new and active mPGES-1 inhibitor with improved margins to chemically induced kidney toxicity in rats has been identified."
],
"offsets": [
[
132,
1726
]
]
}
] | [
{
"id": "23284082_T1",
"type": "CHEMICAL",
"text": [
"amide"
],
"offsets": [
[
1281,
1286
]
],
"normalized": []
},
{
"id": "23284082_T2",
"type": "CHEMICAL",
"text": [
"prostaglandin E"
],
"offsets": [
[
151,
166
]
],
"normalized": []
},
{
"id": "23284082_T3",
"type": "CHEMICAL",
"text": [
"urea"
],
"offsets": [
[
461,
465
]
],
"normalized": []
},
{
"id": "23284082_T4",
"type": "CHEMICAL",
"text": [
"creatinine"
],
"offsets": [
[
470,
480
]
],
"normalized": []
},
{
"id": "23284082_T5",
"type": "CHEMICAL",
"text": [
"bis-sulfonamide"
],
"offsets": [
[
561,
576
]
],
"normalized": []
},
{
"id": "23284082_T6",
"type": "CHEMICAL",
"text": [
"amide"
],
"offsets": [
[
614,
619
]
],
"normalized": []
},
{
"id": "23284082_T7",
"type": "CHEMICAL",
"text": [
"amide"
],
"offsets": [
[
815,
820
]
],
"normalized": []
},
{
"id": "23284082_T8",
"type": "CHEMICAL",
"text": [
"amide"
],
"offsets": [
[
954,
959
]
],
"normalized": []
},
{
"id": "23284082_T9",
"type": "CHEMICAL",
"text": [
"Amide"
],
"offsets": [
[
0,
5
]
],
"normalized": []
},
{
"id": "23284082_T10",
"type": "CHEMICAL",
"text": [
"prostaglandin E"
],
"offsets": [
[
58,
73
]
],
"normalized": []
},
{
"id": "23284082_T11",
"type": "GENE-Y",
"text": [
"mPGES-1"
],
"offsets": [
[
1237,
1244
]
],
"normalized": []
},
{
"id": "23284082_T12",
"type": "GENE-Y",
"text": [
"mPGES-1"
],
"offsets": [
[
1620,
1627
]
],
"normalized": []
},
{
"id": "23284082_T13",
"type": "GENE-Y",
"text": [
"mPGES-1"
],
"offsets": [
[
179,
186
]
],
"normalized": []
},
{
"id": "23284082_T14",
"type": "GENE-Y",
"text": [
"mPGES-1"
],
"offsets": [
[
782,
789
]
],
"normalized": []
},
{
"id": "23284082_T15",
"type": "GENE-Y",
"text": [
"microsomal prostaglandin E synthase 1"
],
"offsets": [
[
140,
177
]
],
"normalized": []
},
{
"id": "23284082_T16",
"type": "GENE-Y",
"text": [
"microsomal prostaglandin E synthase-1"
],
"offsets": [
[
47,
84
]
],
"normalized": []
}
] | [] | [] | [] |
18559268 | 18559268 | [
{
"id": "18559268_title",
"type": "title",
"text": [
"Optimization of taxane binding to microtubules: binding affinity dissection and incremental construction of a high-affinity analog of paclitaxel."
],
"offsets": [
[
0,
145
]
]
},
{
"id": "18559268_abstract",
"type": "abstract",
"text": [
"The microtubule binding affinities of a series of synthetic taxanes have been measured with the aims of dissecting individual group contributions and obtaining a rationale for the design of novel compounds with the ability to overcome drug resistance. As previously observed for epothilones, the positive and negative contributions of the different substituents to the binding free energies are cumulative. By combining the most favorable substitutions we increased the binding affinity of paclitaxel 500-fold. Insight into the structural basis for this improvement was gained with molecular modeling and NMR data obtained for microtubule-bound docetaxel. Taxanes with affinities for microtubules well above their affinities for P-glycoprotein are shown not to be affected by multidrug resistance. This finding strongly indicates that optimization of the ligand-target interaction is a good strategy to overcome multidrug resistance mediated by efflux pumps."
],
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146,
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"id": "18559268_T1",
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425,
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"id": "18559268_T2",
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"text": [
"paclitaxel"
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636,
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206,
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791,
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802,
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"paclitaxel"
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134,
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"taxane"
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16,
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"id": "18559268_T8",
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150,
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"id": "18559268_T9",
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773,
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"microtubules"
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830,
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"id": "18559268_T11",
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875,
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"microtubules"
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34,
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}
] | [] | [] | [
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}
] |
9808077 | 9808077 | [
{
"id": "9808077_title",
"type": "title",
"text": [
"Selective serotonin reuptake inhibitors in affective disorders--I. Basic pharmacology."
],
"offsets": [
[
0,
86
]
]
},
{
"id": "9808077_abstract",
"type": "abstract",
"text": [
"The selective serotonin reuptake inhibitors (SSRIs), citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, are the result of rational research to find drugs that were as effective as the tricyclic antidepressants but with fewer safety and tolerability problems. The SSRIs selectively and powerfully inhibit serotonin reuptake and result in a potentiation of serotonergic neurotransmission. The property of potent serotonin reuptake appears to give a broad spectrum of therapeutic activity in depression, anxiety, obsessional and impulse control disorders. However, despite the sharing of the same principal mechanism of action, SSRIs are structurally diverse with clear variations in their pharmacodynamic and pharmacokinetic profiles. The potency for serotonin reuptake inhibition varies amongst this group, as does the selectivity for serotonin relative to noradrenaline and dopamine reuptake inhibition. The relative potency of sertraline for dopamine reuptake inhibition differentiates it pharmacologically from other SSRIs. Affinity for neuroreceptors, such as sigma1, muscarinic and 5-HT2c, also differs widely. Furthermore, the inhibition of nitric oxide synthetase by paroxetine, and possibly other SSRIs, may have significant pharmacodynamic effects. Citalopram and fluoxetine are racemic mixtures of different chiral forms that possess varying pharmacokinetic and pharmacological profiles. Fluoxetine has a long acting and pharmacologically active metabolite. There are important clinical differences among the SSRIs in their pharmacokinetic characteristics. These include differences in their half-lives, linear versus non-linear pharmacokinetics, effect of age on their clearance and their potential to inhibit drug metabolising cytochrome P450 (CYP) isoenzymes. These pharmacological and pharmacokinetic differences underly the increasingly apparent important clinical differences amongst the SSRIs."
],
"offsets": [
[
87,
2009
]
]
}
] | [
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"id": "9808077_T1",
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"sertraline"
],
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192,
202
]
],
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},
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"id": "9808077_T2",
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"nitric oxide"
],
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1246,
1258
]
],
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},
{
"id": "9808077_T3",
"type": "CHEMICAL",
"text": [
"paroxetine"
],
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1273,
1283
]
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},
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"id": "9808077_T4",
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"Citalopram"
],
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1357,
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]
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"id": "9808077_T5",
"type": "CHEMICAL",
"text": [
"fluoxetine"
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1372,
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]
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"id": "9808077_T6",
"type": "CHEMICAL",
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"Fluoxetine"
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1497,
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]
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"id": "9808077_T7",
"type": "CHEMICAL",
"text": [
"serotonin"
],
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101,
110
]
],
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},
{
"id": "9808077_T8",
"type": "CHEMICAL",
"text": [
"tricyclic"
],
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284,
293
]
],
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},
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"id": "9808077_T9",
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"serotonin"
],
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404,
413
]
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"id": "9808077_T10",
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"serotonin"
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510,
519
]
],
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},
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"id": "9808077_T11",
"type": "CHEMICAL",
"text": [
"citalopram"
],
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[
140,
150
]
],
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},
{
"id": "9808077_T12",
"type": "CHEMICAL",
"text": [
"fluoxetine"
],
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[
152,
162
]
],
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},
{
"id": "9808077_T13",
"type": "CHEMICAL",
"text": [
"serotonin"
],
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849,
858
]
],
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},
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"id": "9808077_T14",
"type": "CHEMICAL",
"text": [
"fluvoxamine"
],
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164,
175
]
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934,
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]
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"id": "9808077_T16",
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"noradrenaline"
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956,
969
]
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},
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"id": "9808077_T17",
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"dopamine"
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974,
982
]
],
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},
{
"id": "9808077_T18",
"type": "CHEMICAL",
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"paroxetine"
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177,
187
]
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},
{
"id": "9808077_T19",
"type": "CHEMICAL",
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"sertraline"
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1028,
1038
]
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"id": "9808077_T20",
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"dopamine"
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1043,
1051
]
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"serotonin"
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10,
19
]
],
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},
{
"id": "9808077_T22",
"type": "GENE-N",
"text": [
"neuroreceptors"
],
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1139,
1153
]
],
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},
{
"id": "9808077_T23",
"type": "GENE-Y",
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"sigma1"
],
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1163,
1169
]
],
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},
{
"id": "9808077_T24",
"type": "GENE-Y",
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"5-HT2c"
],
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[
1186,
1192
]
],
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},
{
"id": "9808077_T25",
"type": "GENE-N",
"text": [
"nitric oxide synthetase"
],
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1246,
1269
]
],
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},
{
"id": "9808077_T26",
"type": "GENE-N",
"text": [
"cytochrome P450"
],
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1838,
1853
]
],
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},
{
"id": "9808077_T27",
"type": "GENE-N",
"text": [
"CYP"
],
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[
1855,
1858
]
],
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}
] | [] | [] | [
{
"id": "9808077_0",
"type": "INHIBITOR",
"arg1_id": "9808077_T3",
"arg2_id": "9808077_T25",
"normalized": []
}
] |
23146871 | 23146871 | [
{
"id": "23146871_title",
"type": "title",
"text": [
"Manganese transport via the transferrin mechanism."
],
"offsets": [
[
0,
50
]
]
},
{
"id": "23146871_abstract",
"type": "abstract",
"text": [
"Excessive manganese (Mn) uptake by brain cells, particularly in regions like the basal ganglia, can lead to toxicity. Mn(2+) is transported into cells via a number of mechanisms, while Mn(3+) is believed to be transported similarly to iron (Fe) via the transferrin (Tf) mechanism. Cellular Mn uptake is therefore determined by the activity of the mechanisms transporting Mn into each type of cell and by the amounts of Mn(2+), Mn(3+) and their complexes to which these cells are exposed; this complicates understanding the contributions of each transporter to Mn toxicity. While uptake of Fe(3+) via the Tf mechanism is well understood, uptake of Mn(3+) via this mechanism has not been systematically studied. The stability of the Mn(3+)Tf complex allowed us to form and purify this complex and label it with a fluorescent (Alexa green) tag. Using purified and labeled Mn(3+)Tf and biophysical tools, we have developed a novel approach to study Mn(3+)Tf transport independently of other Mn transport mechanisms. This approach was used to compare the uptake of Mn(3+)Tf into neuronal cell lines with published descriptions of Fe(3+) uptake via the Tf mechanism, and to obtain quantitative information on Mn uptake via the Tf mechanism. Results confirm that in these cell lines significant Mn(3+) is transported by the Tf mechanism similarly to Fe(3+)Tf transport; although Mn(3+)Tf transport is markedly slower than other Mn transport mechanisms. This novel approach may prove useful for studying Mn toxicity in other systems and cell types."
],
"offsets": [
[
51,
1591
]
]
}
] | [
{
"id": "23146871_T1",
"type": "CHEMICAL",
"text": [
"manganese"
],
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[
61,
70
]
],
"normalized": []
},
{
"id": "23146871_T2",
"type": "CHEMICAL",
"text": [
"Mn(3+)"
],
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[
1111,
1117
]
],
"normalized": []
},
{
"id": "23146871_T3",
"type": "CHEMICAL",
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"Fe(3+)"
],
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1176,
1182
]
],
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},
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"id": "23146871_T4",
"type": "CHEMICAL",
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"Mn(2+)"
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169,
175
]
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},
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"id": "23146871_T5",
"type": "CHEMICAL",
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"Mn"
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1254,
1256
]
],
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},
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"id": "23146871_T6",
"type": "CHEMICAL",
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"Mn(3+)"
],
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1339,
1345
]
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"id": "23146871_T7",
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"Fe(3+)"
],
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1394,
1400
]
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},
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"id": "23146871_T8",
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"Mn(3+)"
],
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1423,
1429
]
],
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},
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"id": "23146871_T9",
"type": "CHEMICAL",
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"Mn"
],
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[
1472,
1474
]
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},
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"id": "23146871_T10",
"type": "CHEMICAL",
"text": [
"Mn"
],
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[
1547,
1549
]
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},
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"id": "23146871_T11",
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"Mn(3+)"
],
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236,
242
]
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},
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"id": "23146871_T12",
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"Mn"
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[
72,
74
]
],
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},
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"id": "23146871_T13",
"type": "CHEMICAL",
"text": [
"iron"
],
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[
286,
290
]
],
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},
{
"id": "23146871_T14",
"type": "CHEMICAL",
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"Fe"
],
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[
292,
294
]
],
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},
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"id": "23146871_T15",
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"Mn"
],
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341,
343
]
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},
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"id": "23146871_T16",
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"Mn"
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[
422,
424
]
],
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},
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"id": "23146871_T17",
"type": "CHEMICAL",
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"Mn(2+)"
],
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[
470,
476
]
],
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},
{
"id": "23146871_T18",
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"Mn(3+)"
],
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[
478,
484
]
],
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},
{
"id": "23146871_T19",
"type": "CHEMICAL",
"text": [
"Mn"
],
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[
611,
613
]
],
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},
{
"id": "23146871_T20",
"type": "CHEMICAL",
"text": [
"Fe(3+)"
],
"offsets": [
[
640,
646
]
],
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},
{
"id": "23146871_T21",
"type": "CHEMICAL",
"text": [
"Mn(3+)"
],
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[
698,
704
]
],
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},
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"id": "23146871_T22",
"type": "CHEMICAL",
"text": [
"Mn(3+)"
],
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[
782,
788
]
],
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},
{
"id": "23146871_T23",
"type": "CHEMICAL",
"text": [
"Alexa green"
],
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[
875,
886
]
],
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},
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"id": "23146871_T24",
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"text": [
"Mn(3+)"
],
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[
920,
926
]
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"id": "23146871_T25",
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"Mn(3+)"
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996,
1002
]
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},
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"id": "23146871_T26",
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"text": [
"Mn"
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[
1038,
1040
]
],
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},
{
"id": "23146871_T27",
"type": "CHEMICAL",
"text": [
"Manganese"
],
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[
0,
9
]
],
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},
{
"id": "23146871_T28",
"type": "GENE-Y",
"text": [
"Tf"
],
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[
1117,
1119
]
],
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},
{
"id": "23146871_T29",
"type": "GENE-Y",
"text": [
"Tf"
],
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[
1198,
1200
]
],
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},
{
"id": "23146871_T30",
"type": "GENE-Y",
"text": [
"Tf"
],
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[
1272,
1274
]
],
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},
{
"id": "23146871_T31",
"type": "GENE-Y",
"text": [
"Tf"
],
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[
1368,
1370
]
],
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},
{
"id": "23146871_T32",
"type": "GENE-Y",
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"Tf"
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[
1400,
1402
]
],
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},
{
"id": "23146871_T33",
"type": "GENE-Y",
"text": [
"Tf"
],
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[
1429,
1431
]
],
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},
{
"id": "23146871_T34",
"type": "GENE-Y",
"text": [
"transferrin"
],
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[
304,
315
]
],
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},
{
"id": "23146871_T35",
"type": "GENE-Y",
"text": [
"Tf"
],
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[
317,
319
]
],
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},
{
"id": "23146871_T36",
"type": "GENE-Y",
"text": [
"Tf"
],
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[
655,
657
]
],
"normalized": []
},
{
"id": "23146871_T37",
"type": "GENE-Y",
"text": [
"Tf"
],
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[
788,
790
]
],
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},
{
"id": "23146871_T38",
"type": "GENE-Y",
"text": [
"Tf"
],
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[
926,
928
]
],
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},
{
"id": "23146871_T39",
"type": "GENE-Y",
"text": [
"Tf"
],
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[
1002,
1004
]
],
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},
{
"id": "23146871_T40",
"type": "GENE-Y",
"text": [
"transferrin"
],
"offsets": [
[
28,
39
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23146871_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "23146871_T22",
"arg2_id": "23146871_T37",
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},
{
"id": "23146871_1",
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"arg1_id": "23146871_T24",
"arg2_id": "23146871_T38",
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},
{
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"arg1_id": "23146871_T25",
"arg2_id": "23146871_T39",
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},
{
"id": "23146871_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "23146871_T2",
"arg2_id": "23146871_T28",
"normalized": []
},
{
"id": "23146871_4",
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},
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},
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"arg2_id": "23146871_T40",
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},
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"id": "23146871_7",
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"arg2_id": "23146871_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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},
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},
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},
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"normalized": []
},
{
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"type": "SUBSTRATE",
"arg1_id": "23146871_T6",
"arg2_id": "23146871_T31",
"normalized": []
}
] |
7909690 | 7909690 | [
{
"id": "7909690_title",
"type": "title",
"text": [
"Cytotoxic effects of inhibitors of de novo pyrimidine biosynthesis upon Plasmodium falciparum."
],
"offsets": [
[
0,
94
]
]
},
{
"id": "7909690_abstract",
"type": "abstract",
"text": [
"The malarial parasite Plasmodium falciparum can only synthesize pyrimidine nucleotides via the de novo pathway which is therefore a suitable target for development of antimalarial drugs. New assay procedures have been developed using high-pressure liquid chromatography (HPLC) which enable concurrent measurement of pyrimidine intermediates in malaria. Synchronized parasites growing in erythrocytes were pulse-labeled with [14C]bicarbonate at 6-h intervals around the 48-h asexual life cycle. Analysis of malarial extracts by HPLC showed tht incorporation of [14C]bicarbonate into pyrimidine nucleotides was maximal during the transition from trophozoites to schizonts. The reaction, N-carbamyl-L-aspartate-->L-dihydroorotate (CA-asp-->DHO) catalyzed by malarial dihydroorotase is inhibited by L-6-thiodihydroorotate (TDHO) in vitro (Ki = 6.5 microM), and TDHO, as the free acid or methyl ester, induces a major accumulation of CA-asp in malaria. Atovaquone, a naphthoquinone, is a moderate inhibitor of dihydroorotate dehydrogenase in vitro (Ki = 27 microM) but induces major accumulations of CA-asp and DHO. Pyrazofurin induces accumulation of orotate and orotidine in malaria, consistent with inhibition of orotidine 5'-monophosphate (OMP) decarboxylase with subsequent dephosphorylation of the OMP accumulated. Although TDHO, atovaquone, and pyrazofurin arrest the growth of P. falciparum, only moderate decreases in UTP, CTP, and dTTP were observed. 5-Fluoroorotate also arrests the growth of P. falciparum with major accumulations of 5-fluorouridine mono-, di-, and triphosphates and the most significant inhibition of de novo biosynthesis of pyrimidine nucleotides."
],
"offsets": [
[
95,
1768
]
]
}
] | [
{
"id": "7909690_T1",
"type": "CHEMICAL",
"text": [
"dihydroorotate"
],
"offsets": [
[
1100,
1114
]
],
"normalized": []
},
{
"id": "7909690_T2",
"type": "CHEMICAL",
"text": [
"CA-asp"
],
"offsets": [
[
1190,
1196
]
],
"normalized": []
},
{
"id": "7909690_T3",
"type": "CHEMICAL",
"text": [
"DHO"
],
"offsets": [
[
1201,
1204
]
],
"normalized": []
},
{
"id": "7909690_T4",
"type": "CHEMICAL",
"text": [
"Pyrazofurin"
],
"offsets": [
[
1206,
1217
]
],
"normalized": []
},
{
"id": "7909690_T5",
"type": "CHEMICAL",
"text": [
"orotate"
],
"offsets": [
[
1242,
1249
]
],
"normalized": []
},
{
"id": "7909690_T6",
"type": "CHEMICAL",
"text": [
"orotidine"
],
"offsets": [
[
1254,
1263
]
],
"normalized": []
},
{
"id": "7909690_T7",
"type": "CHEMICAL",
"text": [
"orotidine 5'-monophosphate"
],
"offsets": [
[
1306,
1332
]
],
"normalized": []
},
{
"id": "7909690_T8",
"type": "CHEMICAL",
"text": [
"OMP"
],
"offsets": [
[
1334,
1337
]
],
"normalized": []
},
{
"id": "7909690_T9",
"type": "CHEMICAL",
"text": [
"OMP"
],
"offsets": [
[
1394,
1397
]
],
"normalized": []
},
{
"id": "7909690_T10",
"type": "CHEMICAL",
"text": [
"TDHO"
],
"offsets": [
[
1420,
1424
]
],
"normalized": []
},
{
"id": "7909690_T11",
"type": "CHEMICAL",
"text": [
"atovaquone"
],
"offsets": [
[
1426,
1436
]
],
"normalized": []
},
{
"id": "7909690_T12",
"type": "CHEMICAL",
"text": [
"pyrazofurin"
],
"offsets": [
[
1442,
1453
]
],
"normalized": []
},
{
"id": "7909690_T13",
"type": "CHEMICAL",
"text": [
"5-Fluoroorotate"
],
"offsets": [
[
1551,
1566
]
],
"normalized": []
},
{
"id": "7909690_T14",
"type": "CHEMICAL",
"text": [
"5-fluorouridine"
],
"offsets": [
[
1636,
1651
]
],
"normalized": []
},
{
"id": "7909690_T15",
"type": "CHEMICAL",
"text": [
"mono-, di-, and triphosphates"
],
"offsets": [
[
1652,
1681
]
],
"normalized": []
},
{
"id": "7909690_T16",
"type": "CHEMICAL",
"text": [
"pyrimidine nucleotides"
],
"offsets": [
[
1745,
1767
]
],
"normalized": []
},
{
"id": "7909690_T17",
"type": "CHEMICAL",
"text": [
"pyrimidine"
],
"offsets": [
[
411,
421
]
],
"normalized": []
},
{
"id": "7909690_T18",
"type": "CHEMICAL",
"text": [
"[14C]bicarbonate"
],
"offsets": [
[
519,
535
]
],
"normalized": []
},
{
"id": "7909690_T19",
"type": "CHEMICAL",
"text": [
"[14C]bicarbonate"
],
"offsets": [
[
655,
671
]
],
"normalized": []
},
{
"id": "7909690_T20",
"type": "CHEMICAL",
"text": [
"pyrimidine nucleotides"
],
"offsets": [
[
677,
699
]
],
"normalized": []
},
{
"id": "7909690_T21",
"type": "CHEMICAL",
"text": [
"pyrimidine nucleotides"
],
"offsets": [
[
159,
181
]
],
"normalized": []
},
{
"id": "7909690_T22",
"type": "CHEMICAL",
"text": [
"N-carbamyl-L-aspartate"
],
"offsets": [
[
780,
802
]
],
"normalized": []
},
{
"id": "7909690_T23",
"type": "CHEMICAL",
"text": [
"L-dihydroorotate"
],
"offsets": [
[
805,
821
]
],
"normalized": []
},
{
"id": "7909690_T24",
"type": "CHEMICAL",
"text": [
"CA-asp"
],
"offsets": [
[
823,
829
]
],
"normalized": []
},
{
"id": "7909690_T25",
"type": "CHEMICAL",
"text": [
"DHO"
],
"offsets": [
[
832,
835
]
],
"normalized": []
},
{
"id": "7909690_T26",
"type": "CHEMICAL",
"text": [
"L-6-thiodihydroorotate"
],
"offsets": [
[
890,
912
]
],
"normalized": []
},
{
"id": "7909690_T27",
"type": "CHEMICAL",
"text": [
"TDHO"
],
"offsets": [
[
914,
918
]
],
"normalized": []
},
{
"id": "7909690_T28",
"type": "CHEMICAL",
"text": [
"TDHO"
],
"offsets": [
[
952,
956
]
],
"normalized": []
},
{
"id": "7909690_T29",
"type": "CHEMICAL",
"text": [
"free acid"
],
"offsets": [
[
965,
974
]
],
"normalized": []
},
{
"id": "7909690_T30",
"type": "CHEMICAL",
"text": [
"methyl ester"
],
"offsets": [
[
978,
990
]
],
"normalized": []
},
{
"id": "7909690_T31",
"type": "CHEMICAL",
"text": [
"CA-asp"
],
"offsets": [
[
1024,
1030
]
],
"normalized": []
},
{
"id": "7909690_T32",
"type": "CHEMICAL",
"text": [
"Atovaquone"
],
"offsets": [
[
1043,
1053
]
],
"normalized": []
},
{
"id": "7909690_T33",
"type": "CHEMICAL",
"text": [
"naphthoquinone"
],
"offsets": [
[
1057,
1071
]
],
"normalized": []
},
{
"id": "7909690_T34",
"type": "CHEMICAL",
"text": [
"pyrimidine"
],
"offsets": [
[
43,
53
]
],
"normalized": []
},
{
"id": "7909690_T35",
"type": "GENE-Y",
"text": [
"dihydroorotate dehydrogenase"
],
"offsets": [
[
1100,
1128
]
],
"normalized": []
},
{
"id": "7909690_T36",
"type": "GENE-Y",
"text": [
"orotidine 5'-monophosphate (OMP) decarboxylase"
],
"offsets": [
[
1306,
1352
]
],
"normalized": []
},
{
"id": "7909690_T37",
"type": "GENE-N",
"text": [
"malarial dihydroorotase"
],
"offsets": [
[
850,
873
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "7909690_0",
"type": "SUBSTRATE",
"arg1_id": "7909690_T22",
"arg2_id": "7909690_T37",
"normalized": []
},
{
"id": "7909690_1",
"type": "SUBSTRATE",
"arg1_id": "7909690_T24",
"arg2_id": "7909690_T37",
"normalized": []
},
{
"id": "7909690_2",
"type": "PRODUCT-OF",
"arg1_id": "7909690_T23",
"arg2_id": "7909690_T37",
"normalized": []
},
{
"id": "7909690_3",
"type": "PRODUCT-OF",
"arg1_id": "7909690_T25",
"arg2_id": "7909690_T37",
"normalized": []
},
{
"id": "7909690_4",
"type": "INHIBITOR",
"arg1_id": "7909690_T26",
"arg2_id": "7909690_T37",
"normalized": []
},
{
"id": "7909690_5",
"type": "INHIBITOR",
"arg1_id": "7909690_T27",
"arg2_id": "7909690_T37",
"normalized": []
},
{
"id": "7909690_6",
"type": "INHIBITOR",
"arg1_id": "7909690_T28",
"arg2_id": "7909690_T37",
"normalized": []
},
{
"id": "7909690_7",
"type": "INHIBITOR",
"arg1_id": "7909690_T33",
"arg2_id": "7909690_T35",
"normalized": []
},
{
"id": "7909690_8",
"type": "INHIBITOR",
"arg1_id": "7909690_T32",
"arg2_id": "7909690_T35",
"normalized": []
},
{
"id": "7909690_9",
"type": "SUBSTRATE",
"arg1_id": "7909690_T2",
"arg2_id": "7909690_T35",
"normalized": []
},
{
"id": "7909690_10",
"type": "PRODUCT-OF",
"arg1_id": "7909690_T3",
"arg2_id": "7909690_T35",
"normalized": []
},
{
"id": "7909690_11",
"type": "SUBSTRATE",
"arg1_id": "7909690_T5",
"arg2_id": "7909690_T36",
"normalized": []
},
{
"id": "7909690_12",
"type": "SUBSTRATE",
"arg1_id": "7909690_T6",
"arg2_id": "7909690_T36",
"normalized": []
},
{
"id": "7909690_13",
"type": "INHIBITOR",
"arg1_id": "7909690_T4",
"arg2_id": "7909690_T36",
"normalized": []
},
{
"id": "7909690_14",
"type": "SUBSTRATE",
"arg1_id": "7909690_T9",
"arg2_id": "7909690_T36",
"normalized": []
}
] |
17251447 | 17251447 | [
{
"id": "17251447_title",
"type": "title",
"text": [
"RPE65 is essential for the function of cone photoreceptors in NRL-deficient mice."
],
"offsets": [
[
0,
81
]
]
},
{
"id": "17251447_abstract",
"type": "abstract",
"text": [
"PURPOSE: Phototransduction in cones is initiated by the bleaching of their visual pigment, which comprises a protein component-cone opsin-and a vitamin A derivative-11-cis retinal. Little is known about the source of 11-cis retinal for cones. In the current study, neural retina leucine zipper-deficient (Nrl(-/-)) and rod opsin (Rho(-/-))-deficient mice were used, two mouse models that have been described as having a \"cone-only\" retina, to analyze the retinoid metabolism of cones. In addition, these mice were bred to retinal pigment epithelial protein 65 (Rpe65(-/-))-deficient mice to study the role of RPE65. METHODS: Mice were analyzed using morphology, Western blot analysis, immunohistochemistry, electroretinography (ERG), and retinoid profiling by HPLC. RESULTS: In comparison to wild-type mice, the retina of Nrl(-/-) mice contained elevated levels of RPE65 and cellular retinaldehyde-binding protein (CRALBP), suggesting a particular role of these two proteins for the retinoid metabolism of cones. In Nrl(-/-) mice, different retinoid species were present in proportions similar to wild type. Ablation of RPE65 in Nrl(-/-) and Rho(-/-) mice led to the absence of 11-cis retinal, but increased the total retinoid content, with retinyl esters representing the most abundant retinoid species. In the absence of RPE65, retinal sensitivity in Nrl(-/-) mice dropped by a factor of a thousand. CONCLUSIONS: The data show that RPE65, previously shown to be essential for rod function, is also indispensable for the production of 11-cis retinal for cones and thus for cone function."
],
"offsets": [
[
82,
1670
]
]
}
] | [
{
"id": "17251447_T1",
"type": "CHEMICAL",
"text": [
"retinoid"
],
"offsets": [
[
1123,
1131
]
],
"normalized": []
},
{
"id": "17251447_T2",
"type": "CHEMICAL",
"text": [
"11-cis retinal"
],
"offsets": [
[
1260,
1274
]
],
"normalized": []
},
{
"id": "17251447_T3",
"type": "CHEMICAL",
"text": [
"retinoid"
],
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[
1300,
1308
]
],
"normalized": []
},
{
"id": "17251447_T4",
"type": "CHEMICAL",
"text": [
"retinyl esters"
],
"offsets": [
[
1323,
1337
]
],
"normalized": []
},
{
"id": "17251447_T5",
"type": "CHEMICAL",
"text": [
"retinoid"
],
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[
1369,
1377
]
],
"normalized": []
},
{
"id": "17251447_T6",
"type": "CHEMICAL",
"text": [
"vitamin A"
],
"offsets": [
[
226,
235
]
],
"normalized": []
},
{
"id": "17251447_T7",
"type": "CHEMICAL",
"text": [
"11-cis retinal"
],
"offsets": [
[
1618,
1632
]
],
"normalized": []
},
{
"id": "17251447_T8",
"type": "CHEMICAL",
"text": [
"11-cis retinal"
],
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[
247,
261
]
],
"normalized": []
},
{
"id": "17251447_T9",
"type": "CHEMICAL",
"text": [
"11-cis retinal"
],
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[
299,
313
]
],
"normalized": []
},
{
"id": "17251447_T10",
"type": "CHEMICAL",
"text": [
"leucine"
],
"offsets": [
[
361,
368
]
],
"normalized": []
},
{
"id": "17251447_T11",
"type": "CHEMICAL",
"text": [
"retinoid"
],
"offsets": [
[
537,
545
]
],
"normalized": []
},
{
"id": "17251447_T12",
"type": "CHEMICAL",
"text": [
"retinoid"
],
"offsets": [
[
820,
828
]
],
"normalized": []
},
{
"id": "17251447_T13",
"type": "CHEMICAL",
"text": [
"retinaldehyde"
],
"offsets": [
[
966,
979
]
],
"normalized": []
},
{
"id": "17251447_T14",
"type": "CHEMICAL",
"text": [
"retinoid"
],
"offsets": [
[
1065,
1073
]
],
"normalized": []
},
{
"id": "17251447_T15",
"type": "GENE-Y",
"text": [
"Nrl"
],
"offsets": [
[
1098,
1101
]
],
"normalized": []
},
{
"id": "17251447_T16",
"type": "GENE-Y",
"text": [
"RPE65"
],
"offsets": [
[
1202,
1207
]
],
"normalized": []
},
{
"id": "17251447_T17",
"type": "GENE-Y",
"text": [
"Nrl"
],
"offsets": [
[
1211,
1214
]
],
"normalized": []
},
{
"id": "17251447_T18",
"type": "GENE-N",
"text": [
"Rho"
],
"offsets": [
[
1224,
1227
]
],
"normalized": []
},
{
"id": "17251447_T19",
"type": "GENE-N",
"text": [
"cone opsin"
],
"offsets": [
[
209,
219
]
],
"normalized": []
},
{
"id": "17251447_T20",
"type": "GENE-Y",
"text": [
"RPE65"
],
"offsets": [
[
1405,
1410
]
],
"normalized": []
},
{
"id": "17251447_T21",
"type": "GENE-Y",
"text": [
"Nrl"
],
"offsets": [
[
1435,
1438
]
],
"normalized": []
},
{
"id": "17251447_T22",
"type": "GENE-Y",
"text": [
"RPE65"
],
"offsets": [
[
1516,
1521
]
],
"normalized": []
},
{
"id": "17251447_T23",
"type": "GENE-Y",
"text": [
"neural retina leucine zipper"
],
"offsets": [
[
347,
375
]
],
"normalized": []
},
{
"id": "17251447_T24",
"type": "GENE-Y",
"text": [
"Nrl"
],
"offsets": [
[
387,
390
]
],
"normalized": []
},
{
"id": "17251447_T25",
"type": "GENE-N",
"text": [
"rod opsin"
],
"offsets": [
[
401,
410
]
],
"normalized": []
},
{
"id": "17251447_T26",
"type": "GENE-N",
"text": [
"Rho"
],
"offsets": [
[
412,
415
]
],
"normalized": []
},
{
"id": "17251447_T27",
"type": "GENE-Y",
"text": [
"retinal pigment epithelial protein 65"
],
"offsets": [
[
604,
641
]
],
"normalized": []
},
{
"id": "17251447_T28",
"type": "GENE-Y",
"text": [
"Rpe65"
],
"offsets": [
[
643,
648
]
],
"normalized": []
},
{
"id": "17251447_T29",
"type": "GENE-Y",
"text": [
"RPE65"
],
"offsets": [
[
691,
696
]
],
"normalized": []
},
{
"id": "17251447_T30",
"type": "GENE-Y",
"text": [
"Nrl"
],
"offsets": [
[
904,
907
]
],
"normalized": []
},
{
"id": "17251447_T31",
"type": "GENE-Y",
"text": [
"RPE65"
],
"offsets": [
[
947,
952
]
],
"normalized": []
},
{
"id": "17251447_T32",
"type": "GENE-Y",
"text": [
"cellular retinaldehyde-binding protein"
],
"offsets": [
[
957,
995
]
],
"normalized": []
},
{
"id": "17251447_T33",
"type": "GENE-Y",
"text": [
"CRALBP"
],
"offsets": [
[
997,
1003
]
],
"normalized": []
},
{
"id": "17251447_T34",
"type": "GENE-Y",
"text": [
"RPE65"
],
"offsets": [
[
0,
5
]
],
"normalized": []
},
{
"id": "17251447_T35",
"type": "GENE-N",
"text": [
"photoreceptors"
],
"offsets": [
[
44,
58
]
],
"normalized": []
},
{
"id": "17251447_T36",
"type": "GENE-Y",
"text": [
"NRL"
],
"offsets": [
[
62,
65
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17251447_0",
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"arg2_id": "17251447_T31",
"normalized": []
},
{
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"arg2_id": "17251447_T22",
"normalized": []
},
{
"id": "17251447_2",
"type": "DIRECT-REGULATOR",
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"arg2_id": "17251447_T32",
"normalized": []
},
{
"id": "17251447_3",
"type": "DIRECT-REGULATOR",
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"arg2_id": "17251447_T33",
"normalized": []
},
{
"id": "17251447_4",
"type": "PRODUCT-OF",
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"arg2_id": "17251447_T16",
"normalized": []
},
{
"id": "17251447_5",
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},
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"id": "17251447_6",
"type": "SUBSTRATE",
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},
{
"id": "17251447_7",
"type": "SUBSTRATE",
"arg1_id": "17251447_T5",
"arg2_id": "17251447_T16",
"normalized": []
}
] |
23300000 | 23300000 | [
{
"id": "23300000_title",
"type": "title",
"text": [
"Influence of rare earth elements on metabolism and related enzyme activity and isozyme expression in Tetrastigma hemsleyanum cell suspension cultures."
],
"offsets": [
[
0,
150
]
]
},
{
"id": "23300000_abstract",
"type": "abstract",
"text": [
"The effects of rare earth elements (REEs) not only on cell growth and flavonoid accumulation of Tetrastigma hemsleyanum suspension cells but also on the isoenzyme patterns and activities of related enzymes were studied in this paper. There were no significant differences in enhancement of flavonoid accumulation in T. hemsleyanum suspension cells among La(3+), Ce(3+), and Nd(3+). Whereas their inductive effects on cell proliferation varied greatly. The most significant effects were achieved with 100 μM Ce(3+)and Nd(3+). Under treatment over a 25-day culture period, the maximal biomass levels reached 1.92- and 1.74-fold and the total flavonoid contents are 1.45- and 1.49-fold, than that of control, respectively. Catalase, phenylalanine ammonia-lyase (PAL), and peroxidase (POD) activity was activated significantly when the REE concentration range from 0 to 300 μM, whereas no significant changes were found in superoxide dismutase activity. Differences of esterase isozymes under REE treatment only laid in expression level, and there were no specific bands. The expression level of some POD isozymes strengthened with increasing concentration of REEs within the range of 50-200 μM. When REE concentration was higher than 300 μM, the expression of some POD isozymes was inhibited; meanwhile, some other new POD isozymes were induced. Our results also showed REEs did not directly influence PAL activity. So, we speculated that 50-200 μM REEs could activate some of antioxidant enzymes, adjust some isozymes expression, trigger the defense responses of T. hemsleyanum suspension cells, and stimulate flavonoid accumulation by inducing PAL activity."
],
"offsets": [
[
151,
1807
]
]
}
] | [
{
"id": "23300000_T1",
"type": "CHEMICAL",
"text": [
"flavonoid"
],
"offsets": [
[
441,
450
]
],
"normalized": []
},
{
"id": "23300000_T2",
"type": "CHEMICAL",
"text": [
"La(3+)"
],
"offsets": [
[
505,
511
]
],
"normalized": []
},
{
"id": "23300000_T3",
"type": "CHEMICAL",
"text": [
"Ce(3+)"
],
"offsets": [
[
513,
519
]
],
"normalized": []
},
{
"id": "23300000_T4",
"type": "CHEMICAL",
"text": [
"Nd(3+)"
],
"offsets": [
[
525,
531
]
],
"normalized": []
},
{
"id": "23300000_T5",
"type": "CHEMICAL",
"text": [
"Ce(3+)"
],
"offsets": [
[
658,
664
]
],
"normalized": []
},
{
"id": "23300000_T6",
"type": "CHEMICAL",
"text": [
"Nd(3+)"
],
"offsets": [
[
668,
674
]
],
"normalized": []
},
{
"id": "23300000_T7",
"type": "CHEMICAL",
"text": [
"flavonoid"
],
"offsets": [
[
791,
800
]
],
"normalized": []
},
{
"id": "23300000_T8",
"type": "CHEMICAL",
"text": [
"flavonoid"
],
"offsets": [
[
221,
230
]
],
"normalized": []
},
{
"id": "23300000_T9",
"type": "CHEMICAL",
"text": [
"phenylalanine"
],
"offsets": [
[
881,
894
]
],
"normalized": []
},
{
"id": "23300000_T10",
"type": "CHEMICAL",
"text": [
"ammonia"
],
"offsets": [
[
895,
902
]
],
"normalized": []
},
{
"id": "23300000_T11",
"type": "CHEMICAL",
"text": [
"superoxide"
],
"offsets": [
[
1070,
1080
]
],
"normalized": []
},
{
"id": "23300000_T12",
"type": "GENE-N",
"text": [
"POD"
],
"offsets": [
[
1248,
1251
]
],
"normalized": []
},
{
"id": "23300000_T13",
"type": "GENE-N",
"text": [
"POD"
],
"offsets": [
[
1413,
1416
]
],
"normalized": []
},
{
"id": "23300000_T14",
"type": "GENE-N",
"text": [
"POD"
],
"offsets": [
[
1467,
1470
]
],
"normalized": []
},
{
"id": "23300000_T15",
"type": "GENE-N",
"text": [
"PAL"
],
"offsets": [
[
1550,
1553
]
],
"normalized": []
},
{
"id": "23300000_T16",
"type": "GENE-N",
"text": [
"PAL"
],
"offsets": [
[
1794,
1797
]
],
"normalized": []
},
{
"id": "23300000_T17",
"type": "GENE-N",
"text": [
"Catalase"
],
"offsets": [
[
871,
879
]
],
"normalized": []
},
{
"id": "23300000_T18",
"type": "GENE-N",
"text": [
"phenylalanine ammonia-lyase"
],
"offsets": [
[
881,
908
]
],
"normalized": []
},
{
"id": "23300000_T19",
"type": "GENE-N",
"text": [
"PAL"
],
"offsets": [
[
910,
913
]
],
"normalized": []
},
{
"id": "23300000_T20",
"type": "GENE-N",
"text": [
"peroxidase"
],
"offsets": [
[
920,
930
]
],
"normalized": []
},
{
"id": "23300000_T21",
"type": "GENE-N",
"text": [
"POD"
],
"offsets": [
[
932,
935
]
],
"normalized": []
},
{
"id": "23300000_T22",
"type": "GENE-N",
"text": [
"superoxide dismutase"
],
"offsets": [
[
1070,
1090
]
],
"normalized": []
},
{
"id": "23300000_T23",
"type": "GENE-N",
"text": [
"esterase"
],
"offsets": [
[
1116,
1124
]
],
"normalized": []
}
] | [] | [] | [] |
15169831 | 15169831 | [
{
"id": "15169831_title",
"type": "title",
"text": [
"Ethanol suppression of ventral tegmental area GABA neuron electrical transmission involves N-methyl-D-aspartate receptors."
],
"offsets": [
[
0,
122
]
]
},
{
"id": "15169831_abstract",
"type": "abstract",
"text": [
"Ventral tegmental area (VTA) GABA neurons are critical substrates modulating the mesocorticolimbic dopamine system implicated in natural and drug reward. The aim of this study was to evaluate the effects of ethanol on glutamatergic and GABAergic modulation of VTA GABA neuron electrical synaptic transmission. We evaluated the effects of systemic ethanol (0.05-2.0 g/kg i.p.), the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801; 0.05-0.2 mg/kg i.v.), the connexin-36 gap junction blocker quinidine (5-20 mg/kg i.v.), the fast-acting barbiturate methohexital (Brevital; 5-10 mg/kg i.v.), and the benzodiazepine chlordiazepoxide (Librium; 5-10 mg/kg i.v.), as well as in situ VTA administration of NMDA and the GABA(A) receptor agonist muscimol, on VTA GABA neuron spontaneous activity and internal capsule stimulus-induced poststimulus spike discharges (ICPSDs). Systemic ethanol, quinidine, and dizocilpine reduced, whereas local NMDA enhanced, and the systemic and local GABA(A) receptor modulators did not significantly alter VTA GABA neuron ICPSDs. Ethanol potentiated dizocilpine inhibition of VTA GABA neuron ICPSDs, but not quinidine inhibition. In situ microelectrophoretic application of dopamine markedly enhanced VTA GABA neuron firing rate (131%), spike duration (124%), and spike coupling, which were blocked by systemic quinidine. These findings indicate that VTA GABA neurons are coupled electrically via gap junctions and that the inhibitory effect of ethanol on electrical transmission is primarily via inhibition of NMDA receptor-mediated excitation, not via enhancement of GABA receptor-mediated inhibition. Thus, the rewarding properties of ethanol may result from inhibitory effects on excitatory glutamatergic neurotransmission between electrically coupled networks of midbrain GABA neurons."
],
"offsets": [
[
123,
1956
]
]
}
] | [
{
"id": "15169831_T1",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
1176,
1180
]
],
"normalized": []
},
{
"id": "15169831_T2",
"type": "CHEMICAL",
"text": [
"Ethanol"
],
"offsets": [
[
1196,
1203
]
],
"normalized": []
},
{
"id": "15169831_T3",
"type": "CHEMICAL",
"text": [
"dizocilpine"
],
"offsets": [
[
1216,
1227
]
],
"normalized": []
},
{
"id": "15169831_T4",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
1246,
1250
]
],
"normalized": []
},
{
"id": "15169831_T5",
"type": "CHEMICAL",
"text": [
"quinidine"
],
"offsets": [
[
1274,
1283
]
],
"normalized": []
},
{
"id": "15169831_T6",
"type": "CHEMICAL",
"text": [
"dopamine"
],
"offsets": [
[
1340,
1348
]
],
"normalized": []
},
{
"id": "15169831_T7",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
1371,
1375
]
],
"normalized": []
},
{
"id": "15169831_T8",
"type": "CHEMICAL",
"text": [
"quinidine"
],
"offsets": [
[
1477,
1486
]
],
"normalized": []
},
{
"id": "15169831_T9",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
1521,
1525
]
],
"normalized": []
},
{
"id": "15169831_T10",
"type": "CHEMICAL",
"text": [
"ethanol"
],
"offsets": [
[
1611,
1618
]
],
"normalized": []
},
{
"id": "15169831_T11",
"type": "CHEMICAL",
"text": [
"NMDA"
],
"offsets": [
[
1677,
1681
]
],
"normalized": []
},
{
"id": "15169831_T12",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
1735,
1739
]
],
"normalized": []
},
{
"id": "15169831_T13",
"type": "CHEMICAL",
"text": [
"ethanol"
],
"offsets": [
[
1804,
1811
]
],
"normalized": []
},
{
"id": "15169831_T14",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
1943,
1947
]
],
"normalized": []
},
{
"id": "15169831_T15",
"type": "CHEMICAL",
"text": [
"ethanol"
],
"offsets": [
[
330,
337
]
],
"normalized": []
},
{
"id": "15169831_T16",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
387,
391
]
],
"normalized": []
},
{
"id": "15169831_T17",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
152,
156
]
],
"normalized": []
},
{
"id": "15169831_T18",
"type": "CHEMICAL",
"text": [
"ethanol"
],
"offsets": [
[
470,
477
]
],
"normalized": []
},
{
"id": "15169831_T19",
"type": "CHEMICAL",
"text": [
"N-methyl-D-aspartate"
],
"offsets": [
[
504,
524
]
],
"normalized": []
},
{
"id": "15169831_T20",
"type": "CHEMICAL",
"text": [
"NMDA"
],
"offsets": [
[
526,
530
]
],
"normalized": []
},
{
"id": "15169831_T21",
"type": "CHEMICAL",
"text": [
"dizocilpine"
],
"offsets": [
[
552,
563
]
],
"normalized": []
},
{
"id": "15169831_T22",
"type": "CHEMICAL",
"text": [
"MK-801"
],
"offsets": [
[
565,
571
]
],
"normalized": []
},
{
"id": "15169831_T23",
"type": "CHEMICAL",
"text": [
"quinidine"
],
"offsets": [
[
632,
641
]
],
"normalized": []
},
{
"id": "15169831_T24",
"type": "CHEMICAL",
"text": [
"barbiturate"
],
"offsets": [
[
677,
688
]
],
"normalized": []
},
{
"id": "15169831_T25",
"type": "CHEMICAL",
"text": [
"methohexital"
],
"offsets": [
[
689,
701
]
],
"normalized": []
},
{
"id": "15169831_T26",
"type": "CHEMICAL",
"text": [
"benzodiazepine"
],
"offsets": [
[
739,
753
]
],
"normalized": []
},
{
"id": "15169831_T27",
"type": "CHEMICAL",
"text": [
"chlordiazepoxide"
],
"offsets": [
[
754,
770
]
],
"normalized": []
},
{
"id": "15169831_T28",
"type": "CHEMICAL",
"text": [
"Librium"
],
"offsets": [
[
772,
779
]
],
"normalized": []
},
{
"id": "15169831_T29",
"type": "CHEMICAL",
"text": [
"NMDA"
],
"offsets": [
[
840,
844
]
],
"normalized": []
},
{
"id": "15169831_T30",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
895,
899
]
],
"normalized": []
},
{
"id": "15169831_T31",
"type": "CHEMICAL",
"text": [
"ethanol"
],
"offsets": [
[
1015,
1022
]
],
"normalized": []
},
{
"id": "15169831_T32",
"type": "CHEMICAL",
"text": [
"quinidine"
],
"offsets": [
[
1024,
1033
]
],
"normalized": []
},
{
"id": "15169831_T33",
"type": "CHEMICAL",
"text": [
"dizocilpine"
],
"offsets": [
[
1039,
1050
]
],
"normalized": []
},
{
"id": "15169831_T34",
"type": "CHEMICAL",
"text": [
"NMDA"
],
"offsets": [
[
1074,
1078
]
],
"normalized": []
},
{
"id": "15169831_T35",
"type": "CHEMICAL",
"text": [
"dopamine"
],
"offsets": [
[
222,
230
]
],
"normalized": []
},
{
"id": "15169831_T36",
"type": "CHEMICAL",
"text": [
"Ethanol"
],
"offsets": [
[
0,
7
]
],
"normalized": []
},
{
"id": "15169831_T37",
"type": "CHEMICAL",
"text": [
"GABA"
],
"offsets": [
[
46,
50
]
],
"normalized": []
},
{
"id": "15169831_T38",
"type": "CHEMICAL",
"text": [
"N-methyl-D-aspartate"
],
"offsets": [
[
91,
111
]
],
"normalized": []
},
{
"id": "15169831_T39",
"type": "GENE-N",
"text": [
"NMDA receptor"
],
"offsets": [
[
1677,
1690
]
],
"normalized": []
},
{
"id": "15169831_T40",
"type": "GENE-N",
"text": [
"GABA receptor"
],
"offsets": [
[
1735,
1748
]
],
"normalized": []
},
{
"id": "15169831_T41",
"type": "GENE-N",
"text": [
"N-methyl-D-aspartate (NMDA) receptor"
],
"offsets": [
[
504,
540
]
],
"normalized": []
},
{
"id": "15169831_T42",
"type": "GENE-Y",
"text": [
"connexin-36"
],
"offsets": [
[
599,
610
]
],
"normalized": []
},
{
"id": "15169831_T43",
"type": "GENE-N",
"text": [
"NMDA and the GABA(A) receptor"
],
"offsets": [
[
840,
869
]
],
"normalized": []
},
{
"id": "15169831_T44",
"type": "GENE-N",
"text": [
"GABA(A) receptor"
],
"offsets": [
[
1116,
1132
]
],
"normalized": []
},
{
"id": "15169831_T45",
"type": "GENE-N",
"text": [
"N-methyl-D-aspartate receptors"
],
"offsets": [
[
91,
121
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "15169831_0",
"type": "ANTAGONIST",
"arg1_id": "15169831_T21",
"arg2_id": "15169831_T41",
"normalized": []
},
{
"id": "15169831_1",
"type": "ANTAGONIST",
"arg1_id": "15169831_T22",
"arg2_id": "15169831_T41",
"normalized": []
},
{
"id": "15169831_2",
"type": "INHIBITOR",
"arg1_id": "15169831_T23",
"arg2_id": "15169831_T42",
"normalized": []
},
{
"id": "15169831_3",
"type": "INHIBITOR",
"arg1_id": "15169831_T10",
"arg2_id": "15169831_T39",
"normalized": []
},
{
"id": "15169831_4",
"type": "INHIBITOR",
"arg1_id": "15169831_T10",
"arg2_id": "15169831_T40",
"normalized": []
}
] |
23524663 | 23524663 | [
{
"id": "23524663_title",
"type": "title",
"text": [
"Metabolism Studies of Unformulated Internally [3H]-labeled siRNAs in Mice."
],
"offsets": [
[
0,
74
]
]
},
{
"id": "23524663_abstract",
"type": "abstract",
"text": [
"Absorption, distribution, metabolism, and excretion properties of two unformulated model siRNAs were determined using a single internal [(3)H]-radiolabeling procedure, where the full-length oligonucleotides were radiolabeled by Br/(3)H-exchange. Tissue distribution, excretion, and mass balance of radioactivity were investigated in male CD-1 mice, following a single intravenous administration of the [(3)H]-siRNAs, at a target dose level of 5 mg/kg. Quantitative whole-body autoradiography (QWBA) and liquid scintillation counting techniques were used to determine tissue distribution. Radiochromatogram profiles were determined in plasma, tissue extracts and urine. Metabolites were separated by liquid chromatography and identified by radiodetection and high-resolution accurate mass spectrometry. In general, there was little difference in the distribution of total radiolabeled components after administration of the two unformulated [(3)H]-siRNAs. The radioactivity was rapidly and widely distributed throughout the body, and remained detectable in all tissues investigated at later time points (24 and 48 hours for [(3)H]-MRP4 and [(3)H]-SSB siRNA, respectively). After an initial rapid decline, concentrations of total radiolabeled components in dried blood declined at a much slower rate. A nearly complete mass balance was obtained for the [(3)H]-SSB siRNA and renal excretion was the main route of elimination (38%). The metabolism of the two model siRNAs was rapid and extensive. Five minutes after administration, no parent compound could be detected in plasma. Instead, radiolabeled nucleosides resulting from nuclease hydrolysis were observed. In the metabolism profiles obtained from various tissues only radiolabeled nucleosides were found, suggesting that siRNAs are rapidly metabolized and that the distribution pattern of total radiolabeled components can be ascribed to small molecular weight metabolites."
],
"offsets": [
[
75,
2002
]
]
}
] | [
{
"id": "23524663_T1",
"type": "CHEMICAL",
"text": [
"(3)H"
],
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[
1199,
1203
]
],
"normalized": []
},
{
"id": "23524663_T2",
"type": "CHEMICAL",
"text": [
"(3)H"
],
"offsets": [
[
1215,
1219
]
],
"normalized": []
},
{
"id": "23524663_T3",
"type": "CHEMICAL",
"text": [
"(3)H"
],
"offsets": [
[
1427,
1431
]
],
"normalized": []
},
{
"id": "23524663_T4",
"type": "CHEMICAL",
"text": [
"(3)H"
],
"offsets": [
[
212,
216
]
],
"normalized": []
},
{
"id": "23524663_T5",
"type": "CHEMICAL",
"text": [
"nucleosides"
],
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[
1673,
1684
]
],
"normalized": []
},
{
"id": "23524663_T6",
"type": "CHEMICAL",
"text": [
"nucleosides"
],
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[
1810,
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]
],
"normalized": []
},
{
"id": "23524663_T7",
"type": "CHEMICAL",
"text": [
"Br"
],
"offsets": [
[
303,
305
]
],
"normalized": []
},
{
"id": "23524663_T8",
"type": "CHEMICAL",
"text": [
"(3)H"
],
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[
306,
310
]
],
"normalized": []
},
{
"id": "23524663_T9",
"type": "CHEMICAL",
"text": [
"(3)H"
],
"offsets": [
[
478,
482
]
],
"normalized": []
},
{
"id": "23524663_T10",
"type": "CHEMICAL",
"text": [
"(3)H"
],
"offsets": [
[
1016,
1020
]
],
"normalized": []
},
{
"id": "23524663_T11",
"type": "CHEMICAL",
"text": [
"3H"
],
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47,
49
]
],
"normalized": []
},
{
"id": "23524663_T12",
"type": "GENE-Y",
"text": [
"MRP4"
],
"offsets": [
[
1205,
1209
]
],
"normalized": []
},
{
"id": "23524663_T13",
"type": "GENE-N",
"text": [
"nuclease"
],
"offsets": [
[
1700,
1708
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23524663_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "23524663_T1",
"arg2_id": "23524663_T12",
"normalized": []
},
{
"id": "23524663_1",
"type": "PRODUCT-OF",
"arg1_id": "23524663_T5",
"arg2_id": "23524663_T13",
"normalized": []
}
] |
23151612 | 23151612 | [
{
"id": "23151612_title",
"type": "title",
"text": [
"A review of anti-inflammatory agents for symptoms of schizophrenia."
],
"offsets": [
[
0,
67
]
]
},
{
"id": "23151612_abstract",
"type": "abstract",
"text": [
"Schizophrenia is a chronic debilitating mental disorder that affects about 1% of the US population. The pathophysiology and etiology remain unknown, thus new treatment targets have been challenging and few novel treatments with new mechanisms of action have come to market in the past few decades. Increasing attention has been paid to the role of inflammation in schizophrenia and new data suggests that decreasing inflammation and inflammatory biomarkers may play some role in schizophrenia treatment. This review summarizes the clinical trial literature regarding medications that possess anti-inflammatory properties that have been tested for schizophrenia symptoms and covers such medications as non-steroidal anti-inflammatory agents, such as the cyclo-oxygenase-2 (COX-2) inhibitors and aspirin, omega-3 fatty acids, neurosteroids and minocycline. Overall, there is accumulating evidence, albeit mostly adjunctive treatments, that agents working on inflammatory pathways have some benefits in people with schizophrenia. In the next few years the field will begin to see data on many treatments with anti-inflammatory properties that are currently under study. Hopefully advancements in understanding inflammation and effective treatments having anti-inflammatory properties may help revolutionize our understanding and provide new targets for prevention and treatment in schizophrenia."
],
"offsets": [
[
68,
1460
]
]
}
] | [
{
"id": "23151612_T1",
"type": "CHEMICAL",
"text": [
"steroidal"
],
"offsets": [
[
773,
782
]
],
"normalized": []
},
{
"id": "23151612_T2",
"type": "CHEMICAL",
"text": [
"aspirin"
],
"offsets": [
[
862,
869
]
],
"normalized": []
},
{
"id": "23151612_T3",
"type": "CHEMICAL",
"text": [
"omega-3 fatty acids"
],
"offsets": [
[
871,
890
]
],
"normalized": []
},
{
"id": "23151612_T4",
"type": "CHEMICAL",
"text": [
"neurosteroids"
],
"offsets": [
[
892,
905
]
],
"normalized": []
},
{
"id": "23151612_T5",
"type": "CHEMICAL",
"text": [
"minocycline"
],
"offsets": [
[
910,
921
]
],
"normalized": []
},
{
"id": "23151612_T6",
"type": "GENE-Y",
"text": [
"cyclo-oxygenase-2"
],
"offsets": [
[
821,
838
]
],
"normalized": []
},
{
"id": "23151612_T7",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
840,
845
]
],
"normalized": []
}
] | [] | [] | [] |
23396185 | 23396185 | [
{
"id": "23396185_title",
"type": "title",
"text": [
"Quercetin prevents protein nitration and glycolytic block of proliferation in hydrogen peroxide insulted cultured neuronal precursor cells (NPCs): Implications on CNS regeneration."
],
"offsets": [
[
0,
180
]
]
},
{
"id": "23396185_abstract",
"type": "abstract",
"text": [
"Survival along with optimal proliferation of neuronal precursors determines the outcomes of the endogenous cellular repair in CNS. Cellular-oxidation based cell death has been described in several neurodegenerative disorders. Therefore, this study was aimed at the identification of the potent targets of oxidative damage to the neuronal precursors and its effective prevention by a natural flavonoid, Quercetin. Neuronal precursor cells (NPCs), Nestin+ and GFAP (Glial fibrillary acidic protein)+ were isolated and cultured from adult rat SVZ (subventricular zone). These cells were challenged with a single dose of H2O2 (50μM) and/or pre-treated with different concentrations of Quercetin. H2O2 severely limited the cellular viability and expansion of the neurospheres. Cellular-oxidation studies revealed reduction in glutathione dependent redox buffering along with depletion of enzymatic cellular antioxidants that might potentiate the nitrite (NO2(-)) and superoxide anion (O2(-)) mediated peroxynitrite (ONOO(-)) formation and irreversible protein nitration. We identified depleted PK-M2 (M2 isoform of pyruvate kinase) activity and apoptosis of NPCs revealed by the genomic DNA fragmentation and elevated PARP (poly ADP ribose polymerase) activity along with increased Caspase activity initiated by severely depolarised mitochondrial membranes. However, the pre-treatment of Quercetin in a dose-response manner prevented these changes and restored the expansion of neurospheres preferably by neutralizing the oxidative conditions and thereby reducing peroxynitrite formation, protein nitration and PK-M2 depletion. Our results unravel the potential interactions of oxidative environment and respiration in the survival and activation of precursors and offer a promise shown by a natural flavonoid in the protective strategy for neuronal precursors of adult brain."
],
"offsets": [
[
181,
2052
]
]
}
] | [
{
"id": "23396185_T1",
"type": "CHEMICAL",
"text": [
"ONOO(-)"
],
"offsets": [
[
1192,
1199
]
],
"normalized": []
},
{
"id": "23396185_T2",
"type": "CHEMICAL",
"text": [
"pyruvate"
],
"offsets": [
[
1291,
1299
]
],
"normalized": []
},
{
"id": "23396185_T3",
"type": "CHEMICAL",
"text": [
"poly ADP ribose"
],
"offsets": [
[
1400,
1415
]
],
"normalized": []
},
{
"id": "23396185_T4",
"type": "CHEMICAL",
"text": [
"Quercetin"
],
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[
1564,
1573
]
],
"normalized": []
},
{
"id": "23396185_T5",
"type": "CHEMICAL",
"text": [
"peroxynitrite"
],
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[
1740,
1753
]
],
"normalized": []
},
{
"id": "23396185_T6",
"type": "CHEMICAL",
"text": [
"flavonoid"
],
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[
1976,
1985
]
],
"normalized": []
},
{
"id": "23396185_T7",
"type": "CHEMICAL",
"text": [
"Quercetin"
],
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[
583,
592
]
],
"normalized": []
},
{
"id": "23396185_T8",
"type": "CHEMICAL",
"text": [
"H2O2"
],
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[
798,
802
]
],
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},
{
"id": "23396185_T9",
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"text": [
"Quercetin"
],
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[
862,
871
]
],
"normalized": []
},
{
"id": "23396185_T10",
"type": "CHEMICAL",
"text": [
"H2O2"
],
"offsets": [
[
873,
877
]
],
"normalized": []
},
{
"id": "23396185_T11",
"type": "CHEMICAL",
"text": [
"glutathione"
],
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[
1002,
1013
]
],
"normalized": []
},
{
"id": "23396185_T12",
"type": "CHEMICAL",
"text": [
"nitrite"
],
"offsets": [
[
1122,
1129
]
],
"normalized": []
},
{
"id": "23396185_T13",
"type": "CHEMICAL",
"text": [
"NO2(-)"
],
"offsets": [
[
1131,
1137
]
],
"normalized": []
},
{
"id": "23396185_T14",
"type": "CHEMICAL",
"text": [
"superoxide"
],
"offsets": [
[
1143,
1153
]
],
"normalized": []
},
{
"id": "23396185_T15",
"type": "CHEMICAL",
"text": [
"O2(-)"
],
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[
1161,
1166
]
],
"normalized": []
},
{
"id": "23396185_T16",
"type": "CHEMICAL",
"text": [
"peroxynitrite"
],
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[
1177,
1190
]
],
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},
{
"id": "23396185_T17",
"type": "CHEMICAL",
"text": [
"Quercetin"
],
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[
0,
9
]
],
"normalized": []
},
{
"id": "23396185_T18",
"type": "CHEMICAL",
"text": [
"hydrogen peroxide"
],
"offsets": [
[
78,
95
]
],
"normalized": []
},
{
"id": "23396185_T19",
"type": "GENE-Y",
"text": [
"PK-M2"
],
"offsets": [
[
1270,
1275
]
],
"normalized": []
},
{
"id": "23396185_T20",
"type": "GENE-Y",
"text": [
"M2 isoform of pyruvate kinase"
],
"offsets": [
[
1277,
1306
]
],
"normalized": []
},
{
"id": "23396185_T21",
"type": "GENE-N",
"text": [
"PARP"
],
"offsets": [
[
1394,
1398
]
],
"normalized": []
},
{
"id": "23396185_T22",
"type": "GENE-N",
"text": [
"poly ADP ribose polymerase"
],
"offsets": [
[
1400,
1426
]
],
"normalized": []
},
{
"id": "23396185_T23",
"type": "GENE-N",
"text": [
"Caspase"
],
"offsets": [
[
1458,
1465
]
],
"normalized": []
},
{
"id": "23396185_T24",
"type": "GENE-Y",
"text": [
"PK-M2"
],
"offsets": [
[
1787,
1792
]
],
"normalized": []
},
{
"id": "23396185_T25",
"type": "GENE-Y",
"text": [
"Nestin"
],
"offsets": [
[
627,
633
]
],
"normalized": []
},
{
"id": "23396185_T26",
"type": "GENE-Y",
"text": [
"GFAP"
],
"offsets": [
[
639,
643
]
],
"normalized": []
},
{
"id": "23396185_T27",
"type": "GENE-Y",
"text": [
"Glial fibrillary acidic protein"
],
"offsets": [
[
645,
676
]
],
"normalized": []
}
] | [] | [] | [] |
23607712 | 23607712 | [
{
"id": "23607712_title",
"type": "title",
"text": [
"Synaptotagmin 1 is required for vesicular Ca(2+) /H(+) -antiport activity."
],
"offsets": [
[
0,
74
]
]
},
{
"id": "23607712_abstract",
"type": "abstract",
"text": [
"A low-affinity Ca(2+) /H(+) -antiport was described in the membrane of mammalian brain synaptic vesicles. Electrophysiological studies showed that this antiport contributes to the extreme brevity of excitation-release coupling in rapid synapses. Synaptotagmin-1, a vesicular protein interacting with membranes upon low-affinity Ca(2+) -binding, plays a major role in excitation-release coupling, by synchronizing calcium entry with fast neurotransmitter release. Here, we report that synaptotagmin-1 is necessary for expression of the vesicular Ca(2+) /H(+) -antiport. We measured Ca(2+) /H(+) -antiport activity in vesicles and granules of pheochromocytoma PC12 cells by three methods: (1) Ca(2+) -induced dissipation of the vesicular H(+) -gradient; (2) bafilomycin-sensitive calcium accumulation and (3) pH-jump-induced calcium accumulation. The results were congruent and highly significant: Ca(2+) /H(+) -antiport activity is detectable only in acidic organelles expressing functional synaptotagmin-1. In contrast, synaptotagmin-1-deficient cells - and cells where transgenically encoded synaptotagmin-1 was acutely photo-inactivated - were devoid of any Ca(2+) /H(+) -antiport activity. Therefore, in addition to its previously described functions, synaptotagmin-1 is involved in a rapid vesicular Ca(2+) sequestration through a Ca(2+) /H(+) antiport. This article is protected by copyright. All rights reserved."
],
"offsets": [
[
75,
1493
]
]
}
] | [
{
"id": "23607712_T1",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
1235,
1241
]
],
"normalized": []
},
{
"id": "23607712_T2",
"type": "CHEMICAL",
"text": [
"H(+)"
],
"offsets": [
[
1243,
1247
]
],
"normalized": []
},
{
"id": "23607712_T3",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
1379,
1385
]
],
"normalized": []
},
{
"id": "23607712_T4",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
1410,
1416
]
],
"normalized": []
},
{
"id": "23607712_T5",
"type": "CHEMICAL",
"text": [
"H(+)"
],
"offsets": [
[
1418,
1422
]
],
"normalized": []
},
{
"id": "23607712_T6",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
90,
96
]
],
"normalized": []
},
{
"id": "23607712_T7",
"type": "CHEMICAL",
"text": [
"H(+)"
],
"offsets": [
[
98,
102
]
],
"normalized": []
},
{
"id": "23607712_T8",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
403,
409
]
],
"normalized": []
},
{
"id": "23607712_T9",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
488,
495
]
],
"normalized": []
},
{
"id": "23607712_T10",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
620,
626
]
],
"normalized": []
},
{
"id": "23607712_T11",
"type": "CHEMICAL",
"text": [
"H(+)"
],
"offsets": [
[
628,
632
]
],
"normalized": []
},
{
"id": "23607712_T12",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
656,
662
]
],
"normalized": []
},
{
"id": "23607712_T13",
"type": "CHEMICAL",
"text": [
"H(+)"
],
"offsets": [
[
664,
668
]
],
"normalized": []
},
{
"id": "23607712_T14",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
766,
772
]
],
"normalized": []
},
{
"id": "23607712_T15",
"type": "CHEMICAL",
"text": [
"H(+)"
],
"offsets": [
[
811,
815
]
],
"normalized": []
},
{
"id": "23607712_T16",
"type": "CHEMICAL",
"text": [
"bafilomycin"
],
"offsets": [
[
831,
842
]
],
"normalized": []
},
{
"id": "23607712_T17",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
853,
860
]
],
"normalized": []
},
{
"id": "23607712_T18",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
898,
905
]
],
"normalized": []
},
{
"id": "23607712_T19",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
971,
977
]
],
"normalized": []
},
{
"id": "23607712_T20",
"type": "CHEMICAL",
"text": [
"H(+)"
],
"offsets": [
[
979,
983
]
],
"normalized": []
},
{
"id": "23607712_T21",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
42,
48
]
],
"normalized": []
},
{
"id": "23607712_T22",
"type": "CHEMICAL",
"text": [
"H(+)"
],
"offsets": [
[
50,
54
]
],
"normalized": []
},
{
"id": "23607712_T23",
"type": "GENE-Y",
"text": [
"synaptotagmin-1"
],
"offsets": [
[
1095,
1110
]
],
"normalized": []
},
{
"id": "23607712_T24",
"type": "GENE-Y",
"text": [
"synaptotagmin-1"
],
"offsets": [
[
1168,
1183
]
],
"normalized": []
},
{
"id": "23607712_T25",
"type": "GENE-Y",
"text": [
"synaptotagmin-1"
],
"offsets": [
[
1330,
1345
]
],
"normalized": []
},
{
"id": "23607712_T26",
"type": "GENE-Y",
"text": [
"Synaptotagmin-1"
],
"offsets": [
[
321,
336
]
],
"normalized": []
},
{
"id": "23607712_T27",
"type": "GENE-Y",
"text": [
"synaptotagmin-1"
],
"offsets": [
[
559,
574
]
],
"normalized": []
},
{
"id": "23607712_T28",
"type": "GENE-Y",
"text": [
"synaptotagmin-1"
],
"offsets": [
[
1065,
1080
]
],
"normalized": []
},
{
"id": "23607712_T29",
"type": "GENE-Y",
"text": [
"Synaptotagmin 1"
],
"offsets": [
[
0,
15
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23607712_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "23607712_T21",
"arg2_id": "23607712_T29",
"normalized": []
},
{
"id": "23607712_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "23607712_T22",
"arg2_id": "23607712_T29",
"normalized": []
},
{
"id": "23607712_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "23607712_T8",
"arg2_id": "23607712_T26",
"normalized": []
},
{
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},
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"type": "DIRECT-REGULATOR",
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"arg2_id": "23607712_T25",
"normalized": []
},
{
"id": "23607712_10",
"type": "DIRECT-REGULATOR",
"arg1_id": "23607712_T5",
"arg2_id": "23607712_T25",
"normalized": []
}
] |
14507899 | 14507899 | [
{
"id": "14507899_title",
"type": "title",
"text": [
"P2Y(2) receptor agonist INS37217 enhances functional recovery after detachment caused by subretinal injection in normal and rds mice."
],
"offsets": [
[
0,
133
]
]
},
{
"id": "14507899_abstract",
"type": "abstract",
"text": [
"PURPOSE: To evaluate the effects of INS37217 on the recovery of retinal function after experimental retinal detachment induced by subretinal injection. METHODS: Subretinal injections of 1 micro L of fluorescent microbeads, saline, or INS37217 (1-200 micro M) were made by the transvitreal method in normal (C57BL/6) mice and in mice heterozygous for the retinal degeneration slow (rds) gene. Control, mock-injected animals underwent corneal puncture without injection. Histologic and ERG evaluations were made at 0 to 1 and 8 hours, and 1, 3, 7, 10, 14, and 60 days post injection (PI). DNA fragmentation was evaluated by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling (TUNEL). RESULTS: A single subretinal injection of saline solution containing fluorescent beads caused a histologically evident retinal detachment and distributed the microbeads to almost all the subretinal space. Spontaneous reattachment occurred within 24 hours after injection and was accompanied by evident retinal folding that appeared largely resolved by 6 days later. Relative to controls, injection of saline resulted in approximately 40% recovery of dark-adapted a-wave amplitude at 24 hours PI and gradually improved to approximately 90% of controls at 2 months PI. Subretinal injection of saline containing INS37217 (10 micro M) significantly increased rod and cone ERG of normal and rds(+/-) mice at 1 and 10 days PI, when compared with injection of saline alone. Additionally, INS37217 reduced the number of TUNEL-positive photoreceptors and the enhanced rate of reattachment. CONCLUSIONS: Enhancement of ERG recovery by INS37217 is likely due to reduced retinal folding and cell death associated with detachment. These results support the use of INS37217 to help restore function after therapies that involve subretinal administration of drugs in animal models of retinal diseases."
],
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134,
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}
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0,
15
]
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}
] | [] | [] | [
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}
] |
6621777 | 6621777 | [
{
"id": "6621777_title",
"type": "title",
"text": [
"The effect of various amino acids and drugs on the para- and meta-hydroxyphenylacetic acid concentrations in the mouse caudate nucleus."
],
"offsets": [
[
0,
135
]
]
},
{
"id": "6621777_abstract",
"type": "abstract",
"text": [
"Injection of L-p-tyrosine (800 mg/kg, 2 h) increased the mouse striatal para-hydroxyphenylacetic acid (p-HPAA) concentrations. A smaller dose of D,L-m-tyrosine (20 mg/kg, 2 h) produced a larger increase in mouse striatal meta-hydroxyphenylacetic acid (m-HPAA) concentrations. The administration of L-phenylalanine to mice caused a slight increase in the p-HPAA concentration in the corpus striatum after 2 h while a larger dose of L-phenylalanine (800 mg/kg) produced a greater increase. Eight hours following L-phenylalanine injection, p-HPAA concentrations were still elevated. With D-phenylalanine a significant increase was observed at eight hours after drug administration. Two drugs which reduce dopamine synthesis, alpha-methyl-para-tyrosine and apomorphine, decreased m-HPAA striatal concentrations without affecting p-HPAA concentrations. From these results, it is proposed that tyrosine hydroxylase activity determines p-HPAA concentrations by regulating p-tyrosine availability. This enzyme may also synthesize m-tyrosine which is subsequently decarboxylated to form m-tyramine and then oxidatively deaminated to form m-HPAA."
],
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136,
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357,
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208,
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]
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889,
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]
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912,
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1024,
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1065,
1071
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1101,
1111
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22,
33
]
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],
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51,
90
]
],
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},
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"tyrosine hydroxylase"
],
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[
1024,
1044
]
],
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}
] | [] | [] | [
{
"id": "6621777_0",
"type": "SUBSTRATE",
"arg1_id": "6621777_T23",
"arg2_id": "6621777_T26",
"normalized": []
}
] |
10953053 | 10953053 | [
{
"id": "10953053_title",
"type": "title",
"text": [
"Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels."
],
"offsets": [
[
0,
88
]
]
},
{
"id": "10953053_abstract",
"type": "abstract",
"text": [
"Retigabine [N-(2-amino-4-[fluorobenzylamino]-phenyl) carbamic acid; D-23129] is a novel anticonvulsant, unrelated to currently available antiepileptic agents, with activity in a broad range of seizure models. In the present study, we sought to determine whether retigabine could enhance current through M-like currents in PC12 cells and KCNQ2/Q3 K(+) channels expressed in Chinese hamster ovary cells (CHO-KCNQ2/Q3). In differentiated PC12 cells, retigabine enhanced a linopirdine-sensitive current. The effect of retigabine was associated with a slowing of M-like tail current deactivation in these cells. Retigabine (0.1 to 10 microM) induced a potassium current and hyperpolarized CHO cells expressing KCNQ2/Q3 cells but not in wild-type cells. Retigabine-induced currents in CHO-KCNQ2/Q3 cells were inhibited by 60.6 +/- 11% (n = 4) by the KCNQ2/Q3 blocker, linopirdine (10 microM), and 82.7 +/- 5.4% (n = 4) by BaCl(2) (10 mM). The mechanism by which retigabine enhanced KCNQ2/Q3 currents involved large, drug-induced, leftward shifts in the voltage dependence of channel activation (-33.1 +/- 2.6 mV, n = 4, by 10 microM retigabine). Retigabine shifted the voltage dependence of channel activation with an EC(50) value of 1.6 +/- 0.3 microM (slope factor was 1.2 +/- 0.1, n = 4 to 5 cells per concentration). Retigabine (0.1 to 10 microM) also slowed the rate of channel deactivation, predominantly by increasing the contribution of a slowly deactivating tail current component. Our findings identify KCNQ2/Q3 channels as a molecular target for retigabine and suggest that activation of KCNQ2/Q3 channels may be responsible for at least some of the anticonvulsant activity of this agent."
],
"offsets": [
[
89,
1782
]
]
}
] | [
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]
],
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1229,
1239
]
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},
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155
]
],
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"K(+)"
],
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435,
439
]
],
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},
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"id": "10953053_T8",
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558,
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]
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},
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603,
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]
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]
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},
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736,
745
]
],
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},
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157,
164
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837,
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951,
962
]
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},
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1005,
1012
]
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},
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1045,
1055
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0,
10
]
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69,
78
]
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},
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1596,
1604
]
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},
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1690
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434
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435,
448
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},
{
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503
]
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802
]
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},
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872,
880
]
],
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},
{
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"KCNQ2/Q3"
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941
]
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},
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"KCNQ2/Q3"
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1065,
1073
]
],
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},
{
"id": "10953053_T28",
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"text": [
"KCNQ2/Q3"
],
"offsets": [
[
60,
68
]
],
"normalized": []
},
{
"id": "10953053_T29",
"type": "GENE-N",
"text": [
"potassium channels"
],
"offsets": [
[
69,
87
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "10953053_0",
"type": "ACTIVATOR",
"arg1_id": "10953053_T17",
"arg2_id": "10953053_T29",
"normalized": []
}
] |
23481676 | 23481676 | [
{
"id": "23481676_title",
"type": "title",
"text": [
"Cytotoxic and Anti-Inflammatory Eunicellin-Based Diterpenoids from the Soft Coral Cladiella krempfi."
],
"offsets": [
[
0,
100
]
]
},
{
"id": "23481676_abstract",
"type": "abstract",
"text": [
"Five new eunicellin-based diterpenoids, krempfielins E-I (1-5) and seven known compounds (6-12) were isolated from the organic extract of a Taiwanese soft coral Cladiella krempfi. The structures of the new metabolites were elucidated on the basis of extensive spectroscopic analysis. Metabolites 5, 6, 10 and 12 were shown to exhibit cytotoxicity against a limited panel of cancer cell lines. Furthermore, compounds 6 and 10 could potently inhibit the accumulation of the pro-inflammatory iNOS protein, and 6 and 12 could significantly reduce the expression of COX-2 protein in LPS-stimulated RAW264.7 macrophage cells."
],
"offsets": [
[
101,
720
]
]
}
] | [
{
"id": "23481676_T1",
"type": "CHEMICAL",
"text": [
"diterpenoids"
],
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[
127,
139
]
],
"normalized": []
},
{
"id": "23481676_T2",
"type": "CHEMICAL",
"text": [
"krempfielins E-I"
],
"offsets": [
[
141,
157
]
],
"normalized": []
},
{
"id": "23481676_T3",
"type": "CHEMICAL",
"text": [
"eunicellin"
],
"offsets": [
[
110,
120
]
],
"normalized": []
},
{
"id": "23481676_T4",
"type": "CHEMICAL",
"text": [
"Eunicellin"
],
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[
32,
42
]
],
"normalized": []
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"id": "23481676_T5",
"type": "CHEMICAL",
"text": [
"Diterpenoids"
],
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[
49,
61
]
],
"normalized": []
},
{
"id": "23481676_T6",
"type": "GENE-Y",
"text": [
"iNOS"
],
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[
590,
594
]
],
"normalized": []
},
{
"id": "23481676_T7",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
662,
667
]
],
"normalized": []
}
] | [] | [] | [] |
22614014 | 22614014 | [
{
"id": "22614014_title",
"type": "title",
"text": [
"Macrophage cathepsin K promotes prostate tumor progression in bone."
],
"offsets": [
[
0,
67
]
]
},
{
"id": "22614014_abstract",
"type": "abstract",
"text": [
"Bone marrow macrophages (BMMs) share common progenitors with osteoclasts and are critical components of bone-tumor microenvironment; however, their function in prostate tumor growth in the skeleton has not been explored. BMMs are the major source of inflammatory factors and proteases, including cysteine protease cathepsin K (CTSK). In this study, utilizing mice deficient in CTSK, we demonstrate the critical involvement of this potent collagenase in tumor progression in bone. We present the evidence that tumor growth and progression in the bone are impaired in the absence of CTSK. Most importantly, we show for the first time that BMM-supplied CTSK may be involved in CCL2- and COX-2-driven pathways that contribute to tumor progression in bone. Together, our data unravel novel roles for CTSK in macrophage-regulated processes, and provide evidence for close interplay between inflammatory, osteolytic and tumor cell-driven events in the bone-tumor microenvironment."
],
"offsets": [
[
68,
1041
]
]
}
] | [
{
"id": "22614014_T1",
"type": "CHEMICAL",
"text": [
"cysteine"
],
"offsets": [
[
364,
372
]
],
"normalized": []
},
{
"id": "22614014_T2",
"type": "GENE-N",
"text": [
"proteases"
],
"offsets": [
[
343,
352
]
],
"normalized": []
},
{
"id": "22614014_T3",
"type": "GENE-N",
"text": [
"cysteine protease"
],
"offsets": [
[
364,
381
]
],
"normalized": []
},
{
"id": "22614014_T4",
"type": "GENE-Y",
"text": [
"cathepsin K"
],
"offsets": [
[
382,
393
]
],
"normalized": []
},
{
"id": "22614014_T5",
"type": "GENE-Y",
"text": [
"CTSK"
],
"offsets": [
[
395,
399
]
],
"normalized": []
},
{
"id": "22614014_T6",
"type": "GENE-Y",
"text": [
"CTSK"
],
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[
445,
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]
],
"normalized": []
},
{
"id": "22614014_T7",
"type": "GENE-N",
"text": [
"collagenase"
],
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[
506,
517
]
],
"normalized": []
},
{
"id": "22614014_T8",
"type": "GENE-Y",
"text": [
"CTSK"
],
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[
649,
653
]
],
"normalized": []
},
{
"id": "22614014_T9",
"type": "GENE-Y",
"text": [
"CTSK"
],
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[
718,
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]
],
"normalized": []
},
{
"id": "22614014_T10",
"type": "GENE-Y",
"text": [
"CCL2"
],
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742,
746
]
],
"normalized": []
},
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"id": "22614014_T11",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
752,
757
]
],
"normalized": []
},
{
"id": "22614014_T12",
"type": "GENE-Y",
"text": [
"CTSK"
],
"offsets": [
[
863,
867
]
],
"normalized": []
},
{
"id": "22614014_T13",
"type": "GENE-Y",
"text": [
"cathepsin K"
],
"offsets": [
[
11,
22
]
],
"normalized": []
}
] | [] | [] | [] |
16477002 | 16477002 | [
{
"id": "16477002_title",
"type": "title",
"text": [
"Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor."
],
"offsets": [
[
0,
97
]
]
},
{
"id": "16477002_abstract",
"type": "abstract",
"text": [
"IL-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits IL-2R alpha, IL-2R beta, and gamma(c). Here, we describe the crystal structure of the trimeric assembly of the human IL-2 receptor ectodomains in complex with IL-2 at 3.0 A resolution. The quaternary structure is consistent with a stepwise assembly from IL-2/IL-2R alpha to IL-2/IL-2R alpha/IL-2R beta to IL-2/IL-2R alpha/IL-2R beta/gamma(c). The IL-2R alpha subunit forms the largest of the three IL-2/IL-2R interfaces, which, together with the high abundance of charge-charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL-2R alpha with IL-2 at the cell surface. Surprisingly, IL-2R alpha makes no contacts with IL-2R beta or gamma(c), and only minor changes are observed in the IL-2 structure in response to receptor binding. These findings support the principal role of IL-2R alpha to deliver IL-2 to the signaling complex and act as regulator of signal transduction. Cooperativity in assembly of the final quaternary complex is easily explained by the extraordinarily extensive set of interfaces found within the fully assembled IL-2 signaling complex, which nearly span the entire length of the IL-2R beta and gamma(c) subunits. Helix A of IL-2 wedges tightly between IL-2R beta and gamma(c) to form a three-way junction that coalesces into a composite binding site for the final gamma(c) recruitment. The IL-2/gamma(c) interface itself exhibits the smallest buried surface and the fewest hydrogen bonds in the complex, which is consistent with its promiscuous use in other cytokine receptor complexes."
],
"offsets": [
[
98,
1847
]
]
}
] | [
{
"id": "16477002_T1",
"type": "CHEMICAL",
"text": [
"hydrogen"
],
"offsets": [
[
1734,
1742
]
],
"normalized": []
},
{
"id": "16477002_T2",
"type": "GENE-Y",
"text": [
"IL-2"
],
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[
98,
102
]
],
"normalized": []
},
{
"id": "16477002_T3",
"type": "GENE-Y",
"text": [
"IL-2R alpha"
],
"offsets": [
[
1113,
1124
]
],
"normalized": []
},
{
"id": "16477002_T4",
"type": "GENE-N",
"text": [
"cytokine"
],
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[
108,
116
]
],
"normalized": []
},
{
"id": "16477002_T5",
"type": "GENE-Y",
"text": [
"IL-2"
],
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[
1136,
1140
]
],
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},
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"id": "16477002_T6",
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"text": [
"IL-2"
],
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[
1373,
1377
]
],
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},
{
"id": "16477002_T7",
"type": "GENE-N",
"text": [
"IL-2R beta and gamma(c)"
],
"offsets": [
[
1440,
1463
]
],
"normalized": []
},
{
"id": "16477002_T8",
"type": "GENE-Y",
"text": [
"IL-2"
],
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[
1485,
1489
]
],
"normalized": []
},
{
"id": "16477002_T9",
"type": "GENE-N",
"text": [
"IL-2R beta and gamma(c)"
],
"offsets": [
[
1513,
1536
]
],
"normalized": []
},
{
"id": "16477002_T10",
"type": "GENE-Y",
"text": [
"IL-2"
],
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[
1651,
1655
]
],
"normalized": []
},
{
"id": "16477002_T11",
"type": "GENE-N",
"text": [
"cytokine receptor"
],
"offsets": [
[
1819,
1836
]
],
"normalized": []
},
{
"id": "16477002_T12",
"type": "GENE-Y",
"text": [
"IL-2R alpha"
],
"offsets": [
[
288,
299
]
],
"normalized": []
},
{
"id": "16477002_T13",
"type": "GENE-N",
"text": [
"IL-2R beta, and gamma(c)"
],
"offsets": [
[
301,
325
]
],
"normalized": []
},
{
"id": "16477002_T14",
"type": "GENE-N",
"text": [
"human IL-2 receptor"
],
"offsets": [
[
399,
418
]
],
"normalized": []
},
{
"id": "16477002_T15",
"type": "GENE-Y",
"text": [
"IL-2"
],
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447,
451
]
],
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},
{
"id": "16477002_T16",
"type": "GENE-Y",
"text": [
"IL-2"
],
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[
542,
546
]
],
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},
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"id": "16477002_T17",
"type": "GENE-Y",
"text": [
"IL-2R alpha"
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[
547,
558
]
],
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},
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"id": "16477002_T18",
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"text": [
"IL-2"
],
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[
562,
566
]
],
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},
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"id": "16477002_T19",
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"text": [
"IL-2R alpha"
],
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[
567,
578
]
],
"normalized": []
},
{
"id": "16477002_T20",
"type": "GENE-Y",
"text": [
"IL-2R beta"
],
"offsets": [
[
579,
589
]
],
"normalized": []
},
{
"id": "16477002_T21",
"type": "GENE-Y",
"text": [
"IL-2"
],
"offsets": [
[
593,
597
]
],
"normalized": []
},
{
"id": "16477002_T22",
"type": "GENE-Y",
"text": [
"IL-2R alpha"
],
"offsets": [
[
598,
609
]
],
"normalized": []
},
{
"id": "16477002_T23",
"type": "GENE-N",
"text": [
"IL-2R beta/gamma(c)"
],
"offsets": [
[
610,
629
]
],
"normalized": []
},
{
"id": "16477002_T24",
"type": "GENE-Y",
"text": [
"IL-2R alpha"
],
"offsets": [
[
635,
646
]
],
"normalized": []
},
{
"id": "16477002_T25",
"type": "GENE-Y",
"text": [
"IL-2"
],
"offsets": [
[
686,
690
]
],
"normalized": []
},
{
"id": "16477002_T26",
"type": "GENE-N",
"text": [
"IL-2R"
],
"offsets": [
[
691,
696
]
],
"normalized": []
},
{
"id": "16477002_T27",
"type": "GENE-Y",
"text": [
"IL-2R alpha"
],
"offsets": [
[
861,
872
]
],
"normalized": []
},
{
"id": "16477002_T28",
"type": "GENE-Y",
"text": [
"IL-2"
],
"offsets": [
[
878,
882
]
],
"normalized": []
},
{
"id": "16477002_T29",
"type": "GENE-Y",
"text": [
"IL-2R alpha"
],
"offsets": [
[
918,
929
]
],
"normalized": []
},
{
"id": "16477002_T30",
"type": "GENE-N",
"text": [
"IL-2R beta or gamma(c)"
],
"offsets": [
[
953,
975
]
],
"normalized": []
},
{
"id": "16477002_T31",
"type": "GENE-Y",
"text": [
"IL-2"
],
"offsets": [
[
1020,
1024
]
],
"normalized": []
},
{
"id": "16477002_T32",
"type": "GENE-Y",
"text": [
"IL-2"
],
"offsets": [
[
25,
29
]
],
"normalized": []
},
{
"id": "16477002_T33",
"type": "GENE-N",
"text": [
"cytokine receptor"
],
"offsets": [
[
79,
96
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16477002_0",
"type": "PART-OF",
"arg1_id": "16477002_T1",
"arg2_id": "16477002_T10",
"normalized": []
}
] |
23299909 | 23299909 | [
{
"id": "23299909_title",
"type": "title",
"text": [
"Interruption or deferral of antiretroviral therapy reduces markers of bone turnover compared with continuous therapy: The SMART Body Composition substudy."
],
"offsets": [
[
0,
154
]
]
},
{
"id": "23299909_abstract",
"type": "abstract",
"text": [
"Bone mineral density (BMD) declines significantly in HIV patients on antiretroviral therapy (ART). We compared the effects of intermittent versus continuous ART on markers of bone turnover in the Body Composition substudy of the Strategies for Management of AntiRetroviral Therapy (SMART) trial and determined whether early changes in markers predicted subsequent change in BMD. For 202 participants (median age 44 years, 17% female, 74% on ART) randomised to continuous or intermittent ART, plasma markers of inflammation and bone turnover were evaluated at baseline, months 4 and 12; BMD at the spine (dual X-ray absorptiometry [DXA] and computed tomography) and hip (DXA) was evaluated annually. Compared to the continuous ART group, mean bone-specific alkaline phosphatase (bALP), osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), N-terminal cross-linking telopeptide of type 1 collagen (NTX), and C-terminal cross-linking telopeptide of type 1 collagen (βCTX) decreased significantly in the intermittent ART group, whereas RANKL and the RANKL:osteoprotegerin (OPG) ratio increased (all p<0.002 at month 4 and month 12). Increases in bALP, osteocalcin, P1NP, NTX, and βCTX at month 4 predicted decrease in hip BMD at month 12, while increases in RANKL and the RANKL:OPG ratio at month 4 predicted increase in hip and spine BMD at month 12. This study has shown that compared with continuous ART, interruption of ART results in a reduction in markers of bone turnover and increase in BMD at hip and spine, and that early changes in markers of bone turnover predict BMD changes at 12 months. © 2013 American Society for Bone and Mineral Research."
],
"offsets": [
[
155,
1815
]
]
}
] | [
{
"id": "23299909_T1",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
972,
973
]
],
"normalized": []
},
{
"id": "23299909_T2",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
1002,
1003
]
],
"normalized": []
},
{
"id": "23299909_T3",
"type": "GENE-Y",
"text": [
"RANKL"
],
"offsets": [
[
1195,
1200
]
],
"normalized": []
},
{
"id": "23299909_T4",
"type": "GENE-Y",
"text": [
"RANKL"
],
"offsets": [
[
1209,
1214
]
],
"normalized": []
},
{
"id": "23299909_T5",
"type": "GENE-Y",
"text": [
"osteoprotegerin"
],
"offsets": [
[
1215,
1230
]
],
"normalized": []
},
{
"id": "23299909_T6",
"type": "GENE-Y",
"text": [
"OPG"
],
"offsets": [
[
1232,
1235
]
],
"normalized": []
},
{
"id": "23299909_T7",
"type": "GENE-Y",
"text": [
"bALP"
],
"offsets": [
[
1305,
1309
]
],
"normalized": []
},
{
"id": "23299909_T8",
"type": "GENE-Y",
"text": [
"osteocalcin"
],
"offsets": [
[
1311,
1322
]
],
"normalized": []
},
{
"id": "23299909_T9",
"type": "GENE-Y",
"text": [
"RANKL"
],
"offsets": [
[
1417,
1422
]
],
"normalized": []
},
{
"id": "23299909_T10",
"type": "GENE-Y",
"text": [
"RANKL"
],
"offsets": [
[
1431,
1436
]
],
"normalized": []
},
{
"id": "23299909_T11",
"type": "GENE-Y",
"text": [
"bone-specific alkaline phosphatase"
],
"offsets": [
[
897,
931
]
],
"normalized": []
},
{
"id": "23299909_T12",
"type": "GENE-Y",
"text": [
"bALP"
],
"offsets": [
[
933,
937
]
],
"normalized": []
},
{
"id": "23299909_T13",
"type": "GENE-Y",
"text": [
"osteocalcin"
],
"offsets": [
[
940,
951
]
],
"normalized": []
}
] | [] | [] | [] |
23643828 | 23643828 | [
{
"id": "23643828_title",
"type": "title",
"text": [
"The C1 domain-targeted isophthalate derivative HMI-1b11 promotes neurite outgrowth and GAP-43 expression through PKCα activation in SH-SY5Y cells."
],
"offsets": [
[
0,
146
]
]
},
{
"id": "23643828_abstract",
"type": "abstract",
"text": [
"Protein kinase C (PKC) is a family of serine/threonine phosphotransferases ubiquitously expressed and involved in multiple cellular functions, such as proliferation, apoptosis and differentiation. The C1 domain of PKC represents an attractive drug target, especially for developing PKC activators. Dialkyl 5-(hydroxymethyl)isophthalates are a novel group of synthetic C1 domain ligands that exhibit antiproliferative effect in HeLa cervical carcinoma cells. Here we selected two isophthalates, HMI-1a3 and HMI-1b11, and characterized their effects in the human neuroblastoma cell line SH-SY5Y. Both of the active isophthalates exhibited significant antiproliferative and differentiation-inducing effects. Since HMI-1b11 did not impair cell survival even at the highest concentration tested (20μM), and supported neurite growth and differentiation of SH-SY5Y cells, we focused on studying its downstream signaling cascades and effects on gene expression. Consistently, genome-wide gene expression microarray and gene set enrichment analysis indicated that HMI-1b11 (10μM) induced changes in genes mainly related to cell differentiation. In particular, further studies revealed that HMI-1b11 exposure induced up-regulation of GAP-43, a marker for neurite sprouting and neuronal differentiation. These effects were induced by a 7-minute HMI-1b11 treatment and specifically depended on PKCα activation, since pretreatment with the selective inhibitor Gö6976 abolished the up-regulation of GAP-43 protein observed at 12hours In parallel, we found that a 7-minute exposure to HMI-1b11 induced PKCα accumulation to the cytoskeleton, an effect that was again prevented by pretreatment with Gö6976. Despite similar binding affinities to PKC, the isophthalates had different effects on PKC-dependent ERK1/2 signaling: HMI-1a3-induced ERK1/2 phosphorylation was transient, while HMI-1b11 induced a rapid but prolonged ERK1/2 phosphorylation. Overall our data are in accordance with previous studies showing that activation of the PKCα and ERK1/2 pathways participate in regulating neuronal differentiation. Furthermore, since PKC has been classified as one of the cognitive kinases, and activation of PKC is considered a potential therapeutic strategy for the treatment of cognitive disorders, our findings suggest that HMI-1b11 represents a promising lead compound in research aimed to prevent or counteract memory impairment."
],
"offsets": [
[
147,
2563
]
]
}
] | [
{
"id": "23643828_T1",
"type": "CHEMICAL",
"text": [
"Gö6976"
],
"offsets": [
[
1594,
1600
]
],
"normalized": []
},
{
"id": "23643828_T2",
"type": "CHEMICAL",
"text": [
"Gö6976"
],
"offsets": [
[
1829,
1835
]
],
"normalized": []
},
{
"id": "23643828_T3",
"type": "CHEMICAL",
"text": [
"Dialkyl 5-(hydroxymethyl)isophthalates"
],
"offsets": [
[
445,
483
]
],
"normalized": []
},
{
"id": "23643828_T4",
"type": "CHEMICAL",
"text": [
"serine"
],
"offsets": [
[
185,
191
]
],
"normalized": []
},
{
"id": "23643828_T5",
"type": "CHEMICAL",
"text": [
"threonine"
],
"offsets": [
[
192,
201
]
],
"normalized": []
},
{
"id": "23643828_T6",
"type": "CHEMICAL",
"text": [
"isophthalates"
],
"offsets": [
[
626,
639
]
],
"normalized": []
},
{
"id": "23643828_T7",
"type": "CHEMICAL",
"text": [
"isophthalates"
],
"offsets": [
[
760,
773
]
],
"normalized": []
},
{
"id": "23643828_T8",
"type": "CHEMICAL",
"text": [
"isophthalate"
],
"offsets": [
[
23,
35
]
],
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},
{
"id": "23643828_T9",
"type": "GENE-N",
"text": [
"Protein kinase C"
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[
147,
163
]
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},
{
"id": "23643828_T10",
"type": "GENE-Y",
"text": [
"GAP-43"
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[
1371,
1377
]
],
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},
{
"id": "23643828_T11",
"type": "GENE-Y",
"text": [
"PKCα"
],
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1529,
1533
]
],
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},
{
"id": "23643828_T12",
"type": "GENE-Y",
"text": [
"GAP-43"
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1632,
1638
]
],
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},
{
"id": "23643828_T13",
"type": "GENE-Y",
"text": [
"PKCα"
],
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[
1734,
1738
]
],
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},
{
"id": "23643828_T14",
"type": "GENE-N",
"text": [
"PKC"
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1875,
1878
]
],
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},
{
"id": "23643828_T15",
"type": "GENE-N",
"text": [
"PKC"
],
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[
1923,
1926
]
],
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},
{
"id": "23643828_T16",
"type": "GENE-N",
"text": [
"ERK1/2"
],
"offsets": [
[
1937,
1943
]
],
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},
{
"id": "23643828_T17",
"type": "GENE-N",
"text": [
"PKC"
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165,
168
]
],
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},
{
"id": "23643828_T18",
"type": "GENE-N",
"text": [
"ERK1/2"
],
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[
1971,
1977
]
],
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},
{
"id": "23643828_T19",
"type": "GENE-N",
"text": [
"ERK1/2"
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2054,
2060
]
],
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},
{
"id": "23643828_T20",
"type": "GENE-N",
"text": [
"C1 domain"
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348,
357
]
],
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},
{
"id": "23643828_T21",
"type": "GENE-Y",
"text": [
"PKCα"
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2166,
2170
]
],
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},
{
"id": "23643828_T22",
"type": "GENE-N",
"text": [
"ERK1/2"
],
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2175,
2181
]
],
"normalized": []
},
{
"id": "23643828_T23",
"type": "GENE-N",
"text": [
"PKC"
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2262,
2265
]
],
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},
{
"id": "23643828_T24",
"type": "GENE-N",
"text": [
"PKC"
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361,
364
]
],
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},
{
"id": "23643828_T25",
"type": "GENE-N",
"text": [
"PKC"
],
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2337,
2340
]
],
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},
{
"id": "23643828_T26",
"type": "GENE-N",
"text": [
"PKC"
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429,
432
]
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"id": "23643828_T27",
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"text": [
"C1 domain"
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515,
524
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],
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},
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"id": "23643828_T28",
"type": "GENE-N",
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"serine/threonine phosphotransferases"
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185,
221
]
],
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},
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"id": "23643828_T29",
"type": "GENE-Y",
"text": [
"PKCα"
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113,
117
]
],
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},
{
"id": "23643828_T30",
"type": "GENE-N",
"text": [
"C1 domain"
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4,
13
]
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},
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"id": "23643828_T31",
"type": "GENE-Y",
"text": [
"GAP-43"
],
"offsets": [
[
87,
93
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23643828_0",
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"arg2_id": "23643828_T27",
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},
{
"id": "23643828_1",
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},
{
"id": "23643828_2",
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"arg2_id": "23643828_T29",
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},
{
"id": "23643828_3",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23643828_T1",
"arg2_id": "23643828_T12",
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},
{
"id": "23643828_4",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23643828_T2",
"arg2_id": "23643828_T13",
"normalized": []
}
] |
23578952 | 23578952 | [
{
"id": "23578952_title",
"type": "title",
"text": [
"Monoacylglycerol lipase inhibition-induced changes in plasma corticosterone levels, anxiety and locomotor activity in male CD1 mice."
],
"offsets": [
[
0,
132
]
]
},
{
"id": "23578952_abstract",
"type": "abstract",
"text": [
"The hypothalamus-pituitary-adrenal-axis is strongly controlled by the endocannabinoid system. The specific impact of enhanced 2-arachidonoylglycerol signaling on corticosterone plasma levels, however, was not investigated so far. Here we studied the effects of the recently developed monoacylglycerol lipase inhibitor JZL184 on basal and stress-induced corticosterone levels in male CD1 mice, and found that this compound dramatically increased basal levels without affecting stress responses. Since acute changes in corticosterone levels can affect behavior, JZL184 was administered concurrently with the corticosterone synthesis inhibitor metyrapone, to investigate whether the previously shown behavioral effects of JZL184 are dependent on corticosterone. We found that in the elevated plus-maze, the effects of JZL184 on \"classical\" anxiety-related measures were abolished by corticosterone synthesis blockade. By contrast, effects on the \"ethological\" measures of anxiety (i.e. risk assessment) were not affected by metyrapone. In the open-field, the locomotion-enhancing effects of the compound were not changed either. These findings show that monoacylglycerol lipase inhibition dramatically increases basal levels of corticosterone. This endocrine effect partly affects the anxiolytic, but not the locomotion-enhancing effects of monoacylglycerol lipase blockade."
],
"offsets": [
[
133,
1504
]
]
}
] | [
{
"id": "23578952_T1",
"type": "CHEMICAL",
"text": [
"metyrapone"
],
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[
1154,
1164
]
],
"normalized": []
},
{
"id": "23578952_T2",
"type": "CHEMICAL",
"text": [
"monoacylglycerol"
],
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[
1284,
1300
]
],
"normalized": []
},
{
"id": "23578952_T3",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
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[
1358,
1372
]
],
"normalized": []
},
{
"id": "23578952_T4",
"type": "CHEMICAL",
"text": [
"2-arachidonoylglycerol"
],
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[
259,
281
]
],
"normalized": []
},
{
"id": "23578952_T5",
"type": "CHEMICAL",
"text": [
"monoacylglycerol"
],
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[
1471,
1487
]
],
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},
{
"id": "23578952_T6",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
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[
295,
309
]
],
"normalized": []
},
{
"id": "23578952_T7",
"type": "CHEMICAL",
"text": [
"monoacylglycerol"
],
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[
417,
433
]
],
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},
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"id": "23578952_T8",
"type": "CHEMICAL",
"text": [
"JZL184"
],
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[
451,
457
]
],
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},
{
"id": "23578952_T9",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
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486,
500
]
],
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},
{
"id": "23578952_T10",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
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[
650,
664
]
],
"normalized": []
},
{
"id": "23578952_T11",
"type": "CHEMICAL",
"text": [
"JZL184"
],
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[
693,
699
]
],
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},
{
"id": "23578952_T12",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
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[
739,
753
]
],
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},
{
"id": "23578952_T13",
"type": "CHEMICAL",
"text": [
"metyrapone"
],
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[
774,
784
]
],
"normalized": []
},
{
"id": "23578952_T14",
"type": "CHEMICAL",
"text": [
"JZL184"
],
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[
852,
858
]
],
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},
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"id": "23578952_T15",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
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[
876,
890
]
],
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},
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"id": "23578952_T16",
"type": "CHEMICAL",
"text": [
"JZL184"
],
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[
948,
954
]
],
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},
{
"id": "23578952_T17",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
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[
1013,
1027
]
],
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},
{
"id": "23578952_T18",
"type": "CHEMICAL",
"text": [
"Monoacylglycerol"
],
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[
0,
16
]
],
"normalized": []
},
{
"id": "23578952_T19",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
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[
61,
75
]
],
"normalized": []
},
{
"id": "23578952_T20",
"type": "GENE-Y",
"text": [
"monoacylglycerol lipase"
],
"offsets": [
[
1284,
1307
]
],
"normalized": []
},
{
"id": "23578952_T21",
"type": "GENE-Y",
"text": [
"monoacylglycerol lipase"
],
"offsets": [
[
1471,
1494
]
],
"normalized": []
},
{
"id": "23578952_T22",
"type": "GENE-Y",
"text": [
"monoacylglycerol lipase"
],
"offsets": [
[
417,
440
]
],
"normalized": []
},
{
"id": "23578952_T23",
"type": "GENE-Y",
"text": [
"Monoacylglycerol lipase"
],
"offsets": [
[
0,
23
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23578952_0",
"type": "INHIBITOR",
"arg1_id": "23578952_T8",
"arg2_id": "23578952_T22",
"normalized": []
}
] |
9710435 | 9710435 | [
{
"id": "9710435_title",
"type": "title",
"text": [
"Ibuprofen inhibits cystic fibrosis transmembrane conductance regulator-mediated Cl- secretion."
],
"offsets": [
[
0,
94
]
]
},
{
"id": "9710435_abstract",
"type": "abstract",
"text": [
"We evaluated the acute effects of ibuprofen and salicylic acid on cAMP-mediated Cl- secretion (Isc) in both colonic and airway epithelia. In T84 cells, ibuprofen inhibited the forskolin-dependent Isc in a concentration-dependent manner, having an apparent Ki of 142 microM. Salicylic acid inhibited Isc with an apparent Ki of 646 microM. We determined whether ibuprofen would also inhibit the forskolin-stimulated Isc in primary cultures of mouse trachea epithelia (MTE) and human bronchial epithelia (HBE). Similar to our results in T84 cells, ibuprofen (500 microM) inhibited the forskolin-induced Isc in MTEs and HBEs by 59+/-4% (n = 11) and 39+/-6% (n = 8), respectively. Nystatin was employed to selectively permeabilize the basolateral or apical membrane to determine the effect of ibuprofen on apical Cl- (ICl) and basolateral K+ (IK) currents after stimulation by forskolin. After forskolin stimulation, ibuprofen (500 microM) reduced both the ICl and IK; reducing ICl and IK by 60 and 15%, respectively. To determine whether this inhibition of ICl was due to the inhibition of CFTR, the effects of ibuprofen and salicylic acid on CFTR Cl- channels in excised, inside-out patches from L-cells were evaluated. Ibuprofen (300 microM) reduced CFTR Cl- current by 60+/-16% and this was explained by a short-lived block (approximately 1.2 ms) which causes an apparent reduction in single channel amplitude from 1.07+/-0.04 pA to 0.59+/-0.04 pA (n = 3). Similarly, salicylic acid (3 mM) reduced CFTR Cl- current by 50+/-8% with an apparent reduction in single channel amplitude from 1.08+/-0.03 pA to 0.48+/-0.06 pA (n = 4). Based on these results, we conclude that the NSAIDs ibuprofen and salicylic acid inhibit cAMP-mediated Cl- secretion in human colonic and airway epithelia via a direct inhibition of CFTR Cl- channels as well as basolateral membrane K+ channels. This may reduce their efficacy in conjunction with other therapeutic strategies designed to increase CFTR expression and/or function in secretory epithelia."
],
"offsets": [
[
95,
2123
]
]
}
] | [
{
"id": "9710435_T1",
"type": "CHEMICAL",
"text": [
"ibuprofen"
],
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[
1202,
1211
]
],
"normalized": []
},
{
"id": "9710435_T2",
"type": "CHEMICAL",
"text": [
"salicylic acid"
],
"offsets": [
[
1216,
1230
]
],
"normalized": []
},
{
"id": "9710435_T3",
"type": "CHEMICAL",
"text": [
"Ibuprofen"
],
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[
1312,
1321
]
],
"normalized": []
},
{
"id": "9710435_T4",
"type": "CHEMICAL",
"text": [
"salicylic acid"
],
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[
1562,
1576
]
],
"normalized": []
},
{
"id": "9710435_T5",
"type": "CHEMICAL",
"text": [
"ibuprofen"
],
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[
247,
256
]
],
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},
{
"id": "9710435_T6",
"type": "CHEMICAL",
"text": [
"ibuprofen"
],
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[
1774,
1783
]
],
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},
{
"id": "9710435_T7",
"type": "CHEMICAL",
"text": [
"salicylic acid"
],
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[
1788,
1802
]
],
"normalized": []
},
{
"id": "9710435_T8",
"type": "CHEMICAL",
"text": [
"cAMP"
],
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[
1811,
1815
]
],
"normalized": []
},
{
"id": "9710435_T9",
"type": "CHEMICAL",
"text": [
"forskolin"
],
"offsets": [
[
271,
280
]
],
"normalized": []
},
{
"id": "9710435_T10",
"type": "CHEMICAL",
"text": [
"K+"
],
"offsets": [
[
1954,
1956
]
],
"normalized": []
},
{
"id": "9710435_T11",
"type": "CHEMICAL",
"text": [
"Salicylic acid"
],
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[
369,
383
]
],
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},
{
"id": "9710435_T12",
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"ibuprofen"
],
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[
129,
138
]
],
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},
{
"id": "9710435_T13",
"type": "CHEMICAL",
"text": [
"ibuprofen"
],
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[
455,
464
]
],
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},
{
"id": "9710435_T14",
"type": "CHEMICAL",
"text": [
"forskolin"
],
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[
488,
497
]
],
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},
{
"id": "9710435_T15",
"type": "CHEMICAL",
"text": [
"salicylic acid"
],
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[
143,
157
]
],
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},
{
"id": "9710435_T16",
"type": "CHEMICAL",
"text": [
"ibuprofen"
],
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[
640,
649
]
],
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},
{
"id": "9710435_T17",
"type": "CHEMICAL",
"text": [
"forskolin"
],
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[
677,
686
]
],
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},
{
"id": "9710435_T18",
"type": "CHEMICAL",
"text": [
"cAMP"
],
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[
161,
165
]
],
"normalized": []
},
{
"id": "9710435_T19",
"type": "CHEMICAL",
"text": [
"Nystatin"
],
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[
771,
779
]
],
"normalized": []
},
{
"id": "9710435_T20",
"type": "CHEMICAL",
"text": [
"ibuprofen"
],
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[
883,
892
]
],
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},
{
"id": "9710435_T21",
"type": "CHEMICAL",
"text": [
"K+"
],
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[
929,
931
]
],
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},
{
"id": "9710435_T22",
"type": "CHEMICAL",
"text": [
"forskolin"
],
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[
967,
976
]
],
"normalized": []
},
{
"id": "9710435_T23",
"type": "CHEMICAL",
"text": [
"forskolin"
],
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[
984,
993
]
],
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},
{
"id": "9710435_T24",
"type": "CHEMICAL",
"text": [
"ibuprofen"
],
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[
1007,
1016
]
],
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},
{
"id": "9710435_T25",
"type": "CHEMICAL",
"text": [
"Ibuprofen"
],
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[
0,
9
]
],
"normalized": []
},
{
"id": "9710435_T26",
"type": "GENE-Y",
"text": [
"CFTR"
],
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[
1181,
1185
]
],
"normalized": []
},
{
"id": "9710435_T27",
"type": "GENE-Y",
"text": [
"CFTR"
],
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[
1234,
1238
]
],
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},
{
"id": "9710435_T28",
"type": "GENE-N",
"text": [
"Cl- channels"
],
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[
1239,
1251
]
],
"normalized": []
},
{
"id": "9710435_T29",
"type": "GENE-Y",
"text": [
"CFTR"
],
"offsets": [
[
1343,
1347
]
],
"normalized": []
},
{
"id": "9710435_T30",
"type": "GENE-Y",
"text": [
"CFTR"
],
"offsets": [
[
1592,
1596
]
],
"normalized": []
},
{
"id": "9710435_T31",
"type": "GENE-Y",
"text": [
"CFTR"
],
"offsets": [
[
1904,
1908
]
],
"normalized": []
},
{
"id": "9710435_T32",
"type": "GENE-N",
"text": [
"Cl- channels"
],
"offsets": [
[
1909,
1921
]
],
"normalized": []
},
{
"id": "9710435_T33",
"type": "GENE-N",
"text": [
"K+ channels"
],
"offsets": [
[
1954,
1965
]
],
"normalized": []
},
{
"id": "9710435_T34",
"type": "GENE-Y",
"text": [
"CFTR"
],
"offsets": [
[
2068,
2072
]
],
"normalized": []
},
{
"id": "9710435_T35",
"type": "GENE-Y",
"text": [
"cystic fibrosis transmembrane conductance regulator"
],
"offsets": [
[
19,
70
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "9710435_0",
"type": "INHIBITOR",
"arg1_id": "9710435_T25",
"arg2_id": "9710435_T35",
"normalized": []
},
{
"id": "9710435_1",
"type": "INHIBITOR",
"arg1_id": "9710435_T3",
"arg2_id": "9710435_T29",
"normalized": []
},
{
"id": "9710435_2",
"type": "INHIBITOR",
"arg1_id": "9710435_T4",
"arg2_id": "9710435_T30",
"normalized": []
},
{
"id": "9710435_3",
"type": "INHIBITOR",
"arg1_id": "9710435_T6",
"arg2_id": "9710435_T31",
"normalized": []
},
{
"id": "9710435_4",
"type": "INHIBITOR",
"arg1_id": "9710435_T7",
"arg2_id": "9710435_T31",
"normalized": []
},
{
"id": "9710435_5",
"type": "INHIBITOR",
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"arg2_id": "9710435_T32",
"normalized": []
},
{
"id": "9710435_6",
"type": "INHIBITOR",
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"normalized": []
},
{
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"arg2_id": "9710435_T33",
"normalized": []
},
{
"id": "9710435_8",
"type": "INHIBITOR",
"arg1_id": "9710435_T7",
"arg2_id": "9710435_T33",
"normalized": []
}
] |
23382381 | 23382381 | [
{
"id": "23382381_title",
"type": "title",
"text": [
"Supervillin-mediated suppression of p53 protein enhances cell survival."
],
"offsets": [
[
0,
71
]
]
},
{
"id": "23382381_abstract",
"type": "abstract",
"text": [
"Integrin-based adhesions promote cell survival as well as cell motility and invasion. We show here that the adhesion regulatory protein supervillin increases cell survival by decreasing levels of the tumor suppressor protein p53 and downstream target genes. RNAi-mediated knockdown of a new splice form of supervillin (isoform 4) or both isoforms 1 and 4 increases the amount of p53 and cell death, whereas p53 levels decrease after overexpression of either supervillin isoform. Cellular responses to DNA damage induced by etoposide or doxorubicin include down-regulation of endogenous supervillin coincident with increases in p53. In DNA-damaged supervillin knockdown cells, p53 knockdown or inhibition partially rescues the loss of cell metabolic activity, a measure of cell proliferation. Knockdown of the p53 deubiquitinating enzyme USP7/HAUSP also reverses the supervillin phenotype, blocking the increase in p53 levels seen after supervillin knockdown and accentuating the decrease in p53 levels triggered by supervillin overexpression. Conversely, supervillin overexpression decreases the association of USP7 and p53 and attenuates USP7-mediated p53 deubiquitination. USP7 binds directly to the supervillin N terminus and can deubiquitinate and stabilize supervillin. Supervillin also is stabilized by derivatization with the ubiquitin-like protein SUMO1. These results show that supervillin regulates cell survival through control of p53 levels and suggest that supervillin and its interaction partners at sites of cell-substrate adhesion constitute a locus for cross-talk between survival signaling and cell motility pathways."
],
"offsets": [
[
72,
1707
]
]
}
] | [
{
"id": "23382381_T1",
"type": "CHEMICAL",
"text": [
"N"
],
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1286,
1287
]
],
"normalized": []
},
{
"id": "23382381_T2",
"type": "CHEMICAL",
"text": [
"etoposide"
],
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595,
604
]
],
"normalized": []
},
{
"id": "23382381_T3",
"type": "CHEMICAL",
"text": [
"doxorubicin"
],
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[
608,
619
]
],
"normalized": []
},
{
"id": "23382381_T4",
"type": "GENE-N",
"text": [
"Integrin"
],
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[
72,
80
]
],
"normalized": []
},
{
"id": "23382381_T5",
"type": "GENE-Y",
"text": [
"supervillin"
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1087,
1098
]
],
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"id": "23382381_T6",
"type": "GENE-Y",
"text": [
"supervillin"
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1127,
1138
]
],
"normalized": []
},
{
"id": "23382381_T7",
"type": "GENE-N",
"text": [
"adhesion regulatory protein"
],
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[
180,
207
]
],
"normalized": []
},
{
"id": "23382381_T8",
"type": "GENE-Y",
"text": [
"USP7"
],
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[
1183,
1187
]
],
"normalized": []
},
{
"id": "23382381_T9",
"type": "GENE-Y",
"text": [
"p53"
],
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1192,
1195
]
],
"normalized": []
},
{
"id": "23382381_T10",
"type": "GENE-N",
"text": [
"USP7"
],
"offsets": [
[
1211,
1215
]
],
"normalized": []
},
{
"id": "23382381_T11",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
1225,
1228
]
],
"normalized": []
},
{
"id": "23382381_T12",
"type": "GENE-N",
"text": [
"USP7"
],
"offsets": [
[
1247,
1251
]
],
"normalized": []
},
{
"id": "23382381_T13",
"type": "GENE-Y",
"text": [
"supervillin"
],
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[
1274,
1285
]
],
"normalized": []
},
{
"id": "23382381_T14",
"type": "GENE-Y",
"text": [
"supervillin"
],
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[
1334,
1345
]
],
"normalized": []
},
{
"id": "23382381_T15",
"type": "GENE-N",
"text": [
"Supervillin"
],
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[
1347,
1358
]
],
"normalized": []
},
{
"id": "23382381_T16",
"type": "GENE-N",
"text": [
"ubiquitin"
],
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[
1405,
1414
]
],
"normalized": []
},
{
"id": "23382381_T17",
"type": "GENE-Y",
"text": [
"SUMO1"
],
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[
1428,
1433
]
],
"normalized": []
},
{
"id": "23382381_T18",
"type": "GENE-Y",
"text": [
"supervillin"
],
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[
208,
219
]
],
"normalized": []
},
{
"id": "23382381_T19",
"type": "GENE-Y",
"text": [
"supervillin"
],
"offsets": [
[
1459,
1470
]
],
"normalized": []
},
{
"id": "23382381_T20",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
1514,
1517
]
],
"normalized": []
},
{
"id": "23382381_T21",
"type": "GENE-Y",
"text": [
"supervillin"
],
"offsets": [
[
1542,
1553
]
],
"normalized": []
},
{
"id": "23382381_T22",
"type": "GENE-N",
"text": [
"tumor suppressor protein"
],
"offsets": [
[
272,
296
]
],
"normalized": []
},
{
"id": "23382381_T23",
"type": "GENE-Y",
"text": [
"p53"
],
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[
297,
300
]
],
"normalized": []
},
{
"id": "23382381_T24",
"type": "GENE-N",
"text": [
"supervillin (isoform 4) or both isoforms 1 and 4"
],
"offsets": [
[
378,
426
]
],
"normalized": []
},
{
"id": "23382381_T25",
"type": "GENE-Y",
"text": [
"p53"
],
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[
451,
454
]
],
"normalized": []
},
{
"id": "23382381_T26",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
479,
482
]
],
"normalized": []
},
{
"id": "23382381_T27",
"type": "GENE-Y",
"text": [
"supervillin"
],
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[
530,
541
]
],
"normalized": []
},
{
"id": "23382381_T28",
"type": "GENE-Y",
"text": [
"supervillin"
],
"offsets": [
[
658,
669
]
],
"normalized": []
},
{
"id": "23382381_T29",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
699,
702
]
],
"normalized": []
},
{
"id": "23382381_T30",
"type": "GENE-Y",
"text": [
"supervillin"
],
"offsets": [
[
719,
730
]
],
"normalized": []
},
{
"id": "23382381_T31",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
748,
751
]
],
"normalized": []
},
{
"id": "23382381_T32",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
881,
884
]
],
"normalized": []
},
{
"id": "23382381_T33",
"type": "GENE-Y",
"text": [
"USP7"
],
"offsets": [
[
909,
913
]
],
"normalized": []
},
{
"id": "23382381_T34",
"type": "GENE-Y",
"text": [
"HAUSP"
],
"offsets": [
[
914,
919
]
],
"normalized": []
},
{
"id": "23382381_T35",
"type": "GENE-Y",
"text": [
"supervillin"
],
"offsets": [
[
938,
949
]
],
"normalized": []
},
{
"id": "23382381_T36",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
986,
989
]
],
"normalized": []
},
{
"id": "23382381_T37",
"type": "GENE-Y",
"text": [
"supervillin"
],
"offsets": [
[
1008,
1019
]
],
"normalized": []
},
{
"id": "23382381_T38",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
1063,
1066
]
],
"normalized": []
},
{
"id": "23382381_T39",
"type": "GENE-Y",
"text": [
"Supervillin"
],
"offsets": [
[
0,
11
]
],
"normalized": []
},
{
"id": "23382381_T40",
"type": "GENE-Y",
"text": [
"p53"
],
"offsets": [
[
36,
39
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23382381_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23382381_T2",
"arg2_id": "23382381_T28",
"normalized": []
},
{
"id": "23382381_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23382381_T2",
"arg2_id": "23382381_T29",
"normalized": []
},
{
"id": "23382381_2",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23382381_T3",
"arg2_id": "23382381_T28",
"normalized": []
},
{
"id": "23382381_3",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23382381_T3",
"arg2_id": "23382381_T29",
"normalized": []
},
{
"id": "23382381_4",
"type": "PART-OF",
"arg1_id": "23382381_T1",
"arg2_id": "23382381_T13",
"normalized": []
}
] |
17203264 | 17203264 | [
{
"id": "17203264_title",
"type": "title",
"text": [
"Fluorescent sensing layer for the determination of L-malic acid in wine."
],
"offsets": [
[
0,
72
]
]
},
{
"id": "17203264_abstract",
"type": "abstract",
"text": [
"An enzymatic method for determining L-malic acid in wine based on an L-malate sensing layer with nicotinamide adenine dinucleotide (NAD+), L-malate dehydrogenase (L-MDH) and diaphorase (DI), immobilized by sol-gel technology, was constructed and evaluated. The sol-gel glass was prepared with tetramethoxysilane (TMOS), water and HCl. L-MDH catalyzes the reaction between L-malate and NAD+, producing NADH, whose fluorescence (lambdaexc=340 nm, lambdaem=430 nm) could be directly related to the amount of L-malate. NADH is converted to NAD+ by applying hexacyanoferrate(III) as oxidant in the presence of DI. Some parameters affecting sol-gel encapsulation and the pH of the enzymatic reaction were studied. The sensing layer has a dynamic range of 0.1-1.0 g/L of L-malate and a long-term storage stability of 25 days. It exhibits acceptable reproducibility [sr(%) approximately 10] and allows six regenerations. The content of L-malic acid was determined for different types of wine, and polyvinylpolypyrrolidone (PVPP) was used as a bleaching agent with red wine. The results obtained for the wine samples using the sensing layer are comparable to those obtained from a reference method based on UV-vis molecular absorption spectrometry, if the matrix effect is corrected for."
],
"offsets": [
[
73,
1351
]
]
}
] | [
{
"id": "17203264_T1",
"type": "CHEMICAL",
"text": [
"PVPP"
],
"offsets": [
[
1088,
1092
]
],
"normalized": []
},
{
"id": "17203264_T2",
"type": "CHEMICAL",
"text": [
"NAD+"
],
"offsets": [
[
205,
209
]
],
"normalized": []
},
{
"id": "17203264_T3",
"type": "CHEMICAL",
"text": [
"L-malate"
],
"offsets": [
[
212,
220
]
],
"normalized": []
},
{
"id": "17203264_T4",
"type": "CHEMICAL",
"text": [
"tetramethoxysilane"
],
"offsets": [
[
366,
384
]
],
"normalized": []
},
{
"id": "17203264_T5",
"type": "CHEMICAL",
"text": [
"TMOS"
],
"offsets": [
[
386,
390
]
],
"normalized": []
},
{
"id": "17203264_T6",
"type": "CHEMICAL",
"text": [
"HCl"
],
"offsets": [
[
403,
406
]
],
"normalized": []
},
{
"id": "17203264_T7",
"type": "CHEMICAL",
"text": [
"L-malic acid"
],
"offsets": [
[
109,
121
]
],
"normalized": []
},
{
"id": "17203264_T8",
"type": "CHEMICAL",
"text": [
"L-malate"
],
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[
445,
453
]
],
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},
{
"id": "17203264_T9",
"type": "CHEMICAL",
"text": [
"NAD+"
],
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[
458,
462
]
],
"normalized": []
},
{
"id": "17203264_T10",
"type": "CHEMICAL",
"text": [
"NADH"
],
"offsets": [
[
474,
478
]
],
"normalized": []
},
{
"id": "17203264_T11",
"type": "CHEMICAL",
"text": [
"L-malate"
],
"offsets": [
[
578,
586
]
],
"normalized": []
},
{
"id": "17203264_T12",
"type": "CHEMICAL",
"text": [
"NADH"
],
"offsets": [
[
588,
592
]
],
"normalized": []
},
{
"id": "17203264_T13",
"type": "CHEMICAL",
"text": [
"NAD+"
],
"offsets": [
[
609,
613
]
],
"normalized": []
},
{
"id": "17203264_T14",
"type": "CHEMICAL",
"text": [
"hexacyanoferrate(III)"
],
"offsets": [
[
626,
647
]
],
"normalized": []
},
{
"id": "17203264_T15",
"type": "CHEMICAL",
"text": [
"L-malate"
],
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[
142,
150
]
],
"normalized": []
},
{
"id": "17203264_T16",
"type": "CHEMICAL",
"text": [
"L-malate"
],
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[
837,
845
]
],
"normalized": []
},
{
"id": "17203264_T17",
"type": "CHEMICAL",
"text": [
"L-malic acid"
],
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[
1001,
1013
]
],
"normalized": []
},
{
"id": "17203264_T18",
"type": "CHEMICAL",
"text": [
"nicotinamide adenine dinucleotide"
],
"offsets": [
[
170,
203
]
],
"normalized": []
},
{
"id": "17203264_T19",
"type": "CHEMICAL",
"text": [
"polyvinylpolypyrrolidone"
],
"offsets": [
[
1062,
1086
]
],
"normalized": []
},
{
"id": "17203264_T20",
"type": "CHEMICAL",
"text": [
"L-malic acid"
],
"offsets": [
[
51,
63
]
],
"normalized": []
},
{
"id": "17203264_T21",
"type": "GENE-N",
"text": [
"L-malate dehydrogenase"
],
"offsets": [
[
212,
234
]
],
"normalized": []
},
{
"id": "17203264_T22",
"type": "GENE-N",
"text": [
"L-MDH"
],
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[
236,
241
]
],
"normalized": []
},
{
"id": "17203264_T23",
"type": "GENE-N",
"text": [
"diaphorase"
],
"offsets": [
[
247,
257
]
],
"normalized": []
},
{
"id": "17203264_T24",
"type": "GENE-N",
"text": [
"L-MDH"
],
"offsets": [
[
408,
413
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17203264_0",
"type": "SUBSTRATE",
"arg1_id": "17203264_T8",
"arg2_id": "17203264_T24",
"normalized": []
},
{
"id": "17203264_1",
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"arg2_id": "17203264_T24",
"normalized": []
},
{
"id": "17203264_2",
"type": "PRODUCT-OF",
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"arg2_id": "17203264_T24",
"normalized": []
},
{
"id": "17203264_3",
"type": "SUBSTRATE",
"arg1_id": "17203264_T11",
"arg2_id": "17203264_T24",
"normalized": []
}
] |
23270965 | 23270965 | [
{
"id": "23270965_title",
"type": "title",
"text": [
"Safrole-2',3'-oxide induces atherosclerotic plaque vulnerability in apolipoprotein E-knockout mice."
],
"offsets": [
[
0,
99
]
]
},
{
"id": "23270965_abstract",
"type": "abstract",
"text": [
"Safrole-2',3'-oxide (SFO) is the major electrophilic metabolite of safrole (4-allyl-1, 2-methylenedioxybenzene), a natural plant constituent found in essential oils of numerous edible herbs and spices and in food containing these herbs, such as pesto sauce, cola beverages and bologna sausages. The effects of SFO in mammalian systems, especially the cardiovascular system, are little known. Disruption of vulnerable atherosclerotic plaques in atherosclerosis, a chronic inflammatory disease, is the main cause of cardiovascular events. In this study, we investigated SFO-induced atherosclerotic plaque vulnerability (possibility of rupture) in apolipoprotein E-knockout (apoE(-/-)) mice. Lipid area in vessel wall reached 59.8% in high dose SFO (SFO-HD) treated group, which is only 31.2% in control group. SFO treatment changed the lesion composition to an unstable phenotype, increased the number of apoptotic cells in plaque and the endothelium in plaques was damaged after SFO treatment. Furthermore, compared with control groups, the plaque endothelium level of p75(NTR) was 3-fold increased and the liver level of p75(NTR) was 17.4-fold increased by SFO-HD. Meanwhile, the serum level of KC (a functional homolog of IL-8 and the main proinflammatory alpha chemokine in mice) in apoE(-/-) mice was up to 357pg/ml in SFO-HD treated group. Thus, SFO contributes to the instability of atherosclerotic plaque in apoE(-/-) mice through activating p75(NTR) and IL-8 and cell apoptosis in plaque."
],
"offsets": [
[
100,
1595
]
]
}
] | [
{
"id": "23270965_T1",
"type": "CHEMICAL",
"text": [
"Safrole-2',3'-oxide"
],
"offsets": [
[
100,
119
]
],
"normalized": []
},
{
"id": "23270965_T2",
"type": "CHEMICAL",
"text": [
"SFO"
],
"offsets": [
[
1257,
1260
]
],
"normalized": []
},
{
"id": "23270965_T3",
"type": "CHEMICAL",
"text": [
"SFO"
],
"offsets": [
[
1422,
1425
]
],
"normalized": []
},
{
"id": "23270965_T4",
"type": "CHEMICAL",
"text": [
"SFO"
],
"offsets": [
[
1450,
1453
]
],
"normalized": []
},
{
"id": "23270965_T5",
"type": "CHEMICAL",
"text": [
"SFO"
],
"offsets": [
[
121,
124
]
],
"normalized": []
},
{
"id": "23270965_T6",
"type": "CHEMICAL",
"text": [
"SFO"
],
"offsets": [
[
410,
413
]
],
"normalized": []
},
{
"id": "23270965_T7",
"type": "CHEMICAL",
"text": [
"SFO"
],
"offsets": [
[
668,
671
]
],
"normalized": []
},
{
"id": "23270965_T8",
"type": "CHEMICAL",
"text": [
"safrole"
],
"offsets": [
[
167,
174
]
],
"normalized": []
},
{
"id": "23270965_T9",
"type": "CHEMICAL",
"text": [
"SFO"
],
"offsets": [
[
842,
845
]
],
"normalized": []
},
{
"id": "23270965_T10",
"type": "CHEMICAL",
"text": [
"SFO"
],
"offsets": [
[
847,
850
]
],
"normalized": []
},
{
"id": "23270965_T11",
"type": "CHEMICAL",
"text": [
"4-allyl-1, 2-methylenedioxybenzene"
],
"offsets": [
[
176,
210
]
],
"normalized": []
},
{
"id": "23270965_T12",
"type": "CHEMICAL",
"text": [
"SFO"
],
"offsets": [
[
908,
911
]
],
"normalized": []
},
{
"id": "23270965_T13",
"type": "CHEMICAL",
"text": [
"SFO"
],
"offsets": [
[
1078,
1081
]
],
"normalized": []
},
{
"id": "23270965_T14",
"type": "CHEMICAL",
"text": [
"Safrole-2',3'-oxide"
],
"offsets": [
[
0,
19
]
],
"normalized": []
},
{
"id": "23270965_T15",
"type": "GENE-Y",
"text": [
"p75(NTR)"
],
"offsets": [
[
1168,
1176
]
],
"normalized": []
},
{
"id": "23270965_T16",
"type": "GENE-Y",
"text": [
"p75(NTR)"
],
"offsets": [
[
1221,
1229
]
],
"normalized": []
},
{
"id": "23270965_T17",
"type": "GENE-N",
"text": [
"IL-8"
],
"offsets": [
[
1323,
1327
]
],
"normalized": []
},
{
"id": "23270965_T18",
"type": "GENE-N",
"text": [
"alpha chemokine"
],
"offsets": [
[
1357,
1372
]
],
"normalized": []
},
{
"id": "23270965_T19",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
1385,
1389
]
],
"normalized": []
},
{
"id": "23270965_T20",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
1514,
1518
]
],
"normalized": []
},
{
"id": "23270965_T21",
"type": "GENE-Y",
"text": [
"p75(NTR)"
],
"offsets": [
[
1548,
1556
]
],
"normalized": []
},
{
"id": "23270965_T22",
"type": "GENE-N",
"text": [
"IL-8"
],
"offsets": [
[
1561,
1565
]
],
"normalized": []
},
{
"id": "23270965_T23",
"type": "GENE-Y",
"text": [
"apolipoprotein E"
],
"offsets": [
[
745,
761
]
],
"normalized": []
},
{
"id": "23270965_T24",
"type": "GENE-Y",
"text": [
"apoE"
],
"offsets": [
[
772,
776
]
],
"normalized": []
},
{
"id": "23270965_T25",
"type": "GENE-Y",
"text": [
"apolipoprotein E"
],
"offsets": [
[
68,
84
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23270965_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23270965_T2",
"arg2_id": "23270965_T15",
"normalized": []
},
{
"id": "23270965_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23270965_T2",
"arg2_id": "23270965_T16",
"normalized": []
},
{
"id": "23270965_2",
"type": "ACTIVATOR",
"arg1_id": "23270965_T4",
"arg2_id": "23270965_T21",
"normalized": []
},
{
"id": "23270965_3",
"type": "ACTIVATOR",
"arg1_id": "23270965_T4",
"arg2_id": "23270965_T22",
"normalized": []
},
{
"id": "23270965_4",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23270965_T3",
"arg2_id": "23270965_T18",
"normalized": []
},
{
"id": "23270965_5",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23270965_T3",
"arg2_id": "23270965_T17",
"normalized": []
}
] |
2506486 | 2506486 | [
{
"id": "2506486_title",
"type": "title",
"text": [
"Effects of monoamine oxidase inhibitors on levels of catechols and homovanillic acid in striatum and plasma."
],
"offsets": [
[
0,
108
]
]
},
{
"id": "2506486_abstract",
"type": "abstract",
"text": [
"Levels of homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG) in plasma and the striatium were measured after inhibition of monoamine oxidase type A (MAO-A) by clorgyline (4 mg/kg i.p.), MAO-B by (-)deprenyl (1 mg/kg i.p.), both MAO-A and MAO-B by nialamide (75 mg/kg i.p.) or peripheral neuronal MAO by debrisoquin (40 mg/kg i.p.). Levels of HVA in plasma decreased by about 60% after single doses of nialamide or clorgyline, by about 80% after repeated doses of nialamide, by about 40% after a single dose of debrisoquin and by about 50% after repeated doses of debrisoquin. The administration of clorgyline, nialamide or debrisoquin significantly decreased concentrations of DOPAC and DHPG in plasma, whereas (-)deprenyl did not affect levels of DHPG or HVA. None of the MAO inhibitors produced more than about 80% depression of levels of any of the deaminated metabolites. The results suggest that most of the HVA in plasma is derived from deamination of DA by MAO-A in peripheral neurons; that DOPAC in plasma is derived from cells outside the central nervous system; that DHPG in plasma is derived virtually exclusively from the metabolism of norepinephrine in sympathetic nerve endings and that residual levels of HVA after treatment with debrisoquin provide an improved but limited indication of central dopaminergic activity."
],
"offsets": [
[
109,
1484
]
]
}
] | [
{
"id": "2506486_T1",
"type": "CHEMICAL",
"text": [
"DA"
],
"offsets": [
[
1109,
1111
]
],
"normalized": []
},
{
"id": "2506486_T2",
"type": "CHEMICAL",
"text": [
"homovanillic acid"
],
"offsets": [
[
119,
136
]
],
"normalized": []
},
{
"id": "2506486_T3",
"type": "CHEMICAL",
"text": [
"DOPAC"
],
"offsets": [
[
1149,
1154
]
],
"normalized": []
},
{
"id": "2506486_T4",
"type": "CHEMICAL",
"text": [
"DHPG"
],
"offsets": [
[
1228,
1232
]
],
"normalized": []
},
{
"id": "2506486_T5",
"type": "CHEMICAL",
"text": [
"norepinephrine"
],
"offsets": [
[
1299,
1313
]
],
"normalized": []
},
{
"id": "2506486_T6",
"type": "CHEMICAL",
"text": [
"HVA"
],
"offsets": [
[
1371,
1374
]
],
"normalized": []
},
{
"id": "2506486_T7",
"type": "CHEMICAL",
"text": [
"debrisoquin"
],
"offsets": [
[
1396,
1407
]
],
"normalized": []
},
{
"id": "2506486_T8",
"type": "CHEMICAL",
"text": [
"monoamine"
],
"offsets": [
[
274,
283
]
],
"normalized": []
},
{
"id": "2506486_T9",
"type": "CHEMICAL",
"text": [
"clorgyline"
],
"offsets": [
[
310,
320
]
],
"normalized": []
},
{
"id": "2506486_T10",
"type": "CHEMICAL",
"text": [
"(-)deprenyl"
],
"offsets": [
[
346,
357
]
],
"normalized": []
},
{
"id": "2506486_T11",
"type": "CHEMICAL",
"text": [
"nialamide"
],
"offsets": [
[
398,
407
]
],
"normalized": []
},
{
"id": "2506486_T12",
"type": "CHEMICAL",
"text": [
"HVA"
],
"offsets": [
[
138,
141
]
],
"normalized": []
},
{
"id": "2506486_T13",
"type": "CHEMICAL",
"text": [
"debrisoquin"
],
"offsets": [
[
454,
465
]
],
"normalized": []
},
{
"id": "2506486_T14",
"type": "CHEMICAL",
"text": [
"dihydroxyphenylacetic acid"
],
"offsets": [
[
144,
170
]
],
"normalized": []
},
{
"id": "2506486_T15",
"type": "CHEMICAL",
"text": [
"HVA"
],
"offsets": [
[
493,
496
]
],
"normalized": []
},
{
"id": "2506486_T16",
"type": "CHEMICAL",
"text": [
"nialamide"
],
"offsets": [
[
552,
561
]
],
"normalized": []
},
{
"id": "2506486_T17",
"type": "CHEMICAL",
"text": [
"clorgyline"
],
"offsets": [
[
565,
575
]
],
"normalized": []
},
{
"id": "2506486_T18",
"type": "CHEMICAL",
"text": [
"nialamide"
],
"offsets": [
[
614,
623
]
],
"normalized": []
},
{
"id": "2506486_T19",
"type": "CHEMICAL",
"text": [
"debrisoquin"
],
"offsets": [
[
661,
672
]
],
"normalized": []
},
{
"id": "2506486_T20",
"type": "CHEMICAL",
"text": [
"debrisoquin"
],
"offsets": [
[
714,
725
]
],
"normalized": []
},
{
"id": "2506486_T21",
"type": "CHEMICAL",
"text": [
"DOPAC"
],
"offsets": [
[
172,
177
]
],
"normalized": []
},
{
"id": "2506486_T22",
"type": "CHEMICAL",
"text": [
"clorgyline"
],
"offsets": [
[
749,
759
]
],
"normalized": []
},
{
"id": "2506486_T23",
"type": "CHEMICAL",
"text": [
"nialamide"
],
"offsets": [
[
761,
770
]
],
"normalized": []
},
{
"id": "2506486_T24",
"type": "CHEMICAL",
"text": [
"debrisoquin"
],
"offsets": [
[
774,
785
]
],
"normalized": []
},
{
"id": "2506486_T25",
"type": "CHEMICAL",
"text": [
"DOPAC"
],
"offsets": [
[
828,
833
]
],
"normalized": []
},
{
"id": "2506486_T26",
"type": "CHEMICAL",
"text": [
"DHPG"
],
"offsets": [
[
838,
842
]
],
"normalized": []
},
{
"id": "2506486_T27",
"type": "CHEMICAL",
"text": [
"dihydroxyphenylglycol"
],
"offsets": [
[
183,
204
]
],
"normalized": []
},
{
"id": "2506486_T28",
"type": "CHEMICAL",
"text": [
"(-)deprenyl"
],
"offsets": [
[
862,
873
]
],
"normalized": []
},
{
"id": "2506486_T29",
"type": "CHEMICAL",
"text": [
"DHPG"
],
"offsets": [
[
899,
903
]
],
"normalized": []
},
{
"id": "2506486_T30",
"type": "CHEMICAL",
"text": [
"HVA"
],
"offsets": [
[
907,
910
]
],
"normalized": []
},
{
"id": "2506486_T31",
"type": "CHEMICAL",
"text": [
"HVA"
],
"offsets": [
[
1064,
1067
]
],
"normalized": []
},
{
"id": "2506486_T32",
"type": "CHEMICAL",
"text": [
"DHPG"
],
"offsets": [
[
206,
210
]
],
"normalized": []
},
{
"id": "2506486_T33",
"type": "CHEMICAL",
"text": [
"monoamine"
],
"offsets": [
[
11,
20
]
],
"normalized": []
},
{
"id": "2506486_T34",
"type": "CHEMICAL",
"text": [
"catechols"
],
"offsets": [
[
53,
62
]
],
"normalized": []
},
{
"id": "2506486_T35",
"type": "CHEMICAL",
"text": [
"homovanillic acid"
],
"offsets": [
[
67,
84
]
],
"normalized": []
},
{
"id": "2506486_T36",
"type": "GENE-Y",
"text": [
"MAO-A"
],
"offsets": [
[
1115,
1120
]
],
"normalized": []
},
{
"id": "2506486_T37",
"type": "GENE-Y",
"text": [
"monoamine oxidase type A"
],
"offsets": [
[
274,
298
]
],
"normalized": []
},
{
"id": "2506486_T38",
"type": "GENE-Y",
"text": [
"MAO-A"
],
"offsets": [
[
300,
305
]
],
"normalized": []
},
{
"id": "2506486_T39",
"type": "GENE-Y",
"text": [
"MAO-B"
],
"offsets": [
[
337,
342
]
],
"normalized": []
},
{
"id": "2506486_T40",
"type": "GENE-Y",
"text": [
"MAO-A"
],
"offsets": [
[
379,
384
]
],
"normalized": []
},
{
"id": "2506486_T41",
"type": "GENE-Y",
"text": [
"MAO-B"
],
"offsets": [
[
389,
394
]
],
"normalized": []
},
{
"id": "2506486_T42",
"type": "GENE-N",
"text": [
"MAO"
],
"offsets": [
[
447,
450
]
],
"normalized": []
},
{
"id": "2506486_T43",
"type": "GENE-N",
"text": [
"MAO"
],
"offsets": [
[
924,
927
]
],
"normalized": []
},
{
"id": "2506486_T44",
"type": "GENE-N",
"text": [
"monoamine oxidase"
],
"offsets": [
[
11,
28
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "2506486_0",
"type": "INHIBITOR",
"arg1_id": "2506486_T9",
"arg2_id": "2506486_T37",
"normalized": []
},
{
"id": "2506486_1",
"type": "INHIBITOR",
"arg1_id": "2506486_T9",
"arg2_id": "2506486_T38",
"normalized": []
},
{
"id": "2506486_2",
"type": "INHIBITOR",
"arg1_id": "2506486_T10",
"arg2_id": "2506486_T39",
"normalized": []
},
{
"id": "2506486_3",
"type": "INHIBITOR",
"arg1_id": "2506486_T11",
"arg2_id": "2506486_T40",
"normalized": []
},
{
"id": "2506486_4",
"type": "INHIBITOR",
"arg1_id": "2506486_T11",
"arg2_id": "2506486_T41",
"normalized": []
},
{
"id": "2506486_5",
"type": "INHIBITOR",
"arg1_id": "2506486_T13",
"arg2_id": "2506486_T42",
"normalized": []
},
{
"id": "2506486_6",
"type": "SUBSTRATE",
"arg1_id": "2506486_T1",
"arg2_id": "2506486_T36",
"normalized": []
},
{
"id": "2506486_7",
"type": "PRODUCT-OF",
"arg1_id": "2506486_T31",
"arg2_id": "2506486_T36",
"normalized": []
}
] |
23613012 | 23613012 | [
{
"id": "23613012_title",
"type": "title",
"text": [
"HDL Cholesterol Subfractions and the Effect of Testosterone Replacement in Hypogonadism."
],
"offsets": [
[
0,
88
]
]
},
{
"id": "23613012_abstract",
"type": "abstract",
"text": [
"Metabolic disorders and cardiovascular events are increased in hypogonadism. Serum HDL composition is a better cardiovascular predictor than the HDL counts. However, there is no information about the HDL subfractions in patients with hypogonadism. We designed a prospective study to investigate the HDL subfractions in treatment naïve subjects with hypogonadism and the effects of 2 different testosterone replacement regimens on the HDL subfractions. Seventy young male patients with congenital hypogonadotropic hypogonadism (CHH) and 70 age and BMI-matched healthy males were enrolled in the present study. The patients were assigned to receive intramuscular injections of testosterone esters 250 mg every 3 weeks and transdermal testosterone applications 50 mg daily. Biochemical investigations including HDL subfractions and insulin resistance were done. Patients with CHH had higher levels of insulin, HOMA-IR, WC, triglyceride, and diastolic blood pressure. Although, the HDL cholesterol concentrations were similar in both groups, hypogonadal patients had lower HDL2 and higher HDL3 levels. The total testosterone levels were independent determinants of the HDL2 subfractions. During the follow-up, a significant increase in the BMI and WC values and a significant decrease in the levels of total cholesterol, HDL cholesterol, and HDL3 were observed. No difference was present between the 2 treatment arms. These results show that patients with hypogonadism have unfavorable HDL compositions in addition to the other dysmetabolic features. However, testosterone replacement for about six months neither improves the metabolic problems nor the HDL composition. Mechanistic studies are warranted to better understand the cardiovascular effects of unfavorable HDL compositions in hypogonadism."
],
"offsets": [
[
89,
1886
]
]
}
] | [
{
"id": "23613012_T1",
"type": "CHEMICAL",
"text": [
"testosterone"
],
"offsets": [
[
1197,
1209
]
],
"normalized": []
},
{
"id": "23613012_T2",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
1393,
1404
]
],
"normalized": []
},
{
"id": "23613012_T3",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
1410,
1421
]
],
"normalized": []
},
{
"id": "23613012_T4",
"type": "CHEMICAL",
"text": [
"testosterone"
],
"offsets": [
[
1645,
1657
]
],
"normalized": []
},
{
"id": "23613012_T5",
"type": "CHEMICAL",
"text": [
"testosterone"
],
"offsets": [
[
482,
494
]
],
"normalized": []
},
{
"id": "23613012_T6",
"type": "CHEMICAL",
"text": [
"testosterone esters"
],
"offsets": [
[
764,
783
]
],
"normalized": []
},
{
"id": "23613012_T7",
"type": "CHEMICAL",
"text": [
"triglyceride"
],
"offsets": [
[
1009,
1021
]
],
"normalized": []
},
{
"id": "23613012_T8",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
1071,
1082
]
],
"normalized": []
},
{
"id": "23613012_T9",
"type": "CHEMICAL",
"text": [
"Cholesterol"
],
"offsets": [
[
4,
15
]
],
"normalized": []
},
{
"id": "23613012_T10",
"type": "CHEMICAL",
"text": [
"Testosterone"
],
"offsets": [
[
47,
59
]
],
"normalized": []
},
{
"id": "23613012_T11",
"type": "GENE-N",
"text": [
"HDL2"
],
"offsets": [
[
1158,
1162
]
],
"normalized": []
},
{
"id": "23613012_T12",
"type": "GENE-N",
"text": [
"HDL3"
],
"offsets": [
[
1174,
1178
]
],
"normalized": []
},
{
"id": "23613012_T13",
"type": "GENE-N",
"text": [
"HDL2"
],
"offsets": [
[
1254,
1258
]
],
"normalized": []
},
{
"id": "23613012_T14",
"type": "GENE-N",
"text": [
"HDL"
],
"offsets": [
[
1406,
1409
]
],
"normalized": []
},
{
"id": "23613012_T15",
"type": "GENE-N",
"text": [
"HDL3"
],
"offsets": [
[
1427,
1431
]
],
"normalized": []
},
{
"id": "23613012_T16",
"type": "GENE-N",
"text": [
"HDL"
],
"offsets": [
[
234,
237
]
],
"normalized": []
},
{
"id": "23613012_T17",
"type": "GENE-N",
"text": [
"HDL"
],
"offsets": [
[
1571,
1574
]
],
"normalized": []
},
{
"id": "23613012_T18",
"type": "GENE-N",
"text": [
"HDL"
],
"offsets": [
[
1739,
1742
]
],
"normalized": []
},
{
"id": "23613012_T19",
"type": "GENE-N",
"text": [
"HDL"
],
"offsets": [
[
1853,
1856
]
],
"normalized": []
},
{
"id": "23613012_T20",
"type": "GENE-N",
"text": [
"HDL"
],
"offsets": [
[
289,
292
]
],
"normalized": []
},
{
"id": "23613012_T21",
"type": "GENE-N",
"text": [
"HDL"
],
"offsets": [
[
388,
391
]
],
"normalized": []
},
{
"id": "23613012_T22",
"type": "GENE-N",
"text": [
"HDL"
],
"offsets": [
[
523,
526
]
],
"normalized": []
},
{
"id": "23613012_T23",
"type": "GENE-N",
"text": [
"Serum HDL"
],
"offsets": [
[
166,
175
]
],
"normalized": []
},
{
"id": "23613012_T24",
"type": "GENE-N",
"text": [
"HDL"
],
"offsets": [
[
897,
900
]
],
"normalized": []
},
{
"id": "23613012_T25",
"type": "GENE-Y",
"text": [
"insulin"
],
"offsets": [
[
918,
925
]
],
"normalized": []
},
{
"id": "23613012_T26",
"type": "GENE-Y",
"text": [
"insulin"
],
"offsets": [
[
987,
994
]
],
"normalized": []
},
{
"id": "23613012_T27",
"type": "GENE-N",
"text": [
"HDL"
],
"offsets": [
[
1067,
1070
]
],
"normalized": []
},
{
"id": "23613012_T28",
"type": "GENE-N",
"text": [
"HDL"
],
"offsets": [
[
0,
3
]
],
"normalized": []
}
] | [] | [] | [] |