id
stringlengths
1
4
document_id
stringlengths
7
8
passages
list
entities
list
events
list
coreferences
list
relations
list
0
10471277
[ { "id": "1", "type": "title and abstract", "text": [ "Probing the salmeterol binding site on the beta 2-adrenergic receptor using a novel photoaffinity ligand, [(125)I]iodoazidosalmeterol.\nSalmeterol is a long-acting beta2-adrenergic receptor (beta 2AR) agonist used clinically to treat asthma. In addition to binding at the active agonist site, it has been proposed that salmeterol also binds with very high affinity at a second site, termed the \"exosite\", and that this exosite contributes to the long duration of action of salmeterol. To determine the position of the phenyl ring of the aralkyloxyalkyl side chain of salmeterol in the beta 2AR binding site, we designed and synthesized the agonist photoaffinity label [(125)I]iodoazidosalmeterol ([125I]IAS). In direct adenylyl cyclase activation, in effects on adenylyl cyclase after pretreatment of intact cells, and in guinea pig tracheal relaxation assays, IAS and the parent drug salmeterol behave essentially the same. Significantly, the photoreactive azide of IAS is positioned on the phenyl ring at the end of the molecule which is thought to be involved in exosite binding. Carrier-free radioiodinated [125I]IAS was used to photolabel epitope-tagged human beta 2AR in membranes prepared from stably transfected HEK 293 cells. Labeling with [(125)I]IAS was blocked by 10 microM (-)-alprenolol and inhibited by addition of GTP gamma S, and [125I]IAS migrated at the same position on an SDS-PAGE gel as the beta 2AR labeled by the antagonist photoaffinity label [125I]iodoazidobenzylpindolol ([125I]IABP). The labeled receptor was purified on a nickel affinity column and cleaved with factor Xa protease at a specific sequence in the large loop between transmembrane segments 5 and 6, yielding two peptides. While the control antagonist photoaffinity label [125I]IABP labeled both the large N-terminal fragment [containing transmembranes (TMs) 1-5] and the smaller C-terminal fragment (containing TMs 6 and 7), essentially all of the [125I]IAS labeling was on the smaller C-terminal peptide containing TMs 6 and 7. This direct biochemical evidence demonstrates that when salmeterol binds to the receptor, its hydrophobic aryloxyalkyl tail is positioned near TM 6 and/or TM 7. A model of IAS binding to the beta 2AR is proposed." ], "offsets": [ [ 0, 2232 ] ] } ]
[ { "id": "2", "type": "CHEMICAL", "text": [ "Salmeterol" ], "offsets": [ [ 135, 145 ] ], "normalized": [] }, { "id": "3", "type": "CHEMICAL", "text": [ "[(125)I]IAS" ], "offsets": [ [ 1248, 1259 ] ], "normalized": [] }, { "id": "4", "type": "CHEMICAL", "text": [ "(-)-alprenolol" ], "offsets": [ [ 1285, 1299 ] ], "normalized": [] }, { "id": "5", "type": "CHEMICAL", "text": [ "GTP" ], "offsets": [ [ 1329, 1332 ] ], "normalized": [] }, { "id": "6", "type": "CHEMICAL", "text": [ "[125I]IAS" ], "offsets": [ [ 1346, 1355 ] ], "normalized": [] }, { "id": "7", "type": "CHEMICAL", "text": [ "[125I]iodoazidobenzylpindolol" ], "offsets": [ [ 1467, 1496 ] ], "normalized": [] }, { "id": "8", "type": "CHEMICAL", "text": [ "[125I]IABP" ], "offsets": [ [ 1498, 1508 ] ], "normalized": [] }, { "id": "9", "type": "CHEMICAL", "text": [ "nickel" ], "offsets": [ [ 1550, 1556 ] ], "normalized": [] }, { "id": "10", "type": "CHEMICAL", "text": [ "[125I]IABP" ], "offsets": [ [ 1762, 1772 ] ], "normalized": [] }, { "id": "11", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 1796, 1797 ] ], "normalized": [] }, { "id": "12", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 1870, 1871 ] ], "normalized": [] }, { "id": "13", "type": "CHEMICAL", "text": [ "[125I]IAS" ], "offsets": [ [ 1939, 1948 ] ], "normalized": [] }, { "id": "14", "type": "CHEMICAL", "text": [ "salmeterol" ], "offsets": [ [ 318, 328 ] ], "normalized": [] }, { "id": "15", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 1977, 1978 ] ], "normalized": [] }, { "id": "16", "type": "CHEMICAL", "text": [ "salmeterol" ], "offsets": [ [ 2076, 2086 ] ], "normalized": [] }, { "id": "17", "type": "CHEMICAL", "text": [ "aryloxyalkyl" ], "offsets": [ [ 2126, 2138 ] ], "normalized": [] }, { "id": "18", "type": "CHEMICAL", "text": [ "IAS" ], "offsets": [ [ 2192, 2195 ] ], "normalized": [] }, { "id": "19", "type": "CHEMICAL", "text": [ "salmeterol" ], "offsets": [ [ 472, 482 ] ], "normalized": [] }, { "id": "20", "type": "CHEMICAL", "text": [ "phenyl" ], "offsets": [ [ 517, 523 ] ], "normalized": [] }, { "id": "21", "type": "CHEMICAL", "text": [ "salmeterol" ], "offsets": [ [ 566, 576 ] ], "normalized": [] }, { "id": "22", "type": "CHEMICAL", "text": [ "[(125)I]iodoazidosalmeterol" ], "offsets": [ [ 667, 694 ] ], "normalized": [] }, { "id": "23", "type": "CHEMICAL", "text": [ "[125I]IAS" ], "offsets": [ [ 696, 705 ] ], "normalized": [] }, { "id": "24", "type": "CHEMICAL", "text": [ "adenylyl" ], "offsets": [ [ 718, 726 ] ], "normalized": [] }, { "id": "25", "type": "CHEMICAL", "text": [ "adenylyl" ], "offsets": [ [ 761, 769 ] ], "normalized": [] }, { "id": "26", "type": "CHEMICAL", "text": [ "IAS" ], "offsets": [ [ 860, 863 ] ], "normalized": [] }, { "id": "27", "type": "CHEMICAL", "text": [ "salmeterol" ], "offsets": [ [ 884, 894 ] ], "normalized": [] }, { "id": "28", "type": "CHEMICAL", "text": [ "azide" ], "offsets": [ [ 957, 962 ] ], "normalized": [] }, { "id": "29", "type": "CHEMICAL", "text": [ "IAS" ], "offsets": [ [ 966, 969 ] ], "normalized": [] }, { "id": "30", "type": "CHEMICAL", "text": [ "phenyl" ], "offsets": [ [ 991, 997 ] ], "normalized": [] }, { "id": "31", "type": "CHEMICAL", "text": [ "[125I]IAS" ], "offsets": [ [ 1110, 1119 ] ], "normalized": [] }, { "id": "32", "type": "CHEMICAL", "text": [ "[(125)I]iodoazidosalmeterol" ], "offsets": [ [ 106, 133 ] ], "normalized": [] }, { "id": "33", "type": "GENE-N", "text": [ "human beta 2AR" ], "offsets": [ [ 1158, 1172 ] ], "normalized": [] }, { "id": "34", "type": "GENE-N", "text": [ "beta 2AR" ], "offsets": [ [ 1412, 1420 ] ], "normalized": [] }, { "id": "35", "type": "GENE-N", "text": [ "factor Xa" ], "offsets": [ [ 1590, 1599 ] ], "normalized": [] }, { "id": "36", "type": "GENE-N", "text": [ "beta 2AR" ], "offsets": [ [ 2211, 2219 ] ], "normalized": [] }, { "id": "37", "type": "GENE-N", "text": [ "beta2-adrenergic receptor" ], "offsets": [ [ 163, 188 ] ], "normalized": [] }, { "id": "38", "type": "GENE-N", "text": [ "beta 2AR" ], "offsets": [ [ 584, 592 ] ], "normalized": [] }, { "id": "39", "type": "GENE-N", "text": [ "beta 2AR" ], "offsets": [ [ 190, 198 ] ], "normalized": [] }, { "id": "40", "type": "GENE-N", "text": [ "beta 2-adrenergic receptor" ], "offsets": [ [ 43, 69 ] ], "normalized": [] }, { "id": "41", "type": "CHEMICAL", "text": [ "salmeterol" ], "offsets": [ [ 12, 22 ] ], "normalized": [] }, { "id": "42", "type": "CHEMICAL", "text": [ "aralkyloxyalkyl" ], "offsets": [ [ 536, 551 ] ], "normalized": [] }, { "id": "43", "type": "GENE-Y", "text": [ "adenylyl cyclase" ], "offsets": [ [ 718, 734 ] ], "normalized": [] }, { "id": "44", "type": "GENE-Y", "text": [ "adenylyl cyclase" ], "offsets": [ [ 761, 777 ] ], "normalized": [] } ]
[]
[]
[ { "id": "45", "type": "Regulator", "arg1_id": "31", "arg2_id": "33", "normalized": [] }, { "id": "46", "type": "Regulator", "arg1_id": "32", "arg2_id": "40", "normalized": [] }, { "id": "47", "type": "Regulator", "arg1_id": "41", "arg2_id": "40", "normalized": [] }, { "id": "48", "type": "Agonist", "arg1_id": "2", "arg2_id": "37", "normalized": [] }, { "id": "49", "type": "Agonist", "arg1_id": "2", "arg2_id": "39", "normalized": [] }, { "id": "50", "type": "Regulator", "arg1_id": "21", "arg2_id": "38", "normalized": [] }, { "id": "51", "type": "Regulator", "arg1_id": "42", "arg2_id": "38", "normalized": [] }, { "id": "52", "type": "Regulator", "arg1_id": "20", "arg2_id": "38", "normalized": [] }, { "id": "53", "type": "Agonist", "arg1_id": "22", "arg2_id": "38", "normalized": [] }, { "id": "54", "type": "Agonist", "arg1_id": "23", "arg2_id": "38", "normalized": [] }, { "id": "55", "type": "Upregulator", "arg1_id": "26", "arg2_id": "43", "normalized": [] }, { "id": "56", "type": "Upregulator", "arg1_id": "27", "arg2_id": "43", "normalized": [] }, { "id": "57", "type": "Upregulator", "arg1_id": "26", "arg2_id": "44", "normalized": [] }, { "id": "58", "type": "Upregulator", "arg1_id": "27", "arg2_id": "44", "normalized": [] }, { "id": "59", "type": "Antagonist", "arg1_id": "7", "arg2_id": "34", "normalized": [] }, { "id": "60", "type": "Antagonist", "arg1_id": "8", "arg2_id": "34", "normalized": [] }, { "id": "61", "type": "Regulator", "arg1_id": "6", "arg2_id": "34", "normalized": [] }, { "id": "62", "type": "Regulator", "arg1_id": "3", "arg2_id": "34", "normalized": [] }, { "id": "63", "type": "Regulator", "arg1_id": "18", "arg2_id": "36", "normalized": [] }, { "id": "64", "type": "Regulator", "arg1_id": "4", "arg2_id": "34", "normalized": [] } ]
65
23150485
[ { "id": "66", "type": "title and abstract", "text": [ "Induction of multidrug resistance transporter ABCG2 by prolactin in human breast cancer cells.\nThe multidrug transporter, breast cancer resistance protein, ABCG2, is up-regulated in certain chemoresistant cancer cells and in the mammary gland during lactation. We investigated the role of the lactogenic hormone prolactin (PRL) in the regulation of ABCG2. PRL dose-dependently induced ABCG2 expression in T-47D human breast cancer cells. This induction was significantly reduced by short-interfering RNA-mediated knockdown of Janus kinase 2 (JAK2). Knockdown or pharmacologic inhibition of the down-stream signal transducer and activator of transcription-5 (STAT5) also blunted the induction of ABCG2 by PRL, suggesting a role for the JAK2/STAT5 pathway in PRL-induced ABCG2 expression. Corroborating these findings, we observed PRL-stimulated STAT5 recruitment to a region containing a putative γ-interferon activation sequence (GAS) element at -434 base pairs upstream of the ABCG2 transcription start site. Introduction of a single mutation to the -434 GAS element significantly attenuated PRL-stimulated activity of a luciferase reporter driven by the ABCG2 gene promoter and 5'-flanking region containing the -434 GAS motif. In addition, this GAS element showed strong copy number dependency in its response to PRL treatment. Interestingly, inhibitors against the mitogen-activated protein kinase and phosphoinositide-3-kinase signaling pathways significantly decreased the induction of ABCG2 by PRL without altering STAT5 recruitment to the GAS element. We conclude that the JAK2/STAT5 pathway is required but not sufficient for the induction of ABCG2 by PRL." ], "offsets": [ [ 0, 1665 ] ] } ]
[ { "id": "67", "type": "CHEMICAL", "text": [ "phosphoinositide" ], "offsets": [ [ 1406, 1422 ] ], "normalized": [] }, { "id": "68", "type": "GENE-N", "text": [ "ABCG2 gene promoter" ], "offsets": [ [ 1156, 1175 ] ], "normalized": [] }, { "id": "69", "type": "GENE-N", "text": [ "-434 GAS motif" ], "offsets": [ [ 1214, 1228 ] ], "normalized": [] }, { "id": "70", "type": "GENE-N", "text": [ "GAS element" ], "offsets": [ [ 1248, 1259 ] ], "normalized": [] }, { "id": "71", "type": "GENE-Y", "text": [ "PRL" ], "offsets": [ [ 1316, 1319 ] ], "normalized": [] }, { "id": "72", "type": "GENE-N", "text": [ "mitogen-activated protein kinase" ], "offsets": [ [ 1369, 1401 ] ], "normalized": [] }, { "id": "73", "type": "GENE-N", "text": [ "phosphoinositide-3-kinase" ], "offsets": [ [ 1406, 1431 ] ], "normalized": [] }, { "id": "74", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 1492, 1497 ] ], "normalized": [] }, { "id": "75", "type": "GENE-Y", "text": [ "PRL" ], "offsets": [ [ 1501, 1504 ] ], "normalized": [] }, { "id": "76", "type": "GENE-Y", "text": [ "STAT5" ], "offsets": [ [ 1522, 1527 ] ], "normalized": [] }, { "id": "77", "type": "GENE-N", "text": [ "GAS element" ], "offsets": [ [ 1547, 1558 ] ], "normalized": [] }, { "id": "78", "type": "GENE-Y", "text": [ "JAK2" ], "offsets": [ [ 1581, 1585 ] ], "normalized": [] }, { "id": "79", "type": "GENE-Y", "text": [ "STAT5" ], "offsets": [ [ 1586, 1591 ] ], "normalized": [] }, { "id": "80", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 1652, 1657 ] ], "normalized": [] }, { "id": "81", "type": "GENE-Y", "text": [ "PRL" ], "offsets": [ [ 1661, 1664 ] ], "normalized": [] }, { "id": "82", "type": "GENE-N", "text": [ "lactogenic hormone" ], "offsets": [ [ 293, 311 ] ], "normalized": [] }, { "id": "83", "type": "GENE-Y", "text": [ "prolactin" ], "offsets": [ [ 312, 321 ] ], "normalized": [] }, { "id": "84", "type": "GENE-Y", "text": [ "PRL" ], "offsets": [ [ 323, 326 ] ], "normalized": [] }, { "id": "85", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 349, 354 ] ], "normalized": [] }, { "id": "86", "type": "GENE-Y", "text": [ "PRL" ], "offsets": [ [ 356, 359 ] ], "normalized": [] }, { "id": "87", "type": "GENE-Y", "text": [ "breast cancer resistance protein" ], "offsets": [ [ 122, 154 ] ], "normalized": [] }, { "id": "88", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 385, 390 ] ], "normalized": [] }, { "id": "89", "type": "GENE-N", "text": [ "multidrug transporter" ], "offsets": [ [ 99, 120 ] ], "normalized": [] }, { "id": "90", "type": "GENE-Y", "text": [ "Janus kinase 2" ], "offsets": [ [ 526, 540 ] ], "normalized": [] }, { "id": "91", "type": "GENE-Y", "text": [ "JAK2" ], "offsets": [ [ 542, 546 ] ], "normalized": [] }, { "id": "92", "type": "GENE-Y", "text": [ "signal transducer and activator of transcription-5" ], "offsets": [ [ 606, 656 ] ], "normalized": [] }, { "id": "93", "type": "GENE-Y", "text": [ "STAT5" ], "offsets": [ [ 658, 663 ] ], "normalized": [] }, { "id": "94", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 695, 700 ] ], "normalized": [] }, { "id": "95", "type": "GENE-Y", "text": [ "PRL" ], "offsets": [ [ 704, 707 ] ], "normalized": [] }, { "id": "96", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 156, 161 ] ], "normalized": [] }, { "id": "97", "type": "GENE-Y", "text": [ "JAK2" ], "offsets": [ [ 735, 739 ] ], "normalized": [] }, { "id": "98", "type": "GENE-Y", "text": [ "STAT5" ], "offsets": [ [ 740, 745 ] ], "normalized": [] }, { "id": "99", "type": "GENE-Y", "text": [ "PRL" ], "offsets": [ [ 757, 760 ] ], "normalized": [] }, { "id": "100", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 769, 774 ] ], "normalized": [] }, { "id": "101", "type": "GENE-Y", "text": [ "PRL" ], "offsets": [ [ 829, 832 ] ], "normalized": [] }, { "id": "102", "type": "GENE-Y", "text": [ "STAT5" ], "offsets": [ [ 844, 849 ] ], "normalized": [] }, { "id": "103", "type": "GENE-N", "text": [ "γ-interferon activation sequence (GAS) element" ], "offsets": [ [ 896, 942 ] ], "normalized": [] }, { "id": "104", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 978, 983 ] ], "normalized": [] }, { "id": "105", "type": "GENE-N", "text": [ "-434 GAS element" ], "offsets": [ [ 1051, 1067 ] ], "normalized": [] }, { "id": "106", "type": "GENE-Y", "text": [ "PRL" ], "offsets": [ [ 1093, 1096 ] ], "normalized": [] }, { "id": "107", "type": "GENE-N", "text": [ "multidrug resistance transporter" ], "offsets": [ [ 13, 45 ] ], "normalized": [] }, { "id": "108", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 46, 51 ] ], "normalized": [] } ]
[]
[]
[]
109
23155202
[ { "id": "110", "type": "title and abstract", "text": [ "Influence of coadministration of artemether and lumefantrine on selected plasma biochemical and erythrocyte oxidative stress indices in female Wistar rats.\nAmong the artemisinin-based combination therapy (ACT) regimens, artemisinin derivative, artemether in combination with lumefantrine (artemether-lumefantrine, AL) has achieved excellent results in the fight against malarial scourge. In this study, we evaluated the toxic potential of these drugs at the therapeutic doses in female Wistar rats. Animals were randomly divided into four groups: those administered 1% Tween 80 (control), those administered artemether (4 mg/kg body weight), those administered lumefantrine (24 mg/kg body weight), and those coadministered artemether (4 mg/kg body weight) and lumefantrine (24 mg/kg body weight). The drugs were orally administered twice daily for 3 days by gastric intubation after which selected plasma biochemical indices, and erythrocytes antioxidant defence and lipid peroxidation markers were evaluated. Coadministration of artemether and lumefantrine raised liver and renal function markers and increased atherogenic index. While reduced glutathione, glucose-6-phosphate dehydrogenase (G6PD) and catalase activities were reduced, glutathione peroxidase and glutathione-s-transferase activities increased in all the treated groups compared to the control group. The drugs caused significant (p < 0.05) elevation of malondialdehyde (MDA) levels compared to the control group. These results imply that coadministration of artemether and lumefantrine may increase the risks of atherosclerosis as well as liver and renal function impairments in the users. In addition, the drugs may also promote oxidative stress in the erythrocytes." ], "offsets": [ [ 0, 1735 ] ] } ]
[ { "id": "111", "type": "CHEMICAL", "text": [ "glucose-6-phosphate" ], "offsets": [ [ 1158, 1177 ] ], "normalized": [] }, { "id": "112", "type": "CHEMICAL", "text": [ "artemisinin" ], "offsets": [ [ 166, 177 ] ], "normalized": [] }, { "id": "113", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 1237, 1248 ] ], "normalized": [] }, { "id": "114", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 1264, 1275 ] ], "normalized": [] }, { "id": "115", "type": "CHEMICAL", "text": [ "lumefantrine" ], "offsets": [ [ 275, 287 ] ], "normalized": [] }, { "id": "116", "type": "CHEMICAL", "text": [ "malondialdehyde" ], "offsets": [ [ 1421, 1436 ] ], "normalized": [] }, { "id": "117", "type": "CHEMICAL", "text": [ "MDA" ], "offsets": [ [ 1438, 1441 ] ], "normalized": [] }, { "id": "118", "type": "CHEMICAL", "text": [ "artemether" ], "offsets": [ [ 289, 299 ] ], "normalized": [] }, { "id": "119", "type": "CHEMICAL", "text": [ "artemether" ], "offsets": [ [ 1526, 1536 ] ], "normalized": [] }, { "id": "120", "type": "CHEMICAL", "text": [ "lumefantrine" ], "offsets": [ [ 1541, 1553 ] ], "normalized": [] }, { "id": "121", "type": "CHEMICAL", "text": [ "lumefantrine" ], "offsets": [ [ 300, 312 ] ], "normalized": [] }, { "id": "122", "type": "CHEMICAL", "text": [ "Tween 80" ], "offsets": [ [ 569, 577 ] ], "normalized": [] }, { "id": "123", "type": "CHEMICAL", "text": [ "artemether" ], "offsets": [ [ 608, 618 ] ], "normalized": [] }, { "id": "124", "type": "CHEMICAL", "text": [ "lumefantrine" ], "offsets": [ [ 661, 673 ] ], "normalized": [] }, { "id": "125", "type": "CHEMICAL", "text": [ "artemether" ], "offsets": [ [ 723, 733 ] ], "normalized": [] }, { "id": "126", "type": "CHEMICAL", "text": [ "lumefantrine" ], "offsets": [ [ 760, 772 ] ], "normalized": [] }, { "id": "127", "type": "CHEMICAL", "text": [ "artemisinin" ], "offsets": [ [ 220, 231 ] ], "normalized": [] }, { "id": "128", "type": "CHEMICAL", "text": [ "artemether" ], "offsets": [ [ 1030, 1040 ] ], "normalized": [] }, { "id": "129", "type": "CHEMICAL", "text": [ "artemether" ], "offsets": [ [ 244, 254 ] ], "normalized": [] }, { "id": "130", "type": "CHEMICAL", "text": [ "lumefantrine" ], "offsets": [ [ 1045, 1057 ] ], "normalized": [] }, { "id": "131", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 1145, 1156 ] ], "normalized": [] }, { "id": "132", "type": "CHEMICAL", "text": [ "artemether" ], "offsets": [ [ 33, 43 ] ], "normalized": [] }, { "id": "133", "type": "CHEMICAL", "text": [ "lumefantrine" ], "offsets": [ [ 48, 60 ] ], "normalized": [] }, { "id": "134", "type": "GENE-N", "text": [ "glucose-6-phosphate dehydrogenase" ], "offsets": [ [ 1158, 1191 ] ], "normalized": [] }, { "id": "135", "type": "GENE-N", "text": [ "G6PD" ], "offsets": [ [ 1193, 1197 ] ], "normalized": [] }, { "id": "136", "type": "GENE-N", "text": [ "glutathione peroxidase" ], "offsets": [ [ 1237, 1259 ] ], "normalized": [] }, { "id": "137", "type": "GENE-N", "text": [ "glutathione-s-transferase" ], "offsets": [ [ 1264, 1289 ] ], "normalized": [] } ]
[]
[]
[]
138
23477624
[ { "id": "139", "type": "title and abstract", "text": [ "Safety and efficacy of polycalcium for improving biomarkers of bone metabolism: a 4-week open-label clinical study.\nPolycalcium is a mixture of Polycan and calcium lactate-gluconate 1:9 (w/w) with demonstrated antiosteoporosis activity in vitro and in vivo studies. These studies were a 4-week open-label, single-center trial to evaluate the efficacy of oral Polycalcium on bone metabolism and safety. In total, 30 healthy women (range 40-60 years) were administered 400 mg of Polycalcium for 4 weeks. The primary efficacy parameter was urinary deoxypyridinoline (DPYR) levels, and serum osteocalcin (OSC), bone-specific alkaline phosphatase (BALP), urinary cross-linked C-telopeptide of type-1 collagen (CTx), urinary cross-linked N-telopeptide of type-1 collagen (NTx), calcium (Ca), and phosphorus (P) levels, which were evaluated for comparison before and after administration of Polycalcium. After 4 weeks of Polycalcium administration, 27 subjects completed the test plan. Three subjects withdrew their consent to participate. The values of blood OSC, BALP, serum Ca, and serum P from baseline to 4 weeks of treatment were changed by -28.44%, 14.37%, 6.11%, and 1.42%, respectively. Biomarkers of bone resorption: urinary DPYR, serum CTx, serum NTx, urinary Ca, and urinary P, at baseline after 4 weeks of treatment were changed by -13.40%, 6.67%, -5.13%, -22.43%, and -3.04%, respectively. Additionally, when considering the subjects' adverse effects and the results of the blood and urine tests over the 4-week trial period, the dose of 400  mg Polycalcium showed efficacy for improving bone metabolism and was well tolerated and safe. Polycalcium was apparently safe and efficacious." ], "offsets": [ [ 0, 1692 ] ] } ]
[ { "id": "140", "type": "CHEMICAL", "text": [ "Polycalcium" ], "offsets": [ [ 116, 127 ] ], "normalized": [] }, { "id": "141", "type": "CHEMICAL", "text": [ "DPYR" ], "offsets": [ [ 1228, 1232 ] ], "normalized": [] }, { "id": "142", "type": "CHEMICAL", "text": [ "Ca" ], "offsets": [ [ 1264, 1266 ] ], "normalized": [] }, { "id": "143", "type": "CHEMICAL", "text": [ "P" ], "offsets": [ [ 1280, 1281 ] ], "normalized": [] }, { "id": "144", "type": "CHEMICAL", "text": [ "Polycalcium" ], "offsets": [ [ 1553, 1564 ] ], "normalized": [] }, { "id": "145", "type": "CHEMICAL", "text": [ "Polycalcium" ], "offsets": [ [ 1644, 1655 ] ], "normalized": [] }, { "id": "146", "type": "CHEMICAL", "text": [ "Polycalcium" ], "offsets": [ [ 359, 370 ] ], "normalized": [] }, { "id": "147", "type": "CHEMICAL", "text": [ "Polycalcium" ], "offsets": [ [ 477, 488 ] ], "normalized": [] }, { "id": "148", "type": "CHEMICAL", "text": [ "calcium lactate-gluconate" ], "offsets": [ [ 156, 181 ] ], "normalized": [] }, { "id": "149", "type": "CHEMICAL", "text": [ "deoxypyridinoline" ], "offsets": [ [ 545, 562 ] ], "normalized": [] }, { "id": "150", "type": "CHEMICAL", "text": [ "DPYR" ], "offsets": [ [ 564, 568 ] ], "normalized": [] }, { "id": "151", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 671, 672 ] ], "normalized": [] }, { "id": "152", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 732, 733 ] ], "normalized": [] }, { "id": "153", "type": "CHEMICAL", "text": [ "calcium" ], "offsets": [ [ 772, 779 ] ], "normalized": [] }, { "id": "154", "type": "CHEMICAL", "text": [ "Ca" ], "offsets": [ [ 781, 783 ] ], "normalized": [] }, { "id": "155", "type": "CHEMICAL", "text": [ "phosphorus" ], "offsets": [ [ 790, 800 ] ], "normalized": [] }, { "id": "156", "type": "CHEMICAL", "text": [ "P" ], "offsets": [ [ 802, 803 ] ], "normalized": [] }, { "id": "157", "type": "CHEMICAL", "text": [ "Polycalcium" ], "offsets": [ [ 884, 895 ] ], "normalized": [] }, { "id": "158", "type": "CHEMICAL", "text": [ "Polycalcium" ], "offsets": [ [ 914, 925 ] ], "normalized": [] }, { "id": "159", "type": "CHEMICAL", "text": [ "Ca" ], "offsets": [ [ 1070, 1072 ] ], "normalized": [] }, { "id": "160", "type": "CHEMICAL", "text": [ "P" ], "offsets": [ [ 1084, 1085 ] ], "normalized": [] }, { "id": "161", "type": "CHEMICAL", "text": [ "polycalcium" ], "offsets": [ [ 23, 34 ] ], "normalized": [] }, { "id": "162", "type": "GENE-N", "text": [ "CTx" ], "offsets": [ [ 1240, 1243 ] ], "normalized": [] }, { "id": "163", "type": "GENE-N", "text": [ "NTx" ], "offsets": [ [ 1251, 1254 ] ], "normalized": [] }, { "id": "164", "type": "GENE-Y", "text": [ "osteocalcin" ], "offsets": [ [ 588, 599 ] ], "normalized": [] }, { "id": "165", "type": "GENE-Y", "text": [ "OSC" ], "offsets": [ [ 601, 604 ] ], "normalized": [] }, { "id": "166", "type": "GENE-Y", "text": [ "bone-specific alkaline phosphatase" ], "offsets": [ [ 607, 641 ] ], "normalized": [] }, { "id": "167", "type": "GENE-Y", "text": [ "BALP" ], "offsets": [ [ 643, 647 ] ], "normalized": [] }, { "id": "168", "type": "GENE-N", "text": [ "C-telopeptide of type-1 collagen" ], "offsets": [ [ 671, 703 ] ], "normalized": [] }, { "id": "169", "type": "GENE-N", "text": [ "CTx" ], "offsets": [ [ 705, 708 ] ], "normalized": [] }, { "id": "170", "type": "GENE-N", "text": [ "N-telopeptide of type-1 collagen" ], "offsets": [ [ 732, 764 ] ], "normalized": [] }, { "id": "171", "type": "GENE-N", "text": [ "NTx" ], "offsets": [ [ 766, 769 ] ], "normalized": [] }, { "id": "172", "type": "GENE-Y", "text": [ "OSC" ], "offsets": [ [ 1053, 1056 ] ], "normalized": [] }, { "id": "173", "type": "GENE-Y", "text": [ "BALP" ], "offsets": [ [ 1058, 1062 ] ], "normalized": [] } ]
[]
[]
[]
174
23044094
[ { "id": "175", "type": "title and abstract", "text": [ "Establishment of an in vitro photoallergy test using NCTC2544 cells and IL-18 production.\nDifferentiation between photoallergenic and phototoxic reactions induced by low molecular weight compounds represents a current problem. The use of keratinocytes as a potential tool for the detection of photoallergens as opposed to photoirritants is considered an interesting strategy for developing in vitro methods. We have previously demonstrated the possibility to use the human keratinocyte cell line NCTC2455 and the production of interleukin-18 (IL-18) to screen low molecular weight sensitizers. The purpose of this work was to explore the possibility to use the NCTC2544 assay to identify photoallergens and discriminate from phototoxic chemicals. First, we identified suitable condition of UV-irradiation (3.5 J/cm(2)) by investigating the effect of UVA irradiation on intracellular IL-18 on untreated or chloropromazine (a representative phototoxic compound)-treated NCTC2544 cells. Then, the effect of UVA-irradiation over NCTC2544 cells treated with increasing concentrations of 15 compounds including photoallergens (benzophenone, 4-ter-butyl-4-methoxy-dibenzoylmethane, 2-ethylexyl-p-methoxycinnamate, ketoprofen, 6-methylcumarin); photoirritant and photoallergen (4-aminobenzoic acid, chlorpromazine, promethazine); photoirritants (acridine, ibuprofen, 8-methoxypsoralen, retinoic acid); and negative compounds (lactic acid, SDS and p-phenilendiamine) was investigated. Twenty-four hours after exposure, cytotoxicity was evaluated by the MTT assay or LDH leakage, while ELISA was used to measure the production of IL-18. At the maximal concentration assayed with non-cytotoxic effects (CV80 under irradiated condition), all tested photoallergens induced a significant and a dose-dependent increase of intracellular IL-18 following UVA irratiation, whereas photoirritants failed. We suggest that this system may be useful for the in vitro evaluation of the photoallergic potential of chemicals." ], "offsets": [ [ 0, 1999 ] ] } ]
[ { "id": "176", "type": "CHEMICAL", "text": [ "benzophenone" ], "offsets": [ [ 1121, 1133 ] ], "normalized": [] }, { "id": "177", "type": "CHEMICAL", "text": [ "4-ter-butyl-4-methoxy-dibenzoylmethane, 2-ethylexyl-p-methoxycinnamate" ], "offsets": [ [ 1135, 1205 ] ], "normalized": [] }, { "id": "178", "type": "CHEMICAL", "text": [ "ketoprofen" ], "offsets": [ [ 1207, 1217 ] ], "normalized": [] }, { "id": "179", "type": "CHEMICAL", "text": [ "6-methylcumarin" ], "offsets": [ [ 1219, 1234 ] ], "normalized": [] }, { "id": "180", "type": "CHEMICAL", "text": [ "4-aminobenzoic acid" ], "offsets": [ [ 1270, 1289 ] ], "normalized": [] }, { "id": "181", "type": "CHEMICAL", "text": [ "chlorpromazine" ], "offsets": [ [ 1291, 1305 ] ], "normalized": [] }, { "id": "182", "type": "CHEMICAL", "text": [ "promethazine" ], "offsets": [ [ 1307, 1319 ] ], "normalized": [] }, { "id": "183", "type": "CHEMICAL", "text": [ "acridine" ], "offsets": [ [ 1338, 1346 ] ], "normalized": [] }, { "id": "184", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 1348, 1357 ] ], "normalized": [] }, { "id": "185", "type": "CHEMICAL", "text": [ "8-methoxypsoralen" ], "offsets": [ [ 1359, 1376 ] ], "normalized": [] }, { "id": "186", "type": "CHEMICAL", "text": [ "retinoic acid" ], "offsets": [ [ 1378, 1391 ] ], "normalized": [] }, { "id": "187", "type": "CHEMICAL", "text": [ "lactic acid" ], "offsets": [ [ 1418, 1429 ] ], "normalized": [] }, { "id": "188", "type": "CHEMICAL", "text": [ "SDS" ], "offsets": [ [ 1431, 1434 ] ], "normalized": [] }, { "id": "189", "type": "CHEMICAL", "text": [ "p-phenilendiamine" ], "offsets": [ [ 1439, 1456 ] ], "normalized": [] }, { "id": "190", "type": "CHEMICAL", "text": [ "MTT" ], "offsets": [ [ 1544, 1547 ] ], "normalized": [] }, { "id": "191", "type": "CHEMICAL", "text": [ "chloropromazine" ], "offsets": [ [ 905, 920 ] ], "normalized": [] }, { "id": "192", "type": "GENE-N", "text": [ "LDH" ], "offsets": [ [ 1557, 1560 ] ], "normalized": [] }, { "id": "193", "type": "GENE-Y", "text": [ "IL-18" ], "offsets": [ [ 1620, 1625 ] ], "normalized": [] }, { "id": "194", "type": "GENE-Y", "text": [ "IL-18" ], "offsets": [ [ 1821, 1826 ] ], "normalized": [] }, { "id": "195", "type": "GENE-Y", "text": [ "interleukin-18" ], "offsets": [ [ 527, 541 ] ], "normalized": [] }, { "id": "196", "type": "GENE-Y", "text": [ "IL-18" ], "offsets": [ [ 543, 548 ] ], "normalized": [] }, { "id": "197", "type": "GENE-Y", "text": [ "IL-18" ], "offsets": [ [ 883, 888 ] ], "normalized": [] }, { "id": "198", "type": "GENE-Y", "text": [ "IL-18" ], "offsets": [ [ 72, 77 ] ], "normalized": [] } ]
[]
[]
[]
199
23220749
[ { "id": "200", "type": "title and abstract", "text": [ "Apomorphine is a bimodal modulator of TRPA1 channels.\nApomorphine is a non-narcotic derivative of morphine, which acts as a dopamine agonist and is clinically used to treat \"off-states\" in patients suffering from Parkinson's disease. Adverse effects of apomorphine treatment include severe emesis and nausea, and ulceration and pain at the injection site. We wanted to test whether sensory transient receptor potential (TRP) channels are a molecular target for apomorphine. Here, we show that rTRPV1, rTRPV2, rTRPV3, and mTRPV4, as well as hTRPM8, and rTRPM3, which are expressed in dorsal root ganglion neurons, are insensitive toward apomorphine treatment. This also applied to the cellular redox sensor hTRPM2. On the contrary, human TRPA1 could be concentration-dependently modulated by apomorphine. Whereas the addition of apomorphine in the low micromolar range produced an irreversible activation of the channel, application of higher concentrations caused a reversible voltage-dependent inhibition of heterologously expressed TRPA1 channels, resulting from a reduction of single-channel open times. In addition, we provide evidence that apomorphine also acts on endogenous TRPA1 in cultured dorsal root ganglion neurons from rats and in the enterochromaffin model cell line QGP-1, from which serotonin is released upon activation of TRPA1. Our study shows that human TRPA1 is a target for apomorphine, suggesting that an activation of TRPA1 might contribute to adverse side effects such as nausea and painful injections, which can occur during treatment with apomorphine." ], "offsets": [ [ 0, 1579 ] ] } ]
[ { "id": "201", "type": "CHEMICAL", "text": [ "Apomorphine" ], "offsets": [ [ 54, 65 ] ], "normalized": [] }, { "id": "202", "type": "CHEMICAL", "text": [ "apomorphine" ], "offsets": [ [ 1145, 1156 ] ], "normalized": [] }, { "id": "203", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 1300, 1309 ] ], "normalized": [] }, { "id": "204", "type": "CHEMICAL", "text": [ "apomorphine" ], "offsets": [ [ 1397, 1408 ] ], "normalized": [] }, { "id": "205", "type": "CHEMICAL", "text": [ "apomorphine" ], "offsets": [ [ 1567, 1578 ] ], "normalized": [] }, { "id": "206", "type": "CHEMICAL", "text": [ "apomorphine" ], "offsets": [ [ 253, 264 ] ], "normalized": [] }, { "id": "207", "type": "CHEMICAL", "text": [ "apomorphine" ], "offsets": [ [ 461, 472 ] ], "normalized": [] }, { "id": "208", "type": "CHEMICAL", "text": [ "morphine" ], "offsets": [ [ 98, 106 ] ], "normalized": [] }, { "id": "209", "type": "CHEMICAL", "text": [ "apomorphine" ], "offsets": [ [ 636, 647 ] ], "normalized": [] }, { "id": "210", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 124, 132 ] ], "normalized": [] }, { "id": "211", "type": "CHEMICAL", "text": [ "apomorphine" ], "offsets": [ [ 791, 802 ] ], "normalized": [] }, { "id": "212", "type": "CHEMICAL", "text": [ "apomorphine" ], "offsets": [ [ 828, 839 ] ], "normalized": [] }, { "id": "213", "type": "CHEMICAL", "text": [ "Apomorphine" ], "offsets": [ [ 0, 11 ] ], "normalized": [] }, { "id": "214", "type": "GENE-N", "text": [ "TRPA1" ], "offsets": [ [ 1181, 1186 ] ], "normalized": [] }, { "id": "215", "type": "GENE-Y", "text": [ "TRPA1" ], "offsets": [ [ 1341, 1346 ] ], "normalized": [] }, { "id": "216", "type": "GENE-Y", "text": [ "human TRPA1" ], "offsets": [ [ 1369, 1380 ] ], "normalized": [] }, { "id": "217", "type": "GENE-Y", "text": [ "TRPA1" ], "offsets": [ [ 1443, 1448 ] ], "normalized": [] }, { "id": "218", "type": "GENE-N", "text": [ "transient receptor potential (TRP) channels" ], "offsets": [ [ 390, 433 ] ], "normalized": [] }, { "id": "219", "type": "GENE-Y", "text": [ "rTRPV1" ], "offsets": [ [ 493, 499 ] ], "normalized": [] }, { "id": "220", "type": "GENE-Y", "text": [ "rTRPV2" ], "offsets": [ [ 501, 507 ] ], "normalized": [] }, { "id": "221", "type": "GENE-Y", "text": [ "rTRPV3" ], "offsets": [ [ 509, 515 ] ], "normalized": [] }, { "id": "222", "type": "GENE-Y", "text": [ "mTRPV4" ], "offsets": [ [ 521, 527 ] ], "normalized": [] }, { "id": "223", "type": "GENE-Y", "text": [ "hTRPM8" ], "offsets": [ [ 540, 546 ] ], "normalized": [] }, { "id": "224", "type": "GENE-Y", "text": [ "rTRPM3" ], "offsets": [ [ 552, 558 ] ], "normalized": [] }, { "id": "225", "type": "GENE-Y", "text": [ "hTRPM2" ], "offsets": [ [ 706, 712 ] ], "normalized": [] }, { "id": "226", "type": "GENE-Y", "text": [ "human TRPA1" ], "offsets": [ [ 731, 742 ] ], "normalized": [] }, { "id": "227", "type": "GENE-Y", "text": [ "TRPA1" ], "offsets": [ [ 1034, 1039 ] ], "normalized": [] }, { "id": "228", "type": "GENE-Y", "text": [ "TRPA1" ], "offsets": [ [ 38, 43 ] ], "normalized": [] } ]
[]
[]
[ { "id": "229", "type": "Regulator", "arg1_id": "213", "arg2_id": "228", "normalized": [] }, { "id": "230", "type": "Not", "arg1_id": "209", "arg2_id": "219", "normalized": [] }, { "id": "231", "type": "Not", "arg1_id": "209", "arg2_id": "220", "normalized": [] }, { "id": "232", "type": "Not", "arg1_id": "209", "arg2_id": "221", "normalized": [] }, { "id": "233", "type": "Not", "arg1_id": "209", "arg2_id": "222", "normalized": [] }, { "id": "234", "type": "Not", "arg1_id": "209", "arg2_id": "223", "normalized": [] }, { "id": "235", "type": "Not", "arg1_id": "209", "arg2_id": "224", "normalized": [] }, { "id": "236", "type": "Regulator", "arg1_id": "211", "arg2_id": "226", "normalized": [] }, { "id": "237", "type": "Downregulator", "arg1_id": "212", "arg2_id": "227", "normalized": [] }, { "id": "238", "type": "Regulator", "arg1_id": "202", "arg2_id": "214", "normalized": [] }, { "id": "239", "type": "Regulator", "arg1_id": "202", "arg2_id": "215", "normalized": [] }, { "id": "240", "type": "Upregulator", "arg1_id": "204", "arg2_id": "216", "normalized": [] }, { "id": "241", "type": "Upregulator", "arg1_id": "204", "arg2_id": "217", "normalized": [] }, { "id": "242", "type": "Upregulator", "arg1_id": "205", "arg2_id": "216", "normalized": [] }, { "id": "243", "type": "Upregulator", "arg1_id": "205", "arg2_id": "217", "normalized": [] }, { "id": "244", "type": "Upregulator", "arg1_id": "212", "arg2_id": "227", "normalized": [] } ]
245
9950599
[ { "id": "246", "type": "title and abstract", "text": [ "Oxidative stress induces differential gene expression in a human lens epithelial cell line.\nPURPOSE: To identify differentially expressed genes in a human lens epithelial cell line exposed to oxidative stress. METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR) differential display was used to evaluate differential gene expression in a human lens epithelial cell line (SRA 01-04) when cells were exposed for 3 hours to a single bolus of 200 microM hydrogen peroxide. Differentially expressed genes were identified through DNA sequencing and a nucleotide database search. Differential expression was confirmed by northern blot and RT-PCR analyses. RESULTS: Using 18 primer sets, 28 RT-PCR products were differentially expressed between control and hydrogen peroxide-treated cells. In stressed cells, mitochondrial transcripts nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 4 and cytochrome b were downregulated 4-fold. Of the cytoplasmic mRNAs, glutamine cyclotransferase decreased 10-fold, whereas cytokine-inducible nuclear protein, alternative splicing factor 2, and beta-hydroxyisobutyryl-coenzyme A hydrolase increased 2-, 4-, and 10-fold, respectively. Analysis of mitochondrial transcripts in a 24-hour time course showed that NADH dehydrogenase subunit 4 mRNA decreased by 2-fold as early as 1 hour after oxidative stress, whereas the rate of decrease was slower for cytochrome b, cytochrome oxidase III, and 16S rRNA. CONCLUSIONS: Oxidative stress induced specific expressed gene changes in hydrogen peroxide-treated lens cells, including genes involved in cellular respiration and mRNA and peptide processing. These early changes may reflect pathways involved in the defense, pathology, or both of the lens epithelium, which is exposed to oxidative stress throughout life." ], "offsets": [ [ 0, 1813 ] ] } ]
[ { "id": "247", "type": "CHEMICAL", "text": [ "beta-hydroxyisobutyryl" ], "offsets": [ [ 1101, 1123 ] ], "normalized": [] }, { "id": "248", "type": "CHEMICAL", "text": [ "coenzyme A" ], "offsets": [ [ 1124, 1134 ] ], "normalized": [] }, { "id": "249", "type": "CHEMICAL", "text": [ "NADH" ], "offsets": [ [ 1265, 1269 ] ], "normalized": [] }, { "id": "250", "type": "CHEMICAL", "text": [ "hydrogen peroxide" ], "offsets": [ [ 1531, 1548 ] ], "normalized": [] }, { "id": "251", "type": "CHEMICAL", "text": [ "hydrogen peroxide" ], "offsets": [ [ 464, 481 ] ], "normalized": [] }, { "id": "252", "type": "CHEMICAL", "text": [ "hydrogen peroxide" ], "offsets": [ [ 763, 780 ] ], "normalized": [] }, { "id": "253", "type": "CHEMICAL", "text": [ "nicotinamide adenine dinucleotide" ], "offsets": [ [ 841, 874 ] ], "normalized": [] }, { "id": "254", "type": "CHEMICAL", "text": [ "NADH" ], "offsets": [ [ 876, 880 ] ], "normalized": [] }, { "id": "255", "type": "CHEMICAL", "text": [ "glutamine" ], "offsets": [ [ 976, 985 ] ], "normalized": [] }, { "id": "256", "type": "GENE-Y", "text": [ "beta-hydroxyisobutyryl-coenzyme A hydrolase" ], "offsets": [ [ 1101, 1144 ] ], "normalized": [] }, { "id": "257", "type": "GENE-Y", "text": [ "NADH dehydrogenase subunit 4" ], "offsets": [ [ 1265, 1293 ] ], "normalized": [] }, { "id": "258", "type": "GENE-Y", "text": [ "cytochrome b" ], "offsets": [ [ 1406, 1418 ] ], "normalized": [] }, { "id": "259", "type": "GENE-Y", "text": [ "cytochrome oxidase III" ], "offsets": [ [ 1420, 1442 ] ], "normalized": [] }, { "id": "260", "type": "GENE-Y", "text": [ "nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 4" ], "offsets": [ [ 841, 905 ] ], "normalized": [] }, { "id": "261", "type": "GENE-Y", "text": [ "cytochrome b" ], "offsets": [ [ 910, 922 ] ], "normalized": [] }, { "id": "262", "type": "GENE-Y", "text": [ "glutamine cyclotransferase" ], "offsets": [ [ 976, 1002 ] ], "normalized": [] }, { "id": "263", "type": "GENE-Y", "text": [ "cytokine-inducible nuclear protein" ], "offsets": [ [ 1030, 1064 ] ], "normalized": [] }, { "id": "264", "type": "GENE-Y", "text": [ "alternative splicing factor 2" ], "offsets": [ [ 1066, 1095 ] ], "normalized": [] } ]
[]
[]
[]
265
23615073
[ { "id": "266", "type": "title and abstract", "text": [ "Vitamin C forestalls cigarette smoke induced NF-κB activation in alveolar epithelial cells.\nCigarette smoking causes cellular oxidative stress resulting in inflammatory diseases of lung wherein transcription factor NF-κB plays an important role. It is possible that vitamin C, an antioxidant, may prevent cigarette smoke (CS)-induced NF-κB activation that involves degradation of I-κBε and nuclear translocation of c-Rel/p50 in alveolar epithelial cells. Therefore, to examine the hypothesis, we verified the effect of vitamin C on CS-induced expression of NF-κB driven luciferase reporter and NF-κB binding at its target DNA by EMSA in alveolar epithelial A549 cells. We also examined the level of I-κBε and sub-cellular distribution of c-Rel by western blotting and immunofluorescence respectively in CSE-treated A549 cells with or without vitamin C pretreatment. We observed a significant reduction in CSE induced luciferase expression, NF-κB DNA binding, I-κBε degradation and c-Rel nuclear translocation in cells pretreated with vitamin C. To further validate the result, we examined sub-cellular distribution of c-Rel in lungs of CS-exposed guinea pigs treated or untreated with vitamin C. Result showed that vitamin C treatment resulted in markedly reduced c-Rel nuclear translocation. All these results demonstrate that vitamin C prevents CS(E)-induced NF-κB activation and thus it could be used for the prevention of CS-induced inflammatory diseases." ], "offsets": [ [ 0, 1459 ] ] } ]
[ { "id": "267", "type": "CHEMICAL", "text": [ "vitamin C" ], "offsets": [ [ 1185, 1194 ] ], "normalized": [] }, { "id": "268", "type": "CHEMICAL", "text": [ "vitamin C" ], "offsets": [ [ 1215, 1224 ] ], "normalized": [] }, { "id": "269", "type": "CHEMICAL", "text": [ "vitamin C" ], "offsets": [ [ 1328, 1337 ] ], "normalized": [] }, { "id": "270", "type": "CHEMICAL", "text": [ "vitamin C" ], "offsets": [ [ 266, 275 ] ], "normalized": [] }, { "id": "271", "type": "CHEMICAL", "text": [ "vitamin C" ], "offsets": [ [ 519, 528 ] ], "normalized": [] }, { "id": "272", "type": "CHEMICAL", "text": [ "vitamin C" ], "offsets": [ [ 842, 851 ] ], "normalized": [] }, { "id": "273", "type": "CHEMICAL", "text": [ "vitamin C" ], "offsets": [ [ 1034, 1043 ] ], "normalized": [] }, { "id": "274", "type": "CHEMICAL", "text": [ "Vitamin C" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "275", "type": "GENE-Y", "text": [ "c-Rel" ], "offsets": [ [ 1118, 1123 ] ], "normalized": [] }, { "id": "276", "type": "GENE-Y", "text": [ "c-Rel" ], "offsets": [ [ 1264, 1269 ] ], "normalized": [] }, { "id": "277", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 215, 220 ] ], "normalized": [] }, { "id": "278", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 1361, 1366 ] ], "normalized": [] }, { "id": "279", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 334, 339 ] ], "normalized": [] }, { "id": "280", "type": "GENE-Y", "text": [ "I-κBε" ], "offsets": [ [ 380, 385 ] ], "normalized": [] }, { "id": "281", "type": "GENE-Y", "text": [ "c-Rel" ], "offsets": [ [ 415, 420 ] ], "normalized": [] }, { "id": "282", "type": "GENE-Y", "text": [ "p50" ], "offsets": [ [ 421, 424 ] ], "normalized": [] }, { "id": "283", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 557, 562 ] ], "normalized": [] }, { "id": "284", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 594, 599 ] ], "normalized": [] }, { "id": "285", "type": "GENE-Y", "text": [ "I-κBε" ], "offsets": [ [ 699, 704 ] ], "normalized": [] }, { "id": "286", "type": "GENE-Y", "text": [ "c-Rel" ], "offsets": [ [ 738, 743 ] ], "normalized": [] }, { "id": "287", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 940, 945 ] ], "normalized": [] }, { "id": "288", "type": "GENE-Y", "text": [ "I-κBε" ], "offsets": [ [ 959, 964 ] ], "normalized": [] }, { "id": "289", "type": "GENE-Y", "text": [ "c-Rel" ], "offsets": [ [ 981, 986 ] ], "normalized": [] }, { "id": "290", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 45, 50 ] ], "normalized": [] } ]
[]
[]
[ { "id": "291", "type": "Downregulator", "arg1_id": "274", "arg2_id": "290", "normalized": [] }, { "id": "292", "type": "Downregulator", "arg1_id": "270", "arg2_id": "279", "normalized": [] }, { "id": "293", "type": "Downregulator", "arg1_id": "270", "arg2_id": "280", "normalized": [] }, { "id": "294", "type": "Regulator", "arg1_id": "270", "arg2_id": "281", "normalized": [] }, { "id": "295", "type": "Regulator", "arg1_id": "270", "arg2_id": "282", "normalized": [] }, { "id": "296", "type": "Downregulator", "arg1_id": "273", "arg2_id": "287", "normalized": [] }, { "id": "297", "type": "Downregulator", "arg1_id": "273", "arg2_id": "288", "normalized": [] }, { "id": "298", "type": "Regulator", "arg1_id": "273", "arg2_id": "289", "normalized": [] }, { "id": "299", "type": "Downregulator", "arg1_id": "268", "arg2_id": "276", "normalized": [] }, { "id": "300", "type": "Downregulator", "arg1_id": "269", "arg2_id": "278", "normalized": [] } ]
301
23147415
[ { "id": "302", "type": "title and abstract", "text": [ "Mice heterozygous for AChE are more sensitive to AChE inhibitors but do not respond to BuChE inhibition.\nAn impaired central cholinergic system is at least partly involved in Alzheimer's disease (AD) pathogenesis, with cholinergic markers such as acetylcholinesterase (AChE) activity and protein levels decreasing as cognitive decline progresses. AD patients receive AChE inhibitor drugs to enhance cholinergic responses in the brain. The present study characterises the cholinergic system of mice heterozygous for AChE (HZ) as a suitable in vivo model for permanently reduced AChE activity. In comparison to homozygous, wild type (WT) mice, HZ mice show a 40% reduction of AChE activity in the brain, while their hippocampal ACh levels are increased by 56% as measured by microdialysis; choline acetyltransferase levels remain unaltered, and choline uptake increases 2-fold. We demonstrate that HZ mice are significantly more sensitive to local AChE inhibition (BW284c51), but remain insensitive to butyrylcholinesterase (BuChE) inhibition (bambuterol). HZ mice are also more sensitive to the peripheral application of the selective AChE inhibitor donepezil or the mixed inhibitor physostigmine; extracellular ACh levels rise significantly after administration of both drugs; also glucose levels are moderately increased indicating potentially non-cholinergic effects of donepezil. Behavioural tests show comparable cognitive function in both mouse strains. Our results are discussed in relation to the use of AChE/BuChE inhibitors in AD patients." ], "offsets": [ [ 0, 1548 ] ] } ]
[ { "id": "303", "type": "CHEMICAL", "text": [ "donepezil" ], "offsets": [ [ 1149, 1158 ] ], "normalized": [] }, { "id": "304", "type": "CHEMICAL", "text": [ "physostigmine" ], "offsets": [ [ 1182, 1195 ] ], "normalized": [] }, { "id": "305", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 1282, 1289 ] ], "normalized": [] }, { "id": "306", "type": "CHEMICAL", "text": [ "donepezil" ], "offsets": [ [ 1372, 1381 ] ], "normalized": [] }, { "id": "307", "type": "CHEMICAL", "text": [ "choline" ], "offsets": [ [ 788, 795 ] ], "normalized": [] }, { "id": "308", "type": "CHEMICAL", "text": [ "choline" ], "offsets": [ [ 843, 850 ] ], "normalized": [] }, { "id": "309", "type": "CHEMICAL", "text": [ "BW284c51" ], "offsets": [ [ 963, 971 ] ], "normalized": [] }, { "id": "310", "type": "CHEMICAL", "text": [ "bambuterol" ], "offsets": [ [ 1042, 1052 ] ], "normalized": [] }, { "id": "311", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 1134, 1138 ] ], "normalized": [] }, { "id": "312", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 1511, 1515 ] ], "normalized": [] }, { "id": "313", "type": "GENE-Y", "text": [ "BuChE" ], "offsets": [ [ 1516, 1521 ] ], "normalized": [] }, { "id": "314", "type": "GENE-N", "text": [ "acetylcholinesterase" ], "offsets": [ [ 247, 267 ] ], "normalized": [] }, { "id": "315", "type": "GENE-N", "text": [ "AChE" ], "offsets": [ [ 269, 273 ] ], "normalized": [] }, { "id": "316", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 367, 371 ] ], "normalized": [] }, { "id": "317", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 515, 519 ] ], "normalized": [] }, { "id": "318", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 577, 581 ] ], "normalized": [] }, { "id": "319", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 674, 678 ] ], "normalized": [] }, { "id": "320", "type": "GENE-N", "text": [ "choline acetyltransferase" ], "offsets": [ [ 788, 813 ] ], "normalized": [] }, { "id": "321", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 946, 950 ] ], "normalized": [] }, { "id": "322", "type": "GENE-Y", "text": [ "butyrylcholinesterase" ], "offsets": [ [ 1000, 1021 ] ], "normalized": [] }, { "id": "323", "type": "GENE-Y", "text": [ "BuChE" ], "offsets": [ [ 1023, 1028 ] ], "normalized": [] }, { "id": "324", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 22, 26 ] ], "normalized": [] }, { "id": "325", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 49, 53 ] ], "normalized": [] }, { "id": "326", "type": "GENE-Y", "text": [ "BuChE" ], "offsets": [ [ 87, 92 ] ], "normalized": [] }, { "id": "327", "type": "CHEMICAL", "text": [ "ACh" ], "offsets": [ [ 1211, 1214 ] ], "normalized": [] } ]
[]
[]
[ { "id": "328", "type": "Substrate", "arg1_id": "308", "arg2_id": "320", "normalized": [] }, { "id": "329", "type": "Downregulator", "arg1_id": "309", "arg2_id": "321", "normalized": [] }, { "id": "330", "type": "Downregulator", "arg1_id": "310", "arg2_id": "322", "normalized": [] }, { "id": "331", "type": "Downregulator", "arg1_id": "310", "arg2_id": "323", "normalized": [] }, { "id": "332", "type": "Downregulator", "arg1_id": "303", "arg2_id": "311", "normalized": [] }, { "id": "333", "type": "Downregulator", "arg1_id": "306", "arg2_id": "311", "normalized": [] }, { "id": "334", "type": "Downregulator", "arg1_id": "304", "arg2_id": "311", "normalized": [] }, { "id": "335", "type": "Substrate", "arg1_id": "327", "arg2_id": "311", "normalized": [] } ]
336
23643664
[ { "id": "337", "type": "title and abstract", "text": [ "Sustained resistance to acute MPTP toxicity by hypothalamic dopamine neurons following chronic neurotoxicant exposure is associated with sustained up-regulation of parkin protein.\nHypothalamic tuberoinfundibular dopamine (TIDA) neurons remain unaffected in Parkinson disease (PD) while there is significant degeneration of midbrain nigrostriatal dopamine (NSDA) neurons. A similar pattern of susceptibility is observed following acute exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and the resistance of TIDA neurons to MPTP is associated with increased expression of parkin and ubiquitin carboxy-terminal hydrolase L-1 (UCHL- 1). In the present study, the response of TIDA and NSDA neurons to acute MPTP administration following chronic MPTP exposure was examined. Mice were treated with ten injections of either MPTP (20 mg/kg; s.c.; every 3.5 days) or saline vehicle (10 ml/kg; s.c.; every 3.5 days). Following a 21 day recovery period, chronic saline- and MPTP-treated mice received an additional injection of either saline (10 ml/kg; s.c.) or MPTP (20 mg/kg; s.c.) and were sacrificed 24 h later. NSDA neurons displayed significant axon terminal degeneration (as indexed by decreases in DA, tyrosine hydroxylase (TH) and DA transporter concentrations in the striatum) as well as loss of TH-immunoreactive (IR) neurons in the substantia nigra (SN) following MPTP, whereas TIDA neurons revealed no overt axon terminal pathology or loss of TH-IR cell bodies. NSDA neuronal pathology was associated with transient decreases in concentrations of parkin and UCHL-1 protein in the SN, which returned to normal levels by 21 days following cessation of chronic neurotoxicant exposure. Resistance of TIDA neurons to MPTP toxicity was correlated with a transient increase in UCHL-1 and a sustained elevation in parkin in the arcuate nucleus. TIDA neurons represent a DA neuron population with a unique and inherent ability to adapt to acute and chronic toxicant administration with a sustained elevation of the neuroprotective protein parkin. The correlation between the ability to increase parkin and UCHL-1 expression and the resistance of DA neurons to neurotoxicant exposure is consistent with a functional link between these features and an underlying differential susceptibility to toxicant-associated neurodegeneration." ], "offsets": [ [ 0, 2356 ] ] } ]
[ { "id": "338", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 1232, 1240 ] ], "normalized": [] }, { "id": "339", "type": "CHEMICAL", "text": [ "MPTP" ], "offsets": [ [ 1398, 1402 ] ], "normalized": [] }, { "id": "340", "type": "CHEMICAL", "text": [ "MPTP" ], "offsets": [ [ 1747, 1751 ] ], "normalized": [] }, { "id": "341", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 346, 354 ] ], "normalized": [] }, { "id": "342", "type": "CHEMICAL", "text": [ "1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine" ], "offsets": [ [ 465, 509 ] ], "normalized": [] }, { "id": "343", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 212, 220 ] ], "normalized": [] }, { "id": "344", "type": "CHEMICAL", "text": [ "MPTP" ], "offsets": [ [ 511, 515 ] ], "normalized": [] }, { "id": "345", "type": "CHEMICAL", "text": [ "MPTP" ], "offsets": [ [ 556, 560 ] ], "normalized": [] }, { "id": "346", "type": "CHEMICAL", "text": [ "carboxy" ], "offsets": [ [ 625, 632 ] ], "normalized": [] }, { "id": "347", "type": "CHEMICAL", "text": [ "MPTP" ], "offsets": [ [ 736, 740 ] ], "normalized": [] }, { "id": "348", "type": "CHEMICAL", "text": [ "MPTP" ], "offsets": [ [ 774, 778 ] ], "normalized": [] }, { "id": "349", "type": "CHEMICAL", "text": [ "MPTP" ], "offsets": [ [ 850, 854 ] ], "normalized": [] }, { "id": "350", "type": "CHEMICAL", "text": [ "MPTP" ], "offsets": [ [ 996, 1000 ] ], "normalized": [] }, { "id": "351", "type": "CHEMICAL", "text": [ "MPTP" ], "offsets": [ [ 1084, 1088 ] ], "normalized": [] }, { "id": "352", "type": "CHEMICAL", "text": [ "MPTP" ], "offsets": [ [ 30, 34 ] ], "normalized": [] }, { "id": "353", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 60, 68 ] ], "normalized": [] }, { "id": "354", "type": "GENE-Y", "text": [ "tyrosine hydroxylase" ], "offsets": [ [ 1232, 1252 ] ], "normalized": [] }, { "id": "355", "type": "GENE-Y", "text": [ "TH" ], "offsets": [ [ 1254, 1256 ] ], "normalized": [] }, { "id": "356", "type": "GENE-Y", "text": [ "DA transporter" ], "offsets": [ [ 1262, 1276 ] ], "normalized": [] }, { "id": "357", "type": "GENE-Y", "text": [ "TH" ], "offsets": [ [ 1328, 1330 ] ], "normalized": [] }, { "id": "358", "type": "GENE-Y", "text": [ "TH" ], "offsets": [ [ 1478, 1480 ] ], "normalized": [] }, { "id": "359", "type": "GENE-Y", "text": [ "parkin" ], "offsets": [ [ 1582, 1588 ] ], "normalized": [] }, { "id": "360", "type": "GENE-Y", "text": [ "UCHL-1" ], "offsets": [ [ 1593, 1599 ] ], "normalized": [] }, { "id": "361", "type": "GENE-Y", "text": [ "UCHL-1" ], "offsets": [ [ 1805, 1811 ] ], "normalized": [] }, { "id": "362", "type": "GENE-Y", "text": [ "parkin" ], "offsets": [ [ 1841, 1847 ] ], "normalized": [] }, { "id": "363", "type": "GENE-Y", "text": [ "parkin" ], "offsets": [ [ 2065, 2071 ] ], "normalized": [] }, { "id": "364", "type": "GENE-Y", "text": [ "parkin" ], "offsets": [ [ 2121, 2127 ] ], "normalized": [] }, { "id": "365", "type": "GENE-Y", "text": [ "UCHL-1" ], "offsets": [ [ 2132, 2138 ] ], "normalized": [] }, { "id": "366", "type": "GENE-Y", "text": [ "parkin" ], "offsets": [ [ 604, 610 ] ], "normalized": [] }, { "id": "367", "type": "GENE-Y", "text": [ "ubiquitin carboxy-terminal hydrolase L-1" ], "offsets": [ [ 615, 655 ] ], "normalized": [] }, { "id": "368", "type": "GENE-Y", "text": [ "UCHL- 1" ], "offsets": [ [ 657, 664 ] ], "normalized": [] }, { "id": "369", "type": "GENE-Y", "text": [ "parkin" ], "offsets": [ [ 164, 170 ] ], "normalized": [] } ]
[]
[]
[ { "id": "370", "type": "Upregulator", "arg1_id": "352", "arg2_id": "369", "normalized": [] }, { "id": "371", "type": "Upregulator", "arg1_id": "342", "arg2_id": "366", "normalized": [] }, { "id": "372", "type": "Upregulator", "arg1_id": "344", "arg2_id": "366", "normalized": [] }, { "id": "373", "type": "Upregulator", "arg1_id": "345", "arg2_id": "366", "normalized": [] }, { "id": "374", "type": "Upregulator", "arg1_id": "342", "arg2_id": "367", "normalized": [] }, { "id": "375", "type": "Upregulator", "arg1_id": "344", "arg2_id": "367", "normalized": [] }, { "id": "376", "type": "Upregulator", "arg1_id": "345", "arg2_id": "367", "normalized": [] }, { "id": "377", "type": "Upregulator", "arg1_id": "342", "arg2_id": "368", "normalized": [] }, { "id": "378", "type": "Upregulator", "arg1_id": "344", "arg2_id": "368", "normalized": [] }, { "id": "379", "type": "Upregulator", "arg1_id": "345", "arg2_id": "368", "normalized": [] }, { "id": "380", "type": "Downregulator", "arg1_id": "339", "arg2_id": "354", "normalized": [] }, { "id": "381", "type": "Downregulator", "arg1_id": "339", "arg2_id": "355", "normalized": [] }, { "id": "382", "type": "Downregulator", "arg1_id": "339", "arg2_id": "356", "normalized": [] }, { "id": "383", "type": "Downregulator", "arg1_id": "339", "arg2_id": "357", "normalized": [] }, { "id": "384", "type": "Upregulator", "arg1_id": "340", "arg2_id": "361", "normalized": [] }, { "id": "385", "type": "Upregulator", "arg1_id": "340", "arg2_id": "362", "normalized": [] }, { "id": "386", "type": "Not", "arg1_id": "339", "arg2_id": "358", "normalized": [] } ]
387
17124432
[ { "id": "388", "type": "title and abstract", "text": [ "Norepinephrine transporter gene (NET) polymorphism in patients with type 2 diabetes.\nBACKGROUND: Norepinephrine transporter (NET) is involved in the regulation of norepinephrine (NE) turnover and metabolism. Neuronal NE reuptake may be impaired in individuals with renal disease and/or hypertension due to dysfunction of the NE transporter. A silent G1287A nucleotide substitution in exon 9 of the NET gene was studied in human conditions involving hypertension. We investigated its effect in patients with type 2 diabetes. METHODS: The study involved 215 type 2 diabetes patients with nephropathy, 95 patients with diabetes duration > or =10 years, free of nephropathy, and 360 healthy subjects. All individuals were genotyped for the NET-8 gene polymorphism with the PCR-RFLP method. Genotype and allele frequencies were compared between the groups. NE was measured by high-performance liquid chromatography and electrochemical detection. RESULTS: We genotyped 310 patients and 360 controls for the NET gene polymorphism. Genotype distribution in both groups was in accordance with the Hardy-Weinberg equilibrium. There were no significant differences in the frequency of genotypes and alleles between patients and controls (p = 0.43). The frequencies were also similar for patients with nephropathy and those without. After dividing the patient group into hypertensive (n = 208) and normotensive (n = 102) subjects, there was a significant increase in the frequency of the AA genotype in patients with hypertension compared to normotensives (19 vs. 10%, p < 0.05). CONCLUSION: No association was found between G1287A polymorphism in the NET gene and diabetes. Our results suggest that this polymorphism has a possible role in increased susceptibility to hypertension in patients with type 2 diabetes." ], "offsets": [ [ 0, 1803 ] ] } ]
[ { "id": "389", "type": "CHEMICAL", "text": [ "Norepinephrine" ], "offsets": [ [ 97, 111 ] ], "normalized": [] }, { "id": "390", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 217, 219 ] ], "normalized": [] }, { "id": "391", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 325, 327 ] ], "normalized": [] }, { "id": "392", "type": "CHEMICAL", "text": [ "nucleotide" ], "offsets": [ [ 357, 367 ] ], "normalized": [] }, { "id": "393", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 852, 854 ] ], "normalized": [] }, { "id": "394", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 163, 177 ] ], "normalized": [] }, { "id": "395", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 179, 181 ] ], "normalized": [] }, { "id": "396", "type": "CHEMICAL", "text": [ "Norepinephrine" ], "offsets": [ [ 0, 14 ] ], "normalized": [] }, { "id": "397", "type": "GENE-Y", "text": [ "Norepinephrine transporter" ], "offsets": [ [ 97, 123 ] ], "normalized": [] }, { "id": "398", "type": "GENE-N", "text": [ "G1287A" ], "offsets": [ [ 1613, 1619 ] ], "normalized": [] }, { "id": "399", "type": "GENE-Y", "text": [ "NET" ], "offsets": [ [ 1640, 1643 ] ], "normalized": [] }, { "id": "400", "type": "GENE-Y", "text": [ "NE transporter" ], "offsets": [ [ 325, 339 ] ], "normalized": [] }, { "id": "401", "type": "GENE-N", "text": [ "G1287A" ], "offsets": [ [ 350, 356 ] ], "normalized": [] }, { "id": "402", "type": "GENE-Y", "text": [ "NET" ], "offsets": [ [ 398, 401 ] ], "normalized": [] }, { "id": "403", "type": "GENE-Y", "text": [ "NET" ], "offsets": [ [ 125, 128 ] ], "normalized": [] }, { "id": "404", "type": "GENE-N", "text": [ "NET-8" ], "offsets": [ [ 736, 741 ] ], "normalized": [] }, { "id": "405", "type": "GENE-Y", "text": [ "NET" ], "offsets": [ [ 1001, 1004 ] ], "normalized": [] }, { "id": "406", "type": "GENE-Y", "text": [ "Norepinephrine transporter" ], "offsets": [ [ 0, 26 ] ], "normalized": [] }, { "id": "407", "type": "GENE-Y", "text": [ "NET" ], "offsets": [ [ 33, 36 ] ], "normalized": [] } ]
[]
[]
[ { "id": "408", "type": "Substrate", "arg1_id": "394", "arg2_id": "397", "normalized": [] }, { "id": "409", "type": "Substrate", "arg1_id": "394", "arg2_id": "403", "normalized": [] }, { "id": "410", "type": "Substrate", "arg1_id": "395", "arg2_id": "403", "normalized": [] }, { "id": "411", "type": "Substrate", "arg1_id": "395", "arg2_id": "397", "normalized": [] }, { "id": "412", "type": "Substrate", "arg1_id": "390", "arg2_id": "400", "normalized": [] } ]
413
23562076
[ { "id": "414", "type": "title and abstract", "text": [ "Improved Insulin Sensitivity despite Increased Visceral Adiposity in Mice Deficient for the Immune Cell Transcription Factor T-bet.\nLow-grade inflammation in fat is associated with insulin resistance, although the mechanisms are unclear. We report that mice deficient in the immune cell transcription factor T-bet have lower energy expenditure and increased visceral fat compared with wild-type mice, yet paradoxically are more insulin sensitive. This striking phenotype, present in young T-bet(-/-) mice, persisted with high-fat diet and increasing host age and was associated with altered immune cell numbers and cytokine secretion specifically in visceral adipose tissue. However, the favorable metabolic phenotype observed in T-bet-deficient hosts was lost in T-bet(-/-) mice also lacking adaptive immunity (T-bet(-/-)xRag2(-/-)), demonstrating that T-bet expression in the adaptive rather than the innate immune system impacts host glucose homeostasis. Indeed, adoptive transfer of T-bet-deficient, but not wild-type, CD4(+) T cells to Rag2(-/-) mice improved insulin sensitivity. Our results reveal a role for T-bet in metabolic physiology and obesity-associated insulin resistance." ], "offsets": [ [ 0, 1188 ] ] } ]
[ { "id": "415", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 937, 944 ] ], "normalized": [] }, { "id": "416", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 1169, 1176 ] ], "normalized": [] }, { "id": "417", "type": "GENE-N", "text": [ "immune cell transcription factor" ], "offsets": [ [ 275, 307 ] ], "normalized": [] }, { "id": "418", "type": "GENE-Y", "text": [ "T-bet" ], "offsets": [ [ 308, 313 ] ], "normalized": [] }, { "id": "419", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 428, 435 ] ], "normalized": [] }, { "id": "420", "type": "GENE-Y", "text": [ "T-bet" ], "offsets": [ [ 489, 494 ] ], "normalized": [] }, { "id": "421", "type": "GENE-N", "text": [ "cytokine" ], "offsets": [ [ 615, 623 ] ], "normalized": [] }, { "id": "422", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 181, 188 ] ], "normalized": [] }, { "id": "423", "type": "GENE-Y", "text": [ "T-bet" ], "offsets": [ [ 730, 735 ] ], "normalized": [] }, { "id": "424", "type": "GENE-Y", "text": [ "T-bet" ], "offsets": [ [ 764, 769 ] ], "normalized": [] }, { "id": "425", "type": "GENE-Y", "text": [ "T-bet" ], "offsets": [ [ 812, 817 ] ], "normalized": [] }, { "id": "426", "type": "GENE-Y", "text": [ "Rag2" ], "offsets": [ [ 823, 827 ] ], "normalized": [] }, { "id": "427", "type": "GENE-Y", "text": [ "T-bet" ], "offsets": [ [ 854, 859 ] ], "normalized": [] }, { "id": "428", "type": "GENE-Y", "text": [ "T-bet" ], "offsets": [ [ 987, 992 ] ], "normalized": [] }, { "id": "429", "type": "GENE-Y", "text": [ "Rag2" ], "offsets": [ [ 1041, 1045 ] ], "normalized": [] }, { "id": "430", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 1065, 1072 ] ], "normalized": [] }, { "id": "431", "type": "GENE-Y", "text": [ "T-bet" ], "offsets": [ [ 1116, 1121 ] ], "normalized": [] }, { "id": "432", "type": "GENE-Y", "text": [ "T-bet" ], "offsets": [ [ 125, 130 ] ], "normalized": [] }, { "id": "433", "type": "GENE-N", "text": [ "Insulin" ], "offsets": [ [ 9, 16 ] ], "normalized": [] }, { "id": "434", "type": "GENE-N", "text": [ "Immune Cell Transcription Factor" ], "offsets": [ [ 92, 124 ] ], "normalized": [] } ]
[]
[]
[]
435
23639738
[ { "id": "436", "type": "title and abstract", "text": [ "Enzyme-responsive surface erosion of poly(ethylene carbonate) for controlled drug release.\nCholesterol esterase (CE) induced surface erosion of poly(ethylene carbonate) (PEC) and drug release from PEC under mild physiological environment was investigated. The degradation process was monitored by changes of mass and molecular weight (MW) and surface morphology of polymer films. During the whole period of degradation, MW of PEC was unchanged. Water uptake of the polymer was only 2.8 and 0.2% for PEC with the MW of 200 kDa (PEC200) and PEC with the MW of 41 kDa (PEC41), respectively. Degradation of less hydrophilic PEC41 with higher density was slower than that of PEC200. By this mechanism, CE-responsive drug in vitro release from PEC in situ forming depots (ISFD) was conducted successfully. As expected, less bovine serum albumin (BSA) was released from PEC41 compared with that of PEC200 in the same time period. In conclusion, this work enabled the in vitro drug release evaluation of existing PEC devices and implied a new candidate for the development of enzyme-responsive systems." ], "offsets": [ [ 0, 1094 ] ] } ]
[ { "id": "437", "type": "CHEMICAL", "text": [ "Cholesterol" ], "offsets": [ [ 91, 102 ] ], "normalized": [] }, { "id": "438", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 197, 200 ] ], "normalized": [] }, { "id": "439", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 426, 429 ] ], "normalized": [] }, { "id": "440", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 499, 502 ] ], "normalized": [] }, { "id": "441", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 527, 530 ] ], "normalized": [] }, { "id": "442", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 539, 542 ] ], "normalized": [] }, { "id": "443", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 566, 569 ] ], "normalized": [] }, { "id": "444", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 620, 623 ] ], "normalized": [] }, { "id": "445", "type": "CHEMICAL", "text": [ "poly(ethylene carbonate)" ], "offsets": [ [ 144, 168 ] ], "normalized": [] }, { "id": "446", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 670, 673 ] ], "normalized": [] }, { "id": "447", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 738, 741 ] ], "normalized": [] }, { "id": "448", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 863, 866 ] ], "normalized": [] }, { "id": "449", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 170, 173 ] ], "normalized": [] }, { "id": "450", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 891, 894 ] ], "normalized": [] }, { "id": "451", "type": "CHEMICAL", "text": [ "PEC" ], "offsets": [ [ 1005, 1008 ] ], "normalized": [] }, { "id": "452", "type": "CHEMICAL", "text": [ "poly(ethylene carbonate)" ], "offsets": [ [ 37, 61 ] ], "normalized": [] }, { "id": "453", "type": "GENE-Y", "text": [ "Cholesterol esterase" ], "offsets": [ [ 91, 111 ] ], "normalized": [] }, { "id": "454", "type": "GENE-Y", "text": [ "CE" ], "offsets": [ [ 113, 115 ] ], "normalized": [] }, { "id": "455", "type": "GENE-Y", "text": [ "CE" ], "offsets": [ [ 697, 699 ] ], "normalized": [] }, { "id": "456", "type": "GENE-Y", "text": [ "bovine serum albumin" ], "offsets": [ [ 818, 838 ] ], "normalized": [] }, { "id": "457", "type": "GENE-Y", "text": [ "BSA" ], "offsets": [ [ 840, 843 ] ], "normalized": [] } ]
[]
[]
[]
458
12477282
[ { "id": "459", "type": "title and abstract", "text": [ "Accumulation of glutathione disulfide mediates NF-kappaB activation during immune stimulation with CpG DNA.\nInnate immune cells recognize pathogens by detecting molecular patterns that are distinct from those of the host. One such pattern is unmethylated CpG dinucleotides, which are common in bacterial DNA but not in vertebrate genomes. Macrophages respond to such CpG motifs in bacterial DNA or synthetic oligodeoxynucleotides (ODN) by inducing NF-kappaB and secreting proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), but the mechanisms regulating this have been unclear. CpG ODN-stimulated cells produce reactive oxygen species (ROS) and have a decreased ratio of intracellular glutathione/glutathione disulfide (GSH/GSSG), indicating a shift to a more oxidized intracellular redox state. To determine whether this may play a role in mediating the CpG-induced macrophage activation, the GSH/GSSG redox state was manipulated in the murine macrophagelike cell line RAW264.7. Treatment of cells with BCNU to inhibit glutathione reductase (GR) enhanced the CpG-induced intracellular oxidation and decreased the GSH/GSSG, with increased activation of NF-kappaB and a doubling in the CpG-induced production of IL-6 and TNF-alpha. Experimental manipulation of the intracellular GSSG concentration during inhibition of cellular prooxidant production demonstrated that increased intracellular GSSG is a primary signal that is directly or indirectly required for CpG-induced NF-kappaB activation but is not in itself sufficient to trigger this in the absence of CpG ODN. These data suggest the existence of a second CpG-induced intracellular signal, independent of GSSG, mediating the activation of innate immunity by bacterial DNA." ], "offsets": [ [ 0, 1778 ] ] } ]
[ { "id": "460", "type": "CHEMICAL", "text": [ "GSH" ], "offsets": [ [ 1163, 1166 ] ], "normalized": [] }, { "id": "461", "type": "CHEMICAL", "text": [ "GSSG" ], "offsets": [ [ 1167, 1171 ] ], "normalized": [] }, { "id": "462", "type": "CHEMICAL", "text": [ "GSSG" ], "offsets": [ [ 1327, 1331 ] ], "normalized": [] }, { "id": "463", "type": "CHEMICAL", "text": [ "GSSG" ], "offsets": [ [ 1440, 1444 ] ], "normalized": [] }, { "id": "464", "type": "CHEMICAL", "text": [ "dinucleotides" ], "offsets": [ [ 259, 272 ] ], "normalized": [] }, { "id": "465", "type": "CHEMICAL", "text": [ "GSSG" ], "offsets": [ [ 1711, 1715 ] ], "normalized": [] }, { "id": "466", "type": "CHEMICAL", "text": [ "oxygen" ], "offsets": [ [ 669, 675 ] ], "normalized": [] }, { "id": "467", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 734, 745 ] ], "normalized": [] }, { "id": "468", "type": "CHEMICAL", "text": [ "glutathione disulfide" ], "offsets": [ [ 746, 767 ] ], "normalized": [] }, { "id": "469", "type": "CHEMICAL", "text": [ "GSH" ], "offsets": [ [ 769, 772 ] ], "normalized": [] }, { "id": "470", "type": "CHEMICAL", "text": [ "GSSG" ], "offsets": [ [ 773, 777 ] ], "normalized": [] }, { "id": "471", "type": "CHEMICAL", "text": [ "GSH" ], "offsets": [ [ 943, 946 ] ], "normalized": [] }, { "id": "472", "type": "CHEMICAL", "text": [ "GSSG" ], "offsets": [ [ 947, 951 ] ], "normalized": [] }, { "id": "473", "type": "CHEMICAL", "text": [ "BCNU" ], "offsets": [ [ 1053, 1057 ] ], "normalized": [] }, { "id": "474", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 1069, 1080 ] ], "normalized": [] }, { "id": "475", "type": "CHEMICAL", "text": [ "glutathione disulfide" ], "offsets": [ [ 16, 37 ] ], "normalized": [] }, { "id": "476", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 1202, 1211 ] ], "normalized": [] }, { "id": "477", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 1260, 1264 ] ], "normalized": [] }, { "id": "478", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 1269, 1278 ] ], "normalized": [] }, { "id": "479", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 1521, 1530 ] ], "normalized": [] }, { "id": "480", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 448, 457 ] ], "normalized": [] }, { "id": "481", "type": "GENE-N", "text": [ "cytokines" ], "offsets": [ [ 488, 497 ] ], "normalized": [] }, { "id": "482", "type": "GENE-Y", "text": [ "interleukin-6" ], "offsets": [ [ 507, 520 ] ], "normalized": [] }, { "id": "483", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 522, 526 ] ], "normalized": [] }, { "id": "484", "type": "GENE-Y", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 532, 559 ] ], "normalized": [] }, { "id": "485", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 561, 570 ] ], "normalized": [] }, { "id": "486", "type": "GENE-Y", "text": [ "glutathione reductase" ], "offsets": [ [ 1069, 1090 ] ], "normalized": [] }, { "id": "487", "type": "GENE-Y", "text": [ "GR" ], "offsets": [ [ 1092, 1094 ] ], "normalized": [] }, { "id": "488", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 47, 56 ] ], "normalized": [] } ]
[]
[]
[ { "id": "489", "type": "Upregulator", "arg1_id": "475", "arg2_id": "488", "normalized": [] }, { "id": "490", "type": "Downregulator", "arg1_id": "473", "arg2_id": "486", "normalized": [] }, { "id": "491", "type": "Downregulator", "arg1_id": "473", "arg2_id": "487", "normalized": [] }, { "id": "492", "type": "Upregulator", "arg1_id": "473", "arg2_id": "476", "normalized": [] }, { "id": "493", "type": "Upregulator", "arg1_id": "473", "arg2_id": "477", "normalized": [] }, { "id": "494", "type": "Upregulator", "arg1_id": "473", "arg2_id": "478", "normalized": [] }, { "id": "495", "type": "Upregulator", "arg1_id": "463", "arg2_id": "479", "normalized": [] }, { "id": "496", "type": "Upregulator", "arg1_id": "462", "arg2_id": "479", "normalized": [] }, { "id": "497", "type": "Downregulator", "arg1_id": "460", "arg2_id": "476", "normalized": [] }, { "id": "498", "type": "Downregulator", "arg1_id": "460", "arg2_id": "477", "normalized": [] }, { "id": "499", "type": "Downregulator", "arg1_id": "460", "arg2_id": "478", "normalized": [] }, { "id": "500", "type": "Upregulator", "arg1_id": "461", "arg2_id": "476", "normalized": [] }, { "id": "501", "type": "Upregulator", "arg1_id": "461", "arg2_id": "477", "normalized": [] }, { "id": "502", "type": "Upregulator", "arg1_id": "461", "arg2_id": "478", "normalized": [] } ]
503
23339966
[ { "id": "504", "type": "title and abstract", "text": [ "5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones as potential anticancer agents with anti-inflammatory properties.\nA series of novel 5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones (3a-z) have been evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells (GI(50)=850 nM), against leukemia SR cancer cells (GI(50)=1.45 μM), and OVCAR-3 (GI(50)=1.26 μM) ovarian cancer cell lines. The structurally related compound 3s had a GI(50) value of 1.77 μM against MDA-MB-435 cells. The N-naphthoyl analogue 3t had GI(50) values of 1.30 and 1.91 μM against HOP-92 non-small cell lung cancer and MDA-MB-435 melanoma cell lines, respectively. The related analogue 3w had GI(50) values of 1.09 μM against HOP-92 non-small cell lung cancer cell lines. Interestingly, docking of the two active molecules 3k and 3w into the active site of COX-2 indicates that these compounds are COX-2 ligands with strong hydrophobic and hydrogen bonding interactions. Thus, compounds 3k, 3t, 3s, and 3w constitute a new class of anticancer/anti-inflammatory agents that may have unique potential for cancer therapy." ], "offsets": [ [ 0, 1263 ] ] } ]
[ { "id": "505", "type": "CHEMICAL", "text": [ "5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones" ], "offsets": [ [ 165, 245 ] ], "normalized": [] }, { "id": "506", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 656, 657 ] ], "normalized": [] }, { "id": "507", "type": "CHEMICAL", "text": [ "naphthoyl" ], "offsets": [ [ 658, 667 ] ], "normalized": [] }, { "id": "508", "type": "CHEMICAL", "text": [ "hydrogen" ], "offsets": [ [ 1085, 1093 ] ], "normalized": [] }, { "id": "509", "type": "CHEMICAL", "text": [ "5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones" ], "offsets": [ [ 0, 80 ] ], "normalized": [] }, { "id": "510", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1002, 1007 ] ], "normalized": [] }, { "id": "511", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1043, 1048 ] ], "normalized": [] } ]
[]
[]
[]
512
10998082
[ { "id": "513", "type": "title and abstract", "text": [ "A 4-trifluoromethyl derivative of salicylate, triflusal, stimulates nitric oxide production by human neutrophils: role in platelet function.\nBACKGROUND: The thrombotic process is a multicellular phenomenon in which not only platelets but also neutrophils are involved. Recent in vitro studies performed in our laboratory have demonstrated that triflusal, a 4-trifluoromethyl derivative of salicylate, reduced platelet aggregation not only by inhibiting thromboxane A2 production but also by stimulating nitric oxide (NO) generation by neutrophils. The aim of the present study was to evaluate whether oral treatment of healthy volunteers with triflusal could modify the ability of their neutrophils to produce NO and to test the role of the NO released by neutrophils in the modulation of ADP-induced platelet aggregation and alpha-granule secretion. METHODS: The study was performed in 12 healthy volunteers who were orally treated with triflusal (600 mg day-1) for 5 days. Flow cytometric detection of platelet surface expression of P-selectin was used as a measure of the ability of platelets to release the contents of their alpha-granules. RESULTS: After treatment with triflusal, there was an increase in NO production by neutrophils and an increase in endothelial nitric oxide synthase (eNOS) protein expression in neutrophils. A potentiation of the inhibition of platelet aggregation by neutrophils was reversed by incubating neutrophils with both an L-arginine antagonist, NG-nitro-L-arginine methyl ester (L-NAME) and an NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline 1-oxyl 3-oxide (C-PTIO). A slight decrease in P-selectin surface expression on platelets was found which was not modified by the presence of neutrophils and therefore by the neutrophil-derived NO. Exogenous NO released by sodium nitroprusside dose-dependently inhibited both ADP-stimulated alpha-granule secretion and platelet aggregation. Therefore, platelet aggregation showed a greater sensitivity to be inhibited by exogenous NO than P-selectin expression. CONCLUSION: Oral treatment of healthy volunteers with triflusal stimulated NO production and eNOS protein expression in their neutrophils. After triflusal treatment, the neutrophils demonstrated a higher ability to prevent ADP-induced platelet aggregation. However, the neutrophils and the endogenous NO generated by them failed to modify P-selectin expression in ADP-activated platelets." ], "offsets": [ [ 0, 2445 ] ] } ]
[ { "id": "514", "type": "CHEMICAL", "text": [ "triflusal" ], "offsets": [ [ 1175, 1184 ] ], "normalized": [] }, { "id": "515", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 1211, 1213 ] ], "normalized": [] }, { "id": "516", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 1271, 1283 ] ], "normalized": [] }, { "id": "517", "type": "CHEMICAL", "text": [ "L-arginine" ], "offsets": [ [ 1459, 1469 ] ], "normalized": [] }, { "id": "518", "type": "CHEMICAL", "text": [ "NG-nitro-L-arginine methyl ester" ], "offsets": [ [ 1482, 1514 ] ], "normalized": [] }, { "id": "519", "type": "CHEMICAL", "text": [ "L-NAME" ], "offsets": [ [ 1516, 1522 ] ], "normalized": [] }, { "id": "520", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 1531, 1533 ] ], "normalized": [] }, { "id": "521", "type": "CHEMICAL", "text": [ "2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline 1-oxyl 3-oxide" ], "offsets": [ [ 1545, 1610 ] ], "normalized": [] }, { "id": "522", "type": "CHEMICAL", "text": [ "C-PTIO" ], "offsets": [ [ 1612, 1618 ] ], "normalized": [] }, { "id": "523", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 1789, 1791 ] ], "normalized": [] }, { "id": "524", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 1803, 1805 ] ], "normalized": [] }, { "id": "525", "type": "CHEMICAL", "text": [ "sodium nitroprusside" ], "offsets": [ [ 1818, 1838 ] ], "normalized": [] }, { "id": "526", "type": "CHEMICAL", "text": [ "ADP" ], "offsets": [ [ 1871, 1874 ] ], "normalized": [] }, { "id": "527", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 2026, 2028 ] ], "normalized": [] }, { "id": "528", "type": "CHEMICAL", "text": [ "triflusal" ], "offsets": [ [ 2111, 2120 ] ], "normalized": [] }, { "id": "529", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 2132, 2134 ] ], "normalized": [] }, { "id": "530", "type": "CHEMICAL", "text": [ "triflusal" ], "offsets": [ [ 344, 353 ] ], "normalized": [] }, { "id": "531", "type": "CHEMICAL", "text": [ "triflusal" ], "offsets": [ [ 2202, 2211 ] ], "normalized": [] }, { "id": "532", "type": "CHEMICAL", "text": [ "ADP" ], "offsets": [ [ 2280, 2283 ] ], "normalized": [] }, { "id": "533", "type": "CHEMICAL", "text": [ "4-trifluoromethyl" ], "offsets": [ [ 357, 374 ] ], "normalized": [] }, { "id": "534", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 2358, 2360 ] ], "normalized": [] }, { "id": "535", "type": "CHEMICAL", "text": [ "ADP" ], "offsets": [ [ 2421, 2424 ] ], "normalized": [] }, { "id": "536", "type": "CHEMICAL", "text": [ "salicylate" ], "offsets": [ [ 389, 399 ] ], "normalized": [] }, { "id": "537", "type": "CHEMICAL", "text": [ "thromboxane A2" ], "offsets": [ [ 453, 467 ] ], "normalized": [] }, { "id": "538", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 503, 515 ] ], "normalized": [] }, { "id": "539", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 517, 519 ] ], "normalized": [] }, { "id": "540", "type": "CHEMICAL", "text": [ "triflusal" ], "offsets": [ [ 643, 652 ] ], "normalized": [] }, { "id": "541", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 710, 712 ] ], "normalized": [] }, { "id": "542", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 741, 743 ] ], "normalized": [] }, { "id": "543", "type": "CHEMICAL", "text": [ "ADP" ], "offsets": [ [ 789, 792 ] ], "normalized": [] }, { "id": "544", "type": "CHEMICAL", "text": [ "triflusal" ], "offsets": [ [ 938, 947 ] ], "normalized": [] }, { "id": "545", "type": "CHEMICAL", "text": [ "4-trifluoromethyl" ], "offsets": [ [ 2, 19 ] ], "normalized": [] }, { "id": "546", "type": "CHEMICAL", "text": [ "salicylate" ], "offsets": [ [ 34, 44 ] ], "normalized": [] }, { "id": "547", "type": "CHEMICAL", "text": [ "triflusal" ], "offsets": [ [ 46, 55 ] ], "normalized": [] }, { "id": "548", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 68, 80 ] ], "normalized": [] }, { "id": "549", "type": "GENE-Y", "text": [ "endothelial nitric oxide synthase" ], "offsets": [ [ 1259, 1292 ] ], "normalized": [] }, { "id": "550", "type": "GENE-Y", "text": [ "eNOS" ], "offsets": [ [ 1294, 1298 ] ], "normalized": [] }, { "id": "551", "type": "GENE-Y", "text": [ "P-selectin" ], "offsets": [ [ 1642, 1652 ] ], "normalized": [] }, { "id": "552", "type": "GENE-Y", "text": [ "P-selectin" ], "offsets": [ [ 2034, 2044 ] ], "normalized": [] }, { "id": "553", "type": "GENE-Y", "text": [ "eNOS" ], "offsets": [ [ 2150, 2154 ] ], "normalized": [] }, { "id": "554", "type": "GENE-Y", "text": [ "P-selectin" ], "offsets": [ [ 2396, 2406 ] ], "normalized": [] }, { "id": "555", "type": "GENE-Y", "text": [ "P-selectin" ], "offsets": [ [ 1035, 1045 ] ], "normalized": [] } ]
[]
[]
[ { "id": "556", "type": "Upregulator", "arg1_id": "514", "arg2_id": "549", "normalized": [] }, { "id": "557", "type": "Upregulator", "arg1_id": "514", "arg2_id": "550", "normalized": [] }, { "id": "558", "type": "Not", "arg1_id": "523", "arg2_id": "551", "normalized": [] }, { "id": "559", "type": "Upregulator", "arg1_id": "528", "arg2_id": "553", "normalized": [] }, { "id": "560", "type": "Not", "arg1_id": "534", "arg2_id": "554", "normalized": [] } ]
561
12453616
[ { "id": "562", "type": "title and abstract", "text": [ "Methamphetamine increases the hippocampal alpha(2A)-adrenergic receptor and Galpha(o) in mice.\nThis study investigates the involvement of alpha(2)-adrenergic receptors (AR) in mouse brain induced by a low dose of methamphetamine (METH, 2 mg/kg). Immunohistochemical studies show that alpha(2A)-AR increased in the dentate gyrus area of the hippocampus 24 h after five repeated administrations of METH. The hippocampal alpha(2A)-AR proteins rose 3.2-fold when compared to the saline-administered mice. The other adrenergic receptor, alpha(1D)-AR, were not changed by the treatment. Moreover, alpha(o)-subunits of GTP-binding proteins (Galpha(o)), one of the downstream molecules of alpha(2A)-AR, was also increased by the treatment. These suggest that the repeated administration of low-doses of METH causes quantitative changes of the signaling of alpha(2A)-AR in the mouse hippocampus." ], "offsets": [ [ 0, 886 ] ] } ]
[ { "id": "563", "type": "CHEMICAL", "text": [ "methamphetamine" ], "offsets": [ [ 213, 228 ] ], "normalized": [] }, { "id": "564", "type": "CHEMICAL", "text": [ "METH" ], "offsets": [ [ 230, 234 ] ], "normalized": [] }, { "id": "565", "type": "CHEMICAL", "text": [ "METH" ], "offsets": [ [ 396, 400 ] ], "normalized": [] }, { "id": "566", "type": "CHEMICAL", "text": [ "GTP" ], "offsets": [ [ 612, 615 ] ], "normalized": [] }, { "id": "567", "type": "CHEMICAL", "text": [ "METH" ], "offsets": [ [ 795, 799 ] ], "normalized": [] }, { "id": "568", "type": "CHEMICAL", "text": [ "Methamphetamine" ], "offsets": [ [ 0, 15 ] ], "normalized": [] }, { "id": "569", "type": "GENE-Y", "text": [ "alpha(2A)-AR" ], "offsets": [ [ 284, 296 ] ], "normalized": [] }, { "id": "570", "type": "GENE-Y", "text": [ "alpha(2A)-AR" ], "offsets": [ [ 418, 430 ] ], "normalized": [] }, { "id": "571", "type": "GENE-N", "text": [ "adrenergic receptor" ], "offsets": [ [ 511, 530 ] ], "normalized": [] }, { "id": "572", "type": "GENE-N", "text": [ "alpha(2)-adrenergic receptors" ], "offsets": [ [ 138, 167 ] ], "normalized": [] }, { "id": "573", "type": "GENE-Y", "text": [ "alpha(1D)-AR" ], "offsets": [ [ 532, 544 ] ], "normalized": [] }, { "id": "574", "type": "GENE-Y", "text": [ "alpha(o)-subunits of GTP-binding proteins" ], "offsets": [ [ 591, 632 ] ], "normalized": [] }, { "id": "575", "type": "GENE-Y", "text": [ "Galpha(o)" ], "offsets": [ [ 634, 643 ] ], "normalized": [] }, { "id": "576", "type": "GENE-Y", "text": [ "alpha(2A)-AR" ], "offsets": [ [ 681, 693 ] ], "normalized": [] }, { "id": "577", "type": "GENE-N", "text": [ "AR" ], "offsets": [ [ 169, 171 ] ], "normalized": [] }, { "id": "578", "type": "GENE-Y", "text": [ "alpha(2A)-AR" ], "offsets": [ [ 848, 860 ] ], "normalized": [] }, { "id": "579", "type": "GENE-Y", "text": [ "alpha(2A)-adrenergic receptor" ], "offsets": [ [ 42, 71 ] ], "normalized": [] }, { "id": "580", "type": "GENE-Y", "text": [ "Galpha(o)" ], "offsets": [ [ 76, 85 ] ], "normalized": [] } ]
[]
[]
[ { "id": "581", "type": "Upregulator", "arg1_id": "568", "arg2_id": "579", "normalized": [] }, { "id": "582", "type": "Upregulator", "arg1_id": "568", "arg2_id": "580", "normalized": [] }, { "id": "583", "type": "Upregulator", "arg1_id": "563", "arg2_id": "572", "normalized": [] }, { "id": "584", "type": "Upregulator", "arg1_id": "563", "arg2_id": "577", "normalized": [] }, { "id": "585", "type": "Upregulator", "arg1_id": "564", "arg2_id": "572", "normalized": [] }, { "id": "586", "type": "Upregulator", "arg1_id": "564", "arg2_id": "577", "normalized": [] }, { "id": "587", "type": "Upregulator", "arg1_id": "565", "arg2_id": "569", "normalized": [] }, { "id": "588", "type": "Regulator", "arg1_id": "567", "arg2_id": "578", "normalized": [] } ]
589
6706930
[ { "id": "590", "type": "title and abstract", "text": [ "Mechanism of iodide-dependent catalatic activity of thyroid peroxidase and lactoperoxidase.\nMechanisms that have been proposed for peroxidase-catalyzed iodination require the utilization of 1 mol of H2O2 for organic binding of 1 mol of iodide. When we measured the stoichiometry of this reaction using thyroid peroxidase or lactoperoxidase at pH 7.0, we consistently obtained a ratio less than 1.0. This was shown to be attributable to catalase-like activity of these enzymes, resulting in unproductive cleavage of H2O2. This catalatic activity was completely iodide-dependent. To elucidate the mechanism of the iodide-dependent catalatic activity, the effects of various agents were investigated. The major observations may be summarized as follows: 1) The catalatic activity was inhibited in the presence of an iodine acceptor such as tyrosine. 2) The pseudohalide, SCN-, could not replace I- as a promoter of catalatic activity. 3) The inhibitory effects of the thioureylene drugs, methimazole and carbimazole, on the iodide-dependent catalatic activity were very similar to those reported previously for thyroid peroxidase-catalyzed iodination. 4) High concentrations of I- inhibited the catalatic activity of thyroid peroxidase and lactoperoxidase in a manner similar to that described previously for peroxidase-catalyzed iodination. On the basis of these observations and other findings, we have proposed a scheme which offers a possible explanation for iodide-dependent catalatic activity of thyroid peroxidase and lactoperoxidase. Compound I of the peroxidases is represented as EO, and oxidation of I- by EO is postulated to form enzyme-bound hypoiodite, represented in our scheme as [EOI]-. We suggest that the latter can react with H2O2 in a catalase-like reaction, with evolution of O2. We postulate further that the same form of oxidized iodine is also involved in iodination of tyrosine, oxidation of thioureylene drugs, and oxidation of I-, and that inhibition of catalatic activity by these agents occurs through competition with H2O2 for oxidized iodine." ], "offsets": [ [ 0, 2071 ] ] } ]
[ { "id": "591", "type": "CHEMICAL", "text": [ "H2O2" ], "offsets": [ [ 199, 203 ] ], "normalized": [] }, { "id": "592", "type": "CHEMICAL", "text": [ "I-" ], "offsets": [ [ 1175, 1177 ] ], "normalized": [] }, { "id": "593", "type": "CHEMICAL", "text": [ "iodide" ], "offsets": [ [ 1460, 1466 ] ], "normalized": [] }, { "id": "594", "type": "CHEMICAL", "text": [ "iodide" ], "offsets": [ [ 236, 242 ] ], "normalized": [] }, { "id": "595", "type": "CHEMICAL", "text": [ "H2O2" ], "offsets": [ [ 1743, 1747 ] ], "normalized": [] }, { "id": "596", "type": "CHEMICAL", "text": [ "O2" ], "offsets": [ [ 1795, 1797 ] ], "normalized": [] }, { "id": "597", "type": "CHEMICAL", "text": [ "iodine" ], "offsets": [ [ 1851, 1857 ] ], "normalized": [] }, { "id": "598", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 1892, 1900 ] ], "normalized": [] }, { "id": "599", "type": "CHEMICAL", "text": [ "thioureylene" ], "offsets": [ [ 1915, 1927 ] ], "normalized": [] }, { "id": "600", "type": "CHEMICAL", "text": [ "I-" ], "offsets": [ [ 1952, 1954 ] ], "normalized": [] }, { "id": "601", "type": "CHEMICAL", "text": [ "H2O2" ], "offsets": [ [ 2046, 2050 ] ], "normalized": [] }, { "id": "602", "type": "CHEMICAL", "text": [ "iodine" ], "offsets": [ [ 2064, 2070 ] ], "normalized": [] }, { "id": "603", "type": "CHEMICAL", "text": [ "H2O2" ], "offsets": [ [ 515, 519 ] ], "normalized": [] }, { "id": "604", "type": "CHEMICAL", "text": [ "iodide" ], "offsets": [ [ 560, 566 ] ], "normalized": [] }, { "id": "605", "type": "CHEMICAL", "text": [ "iodide" ], "offsets": [ [ 612, 618 ] ], "normalized": [] }, { "id": "606", "type": "CHEMICAL", "text": [ "iodine" ], "offsets": [ [ 813, 819 ] ], "normalized": [] }, { "id": "607", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 837, 845 ] ], "normalized": [] }, { "id": "608", "type": "CHEMICAL", "text": [ "pseudohalide" ], "offsets": [ [ 854, 866 ] ], "normalized": [] }, { "id": "609", "type": "CHEMICAL", "text": [ "SCN-" ], "offsets": [ [ 868, 872 ] ], "normalized": [] }, { "id": "610", "type": "CHEMICAL", "text": [ "I-" ], "offsets": [ [ 892, 894 ] ], "normalized": [] }, { "id": "611", "type": "CHEMICAL", "text": [ "thioureylene" ], "offsets": [ [ 965, 977 ] ], "normalized": [] }, { "id": "612", "type": "CHEMICAL", "text": [ "methimazole" ], "offsets": [ [ 985, 996 ] ], "normalized": [] }, { "id": "613", "type": "CHEMICAL", "text": [ "carbimazole" ], "offsets": [ [ 1001, 1012 ] ], "normalized": [] }, { "id": "614", "type": "CHEMICAL", "text": [ "iodide" ], "offsets": [ [ 1021, 1027 ] ], "normalized": [] }, { "id": "615", "type": "CHEMICAL", "text": [ "iodide" ], "offsets": [ [ 13, 19 ] ], "normalized": [] }, { "id": "616", "type": "GENE-Y", "text": [ "thyroid peroxidase" ], "offsets": [ [ 1108, 1126 ] ], "normalized": [] }, { "id": "617", "type": "GENE-Y", "text": [ "thyroid peroxidase" ], "offsets": [ [ 1214, 1232 ] ], "normalized": [] }, { "id": "618", "type": "GENE-Y", "text": [ "lactoperoxidase" ], "offsets": [ [ 1237, 1252 ] ], "normalized": [] }, { "id": "619", "type": "GENE-N", "text": [ "peroxidase" ], "offsets": [ [ 1306, 1316 ] ], "normalized": [] }, { "id": "620", "type": "GENE-Y", "text": [ "thyroid peroxidase" ], "offsets": [ [ 1499, 1517 ] ], "normalized": [] }, { "id": "621", "type": "GENE-Y", "text": [ "lactoperoxidase" ], "offsets": [ [ 1522, 1537 ] ], "normalized": [] }, { "id": "622", "type": "GENE-N", "text": [ "peroxidases" ], "offsets": [ [ 1557, 1568 ] ], "normalized": [] }, { "id": "623", "type": "GENE-N", "text": [ "EO" ], "offsets": [ [ 1587, 1589 ] ], "normalized": [] }, { "id": "624", "type": "GENE-N", "text": [ "EO" ], "offsets": [ [ 1614, 1616 ] ], "normalized": [] }, { "id": "625", "type": "GENE-Y", "text": [ "catalase" ], "offsets": [ [ 1753, 1761 ] ], "normalized": [] }, { "id": "626", "type": "GENE-Y", "text": [ "thyroid peroxidase" ], "offsets": [ [ 302, 320 ] ], "normalized": [] }, { "id": "627", "type": "GENE-Y", "text": [ "lactoperoxidase" ], "offsets": [ [ 324, 339 ] ], "normalized": [] }, { "id": "628", "type": "GENE-Y", "text": [ "catalase" ], "offsets": [ [ 436, 444 ] ], "normalized": [] }, { "id": "629", "type": "GENE-N", "text": [ "peroxidase" ], "offsets": [ [ 131, 141 ] ], "normalized": [] }, { "id": "630", "type": "GENE-Y", "text": [ "thyroid peroxidase" ], "offsets": [ [ 52, 70 ] ], "normalized": [] }, { "id": "631", "type": "GENE-Y", "text": [ "lactoperoxidase" ], "offsets": [ [ 75, 90 ] ], "normalized": [] }, { "id": "632", "type": "CHEMICAL", "text": [ "hypoiodite" ], "offsets": [ [ 1652, 1662 ] ], "normalized": [] }, { "id": "633", "type": "CHEMICAL", "text": [ "EOI" ], "offsets": [ [ 1694, 1697 ] ], "normalized": [] }, { "id": "634", "type": "CHEMICAL", "text": [ "I-" ], "offsets": [ [ 1608, 1610 ] ], "normalized": [] } ]
[]
[]
[ { "id": "635", "type": "Regulator", "arg1_id": "615", "arg2_id": "630", "normalized": [] }, { "id": "636", "type": "Regulator", "arg1_id": "615", "arg2_id": "631", "normalized": [] }, { "id": "637", "type": "Cofactor", "arg1_id": "591", "arg2_id": "629", "normalized": [] }, { "id": "638", "type": "Substrate", "arg1_id": "594", "arg2_id": "629", "normalized": [] }, { "id": "639", "type": "Substrate", "arg1_id": "603", "arg2_id": "628", "normalized": [] }, { "id": "640", "type": "Downregulator", "arg1_id": "611", "arg2_id": "616", "normalized": [] }, { "id": "641", "type": "Downregulator", "arg1_id": "612", "arg2_id": "616", "normalized": [] }, { "id": "642", "type": "Downregulator", "arg1_id": "613", "arg2_id": "616", "normalized": [] }, { "id": "643", "type": "Downregulator", "arg1_id": "592", "arg2_id": "617", "normalized": [] }, { "id": "644", "type": "Downregulator", "arg1_id": "592", "arg2_id": "618", "normalized": [] }, { "id": "645", "type": "Downregulator", "arg1_id": "592", "arg2_id": "619", "normalized": [] }, { "id": "646", "type": "Regulator", "arg1_id": "593", "arg2_id": "620", "normalized": [] }, { "id": "647", "type": "Regulator", "arg1_id": "593", "arg2_id": "621", "normalized": [] }, { "id": "648", "type": "Substrate", "arg1_id": "632", "arg2_id": "624", "normalized": [] }, { "id": "649", "type": "Substrate", "arg1_id": "633", "arg2_id": "624", "normalized": [] }, { "id": "650", "type": "Substrate", "arg1_id": "632", "arg2_id": "622", "normalized": [] }, { "id": "651", "type": "Substrate", "arg1_id": "632", "arg2_id": "623", "normalized": [] }, { "id": "652", "type": "Substrate", "arg1_id": "633", "arg2_id": "623", "normalized": [] }, { "id": "653", "type": "Substrate", "arg1_id": "633", "arg2_id": "622", "normalized": [] }, { "id": "654", "type": "Substrate", "arg1_id": "634", "arg2_id": "622", "normalized": [] }, { "id": "655", "type": "Substrate", "arg1_id": "634", "arg2_id": "623", "normalized": [] }, { "id": "656", "type": "Substrate", "arg1_id": "634", "arg2_id": "624", "normalized": [] }, { "id": "657", "type": "Substrate", "arg1_id": "595", "arg2_id": "625", "normalized": [] }, { "id": "658", "type": "Substrate", "arg1_id": "596", "arg2_id": "625", "normalized": [] } ]
659
23188391
[ { "id": "660", "type": "title and abstract", "text": [ "Lipotoxicity impairs incretin signalling.\nThe incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide are secreted by enteroendocrine cells and augment glucose-induced insulin secretion in response to food ingestion in a glucose-dependent manner. This mechanism forms the basis for incretin-based therapies in type 2 diabetes. However, the insulinotropic effect of incretins is diminished in type 2 diabetic patients, due in part to reduced expression of incretin receptors as a consequence of glucotoxicity. In this issue of Diabetologia, Kang et al (DOI: 10.1007/s00125-012-2776-x ) provide evidence that in addition to glucotoxicity, lipotoxicity also affects incretin receptor expression and signalling in insulin-secreting cells and isolated islets. In animal models of diabetes, the authors show that co-administration of a lipid-lowering drug with a dipeptidyl peptidase-4 inhibitor or a glucagon-like peptide-1 agonist improved glucose tolerance and beta cell mass. These novel findings provide convincing support for the notion that restoring normal circulating lipid levels in type 2 diabetes might help improve the efficacy of incretin-based therapies." ], "offsets": [ [ 0, 1194 ] ] } ]
[ { "id": "661", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 183, 190 ] ], "normalized": [] }, { "id": "662", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 252, 259 ] ], "normalized": [] }, { "id": "663", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 92, 99 ] ], "normalized": [] }, { "id": "664", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 967, 974 ] ], "normalized": [] }, { "id": "665", "type": "GENE-N", "text": [ "incretin" ], "offsets": [ [ 1169, 1177 ] ], "normalized": [] }, { "id": "666", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 199, 206 ] ], "normalized": [] }, { "id": "667", "type": "GENE-Y", "text": [ "glucagon-like peptide-1" ], "offsets": [ [ 64, 87 ] ], "normalized": [] }, { "id": "668", "type": "GENE-N", "text": [ "incretin" ], "offsets": [ [ 313, 321 ] ], "normalized": [] }, { "id": "669", "type": "GENE-N", "text": [ "incretins" ], "offsets": [ [ 396, 405 ] ], "normalized": [] }, { "id": "670", "type": "GENE-N", "text": [ "incretin hormones" ], "offsets": [ [ 46, 63 ] ], "normalized": [] }, { "id": "671", "type": "GENE-N", "text": [ "incretin receptors" ], "offsets": [ [ 486, 504 ] ], "normalized": [] }, { "id": "672", "type": "GENE-Y", "text": [ "glucose-dependent insulinotropic peptide" ], "offsets": [ [ 92, 132 ] ], "normalized": [] }, { "id": "673", "type": "GENE-N", "text": [ "incretin receptor" ], "offsets": [ [ 694, 711 ] ], "normalized": [] }, { "id": "674", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 741, 748 ] ], "normalized": [] }, { "id": "675", "type": "GENE-Y", "text": [ "dipeptidyl peptidase-4" ], "offsets": [ [ 888, 910 ] ], "normalized": [] }, { "id": "676", "type": "GENE-Y", "text": [ "glucagon-like peptide-1" ], "offsets": [ [ 926, 949 ] ], "normalized": [] }, { "id": "677", "type": "GENE-N", "text": [ "incretin" ], "offsets": [ [ 21, 29 ] ], "normalized": [] } ]
[]
[]
[ { "id": "678", "type": "Upregulator", "arg1_id": "661", "arg2_id": "666", "normalized": [] }, { "id": "679", "type": "Upregulator", "arg1_id": "662", "arg2_id": "666", "normalized": [] } ]
680
9399970
[ { "id": "681", "type": "title and abstract", "text": [ "Discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine: cross-substitution by mu and delta opioid agonists.\nThe purpose of this investigation was to evaluate the discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine. In pigeons trained to discriminate 1.7 mg/kg dezocine from saline, a series of opioids with activity at the mu opioid receptor substituted completely for the dezocine stimulus with a rank order of potency similar to that obtained in other assays sensitive to the effects of mu agonists (i.e., fentanyl >[-]-cyclazocine >buprenorphine = butorphanol >l-methadone >nalbuphine >[-]-metazocine >morphine). (-)-N-allylnormetazocine and (+)-propoxyphene substituted partially for the dezocine stimulus, an effect obtained even when tested up to doses that suppressed responding. Naloxone (0.1 - 10 mg/kg) antagonized the stimulus effects of dezocine, (+)-propoxyphene and fentanyl in a dose-related manner, whereas doses of naloxone that antagonized fentanyl's rate-decreasing effects failed to antagonize the rate-decreasing effects of dezocine and (+)-propoxyphene. A 10-mg/kg dose of the mu-selective, noncompetitive antagonist beta-funaltrexamine was more effective against the stimulus effects of dezocine and nalbuphine than against morphine and fentanyl. As was observed with naloxone, beta-funaltrexamine failed to antagonize dezocine's rate-decreasing effects. The delta agonists BW373U86 and SNC80 substituted partially for the dezocine stimulus, and these effects were reversed by doses of the delta-selective antagonist naltrindole (0.1 and 1.0 mg/kg) that had no effect on the dezocine stimulus. Naltrindole also antagonized the rate-decreasing effects produced by BW373U86 and SNC80, but not those of dezocine. The kappa agonists bremazocine, spiradoline, U50,488 and U69,593 failed to substitute for the dezocine stimulus. The kappa-selective antagonist norbinaltorphimine (1.0 mg/kg) failed to antagonize dezocine's stimulus or rate-decreasing effects. The present findings indicate that dezocine shares similar stimulus effects with both mu and delta agonists, its stimulus effects are reversed by mu-selective antagonists, and its rate-decreasing effects are not mediated by activity at mu, kappa or delta opioid receptors." ], "offsets": [ [ 0, 2302 ] ] } ]
[ { "id": "682", "type": "CHEMICAL", "text": [ "beta-funaltrexamine" ], "offsets": [ [ 1192, 1211 ] ], "normalized": [] }, { "id": "683", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 1263, 1271 ] ], "normalized": [] }, { "id": "684", "type": "CHEMICAL", "text": [ "nalbuphine" ], "offsets": [ [ 1276, 1286 ] ], "normalized": [] }, { "id": "685", "type": "CHEMICAL", "text": [ "morphine" ], "offsets": [ [ 1300, 1308 ] ], "normalized": [] }, { "id": "686", "type": "CHEMICAL", "text": [ "fentanyl" ], "offsets": [ [ 1313, 1321 ] ], "normalized": [] }, { "id": "687", "type": "CHEMICAL", "text": [ "naloxone" ], "offsets": [ [ 1344, 1352 ] ], "normalized": [] }, { "id": "688", "type": "CHEMICAL", "text": [ "beta-funaltrexamine" ], "offsets": [ [ 1354, 1373 ] ], "normalized": [] }, { "id": "689", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 258, 266 ] ], "normalized": [] }, { "id": "690", "type": "CHEMICAL", "text": [ "BW373U86" ], "offsets": [ [ 1450, 1458 ] ], "normalized": [] }, { "id": "691", "type": "CHEMICAL", "text": [ "SNC80" ], "offsets": [ [ 1463, 1468 ] ], "normalized": [] }, { "id": "692", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 1499, 1507 ] ], "normalized": [] }, { "id": "693", "type": "CHEMICAL", "text": [ "naltrindole" ], "offsets": [ [ 1593, 1604 ] ], "normalized": [] }, { "id": "694", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 1651, 1659 ] ], "normalized": [] }, { "id": "695", "type": "CHEMICAL", "text": [ "Naltrindole" ], "offsets": [ [ 1670, 1681 ] ], "normalized": [] }, { "id": "696", "type": "CHEMICAL", "text": [ "BW373U86" ], "offsets": [ [ 1739, 1747 ] ], "normalized": [] }, { "id": "697", "type": "CHEMICAL", "text": [ "SNC80" ], "offsets": [ [ 1752, 1757 ] ], "normalized": [] }, { "id": "698", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 1776, 1784 ] ], "normalized": [] }, { "id": "699", "type": "CHEMICAL", "text": [ "bremazocine" ], "offsets": [ [ 1805, 1816 ] ], "normalized": [] }, { "id": "700", "type": "CHEMICAL", "text": [ "spiradoline" ], "offsets": [ [ 1818, 1829 ] ], "normalized": [] }, { "id": "701", "type": "CHEMICAL", "text": [ "U50,488" ], "offsets": [ [ 1831, 1838 ] ], "normalized": [] }, { "id": "702", "type": "CHEMICAL", "text": [ "U69,593" ], "offsets": [ [ 1843, 1850 ] ], "normalized": [] }, { "id": "703", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 1880, 1888 ] ], "normalized": [] }, { "id": "704", "type": "CHEMICAL", "text": [ "norbinaltorphimine" ], "offsets": [ [ 1930, 1948 ] ], "normalized": [] }, { "id": "705", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 313, 321 ] ], "normalized": [] }, { "id": "706", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 2065, 2073 ] ], "normalized": [] }, { "id": "707", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 426, 434 ] ], "normalized": [] }, { "id": "708", "type": "CHEMICAL", "text": [ "fentanyl" ], "offsets": [ [ 561, 569 ] ], "normalized": [] }, { "id": "709", "type": "CHEMICAL", "text": [ "[-]-cyclazocine" ], "offsets": [ [ 571, 586 ] ], "normalized": [] }, { "id": "710", "type": "CHEMICAL", "text": [ "buprenorphine" ], "offsets": [ [ 588, 601 ] ], "normalized": [] }, { "id": "711", "type": "CHEMICAL", "text": [ "butorphanol" ], "offsets": [ [ 604, 615 ] ], "normalized": [] }, { "id": "712", "type": "CHEMICAL", "text": [ "l-methadone" ], "offsets": [ [ 617, 628 ] ], "normalized": [] }, { "id": "713", "type": "CHEMICAL", "text": [ "nalbuphine" ], "offsets": [ [ 630, 640 ] ], "normalized": [] }, { "id": "714", "type": "CHEMICAL", "text": [ "[-]-metazocine" ], "offsets": [ [ 642, 656 ] ], "normalized": [] }, { "id": "715", "type": "CHEMICAL", "text": [ "morphine" ], "offsets": [ [ 658, 666 ] ], "normalized": [] }, { "id": "716", "type": "CHEMICAL", "text": [ "(-)-N-allylnormetazocine" ], "offsets": [ [ 669, 693 ] ], "normalized": [] }, { "id": "717", "type": "CHEMICAL", "text": [ "(+)-propoxyphene" ], "offsets": [ [ 698, 714 ] ], "normalized": [] }, { "id": "718", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 745, 753 ] ], "normalized": [] }, { "id": "719", "type": "CHEMICAL", "text": [ "Naloxone" ], "offsets": [ [ 840, 848 ] ], "normalized": [] }, { "id": "720", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 902, 910 ] ], "normalized": [] }, { "id": "721", "type": "CHEMICAL", "text": [ "(+)-propoxyphene" ], "offsets": [ [ 912, 928 ] ], "normalized": [] }, { "id": "722", "type": "CHEMICAL", "text": [ "fentanyl" ], "offsets": [ [ 933, 941 ] ], "normalized": [] }, { "id": "723", "type": "CHEMICAL", "text": [ "naloxone" ], "offsets": [ [ 985, 993 ] ], "normalized": [] }, { "id": "724", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 1098, 1106 ] ], "normalized": [] }, { "id": "725", "type": "CHEMICAL", "text": [ "(+)-propoxyphene" ], "offsets": [ [ 1111, 1127 ] ], "normalized": [] }, { "id": "726", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 71, 79 ] ], "normalized": [] }, { "id": "727", "type": "GENE-N", "text": [ "mu, kappa or delta opioid receptors" ], "offsets": [ [ 2266, 2301 ] ], "normalized": [] }, { "id": "728", "type": "GENE-N", "text": [ "mu opioid receptor" ], "offsets": [ [ 376, 394 ] ], "normalized": [] }, { "id": "729", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 1395, 1403 ] ], "normalized": [] }, { "id": "730", "type": "CHEMICAL", "text": [ "dezocine" ], "offsets": [ [ 1982, 1990 ] ], "normalized": [] }, { "id": "731", "type": "GENE-N", "text": [ "mu and delta opioid" ], "offsets": [ [ 103, 122 ] ], "normalized": [] }, { "id": "732", "type": "GENE-N", "text": [ "mu and delta" ], "offsets": [ [ 2116, 2128 ] ], "normalized": [] } ]
[]
[]
[ { "id": "733", "type": "Regulator", "arg1_id": "705", "arg2_id": "728", "normalized": [] }, { "id": "734", "type": "Regulator", "arg1_id": "707", "arg2_id": "728", "normalized": [] }, { "id": "735", "type": "Agonist", "arg1_id": "708", "arg2_id": "728", "normalized": [] }, { "id": "736", "type": "Agonist", "arg1_id": "709", "arg2_id": "728", "normalized": [] }, { "id": "737", "type": "Agonist", "arg1_id": "710", "arg2_id": "728", "normalized": [] }, { "id": "738", "type": "Agonist", "arg1_id": "711", "arg2_id": "728", "normalized": [] }, { "id": "739", "type": "Agonist", "arg1_id": "712", "arg2_id": "728", "normalized": [] }, { "id": "740", "type": "Agonist", "arg1_id": "713", "arg2_id": "728", "normalized": [] }, { "id": "741", "type": "Agonist", "arg1_id": "714", "arg2_id": "728", "normalized": [] }, { "id": "742", "type": "Agonist", "arg1_id": "715", "arg2_id": "728", "normalized": [] }, { "id": "743", "type": "Regulator", "arg1_id": "726", "arg2_id": "731", "normalized": [] }, { "id": "744", "type": "Not", "arg1_id": "706", "arg2_id": "727", "normalized": [] }, { "id": "745", "type": "Agonist", "arg1_id": "706", "arg2_id": "732", "normalized": [] } ]
746
23103563
[ { "id": "747", "type": "title and abstract", "text": [ "Ibandronate increases the expression of the pro-apoptotic gene FAS by epigenetic mechanisms in tumor cells.\nThere is growing evidence that aminobisphosphonates like ibandronate show anticancer activity by an unknown mechanism. Biochemically, they prevent posttranslational isoprenylation of small GTPases, thus inhibiting their activity. In tumor cells, activated RAS-GTPase, the founding member of the gene family, down-regulates the expression of the pro-apoptotic gene FAS via epigenetic DNA-methylation by DNMT1. We compared ibandronate treatment in neoplastic human U-2 osteosarcoma and in mouse CCL-51 breast cancer cells as well as in the immortalized non-neoplastic MC3T3-E1 osteoblastic cells. Ibandronate attenuated cell proliferation in all cell lines tested. In the neoplastic cells we found up-regulation of caspases suggesting apoptosis. Further we found stimulation of FAS-expression as a result of epigenetic DNA demethylation that was due to down-regulation of DNMT1, which was rescued by re-isoprenylation by both geranylgeranyl-pyrophosphate and farnesylpyrophosphate. In contrast, ibandronate did not affect FAS and DNMT1 expression in MC3T3-E1 non-neoplastic cells. Data suggest that bisphosphonates via modulation of the activity of small-GTPases induce apoptosis in neoplastic cells by DNA-CpG-demethylation and stimulation of FAS-expression. In conclusion the shown epigenetic mechanism underlying the anti-neoplastic activity of farnesyl-transferase-inhibition, also explains the clinical success of other drugs, which target this pathway." ], "offsets": [ [ 0, 1564 ] ] } ]
[ { "id": "748", "type": "CHEMICAL", "text": [ "bisphosphonates" ], "offsets": [ [ 1205, 1220 ] ], "normalized": [] }, { "id": "749", "type": "CHEMICAL", "text": [ "CpG" ], "offsets": [ [ 1313, 1316 ] ], "normalized": [] }, { "id": "750", "type": "CHEMICAL", "text": [ "farnesyl" ], "offsets": [ [ 1454, 1462 ] ], "normalized": [] }, { "id": "751", "type": "CHEMICAL", "text": [ "aminobisphosphonates" ], "offsets": [ [ 139, 159 ] ], "normalized": [] }, { "id": "752", "type": "CHEMICAL", "text": [ "ibandronate" ], "offsets": [ [ 529, 540 ] ], "normalized": [] }, { "id": "753", "type": "CHEMICAL", "text": [ "ibandronate" ], "offsets": [ [ 165, 176 ] ], "normalized": [] }, { "id": "754", "type": "CHEMICAL", "text": [ "Ibandronate" ], "offsets": [ [ 703, 714 ] ], "normalized": [] }, { "id": "755", "type": "CHEMICAL", "text": [ "geranylgeranyl-pyrophosphate" ], "offsets": [ [ 1032, 1060 ] ], "normalized": [] }, { "id": "756", "type": "CHEMICAL", "text": [ "farnesylpyrophosphate" ], "offsets": [ [ 1065, 1086 ] ], "normalized": [] }, { "id": "757", "type": "CHEMICAL", "text": [ "ibandronate" ], "offsets": [ [ 1101, 1112 ] ], "normalized": [] }, { "id": "758", "type": "CHEMICAL", "text": [ "Ibandronate" ], "offsets": [ [ 0, 11 ] ], "normalized": [] }, { "id": "759", "type": "GENE-Y", "text": [ "FAS" ], "offsets": [ [ 1128, 1131 ] ], "normalized": [] }, { "id": "760", "type": "GENE-Y", "text": [ "DNMT1" ], "offsets": [ [ 1136, 1141 ] ], "normalized": [] }, { "id": "761", "type": "GENE-N", "text": [ "GTPases" ], "offsets": [ [ 1261, 1268 ] ], "normalized": [] }, { "id": "762", "type": "GENE-N", "text": [ "CpG" ], "offsets": [ [ 1313, 1316 ] ], "normalized": [] }, { "id": "763", "type": "GENE-Y", "text": [ "FAS" ], "offsets": [ [ 1350, 1353 ] ], "normalized": [] }, { "id": "764", "type": "GENE-N", "text": [ "farnesyl-transferase" ], "offsets": [ [ 1454, 1474 ] ], "normalized": [] }, { "id": "765", "type": "GENE-N", "text": [ "GTPases" ], "offsets": [ [ 297, 304 ] ], "normalized": [] }, { "id": "766", "type": "GENE-N", "text": [ "RAS-GTPase" ], "offsets": [ [ 364, 374 ] ], "normalized": [] }, { "id": "767", "type": "GENE-Y", "text": [ "FAS" ], "offsets": [ [ 472, 475 ] ], "normalized": [] }, { "id": "768", "type": "GENE-Y", "text": [ "DNMT1" ], "offsets": [ [ 510, 515 ] ], "normalized": [] }, { "id": "769", "type": "GENE-N", "text": [ "caspases" ], "offsets": [ [ 821, 829 ] ], "normalized": [] }, { "id": "770", "type": "GENE-Y", "text": [ "FAS" ], "offsets": [ [ 884, 887 ] ], "normalized": [] }, { "id": "771", "type": "GENE-Y", "text": [ "DNMT1" ], "offsets": [ [ 978, 983 ] ], "normalized": [] }, { "id": "772", "type": "GENE-Y", "text": [ "FAS" ], "offsets": [ [ 63, 66 ] ], "normalized": [] } ]
[]
[]
[ { "id": "773", "type": "Upregulator", "arg1_id": "758", "arg2_id": "772", "normalized": [] }, { "id": "774", "type": "Upregulator", "arg1_id": "755", "arg2_id": "770", "normalized": [] }, { "id": "775", "type": "Upregulator", "arg1_id": "755", "arg2_id": "771", "normalized": [] }, { "id": "776", "type": "Upregulator", "arg1_id": "756", "arg2_id": "770", "normalized": [] }, { "id": "777", "type": "Upregulator", "arg1_id": "756", "arg2_id": "771", "normalized": [] }, { "id": "778", "type": "Not", "arg1_id": "757", "arg2_id": "759", "normalized": [] }, { "id": "779", "type": "Not", "arg1_id": "757", "arg2_id": "760", "normalized": [] }, { "id": "780", "type": "Regulator", "arg1_id": "748", "arg2_id": "761", "normalized": [] }, { "id": "781", "type": "Upregulator", "arg1_id": "748", "arg2_id": "763", "normalized": [] } ]
782
23174265
[ { "id": "783", "type": "title and abstract", "text": [ "Cannabinoid agonists increase the interaction between β-Arrestin 2 and ERK1/2 and upregulate β-Arrestin 2 and 5-HT(2A) receptors.\nWe have recently reported that selective cannabinoid 2 (CB(2)) receptor agonists upregulate 5-HT(2A) receptors by enhancing ERK1/2 signaling in prefrontal cortex (PFCx). Increased activity of cortical 5-HT(2A) receptors has been associated with several neuropsychiatric disorders such as anxiety and schizophrenia. Here we examine the mechanisms involved in this enhanced ERK1/2 activation in rat PFCx and in a neuronal cell model. Sprague-Dawley rats treated with a non-selective cannabinoid agonist (CP55940, 50μg/kg, 7 days, i.p.) showed enhanced co-immunoprecipitation of β-Arrestin 2 and ERK1/2, enhanced pERK protein levels, and enhanced expression of β-Arrestin 2 mRNA and protein levels in PFCx. In a neuronal cell line, we found that selective CB(2) receptor agonists upregulate β-Arrestin 2, an effect that was prevented by selective CB(2) receptor antagonist JTE-907 and CB(2) shRNA lentiviral particles. Additionally, inhibition of clathrin-mediated endocytosis, ERK1/2, and the AP-1 transcription factor also prevented the cannabinoid receptor-induced upregulation of β-Arrestin 2. Our results suggest that sustained activation of CB(2) receptors would enhance β-Arrestin 2 expression possibly contributing to its increased interaction with ERK1/2, thereby driving the upregulation of 5-HT(2A) receptors. The CB(2) receptor-mediated upregulation of β-Arrestin 2 would be mediated, at least in part, by an ERK1/2-dependent activation of AP-1. These data could provide the rationale for some of the adverse effects associated with repeated cannabinoid exposure and shed light on some CB(2) receptor agonists that could represent an alternative therapeutic because of their minimal effect on serotonergic neurotransmission." ], "offsets": [ [ 0, 1863 ] ] } ]
[ { "id": "784", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 1428, 1432 ] ], "normalized": [] }, { "id": "785", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 331, 335 ] ], "normalized": [] }, { "id": "786", "type": "CHEMICAL", "text": [ "CP55940" ], "offsets": [ [ 632, 639 ] ], "normalized": [] }, { "id": "787", "type": "CHEMICAL", "text": [ "JTE-907" ], "offsets": [ [ 1000, 1007 ] ], "normalized": [] }, { "id": "788", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 222, 226 ] ], "normalized": [] }, { "id": "789", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 110, 114 ] ], "normalized": [] }, { "id": "790", "type": "GENE-N", "text": [ "cannabinoid receptor" ], "offsets": [ [ 1166, 1186 ] ], "normalized": [] }, { "id": "791", "type": "GENE-Y", "text": [ "β-Arrestin 2" ], "offsets": [ [ 1211, 1223 ] ], "normalized": [] }, { "id": "792", "type": "GENE-Y", "text": [ "CB(2)" ], "offsets": [ [ 1274, 1279 ] ], "normalized": [] }, { "id": "793", "type": "GENE-Y", "text": [ "β-Arrestin 2" ], "offsets": [ [ 1304, 1316 ] ], "normalized": [] }, { "id": "794", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 254, 260 ] ], "normalized": [] }, { "id": "795", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 1384, 1390 ] ], "normalized": [] }, { "id": "796", "type": "GENE-Y", "text": [ "5-HT(2A)" ], "offsets": [ [ 1428, 1436 ] ], "normalized": [] }, { "id": "797", "type": "GENE-Y", "text": [ "CB(2)" ], "offsets": [ [ 1452, 1457 ] ], "normalized": [] }, { "id": "798", "type": "GENE-Y", "text": [ "β-Arrestin 2" ], "offsets": [ [ 1492, 1504 ] ], "normalized": [] }, { "id": "799", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 1548, 1554 ] ], "normalized": [] }, { "id": "800", "type": "GENE-Y", "text": [ "AP-1" ], "offsets": [ [ 1579, 1583 ] ], "normalized": [] }, { "id": "801", "type": "GENE-Y", "text": [ "CB(2)" ], "offsets": [ [ 1725, 1730 ] ], "normalized": [] }, { "id": "802", "type": "GENE-Y", "text": [ "5-HT(2A)" ], "offsets": [ [ 331, 339 ] ], "normalized": [] }, { "id": "803", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 502, 508 ] ], "normalized": [] }, { "id": "804", "type": "GENE-Y", "text": [ "cannabinoid 2 (CB(2)) receptor" ], "offsets": [ [ 171, 201 ] ], "normalized": [] }, { "id": "805", "type": "GENE-Y", "text": [ "β-Arrestin 2" ], "offsets": [ [ 706, 718 ] ], "normalized": [] }, { "id": "806", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 723, 729 ] ], "normalized": [] }, { "id": "807", "type": "GENE-N", "text": [ "pERK" ], "offsets": [ [ 740, 744 ] ], "normalized": [] }, { "id": "808", "type": "GENE-Y", "text": [ "β-Arrestin 2" ], "offsets": [ [ 788, 800 ] ], "normalized": [] }, { "id": "809", "type": "GENE-Y", "text": [ "CB(2)" ], "offsets": [ [ 883, 888 ] ], "normalized": [] }, { "id": "810", "type": "GENE-Y", "text": [ "β-Arrestin 2" ], "offsets": [ [ 918, 930 ] ], "normalized": [] }, { "id": "811", "type": "GENE-Y", "text": [ "CB(2)" ], "offsets": [ [ 974, 979 ] ], "normalized": [] }, { "id": "812", "type": "GENE-Y", "text": [ "CB(2)" ], "offsets": [ [ 1012, 1017 ] ], "normalized": [] }, { "id": "813", "type": "GENE-Y", "text": [ "5-HT(2A)" ], "offsets": [ [ 222, 230 ] ], "normalized": [] }, { "id": "814", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 1105, 1111 ] ], "normalized": [] }, { "id": "815", "type": "GENE-Y", "text": [ "AP-1" ], "offsets": [ [ 1121, 1125 ] ], "normalized": [] }, { "id": "816", "type": "GENE-Y", "text": [ "5-HT(2A)" ], "offsets": [ [ 110, 118 ] ], "normalized": [] }, { "id": "817", "type": "GENE-Y", "text": [ "β-Arrestin 2" ], "offsets": [ [ 54, 66 ] ], "normalized": [] }, { "id": "818", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 71, 77 ] ], "normalized": [] }, { "id": "819", "type": "GENE-Y", "text": [ "β-Arrestin 2" ], "offsets": [ [ 93, 105 ] ], "normalized": [] } ]
[]
[]
[ { "id": "820", "type": "Upregulator", "arg1_id": "786", "arg2_id": "805", "normalized": [] }, { "id": "821", "type": "Upregulator", "arg1_id": "786", "arg2_id": "806", "normalized": [] }, { "id": "822", "type": "Upregulator", "arg1_id": "786", "arg2_id": "807", "normalized": [] }, { "id": "823", "type": "Upregulator", "arg1_id": "786", "arg2_id": "808", "normalized": [] }, { "id": "824", "type": "Antagonist", "arg1_id": "787", "arg2_id": "811", "normalized": [] }, { "id": "825", "type": "Antagonist", "arg1_id": "787", "arg2_id": "809", "normalized": [] }, { "id": "826", "type": "Antagonist", "arg1_id": "787", "arg2_id": "812", "normalized": [] }, { "id": "827", "type": "Downregulator", "arg1_id": "787", "arg2_id": "810", "normalized": [] } ]
828
23103450
[ { "id": "829", "type": "title and abstract", "text": [ "Arsenic trioxide-induced hERG K(+) channel deficiency can be rescued by matrine and oxymatrine through up-regulating transcription factor Sp1 expression.\nThe human ether-a-go-go-related gene (hERG) encodes the rapidly activating, delayed rectifier potassium channel (IKr) important for cardiac repolarization. Dysfunction of the hERG channel can cause Long QT Syndrome (LQTS). A wide variety of structurally diverse therapeutic compounds reduce the hERG current by acute direct inhibition of the hERG current or/and selective disruption of hERG protein expression. Arsenic trioxide (As(2)O(3)), which is used to treat acute promyelocytic leukemia, can cause LQTS type 2 (LQT2) by reducing the hERG current through the diversion of hERG trafficking to the cytoplasmic membrane. This cardiotoxicity limits its clinical applications. Our aim was to develop cardioprotective agents to decrease As(2)O(3)-induced cardiotoxicity. We reported that superfusion of hERG-expressing HEK293 (hERG-HEK) cells with matrine (1, 10 μM) increased the hERG current by promoting hERG channel activation. Long-term treatment with 1 μM matrine or oxymatrine increased expression of the hERG protein and rescued the hERG surface expression disrupted by As(2)O(3). In addition, Matrine and oxymatrine significantly shortened action potential duration prolonged by As(2)O(3) in guinea pig ventricular myocytes. These results were ascribed to the up-regulation of hERG at both mRNA and protein levels via an increase in the expression of transcription factor Sp1, an established transactivator of the hERG gene. Therefore, matrine and oxymatrine may have the potential to cure LQT2 as a potassium channel activator by promoting hERG channel activation and increasing hERG channel expression." ], "offsets": [ [ 0, 1766 ] ] } ]
[ { "id": "830", "type": "CHEMICAL", "text": [ "ether" ], "offsets": [ [ 164, 169 ] ], "normalized": [] }, { "id": "831", "type": "CHEMICAL", "text": [ "As(2)O(3)" ], "offsets": [ [ 1231, 1240 ] ], "normalized": [] }, { "id": "832", "type": "CHEMICAL", "text": [ "Matrine" ], "offsets": [ [ 1255, 1262 ] ], "normalized": [] }, { "id": "833", "type": "CHEMICAL", "text": [ "oxymatrine" ], "offsets": [ [ 1267, 1277 ] ], "normalized": [] }, { "id": "834", "type": "CHEMICAL", "text": [ "As(2)O(3)" ], "offsets": [ [ 1341, 1350 ] ], "normalized": [] }, { "id": "835", "type": "CHEMICAL", "text": [ "matrine" ], "offsets": [ [ 1598, 1605 ] ], "normalized": [] }, { "id": "836", "type": "CHEMICAL", "text": [ "oxymatrine" ], "offsets": [ [ 1610, 1620 ] ], "normalized": [] }, { "id": "837", "type": "CHEMICAL", "text": [ "potassium" ], "offsets": [ [ 1662, 1671 ] ], "normalized": [] }, { "id": "838", "type": "CHEMICAL", "text": [ "Arsenic trioxide" ], "offsets": [ [ 565, 581 ] ], "normalized": [] }, { "id": "839", "type": "CHEMICAL", "text": [ "As(2)O(3)" ], "offsets": [ [ 583, 592 ] ], "normalized": [] }, { "id": "840", "type": "CHEMICAL", "text": [ "As(2)O(3)" ], "offsets": [ [ 890, 899 ] ], "normalized": [] }, { "id": "841", "type": "CHEMICAL", "text": [ "matrine" ], "offsets": [ [ 1001, 1008 ] ], "normalized": [] }, { "id": "842", "type": "CHEMICAL", "text": [ "potassium" ], "offsets": [ [ 248, 257 ] ], "normalized": [] }, { "id": "843", "type": "CHEMICAL", "text": [ "matrine" ], "offsets": [ [ 1115, 1122 ] ], "normalized": [] }, { "id": "844", "type": "CHEMICAL", "text": [ "oxymatrine" ], "offsets": [ [ 1126, 1136 ] ], "normalized": [] }, { "id": "845", "type": "CHEMICAL", "text": [ "Arsenic trioxide" ], "offsets": [ [ 0, 16 ] ], "normalized": [] }, { "id": "846", "type": "CHEMICAL", "text": [ "K(+)" ], "offsets": [ [ 30, 34 ] ], "normalized": [] }, { "id": "847", "type": "CHEMICAL", "text": [ "matrine" ], "offsets": [ [ 72, 79 ] ], "normalized": [] }, { "id": "848", "type": "CHEMICAL", "text": [ "oxymatrine" ], "offsets": [ [ 84, 94 ] ], "normalized": [] }, { "id": "849", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 1165, 1169 ] ], "normalized": [] }, { "id": "850", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 1194, 1198 ] ], "normalized": [] }, { "id": "851", "type": "GENE-Y", "text": [ "IKr" ], "offsets": [ [ 267, 270 ] ], "normalized": [] }, { "id": "852", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 1439, 1443 ] ], "normalized": [] }, { "id": "853", "type": "GENE-Y", "text": [ "transcription factor Sp1" ], "offsets": [ [ 1513, 1537 ] ], "normalized": [] }, { "id": "854", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 1576, 1580 ] ], "normalized": [] }, { "id": "855", "type": "GENE-N", "text": [ "potassium channel" ], "offsets": [ [ 1662, 1679 ] ], "normalized": [] }, { "id": "856", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 1703, 1707 ] ], "normalized": [] }, { "id": "857", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 1742, 1746 ] ], "normalized": [] }, { "id": "858", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 329, 333 ] ], "normalized": [] }, { "id": "859", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 449, 453 ] ], "normalized": [] }, { "id": "860", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 496, 500 ] ], "normalized": [] }, { "id": "861", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 192, 196 ] ], "normalized": [] }, { "id": "862", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 540, 544 ] ], "normalized": [] }, { "id": "863", "type": "GENE-Y", "text": [ "human ether-a-go-go-related gene" ], "offsets": [ [ 158, 190 ] ], "normalized": [] }, { "id": "864", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 693, 697 ] ], "normalized": [] }, { "id": "865", "type": "GENE-Y", "text": [ "rapidly activating, delayed rectifier potassium channel" ], "offsets": [ [ 210, 265 ] ], "normalized": [] }, { "id": "866", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 731, 735 ] ], "normalized": [] }, { "id": "867", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 956, 960 ] ], "normalized": [] }, { "id": "868", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 980, 984 ] ], "normalized": [] }, { "id": "869", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 1034, 1038 ] ], "normalized": [] }, { "id": "870", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 1060, 1064 ] ], "normalized": [] }, { "id": "871", "type": "GENE-Y", "text": [ "transcription factor Sp1" ], "offsets": [ [ 117, 141 ] ], "normalized": [] }, { "id": "872", "type": "GENE-Y", "text": [ "hERG" ], "offsets": [ [ 25, 29 ] ], "normalized": [] }, { "id": "873", "type": "GENE-N", "text": [ "K(+) channel" ], "offsets": [ [ 30, 42 ] ], "normalized": [] } ]
[]
[]
[ { "id": "874", "type": "Upregulator", "arg1_id": "847", "arg2_id": "871", "normalized": [] }, { "id": "875", "type": "Upregulator", "arg1_id": "848", "arg2_id": "871", "normalized": [] }, { "id": "876", "type": "Downregulator", "arg1_id": "845", "arg2_id": "872", "normalized": [] }, { "id": "877", "type": "Downregulator", "arg1_id": "845", "arg2_id": "873", "normalized": [] }, { "id": "878", "type": "Upregulator", "arg1_id": "847", "arg2_id": "872", "normalized": [] }, { "id": "879", "type": "Upregulator", "arg1_id": "847", "arg2_id": "873", "normalized": [] }, { "id": "880", "type": "Upregulator", "arg1_id": "848", "arg2_id": "872", "normalized": [] }, { "id": "881", "type": "Upregulator", "arg1_id": "848", "arg2_id": "873", "normalized": [] }, { "id": "882", "type": "Downregulator", "arg1_id": "838", "arg2_id": "864", "normalized": [] }, { "id": "883", "type": "Downregulator", "arg1_id": "838", "arg2_id": "866", "normalized": [] }, { "id": "884", "type": "Downregulator", "arg1_id": "839", "arg2_id": "864", "normalized": [] }, { "id": "885", "type": "Downregulator", "arg1_id": "839", "arg2_id": "866", "normalized": [] }, { "id": "886", "type": "Upregulator", "arg1_id": "841", "arg2_id": "867", "normalized": [] }, { "id": "887", "type": "Upregulator", "arg1_id": "841", "arg2_id": "868", "normalized": [] }, { "id": "888", "type": "Upregulator", "arg1_id": "841", "arg2_id": "869", "normalized": [] }, { "id": "889", "type": "Upregulator", "arg1_id": "841", "arg2_id": "870", "normalized": [] }, { "id": "890", "type": "Upregulator", "arg1_id": "843", "arg2_id": "849", "normalized": [] }, { "id": "891", "type": "Upregulator", "arg1_id": "844", "arg2_id": "849", "normalized": [] }, { "id": "892", "type": "Upregulator", "arg1_id": "843", "arg2_id": "850", "normalized": [] }, { "id": "893", "type": "Upregulator", "arg1_id": "844", "arg2_id": "850", "normalized": [] }, { "id": "894", "type": "Downregulator", "arg1_id": "831", "arg2_id": "850", "normalized": [] }, { "id": "895", "type": "Downregulator", "arg1_id": "831", "arg2_id": "849", "normalized": [] }, { "id": "896", "type": "Upregulator", "arg1_id": "836", "arg2_id": "856", "normalized": [] }, { "id": "897", "type": "Upregulator", "arg1_id": "835", "arg2_id": "856", "normalized": [] }, { "id": "898", "type": "Upregulator", "arg1_id": "835", "arg2_id": "857", "normalized": [] }, { "id": "899", "type": "Upregulator", "arg1_id": "836", "arg2_id": "857", "normalized": [] } ]
900
7768269
[ { "id": "901", "type": "title and abstract", "text": [ "Discriminative stimulus effects of esteratic local anesthetics in squirrel monkeys.\nA number of esteratic local anesthetics serve as positive reinforcers and produce cocaine-like discriminative stimulus effects in animals. It has been suggested that the affinity of these compounds for a site on the dopamine transporter, and not their local anesthetic actions, is responsible for these abuse-related behavioral effects. In the present study, three local anesthetics previously shown to be self-administered in animals were examined in squirrel monkeys trained to discriminate cocaine (0.3 mg/kg) from saline in a two-lever, food-reinforced procedure. Dimethocaine (0.1-3.0 mg/kg) fully and dose-dependently substituted for cocaine. Doses of dimethocaine (1.7 mg/kg) and cocaine (0.3 mg/kg) which produced full (> 80%) substitution for cocaine were administered in combination with the dopamine D1 receptor antagonist SCH 39166 ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo [d]naphtho-(2,1-b)azepine) and the dopamine D2 receptor antagonist raclopride (both at 0.003-0.03 mg/kg). SCH 39166 fully blocked the cocaine-like discriminative stimulus effects of dimethocaine and cocaine, but raclopride produced only partial antagonism of cocaine-lever selection. In addition, there was some evidence that raclopride blocked cocaine-lever responding produced by a lower dose of dimethocaine. In substitution studies, neither procaine (1-10 mg/kg) nor chloroprocaine (1-30 mg/kg) produced cocaine-like effects. These results support a role for dopamine in the behavioral effects of some local anesthetics." ], "offsets": [ [ 0, 1626 ] ] } ]
[ { "id": "902", "type": "CHEMICAL", "text": [ "SCH 39166" ], "offsets": [ [ 1108, 1117 ] ], "normalized": [] }, { "id": "903", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 1136, 1143 ] ], "normalized": [] }, { "id": "904", "type": "CHEMICAL", "text": [ "dimethocaine" ], "offsets": [ [ 1184, 1196 ] ], "normalized": [] }, { "id": "905", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 1201, 1208 ] ], "normalized": [] }, { "id": "906", "type": "CHEMICAL", "text": [ "raclopride" ], "offsets": [ [ 1214, 1224 ] ], "normalized": [] }, { "id": "907", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 1261, 1268 ] ], "normalized": [] }, { "id": "908", "type": "CHEMICAL", "text": [ "raclopride" ], "offsets": [ [ 1328, 1338 ] ], "normalized": [] }, { "id": "909", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 1347, 1354 ] ], "normalized": [] }, { "id": "910", "type": "CHEMICAL", "text": [ "dimethocaine" ], "offsets": [ [ 1400, 1412 ] ], "normalized": [] }, { "id": "911", "type": "CHEMICAL", "text": [ "procaine" ], "offsets": [ [ 1447, 1455 ] ], "normalized": [] }, { "id": "912", "type": "CHEMICAL", "text": [ "chloroprocaine" ], "offsets": [ [ 1473, 1487 ] ], "normalized": [] }, { "id": "913", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 1510, 1517 ] ], "normalized": [] }, { "id": "914", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 1565, 1573 ] ], "normalized": [] }, { "id": "915", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 300, 308 ] ], "normalized": [] }, { "id": "916", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 577, 584 ] ], "normalized": [] }, { "id": "917", "type": "CHEMICAL", "text": [ "Dimethocaine" ], "offsets": [ [ 652, 664 ] ], "normalized": [] }, { "id": "918", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 724, 731 ] ], "normalized": [] }, { "id": "919", "type": "CHEMICAL", "text": [ "dimethocaine" ], "offsets": [ [ 742, 754 ] ], "normalized": [] }, { "id": "920", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 771, 778 ] ], "normalized": [] }, { "id": "921", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 836, 843 ] ], "normalized": [] }, { "id": "922", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 886, 894 ] ], "normalized": [] }, { "id": "923", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 166, 173 ] ], "normalized": [] }, { "id": "924", "type": "CHEMICAL", "text": [ "SCH 39166" ], "offsets": [ [ 918, 927 ] ], "normalized": [] }, { "id": "925", "type": "CHEMICAL", "text": [ "(-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo [d]naphtho-(2,1-b)azepine" ], "offsets": [ [ 929, 1027 ] ], "normalized": [] }, { "id": "926", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 1037, 1045 ] ], "normalized": [] }, { "id": "927", "type": "CHEMICAL", "text": [ "raclopride" ], "offsets": [ [ 1069, 1079 ] ], "normalized": [] }, { "id": "928", "type": "GENE-Y", "text": [ "dopamine transporter" ], "offsets": [ [ 300, 320 ] ], "normalized": [] }, { "id": "929", "type": "GENE-Y", "text": [ "dopamine D1 receptor" ], "offsets": [ [ 886, 906 ] ], "normalized": [] }, { "id": "930", "type": "GENE-Y", "text": [ "dopamine D2 receptor" ], "offsets": [ [ 1037, 1057 ] ], "normalized": [] } ]
[]
[]
[ { "id": "931", "type": "Antagonist", "arg1_id": "924", "arg2_id": "929", "normalized": [] }, { "id": "932", "type": "Antagonist", "arg1_id": "925", "arg2_id": "929", "normalized": [] }, { "id": "933", "type": "Antagonist", "arg1_id": "927", "arg2_id": "930", "normalized": [] } ]
934
15967876
[ { "id": "935", "type": "title and abstract", "text": [ "Intracellular K+ is required for the inactivation-induced high-affinity binding of cisapride to HERG channels.\nMany commonly used medications can cause long QT syndrome and thus increase the risk of life-threatening arrhythmias. High-affinity human Ether-a-go-go-related gene (HERG) potassium channel blockade by structurally diverse compounds is almost exclusively responsible for this side effect. Understanding drug-HERG channel interactions is an important step in avoiding drug-induced long QT syndromes. Previous studies have found that disrupting HERG inactivation reduces the degree of drug block and have suggested that the inactivated state is the preferential state for drug binding to HERG channels. However, recent studies have also shown that inactivation does not dictate drug sensitivity of HERG channels. In the present study, we examined the effect of inactivation gating on cisapride block of HERG. Modulation of HERG inactivation was achieved by either changing extracellular K+ or Cs+ concentrations or by mutations of the channel. We found that although inactivation facilitated cisapride block of the HERG K+ current, it was not coupled with cisapride block of HERG when the Cs+ current was recorded. Furthermore, cisapride block of the HERG K+ current was not linked with inactivation in the mutant HERG channels F656V and F656M. Our results suggest that inactivation facilitates cisapride block of HERG channels through affecting the positioning of Phe-656." ], "offsets": [ [ 0, 1482 ] ] } ]
[ { "id": "936", "type": "CHEMICAL", "text": [ "K+" ], "offsets": [ [ 1129, 1131 ] ], "normalized": [] }, { "id": "937", "type": "CHEMICAL", "text": [ "Cs+" ], "offsets": [ [ 1198, 1201 ] ], "normalized": [] }, { "id": "938", "type": "CHEMICAL", "text": [ "K+" ], "offsets": [ [ 1265, 1267 ] ], "normalized": [] }, { "id": "939", "type": "CHEMICAL", "text": [ "cisapride" ], "offsets": [ [ 1404, 1413 ] ], "normalized": [] }, { "id": "940", "type": "CHEMICAL", "text": [ "Phe" ], "offsets": [ [ 1474, 1477 ] ], "normalized": [] }, { "id": "941", "type": "CHEMICAL", "text": [ "potassium" ], "offsets": [ [ 283, 292 ] ], "normalized": [] }, { "id": "942", "type": "CHEMICAL", "text": [ "cisapride" ], "offsets": [ [ 893, 902 ] ], "normalized": [] }, { "id": "943", "type": "CHEMICAL", "text": [ "K+" ], "offsets": [ [ 996, 998 ] ], "normalized": [] }, { "id": "944", "type": "CHEMICAL", "text": [ "Cs+" ], "offsets": [ [ 1002, 1005 ] ], "normalized": [] }, { "id": "945", "type": "CHEMICAL", "text": [ "cisapride" ], "offsets": [ [ 1101, 1110 ] ], "normalized": [] }, { "id": "946", "type": "CHEMICAL", "text": [ "K+" ], "offsets": [ [ 14, 16 ] ], "normalized": [] }, { "id": "947", "type": "CHEMICAL", "text": [ "cisapride" ], "offsets": [ [ 83, 92 ] ], "normalized": [] }, { "id": "948", "type": "GENE-Y", "text": [ "HERG" ], "offsets": [ [ 1124, 1128 ] ], "normalized": [] }, { "id": "949", "type": "GENE-Y", "text": [ "HERG" ], "offsets": [ [ 1184, 1188 ] ], "normalized": [] }, { "id": "950", "type": "GENE-Y", "text": [ "HERG" ], "offsets": [ [ 1260, 1264 ] ], "normalized": [] }, { "id": "951", "type": "GENE-Y", "text": [ "HERG" ], "offsets": [ [ 1323, 1327 ] ], "normalized": [] }, { "id": "952", "type": "GENE-N", "text": [ "F656V" ], "offsets": [ [ 1337, 1342 ] ], "normalized": [] }, { "id": "953", "type": "GENE-N", "text": [ "F656M" ], "offsets": [ [ 1347, 1352 ] ], "normalized": [] }, { "id": "954", "type": "GENE-Y", "text": [ "HERG" ], "offsets": [ [ 1423, 1427 ] ], "normalized": [] }, { "id": "955", "type": "GENE-Y", "text": [ "human Ether-a-go-go-related gene (HERG) potassium channel" ], "offsets": [ [ 243, 300 ] ], "normalized": [] }, { "id": "956", "type": "GENE-Y", "text": [ "HERG" ], "offsets": [ [ 419, 423 ] ], "normalized": [] }, { "id": "957", "type": "GENE-Y", "text": [ "HERG" ], "offsets": [ [ 554, 558 ] ], "normalized": [] }, { "id": "958", "type": "GENE-Y", "text": [ "HERG" ], "offsets": [ [ 697, 701 ] ], "normalized": [] }, { "id": "959", "type": "GENE-Y", "text": [ "HERG" ], "offsets": [ [ 807, 811 ] ], "normalized": [] }, { "id": "960", "type": "GENE-Y", "text": [ "HERG" ], "offsets": [ [ 912, 916 ] ], "normalized": [] }, { "id": "961", "type": "GENE-Y", "text": [ "HERG" ], "offsets": [ [ 932, 936 ] ], "normalized": [] }, { "id": "962", "type": "GENE-Y", "text": [ "HERG" ], "offsets": [ [ 96, 100 ] ], "normalized": [] }, { "id": "963", "type": "CHEMICAL", "text": [ "cisapride" ], "offsets": [ [ 1165, 1174 ] ], "normalized": [] }, { "id": "964", "type": "CHEMICAL", "text": [ "cisapride" ], "offsets": [ [ 1237, 1246 ] ], "normalized": [] } ]
[]
[]
[ { "id": "965", "type": "Regulator", "arg1_id": "947", "arg2_id": "962", "normalized": [] }, { "id": "966", "type": "Regulator", "arg1_id": "946", "arg2_id": "962", "normalized": [] }, { "id": "967", "type": "Downregulator", "arg1_id": "942", "arg2_id": "960", "normalized": [] }, { "id": "968", "type": "Regulator", "arg1_id": "943", "arg2_id": "961", "normalized": [] }, { "id": "969", "type": "Regulator", "arg1_id": "944", "arg2_id": "961", "normalized": [] }, { "id": "970", "type": "Downregulator", "arg1_id": "945", "arg2_id": "948", "normalized": [] }, { "id": "971", "type": "Downregulator", "arg1_id": "945", "arg2_id": "949", "normalized": [] }, { "id": "972", "type": "Downregulator", "arg1_id": "963", "arg2_id": "949", "normalized": [] }, { "id": "973", "type": "Downregulator", "arg1_id": "963", "arg2_id": "948", "normalized": [] }, { "id": "974", "type": "Substrate", "arg1_id": "936", "arg2_id": "948", "normalized": [] }, { "id": "975", "type": "Substrate", "arg1_id": "937", "arg2_id": "949", "normalized": [] }, { "id": "976", "type": "Substrate", "arg1_id": "936", "arg2_id": "949", "normalized": [] }, { "id": "977", "type": "Substrate", "arg1_id": "937", "arg2_id": "948", "normalized": [] }, { "id": "978", "type": "Downregulator", "arg1_id": "964", "arg2_id": "950", "normalized": [] }, { "id": "979", "type": "Substrate", "arg1_id": "938", "arg2_id": "950", "normalized": [] }, { "id": "980", "type": "Downregulator", "arg1_id": "964", "arg2_id": "951", "normalized": [] }, { "id": "981", "type": "Substrate", "arg1_id": "938", "arg2_id": "951", "normalized": [] }, { "id": "982", "type": "Downregulator", "arg1_id": "939", "arg2_id": "954", "normalized": [] }, { "id": "983", "type": "Part_of", "arg1_id": "940", "arg2_id": "954", "normalized": [] } ]
984
17251447
[ { "id": "985", "type": "title and abstract", "text": [ "RPE65 is essential for the function of cone photoreceptors in NRL-deficient mice.\nPURPOSE: 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": [ [ 0, 1670 ] ] } ]
[ { "id": "986", "type": "CHEMICAL", "text": [ "retinoid" ], "offsets": [ [ 1123, 1131 ] ], "normalized": [] }, { "id": "987", "type": "CHEMICAL", "text": [ "11-cis retinal" ], "offsets": [ [ 1260, 1274 ] ], "normalized": [] }, { "id": "988", "type": "CHEMICAL", "text": [ "retinoid" ], "offsets": [ [ 1300, 1308 ] ], "normalized": [] }, { "id": "989", "type": "CHEMICAL", "text": [ "retinyl esters" ], "offsets": [ [ 1323, 1337 ] ], "normalized": [] }, { "id": "990", "type": "CHEMICAL", "text": [ "retinoid" ], "offsets": [ [ 1369, 1377 ] ], "normalized": [] }, { "id": "991", "type": "CHEMICAL", "text": [ "vitamin A" ], "offsets": [ [ 226, 235 ] ], "normalized": [] }, { "id": "992", "type": "CHEMICAL", "text": [ "11-cis retinal" ], "offsets": [ [ 1618, 1632 ] ], "normalized": [] }, { "id": "993", "type": "CHEMICAL", "text": [ "11-cis retinal" ], "offsets": [ [ 247, 261 ] ], "normalized": [] }, { "id": "994", "type": "CHEMICAL", "text": [ "11-cis retinal" ], "offsets": [ [ 299, 313 ] ], "normalized": [] }, { "id": "995", "type": "CHEMICAL", "text": [ "leucine" ], "offsets": [ [ 361, 368 ] ], "normalized": [] }, { "id": "996", "type": "CHEMICAL", "text": [ "retinoid" ], "offsets": [ [ 537, 545 ] ], "normalized": [] }, { "id": "997", "type": "CHEMICAL", "text": [ "retinoid" ], "offsets": [ [ 820, 828 ] ], "normalized": [] }, { "id": "998", "type": "CHEMICAL", "text": [ "retinaldehyde" ], "offsets": [ [ 966, 979 ] ], "normalized": [] }, { "id": "999", "type": "CHEMICAL", "text": [ "retinoid" ], "offsets": [ [ 1065, 1073 ] ], "normalized": [] }, { "id": "1000", "type": "GENE-Y", "text": [ "Nrl" ], "offsets": [ [ 1098, 1101 ] ], "normalized": [] }, { "id": "1001", "type": "GENE-Y", "text": [ "RPE65" ], "offsets": [ [ 1202, 1207 ] ], "normalized": [] }, { "id": "1002", "type": "GENE-Y", "text": [ "Nrl" ], "offsets": [ [ 1211, 1214 ] ], "normalized": [] }, { "id": "1003", "type": "GENE-N", "text": [ "Rho" ], "offsets": [ [ 1224, 1227 ] ], "normalized": [] }, { "id": "1004", "type": "GENE-N", "text": [ "cone opsin" ], "offsets": [ [ 209, 219 ] ], "normalized": [] }, { "id": "1005", "type": "GENE-Y", "text": [ "RPE65" ], "offsets": [ [ 1405, 1410 ] ], "normalized": [] }, { "id": "1006", "type": "GENE-Y", "text": [ "Nrl" ], "offsets": [ [ 1435, 1438 ] ], "normalized": [] }, { "id": "1007", "type": "GENE-Y", "text": [ "RPE65" ], "offsets": [ [ 1516, 1521 ] ], "normalized": [] }, { "id": "1008", "type": "GENE-Y", "text": [ "neural retina leucine zipper" ], "offsets": [ [ 347, 375 ] ], "normalized": [] }, { "id": "1009", "type": "GENE-Y", "text": [ "Nrl" ], "offsets": [ [ 387, 390 ] ], "normalized": [] }, { "id": "1010", "type": "GENE-N", "text": [ "rod opsin" ], "offsets": [ [ 401, 410 ] ], "normalized": [] }, { "id": "1011", "type": "GENE-N", "text": [ "Rho" ], "offsets": [ [ 412, 415 ] ], "normalized": [] }, { "id": "1012", "type": "GENE-Y", "text": [ "retinal pigment epithelial protein 65" ], "offsets": [ [ 604, 641 ] ], "normalized": [] }, { "id": "1013", "type": "GENE-Y", "text": [ "Rpe65" ], "offsets": [ [ 643, 648 ] ], "normalized": [] }, { "id": "1014", "type": "GENE-Y", "text": [ "RPE65" ], "offsets": [ [ 691, 696 ] ], "normalized": [] }, { "id": "1015", "type": "GENE-Y", "text": [ "Nrl" ], "offsets": [ [ 904, 907 ] ], "normalized": [] }, { "id": "1016", "type": "GENE-Y", "text": [ "RPE65" ], "offsets": [ [ 947, 952 ] ], "normalized": [] }, { "id": "1017", "type": "GENE-Y", "text": [ "cellular retinaldehyde-binding protein" ], "offsets": [ [ 957, 995 ] ], "normalized": [] }, { "id": "1018", "type": "GENE-Y", "text": [ "CRALBP" ], "offsets": [ [ 997, 1003 ] ], "normalized": [] }, { "id": "1019", "type": "GENE-Y", "text": [ "RPE65" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "1020", "type": "GENE-N", "text": [ "photoreceptors" ], "offsets": [ [ 44, 58 ] ], "normalized": [] }, { "id": "1021", "type": "GENE-Y", "text": [ "NRL" ], "offsets": [ [ 62, 65 ] ], "normalized": [] } ]
[]
[]
[]
1022
23360475
[ { "id": "1023", "type": "title and abstract", "text": [ "Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents.\nThe natural product tryptanthrin (1a) represents a potential lead for new tuberculosis (TB) drugs since tryptanthrin and its synthetic analogues possess potent in vitro activity against Mycobacterium tuberculosis (Mtb). However, in spite of their in vitro activity, none of these agents have been shown to be efficacious in vivo against animal models of TB. Described herein are syntheses of new tryptanthrin analogues together with a systematic investigation of their in vitro antitubercular activity and ADME properties followed by pharmacokinetic characterization in rodents for the most promising compounds. Those with the best potency and oral bioavailability were progressed to evaluations of efficacy against acute murine TB. The work aimed to prove the concept that this compound class can limit growth of Mtb during infection as well as to establish the SAR for in vitro activity against Mtb and the range of in vitro ADME parameters for this class of natural products. Novel C-11-deoxy (5b) and A-ring-saturated (6) tryptanthrin analogues were discovered that maintained activity against Mtb and showed improved solubility compared to tryptanthrin as well as evidence of oral bioavailability in rodents. However, neither 5b nor 6 demonstrated efficacy against acute murine TB following administration at doses up to 400 mg/kg daily for 4 weeks. Although 5b and 6 failed to inhibit replication or kill Mtb in vivo, they illuminate a path to new structural variations of the tryptanthrin scaffold that may maximize the potential of this class of compounds against TB." ], "offsets": [ [ 0, 1681 ] ] } ]
[ { "id": "1024", "type": "CHEMICAL", "text": [ "tryptanthrin" ], "offsets": [ [ 1132, 1144 ] ], "normalized": [] }, { "id": "1025", "type": "CHEMICAL", "text": [ "tryptanthrin" ], "offsets": [ [ 210, 222 ] ], "normalized": [] }, { "id": "1026", "type": "CHEMICAL", "text": [ "tryptanthrin" ], "offsets": [ [ 1251, 1263 ] ], "normalized": [] }, { "id": "1027", "type": "CHEMICAL", "text": [ "tryptanthrin" ], "offsets": [ [ 1589, 1601 ] ], "normalized": [] }, { "id": "1028", "type": "CHEMICAL", "text": [ "tryptanthrin" ], "offsets": [ [ 126, 138 ] ], "normalized": [] }, { "id": "1029", "type": "CHEMICAL", "text": [ "tryptanthrin" ], "offsets": [ [ 502, 514 ] ], "normalized": [] }, { "id": "1030", "type": "CHEMICAL", "text": [ "tryptanthrins" ], "offsets": [ [ 66, 79 ] ], "normalized": [] } ]
[]
[]
[]
1031
15110853
[ { "id": "1032", "type": "title and abstract", "text": [ "Carbonic anhydrase inhibitors: aromatic and heterocyclic sulfonamides incorporating adamantyl moieties with strong anticonvulsant activity.\nA series of aromatic/heterocyclic sulfonamides incorporating adamantyl moieties were prepared by reaction of aromatic/heterocyclic aminosulfonamides with the acyl chlorides derived from adamantyl-1-carboxylic acid and 1-adamantyl-acetic acid. Related derivatives were obtained from the above-mentioned aminosulfonamides with adamantyl isocyanate and adamantyl isothiocyanate, respectively. Some of these derivatives showed good inhibitory potency against two human CA isozymes involved in important physiological processes, CA I, and CA II, of the same order of magnitude as the clinically used drugs acetazolamide and methazolamide. The lipophilicity of the best CA inhibitors was determined and expressed as their experimental log k' IAM and theoretical ClogP value. Their lipophilicity was propitious with the crossing of the blood-brain barrier (log k' > IAM > 1.35). The anticonvulsant activity of some of the best CA inhibitors reported here has been evaluated in a MES test in mice. After intraperitoneal injection (30 mg kg(-1)), compounds A8 and A9 exhibited a high protection against electrically induced convulsions (> 90%). Their ED50 was 3.5 and 2.6 mg kg(-1), respectively." ], "offsets": [ [ 0, 1327 ] ] } ]
[ { "id": "1033", "type": "CHEMICAL", "text": [ "aromatic/heterocyclic aminosulfonamides" ], "offsets": [ [ 249, 288 ] ], "normalized": [] }, { "id": "1034", "type": "CHEMICAL", "text": [ "aromatic/heterocyclic sulfonamides" ], "offsets": [ [ 152, 186 ] ], "normalized": [] }, { "id": "1035", "type": "CHEMICAL", "text": [ "acyl chlorides" ], "offsets": [ [ 298, 312 ] ], "normalized": [] }, { "id": "1036", "type": "CHEMICAL", "text": [ "adamantyl-1-carboxylic acid" ], "offsets": [ [ 326, 353 ] ], "normalized": [] }, { "id": "1037", "type": "CHEMICAL", "text": [ "1-adamantyl-acetic acid" ], "offsets": [ [ 358, 381 ] ], "normalized": [] }, { "id": "1038", "type": "CHEMICAL", "text": [ "aminosulfonamides" ], "offsets": [ [ 442, 459 ] ], "normalized": [] }, { "id": "1039", "type": "CHEMICAL", "text": [ "adamantyl isocyanate" ], "offsets": [ [ 465, 485 ] ], "normalized": [] }, { "id": "1040", "type": "CHEMICAL", "text": [ "adamantyl isothiocyanate" ], "offsets": [ [ 490, 514 ] ], "normalized": [] }, { "id": "1041", "type": "CHEMICAL", "text": [ "acetazolamide" ], "offsets": [ [ 741, 754 ] ], "normalized": [] }, { "id": "1042", "type": "CHEMICAL", "text": [ "adamantyl" ], "offsets": [ [ 201, 210 ] ], "normalized": [] }, { "id": "1043", "type": "CHEMICAL", "text": [ "methazolamide" ], "offsets": [ [ 759, 772 ] ], "normalized": [] }, { "id": "1044", "type": "CHEMICAL", "text": [ "aromatic and heterocyclic sulfonamides" ], "offsets": [ [ 31, 69 ] ], "normalized": [] }, { "id": "1045", "type": "CHEMICAL", "text": [ "adamantyl" ], "offsets": [ [ 84, 93 ] ], "normalized": [] }, { "id": "1046", "type": "GENE-N", "text": [ "human CA" ], "offsets": [ [ 599, 607 ] ], "normalized": [] }, { "id": "1047", "type": "GENE-Y", "text": [ "CA I" ], "offsets": [ [ 664, 668 ] ], "normalized": [] }, { "id": "1048", "type": "GENE-Y", "text": [ "CA II" ], "offsets": [ [ 674, 679 ] ], "normalized": [] }, { "id": "1049", "type": "GENE-N", "text": [ "CA" ], "offsets": [ [ 804, 806 ] ], "normalized": [] }, { "id": "1050", "type": "GENE-N", "text": [ "CA" ], "offsets": [ [ 1060, 1062 ] ], "normalized": [] }, { "id": "1051", "type": "GENE-N", "text": [ "Carbonic anhydrase" ], "offsets": [ [ 0, 18 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1052", "type": "Downregulator", "arg1_id": "1044", "arg2_id": "1051", "normalized": [] }, { "id": "1053", "type": "Downregulator", "arg1_id": "1045", "arg2_id": "1051", "normalized": [] }, { "id": "1054", "type": "Downregulator", "arg1_id": "1041", "arg2_id": "1046", "normalized": [] }, { "id": "1055", "type": "Downregulator", "arg1_id": "1041", "arg2_id": "1047", "normalized": [] }, { "id": "1056", "type": "Downregulator", "arg1_id": "1041", "arg2_id": "1048", "normalized": [] }, { "id": "1057", "type": "Downregulator", "arg1_id": "1043", "arg2_id": "1046", "normalized": [] }, { "id": "1058", "type": "Downregulator", "arg1_id": "1043", "arg2_id": "1047", "normalized": [] }, { "id": "1059", "type": "Downregulator", "arg1_id": "1043", "arg2_id": "1048", "normalized": [] } ]
1060
23578391
[ { "id": "1061", "type": "title and abstract", "text": [ "Perinatal exposure to BDE-99 causes learning disorders and decreases serum thyroid hormone levels and BDNF gene expression in hippocampus in rat offspring.\nExposure of pregnant women to polybrominated diphenyl ethers (PBDEs) may mean serious health risks. The main goal of the present study was to examine the neurobehavioral changes in rat offspring that were perinatally exposed to one of the most prevalent PBDEs congeners found in humans, 2,2',4,4',5-pentaBDE (BDE-99). Rat dams were exposed to 0, 1 and 2mg/kg/day of BDE-99 from gestation day 6 to post-natal day 21. When pups were weaning, cortex and hippocampal gene expressions of brain-derived neurotrophic factor (BDNF) of the different isoforms of the thyroid hormone (TH) receptors (TRs) were evaluated. Serum TH levels were also determined. The remaining pups were assessed by neurobehavioral testing for learning and memory function. The results showed that maternal transference of BDE-99 produced a delay in the spatial learning task in the water maze test. Moreover, the open-field test revealed a significant dose-response anxiolytic effect. It was also found that the serum levels of triiodothyronine (T3), tetraiiodothyronine (T4) and free-T4 (FT4) decreased. Although no effect on the gene expression of the different isoforms of TRs was observed, the expression of the TH-mediated gene BDNF was down-regulated in the hippocampus. These results indicate a clear signal disruption of TH and reinforce previous studies in which neurotoxic effects of PBDEs in animal research were observed at levels comparable to those found in humans." ], "offsets": [ [ 0, 1604 ] ] } ]
[ { "id": "1062", "type": "CHEMICAL", "text": [ "tetraiiodothyronine" ], "offsets": [ [ 1176, 1195 ] ], "normalized": [] }, { "id": "1063", "type": "CHEMICAL", "text": [ "PBDEs" ], "offsets": [ [ 1519, 1524 ] ], "normalized": [] }, { "id": "1064", "type": "CHEMICAL", "text": [ "PBDEs" ], "offsets": [ [ 410, 415 ] ], "normalized": [] }, { "id": "1065", "type": "CHEMICAL", "text": [ "2,2',4,4',5-pentaBDE" ], "offsets": [ [ 443, 463 ] ], "normalized": [] }, { "id": "1066", "type": "CHEMICAL", "text": [ "polybrominated diphenyl ethers" ], "offsets": [ [ 186, 216 ] ], "normalized": [] }, { "id": "1067", "type": "CHEMICAL", "text": [ "BDE-99" ], "offsets": [ [ 465, 471 ] ], "normalized": [] }, { "id": "1068", "type": "CHEMICAL", "text": [ "BDE-99" ], "offsets": [ [ 522, 528 ] ], "normalized": [] }, { "id": "1069", "type": "CHEMICAL", "text": [ "thyroid hormone" ], "offsets": [ [ 713, 728 ] ], "normalized": [] }, { "id": "1070", "type": "CHEMICAL", "text": [ "PBDEs" ], "offsets": [ [ 218, 223 ] ], "normalized": [] }, { "id": "1071", "type": "CHEMICAL", "text": [ "BDE-99" ], "offsets": [ [ 947, 953 ] ], "normalized": [] }, { "id": "1072", "type": "CHEMICAL", "text": [ "triiodothyronine" ], "offsets": [ [ 1153, 1169 ] ], "normalized": [] }, { "id": "1073", "type": "CHEMICAL", "text": [ "BDE-99" ], "offsets": [ [ 22, 28 ] ], "normalized": [] }, { "id": "1074", "type": "CHEMICAL", "text": [ "thyroid hormone" ], "offsets": [ [ 75, 90 ] ], "normalized": [] }, { "id": "1075", "type": "GENE-N", "text": [ "TRs" ], "offsets": [ [ 1301, 1304 ] ], "normalized": [] }, { "id": "1076", "type": "GENE-Y", "text": [ "BDNF" ], "offsets": [ [ 1358, 1362 ] ], "normalized": [] }, { "id": "1077", "type": "GENE-Y", "text": [ "brain-derived neurotrophic factor" ], "offsets": [ [ 639, 672 ] ], "normalized": [] }, { "id": "1078", "type": "GENE-Y", "text": [ "BDNF" ], "offsets": [ [ 674, 678 ] ], "normalized": [] }, { "id": "1079", "type": "GENE-N", "text": [ "thyroid hormone (TH) receptors" ], "offsets": [ [ 713, 743 ] ], "normalized": [] }, { "id": "1080", "type": "GENE-N", "text": [ "TRs" ], "offsets": [ [ 745, 748 ] ], "normalized": [] }, { "id": "1081", "type": "GENE-Y", "text": [ "BDNF" ], "offsets": [ [ 102, 106 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1082", "type": "Downregulator", "arg1_id": "1073", "arg2_id": "1081", "normalized": [] } ]
1083
23432095
[ { "id": "1084", "type": "title and abstract", "text": [ "Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer.\nCastrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5α-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3·NADP(+)·2'-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC." ], "offsets": [ [ 0, 1372 ] ] } ]
[ { "id": "1085", "type": "CHEMICAL", "text": [ "androgen" ], "offsets": [ [ 329, 337 ] ], "normalized": [] }, { "id": "1086", "type": "CHEMICAL", "text": [ "androgen" ], "offsets": [ [ 361, 369 ] ], "normalized": [] }, { "id": "1087", "type": "CHEMICAL", "text": [ "androgen" ], "offsets": [ [ 418, 426 ] ], "normalized": [] }, { "id": "1088", "type": "CHEMICAL", "text": [ "androgens" ], "offsets": [ [ 514, 523 ] ], "normalized": [] }, { "id": "1089", "type": "CHEMICAL", "text": [ "5α-dihydrotestosterone" ], "offsets": [ [ 648, 670 ] ], "normalized": [] }, { "id": "1090", "type": "CHEMICAL", "text": [ "Indomethacin" ], "offsets": [ [ 672, 684 ] ], "normalized": [] }, { "id": "1091", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 849, 861 ] ], "normalized": [] }, { "id": "1092", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 1108, 1120 ] ], "normalized": [] }, { "id": "1093", "type": "CHEMICAL", "text": [ "NADP(+)" ], "offsets": [ [ 1165, 1172 ] ], "normalized": [] }, { "id": "1094", "type": "CHEMICAL", "text": [ "2'-des-methyl-indomethacin" ], "offsets": [ [ 1173, 1199 ] ], "normalized": [] }, { "id": "1095", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 36, 48 ] ], "normalized": [] }, { "id": "1096", "type": "CHEMICAL", "text": [ "17β-hydroxysteroid" ], "offsets": [ [ 96, 114 ] ], "normalized": [] }, { "id": "1097", "type": "GENE-Y", "text": [ "androgen receptor" ], "offsets": [ [ 361, 378 ] ], "normalized": [] }, { "id": "1098", "type": "GENE-Y", "text": [ "AKR1C3" ], "offsets": [ [ 441, 447 ] ], "normalized": [] }, { "id": "1099", "type": "GENE-Y", "text": [ "AKR1C3" ], "offsets": [ [ 536, 542 ] ], "normalized": [] }, { "id": "1100", "type": "GENE-Y", "text": [ "AKR1C3" ], "offsets": [ [ 579, 585 ] ], "normalized": [] }, { "id": "1101", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 616, 622 ] ], "normalized": [] }, { "id": "1102", "type": "GENE-Y", "text": [ "AKR1C2" ], "offsets": [ [ 623, 629 ] ], "normalized": [] }, { "id": "1103", "type": "GENE-N", "text": [ "cyclooxygenase" ], "offsets": [ [ 702, 716 ] ], "normalized": [] }, { "id": "1104", "type": "GENE-Y", "text": [ "AKR1C3" ], "offsets": [ [ 732, 738 ] ], "normalized": [] }, { "id": "1105", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 769, 775 ] ], "normalized": [] }, { "id": "1106", "type": "GENE-Y", "text": [ "AKR1C2" ], "offsets": [ [ 776, 782 ] ], "normalized": [] }, { "id": "1107", "type": "GENE-N", "text": [ "cyclooxygenase" ], "offsets": [ [ 895, 909 ] ], "normalized": [] }, { "id": "1108", "type": "GENE-Y", "text": [ "AKR1C3" ], "offsets": [ [ 941, 947 ] ], "normalized": [] }, { "id": "1109", "type": "GENE-Y", "text": [ "AKR1C3" ], "offsets": [ [ 1013, 1019 ] ], "normalized": [] }, { "id": "1110", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 1081, 1087 ] ], "normalized": [] }, { "id": "1111", "type": "GENE-Y", "text": [ "AKR1C2" ], "offsets": [ [ 1088, 1094 ] ], "normalized": [] }, { "id": "1112", "type": "GENE-Y", "text": [ "AKR1C3" ], "offsets": [ [ 1140, 1146 ] ], "normalized": [] }, { "id": "1113", "type": "GENE-Y", "text": [ "AKR1C3" ], "offsets": [ [ 1158, 1164 ] ], "normalized": [] }, { "id": "1114", "type": "GENE-Y", "text": [ "prostaglandin F synthase" ], "offsets": [ [ 129, 153 ] ], "normalized": [] }, { "id": "1115", "type": "GENE-Y", "text": [ "AKR1C3" ], "offsets": [ [ 81, 87 ] ], "normalized": [] }, { "id": "1116", "type": "GENE-Y", "text": [ "Type 5 17β-hydroxysteroid dehydrogenase" ], "offsets": [ [ 89, 128 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1117", "type": "Downregulator", "arg1_id": "1095", "arg2_id": "1115", "normalized": [] }, { "id": "1118", "type": "Downregulator", "arg1_id": "1095", "arg2_id": "1116", "normalized": [] }, { "id": "1119", "type": "Downregulator", "arg1_id": "1095", "arg2_id": "1114", "normalized": [] }, { "id": "1120", "type": "Substrate", "arg1_id": "1088", "arg2_id": "1098", "normalized": [] }, { "id": "1121", "type": "Downregulator", "arg1_id": "1090", "arg2_id": "1103", "normalized": [] }, { "id": "1122", "type": "Downregulator", "arg1_id": "1090", "arg2_id": "1104", "normalized": [] }, { "id": "1123", "type": "Downregulator", "arg1_id": "1091", "arg2_id": "1107", "normalized": [] }, { "id": "1124", "type": "Downregulator", "arg1_id": "1091", "arg2_id": "1108", "normalized": [] }, { "id": "1125", "type": "Regulator", "arg1_id": "1093", "arg2_id": "1113", "normalized": [] }, { "id": "1126", "type": "Regulator", "arg1_id": "1094", "arg2_id": "1113", "normalized": [] }, { "id": "1127", "type": "Substrate", "arg1_id": "1085", "arg2_id": "1097", "normalized": [] }, { "id": "1128", "type": "Substrate", "arg1_id": "1087", "arg2_id": "1097", "normalized": [] }, { "id": "1129", "type": "Not", "arg1_id": "1090", "arg2_id": "1105", "normalized": [] }, { "id": "1130", "type": "Not", "arg1_id": "1090", "arg2_id": "1106", "normalized": [] } ]
1131
23613080
[ { "id": "1132", "type": "title and abstract", "text": [ "Hierarchical NiO microflake films with high coloration efficiency, cyclic stability and low power consumption for applications in a complementary electrochromic device.\nWe have demonstrated that thin films of hierarchical NiO microflakes assembled from nanoleaves can be grown directly on FTO-coated glass substrates using a facile and template-free hydrothermal technique. This hierarchical structure holds the advantages of both nanometre-sized building blocks and microsized assemblies. Thus, the films exhibit highly enhanced electrochromic performances and cyclic stability due to their high surface area and good electrochemical stability. Moreover, a complementary electrochromic device combining the hierarchical NiO microflake film with a self-weaving WO3 nanoflake film is fabricated to further improve the electrochromic performance. As a result, the complementary electrochromic device shows a high optical modulation (73.2% at 550 nm), large coloration efficiency (146.9 cm(2) C(-1) at 550 nm by applying a low coloration voltage of -1.0 V) and fast switching responses with a coloring time of 1.8 s and a bleaching time of 3.2 s. It is also observed that there is no significant degradation of the electrochromic properties after 2000 continuous coloration/bleaching cycles, making it attractive for practical applications." ], "offsets": [ [ 0, 1337 ] ] } ]
[ { "id": "1133", "type": "CHEMICAL", "text": [ "FTO" ], "offsets": [ [ 289, 292 ] ], "normalized": [] }, { "id": "1134", "type": "CHEMICAL", "text": [ "NiO" ], "offsets": [ [ 222, 225 ] ], "normalized": [] }, { "id": "1135", "type": "CHEMICAL", "text": [ "NiO" ], "offsets": [ [ 721, 724 ] ], "normalized": [] }, { "id": "1136", "type": "CHEMICAL", "text": [ "WO3" ], "offsets": [ [ 761, 764 ] ], "normalized": [] }, { "id": "1137", "type": "CHEMICAL", "text": [ "NiO" ], "offsets": [ [ 13, 16 ] ], "normalized": [] } ]
[]
[]
[]
1138
15132128
[ { "id": "1139", "type": "title and abstract", "text": [ "Enzyme expression profiles suggest the novel tumor-activated fluoropyrimidine carbamate capecitabine (Xeloda) might be effective against papillary thyroid cancers of children and young adults.\nPURPOSE: The fluoropyrimidine carbamate (capecitabine) is converted to 5-fluorouracil (5-FU) by thymidine phosphorylase (TP) inside target tissues. 5-FU interferes with DNA synthesis by blocking thymidylate synthase (TS) but is inactivated by dihydropyrimidine dehydrogenase (DPD). Favorable enzyme profiles (high TP and low DPD) generate high intratumor levels of 5-FU that are effective against many tumors, especially those with low TS. Capecitabine has not been tested against thyroid cancers, and it is not known to what extent thyroid cancers express TP, TS or DPD. METHODS: To test this, we determined TP, TS and DPD in 19 thyroid cancers from young patients (14 papillary, 4 follicular, 1 medullary) by immunohistochemistry. After approval by the Human Use Committee, the intensity of TP, TS, and DPD staining was determined by two independent examiners and graded (absent=0 to intense=3) with >90% concordance. RESULTS: TS was detected in 7/19 cancers (37%), TP in 14/19 cancers (74%) and DPD in 14/19 cancers (74%). In six tumors, TP was more intense that DPD, suggesting capecitabine sensitivity. Only five tumors failed to express TP but four of these expressed DPD, suggesting capecitabine resistance. Overall, 6/19 tumors (32% of the total) had a favorable expression profile, and all of them were papillary cancers. CONCLUSIONS: We conclude that the majority of differentiated thyroid cancers (74%) express TP and low levels of TS (63% undetectable). The results support the hypothesis that capecitabine is activated in the majority of differentiated thyroid cancers and that 32% have favorable expression of all three enzymes (TP, TS, and DPD)." ], "offsets": [ [ 0, 1853 ] ] } ]
[ { "id": "1140", "type": "CHEMICAL", "text": [ "capecitabine" ], "offsets": [ [ 1383, 1395 ] ], "normalized": [] }, { "id": "1141", "type": "CHEMICAL", "text": [ "fluoropyrimidine carbamate" ], "offsets": [ [ 206, 232 ] ], "normalized": [] }, { "id": "1142", "type": "CHEMICAL", "text": [ "5-FU" ], "offsets": [ [ 341, 345 ] ], "normalized": [] }, { "id": "1143", "type": "CHEMICAL", "text": [ "capecitabine" ], "offsets": [ [ 1699, 1711 ] ], "normalized": [] }, { "id": "1144", "type": "CHEMICAL", "text": [ "thymidylate" ], "offsets": [ [ 388, 399 ] ], "normalized": [] }, { "id": "1145", "type": "CHEMICAL", "text": [ "dihydropyrimidine" ], "offsets": [ [ 436, 453 ] ], "normalized": [] }, { "id": "1146", "type": "CHEMICAL", "text": [ "5-FU" ], "offsets": [ [ 558, 562 ] ], "normalized": [] }, { "id": "1147", "type": "CHEMICAL", "text": [ "capecitabine" ], "offsets": [ [ 234, 246 ] ], "normalized": [] }, { "id": "1148", "type": "CHEMICAL", "text": [ "Capecitabine" ], "offsets": [ [ 633, 645 ] ], "normalized": [] }, { "id": "1149", "type": "CHEMICAL", "text": [ "5-fluorouracil" ], "offsets": [ [ 264, 278 ] ], "normalized": [] }, { "id": "1150", "type": "CHEMICAL", "text": [ "5-FU" ], "offsets": [ [ 280, 284 ] ], "normalized": [] }, { "id": "1151", "type": "CHEMICAL", "text": [ "thymidine" ], "offsets": [ [ 289, 298 ] ], "normalized": [] }, { "id": "1152", "type": "CHEMICAL", "text": [ "Xeloda" ], "offsets": [ [ 102, 108 ] ], "normalized": [] }, { "id": "1153", "type": "CHEMICAL", "text": [ "fluoropyrimidine carbamate" ], "offsets": [ [ 61, 87 ] ], "normalized": [] }, { "id": "1154", "type": "CHEMICAL", "text": [ "capecitabine" ], "offsets": [ [ 88, 100 ] ], "normalized": [] }, { "id": "1155", "type": "GENE-Y", "text": [ "TP" ], "offsets": [ [ 1234, 1236 ] ], "normalized": [] }, { "id": "1156", "type": "GENE-Y", "text": [ "DPD" ], "offsets": [ [ 1259, 1262 ] ], "normalized": [] }, { "id": "1157", "type": "GENE-Y", "text": [ "TP" ], "offsets": [ [ 1336, 1338 ] ], "normalized": [] }, { "id": "1158", "type": "GENE-Y", "text": [ "DPD" ], "offsets": [ [ 1367, 1370 ] ], "normalized": [] }, { "id": "1159", "type": "GENE-Y", "text": [ "TP" ], "offsets": [ [ 314, 316 ] ], "normalized": [] }, { "id": "1160", "type": "GENE-Y", "text": [ "TP" ], "offsets": [ [ 1615, 1617 ] ], "normalized": [] }, { "id": "1161", "type": "GENE-Y", "text": [ "TS" ], "offsets": [ [ 1636, 1638 ] ], "normalized": [] }, { "id": "1162", "type": "GENE-Y", "text": [ "TP" ], "offsets": [ [ 1836, 1838 ] ], "normalized": [] }, { "id": "1163", "type": "GENE-Y", "text": [ "TS" ], "offsets": [ [ 1840, 1842 ] ], "normalized": [] }, { "id": "1164", "type": "GENE-Y", "text": [ "DPD" ], "offsets": [ [ 1848, 1851 ] ], "normalized": [] }, { "id": "1165", "type": "GENE-Y", "text": [ "thymidylate synthase" ], "offsets": [ [ 388, 408 ] ], "normalized": [] }, { "id": "1166", "type": "GENE-Y", "text": [ "TS" ], "offsets": [ [ 410, 412 ] ], "normalized": [] }, { "id": "1167", "type": "GENE-Y", "text": [ "dihydropyrimidine dehydrogenase" ], "offsets": [ [ 436, 467 ] ], "normalized": [] }, { "id": "1168", "type": "GENE-Y", "text": [ "DPD" ], "offsets": [ [ 469, 472 ] ], "normalized": [] }, { "id": "1169", "type": "GENE-Y", "text": [ "TP" ], "offsets": [ [ 507, 509 ] ], "normalized": [] }, { "id": "1170", "type": "GENE-Y", "text": [ "DPD" ], "offsets": [ [ 518, 521 ] ], "normalized": [] }, { "id": "1171", "type": "GENE-Y", "text": [ "TS" ], "offsets": [ [ 629, 631 ] ], "normalized": [] }, { "id": "1172", "type": "GENE-Y", "text": [ "TP" ], "offsets": [ [ 750, 752 ] ], "normalized": [] }, { "id": "1173", "type": "GENE-Y", "text": [ "TS" ], "offsets": [ [ 754, 756 ] ], "normalized": [] }, { "id": "1174", "type": "GENE-Y", "text": [ "DPD" ], "offsets": [ [ 760, 763 ] ], "normalized": [] }, { "id": "1175", "type": "GENE-Y", "text": [ "TP" ], "offsets": [ [ 802, 804 ] ], "normalized": [] }, { "id": "1176", "type": "GENE-Y", "text": [ "TS" ], "offsets": [ [ 806, 808 ] ], "normalized": [] }, { "id": "1177", "type": "GENE-Y", "text": [ "DPD" ], "offsets": [ [ 813, 816 ] ], "normalized": [] }, { "id": "1178", "type": "GENE-Y", "text": [ "TP" ], "offsets": [ [ 986, 988 ] ], "normalized": [] }, { "id": "1179", "type": "GENE-Y", "text": [ "TS" ], "offsets": [ [ 990, 992 ] ], "normalized": [] }, { "id": "1180", "type": "GENE-Y", "text": [ "DPD" ], "offsets": [ [ 998, 1001 ] ], "normalized": [] }, { "id": "1181", "type": "GENE-Y", "text": [ "TS" ], "offsets": [ [ 1122, 1124 ] ], "normalized": [] }, { "id": "1182", "type": "GENE-Y", "text": [ "thymidine phosphorylase" ], "offsets": [ [ 289, 312 ] ], "normalized": [] }, { "id": "1183", "type": "GENE-Y", "text": [ "TP" ], "offsets": [ [ 1161, 1163 ] ], "normalized": [] }, { "id": "1184", "type": "GENE-Y", "text": [ "DPD" ], "offsets": [ [ 1191, 1194 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1185", "type": "Substrate", "arg1_id": "1141", "arg2_id": "1182", "normalized": [] }, { "id": "1186", "type": "Substrate", "arg1_id": "1147", "arg2_id": "1182", "normalized": [] }, { "id": "1187", "type": "Substrate", "arg1_id": "1141", "arg2_id": "1159", "normalized": [] }, { "id": "1188", "type": "Substrate", "arg1_id": "1147", "arg2_id": "1159", "normalized": [] }, { "id": "1189", "type": "Substrate", "arg1_id": "1149", "arg2_id": "1182", "normalized": [] }, { "id": "1190", "type": "Substrate", "arg1_id": "1150", "arg2_id": "1182", "normalized": [] }, { "id": "1191", "type": "Substrate", "arg1_id": "1149", "arg2_id": "1159", "normalized": [] }, { "id": "1192", "type": "Substrate", "arg1_id": "1150", "arg2_id": "1159", "normalized": [] }, { "id": "1193", "type": "Downregulator", "arg1_id": "1142", "arg2_id": "1165", "normalized": [] }, { "id": "1194", "type": "Downregulator", "arg1_id": "1142", "arg2_id": "1166", "normalized": [] }, { "id": "1195", "type": "Substrate", "arg1_id": "1142", "arg2_id": "1167", "normalized": [] }, { "id": "1196", "type": "Substrate", "arg1_id": "1142", "arg2_id": "1168", "normalized": [] } ]
1197
23576111
[ { "id": "1198", "type": "title and abstract", "text": [ "Protective effects of green tea on antioxidative biomarkers in chemical laboratory workers.\nChemical materials are environmental contaminants, are extensively used in laboratories, and may cause various forms of health hazards in laboratory workers. Therefore, this toxicity most likely is a result of the oxidative metabolism of chemical to reactive products. As green tea (GT) possesses antioxidant effects, the objective of this study was to examine any amelioration oxidative stress in chemical laboratory workers drinking one cup (3 g/300 ml water) of freshly prepared tea once daily. Baseline characteristics including age, sex, smoking, fruit consumption, and duration of exposure were recorded via questionnaire to the subjects. Saliva level oxidative stress parameters such as total antioxidant capacity (TAC), glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) were estimated before and after consumption of GT in these workers. Treatment of subjects with GT induced a significant reduction in saliva GPx activity (406.61 ± 22.07 vs. 238.96 ± 16.26 U/l p = 0.001) and induction in TAC (0.46 ± 0.029 μmol/ml vs. 0.56 ± 0.031, p = 0.016). No statistically significant alteration was found for saliva SOD (0.080 ± 0.0019 vs. 0.079 ± 0.0014, p > 0.05) and CAT (20.36 ± 0.69 vs. 19.78 ± 0.71, p > 0.05) after 28 days treatment by GT. These results demonstrate that drinking GT during chemical exposure can reduce several parameters indicative of oxidative stress. In conclusion, using GT as a dietary supplement can be a rational protocol to control source of hazards in chemical laboratory workers." ], "offsets": [ [ 0, 1630 ] ] } ]
[ { "id": "1199", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 820, 831 ] ], "normalized": [] }, { "id": "1200", "type": "CHEMICAL", "text": [ "superoxide" ], "offsets": [ [ 870, 880 ] ], "normalized": [] }, { "id": "1201", "type": "GENE-N", "text": [ "SOD" ], "offsets": [ [ 1234, 1237 ] ], "normalized": [] }, { "id": "1202", "type": "GENE-Y", "text": [ "CAT" ], "offsets": [ [ 1288, 1291 ] ], "normalized": [] }, { "id": "1203", "type": "GENE-N", "text": [ "glutathione peroxidase" ], "offsets": [ [ 820, 842 ] ], "normalized": [] }, { "id": "1204", "type": "GENE-N", "text": [ "GPx" ], "offsets": [ [ 844, 847 ] ], "normalized": [] }, { "id": "1205", "type": "GENE-Y", "text": [ "catalase" ], "offsets": [ [ 850, 858 ] ], "normalized": [] }, { "id": "1206", "type": "GENE-Y", "text": [ "CAT" ], "offsets": [ [ 860, 863 ] ], "normalized": [] }, { "id": "1207", "type": "GENE-N", "text": [ "superoxide dismutase" ], "offsets": [ [ 870, 890 ] ], "normalized": [] }, { "id": "1208", "type": "GENE-N", "text": [ "SOD" ], "offsets": [ [ 892, 895 ] ], "normalized": [] }, { "id": "1209", "type": "GENE-N", "text": [ "GPx" ], "offsets": [ [ 1037, 1040 ] ], "normalized": [] } ]
[]
[]
[]
1210
6645495
[ { "id": "1211", "type": "title and abstract", "text": [ "Binding of progestagens to receptor proteins in MCF-7 cells.\nWith the aim of finding an explanation for the biological properties of progestagens currently used for contraceptive purposes, we have assessed their specificity for progesterone, androgen and oestrogen receptors in MCF-7 cells. The specificity of progestagens for the progesterone receptors in the cytosol fraction of MCF-7 cells was similar to that for progesterone receptors in human and rabbit myometrial cytosol but different from that for the progesterone receptor in rat myometrial cytosol. At 37 degrees C the relative affinity of 3-keto-desogestrel, the major metabolite of desogestrel, for the progesterone receptor in intact MCF-7 cells was twice that of levonorgestrel and Org 2058, three times that of medroxy-progesterone acetate (MPA), 4.5 times that of norethisterone and 5 times that of progesterone and cyproterone acetate whereas at 4 degrees C in the cytosol fraction of MCF-7 cells exposed to molybdate (nontransformed receptor complexes) 3-keto-desogestrel and Org 2058 displayed similar affinity. The stronger binding of 3-keto-desogestrel in intact cells was due to the higher stability of its complex with the progesterone receptor. At 37 degrees C the relative affinity of 3-keto-desogestrel for the androgen receptor in intact MCF-7 cells was half that of levonorgestrel, similar to that of norethisterone and medroxyprogesterone acetate (MPA) and at least three times higher than that of progestagens with anti-androgenic activity whereas at 4 degrees C in the cytosol fraction exposed to molybdate there was no clear difference between the relative affinities of progestagens with androgenic and anti-androgenic properties. Of the progestagens tested in this study, only norethinodrel displayed measurable but very low relative affinity for the oestrogen receptor in MCF-7 cells. We conclude that the present results of binding studies with intact MCF-7 cells correlate better with the known hormonal properties of progestagens than those obtained with the cytosol fraction exposed to molybdate at 4 degrees C." ], "offsets": [ [ 0, 2101 ] ] } ]
[ { "id": "1212", "type": "CHEMICAL", "text": [ "3-keto-desogestrel" ], "offsets": [ [ 1106, 1124 ] ], "normalized": [] }, { "id": "1213", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 1197, 1209 ] ], "normalized": [] }, { "id": "1214", "type": "CHEMICAL", "text": [ "3-keto-desogestrel" ], "offsets": [ [ 1261, 1279 ] ], "normalized": [] }, { "id": "1215", "type": "CHEMICAL", "text": [ "levonorgestrel" ], "offsets": [ [ 1345, 1359 ] ], "normalized": [] }, { "id": "1216", "type": "CHEMICAL", "text": [ "norethisterone" ], "offsets": [ [ 1380, 1394 ] ], "normalized": [] }, { "id": "1217", "type": "CHEMICAL", "text": [ "medroxyprogesterone acetate" ], "offsets": [ [ 1399, 1426 ] ], "normalized": [] }, { "id": "1218", "type": "CHEMICAL", "text": [ "MPA" ], "offsets": [ [ 1428, 1431 ] ], "normalized": [] }, { "id": "1219", "type": "CHEMICAL", "text": [ "progestagens" ], "offsets": [ [ 1478, 1490 ] ], "normalized": [] }, { "id": "1220", "type": "CHEMICAL", "text": [ "molybdate" ], "offsets": [ [ 1579, 1588 ] ], "normalized": [] }, { "id": "1221", "type": "CHEMICAL", "text": [ "progestagens" ], "offsets": [ [ 1654, 1666 ] ], "normalized": [] }, { "id": "1222", "type": "CHEMICAL", "text": [ "progestagens" ], "offsets": [ [ 1722, 1734 ] ], "normalized": [] }, { "id": "1223", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 228, 240 ] ], "normalized": [] }, { "id": "1224", "type": "CHEMICAL", "text": [ "norethinodrel" ], "offsets": [ [ 1762, 1775 ] ], "normalized": [] }, { "id": "1225", "type": "CHEMICAL", "text": [ "oestrogen" ], "offsets": [ [ 1836, 1845 ] ], "normalized": [] }, { "id": "1226", "type": "CHEMICAL", "text": [ "androgen" ], "offsets": [ [ 242, 250 ] ], "normalized": [] }, { "id": "1227", "type": "CHEMICAL", "text": [ "oestrogen" ], "offsets": [ [ 255, 264 ] ], "normalized": [] }, { "id": "1228", "type": "CHEMICAL", "text": [ "progestagens" ], "offsets": [ [ 2006, 2018 ] ], "normalized": [] }, { "id": "1229", "type": "CHEMICAL", "text": [ "molybdate" ], "offsets": [ [ 2076, 2085 ] ], "normalized": [] }, { "id": "1230", "type": "CHEMICAL", "text": [ "progestagens" ], "offsets": [ [ 310, 322 ] ], "normalized": [] }, { "id": "1231", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 331, 343 ] ], "normalized": [] }, { "id": "1232", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 417, 429 ] ], "normalized": [] }, { "id": "1233", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 511, 523 ] ], "normalized": [] }, { "id": "1234", "type": "CHEMICAL", "text": [ "3-keto-desogestrel" ], "offsets": [ [ 601, 619 ] ], "normalized": [] }, { "id": "1235", "type": "CHEMICAL", "text": [ "desogestrel" ], "offsets": [ [ 645, 656 ] ], "normalized": [] }, { "id": "1236", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 666, 678 ] ], "normalized": [] }, { "id": "1237", "type": "CHEMICAL", "text": [ "levonorgestrel" ], "offsets": [ [ 728, 742 ] ], "normalized": [] }, { "id": "1238", "type": "CHEMICAL", "text": [ "Org 2058" ], "offsets": [ [ 747, 755 ] ], "normalized": [] }, { "id": "1239", "type": "CHEMICAL", "text": [ "medroxy-progesterone acetate" ], "offsets": [ [ 777, 805 ] ], "normalized": [] }, { "id": "1240", "type": "CHEMICAL", "text": [ "progestagens" ], "offsets": [ [ 133, 145 ] ], "normalized": [] }, { "id": "1241", "type": "CHEMICAL", "text": [ "MPA" ], "offsets": [ [ 807, 810 ] ], "normalized": [] }, { "id": "1242", "type": "CHEMICAL", "text": [ "norethisterone" ], "offsets": [ [ 831, 845 ] ], "normalized": [] }, { "id": "1243", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 866, 878 ] ], "normalized": [] }, { "id": "1244", "type": "CHEMICAL", "text": [ "cyproterone acetate" ], "offsets": [ [ 883, 902 ] ], "normalized": [] }, { "id": "1245", "type": "CHEMICAL", "text": [ "molybdate" ], "offsets": [ [ 976, 985 ] ], "normalized": [] }, { "id": "1246", "type": "CHEMICAL", "text": [ "3-keto-desogestrel" ], "offsets": [ [ 1022, 1040 ] ], "normalized": [] }, { "id": "1247", "type": "CHEMICAL", "text": [ "Org 2058" ], "offsets": [ [ 1045, 1053 ] ], "normalized": [] }, { "id": "1248", "type": "CHEMICAL", "text": [ "progestagens" ], "offsets": [ [ 11, 23 ] ], "normalized": [] }, { "id": "1249", "type": "GENE-Y", "text": [ "progesterone receptor" ], "offsets": [ [ 1197, 1218 ] ], "normalized": [] }, { "id": "1250", "type": "GENE-Y", "text": [ "androgen receptor" ], "offsets": [ [ 1288, 1305 ] ], "normalized": [] }, { "id": "1251", "type": "GENE-N", "text": [ "progesterone, androgen and oestrogen receptors" ], "offsets": [ [ 228, 274 ] ], "normalized": [] }, { "id": "1252", "type": "GENE-Y", "text": [ "oestrogen receptor" ], "offsets": [ [ 1836, 1854 ] ], "normalized": [] }, { "id": "1253", "type": "GENE-Y", "text": [ "progesterone receptors" ], "offsets": [ [ 331, 353 ] ], "normalized": [] }, { "id": "1254", "type": "GENE-Y", "text": [ "progesterone receptors" ], "offsets": [ [ 417, 439 ] ], "normalized": [] }, { "id": "1255", "type": "GENE-Y", "text": [ "progesterone receptor" ], "offsets": [ [ 511, 532 ] ], "normalized": [] }, { "id": "1256", "type": "GENE-Y", "text": [ "progesterone receptor" ], "offsets": [ [ 666, 687 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1257", "type": "Regulator", "arg1_id": "1230", "arg2_id": "1253", "normalized": [] }, { "id": "1258", "type": "Regulator", "arg1_id": "1230", "arg2_id": "1254", "normalized": [] }, { "id": "1259", "type": "Regulator", "arg1_id": "1230", "arg2_id": "1255", "normalized": [] }, { "id": "1260", "type": "Regulator", "arg1_id": "1234", "arg2_id": "1256", "normalized": [] }, { "id": "1261", "type": "Regulator", "arg1_id": "1237", "arg2_id": "1256", "normalized": [] }, { "id": "1262", "type": "Regulator", "arg1_id": "1238", "arg2_id": "1256", "normalized": [] }, { "id": "1263", "type": "Regulator", "arg1_id": "1239", "arg2_id": "1256", "normalized": [] }, { "id": "1264", "type": "Regulator", "arg1_id": "1241", "arg2_id": "1256", "normalized": [] }, { "id": "1265", "type": "Regulator", "arg1_id": "1242", "arg2_id": "1256", "normalized": [] }, { "id": "1266", "type": "Regulator", "arg1_id": "1243", "arg2_id": "1256", "normalized": [] }, { "id": "1267", "type": "Regulator", "arg1_id": "1244", "arg2_id": "1256", "normalized": [] }, { "id": "1268", "type": "Regulator", "arg1_id": "1246", "arg2_id": "1256", "normalized": [] }, { "id": "1269", "type": "Regulator", "arg1_id": "1247", "arg2_id": "1256", "normalized": [] }, { "id": "1270", "type": "Regulator", "arg1_id": "1212", "arg2_id": "1249", "normalized": [] }, { "id": "1271", "type": "Regulator", "arg1_id": "1214", "arg2_id": "1250", "normalized": [] }, { "id": "1272", "type": "Regulator", "arg1_id": "1215", "arg2_id": "1250", "normalized": [] }, { "id": "1273", "type": "Regulator", "arg1_id": "1216", "arg2_id": "1250", "normalized": [] }, { "id": "1274", "type": "Regulator", "arg1_id": "1217", "arg2_id": "1250", "normalized": [] }, { "id": "1275", "type": "Regulator", "arg1_id": "1218", "arg2_id": "1250", "normalized": [] }, { "id": "1276", "type": "Regulator", "arg1_id": "1219", "arg2_id": "1250", "normalized": [] }, { "id": "1277", "type": "Regulator", "arg1_id": "1221", "arg2_id": "1250", "normalized": [] }, { "id": "1278", "type": "Regulator", "arg1_id": "1224", "arg2_id": "1252", "normalized": [] }, { "id": "1279", "type": "Regulator", "arg1_id": "1222", "arg2_id": "1252", "normalized": [] } ]
1280
19428322
[ { "id": "1281", "type": "title and abstract", "text": [ "AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C.\nWe investigated the effect of compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), on proliferation and viability of human U251 and rat C6 glioma cell lines. Compound C caused G(2)/M cell cycle block, accompanied by apoptotic glioma cell death characterized by caspase activation, phosphatidylserine exposure and DNA fragmentation. The mechanisms underlying the pro-apoptotic action of compound C involved induction of oxidative stress and downregulation of antiapoptotic molecule Bcl-2, while no alteration of pro-apoptotic Bax was observed. Compound C diminished AMPK phosphorylation and enzymatic activity, resulting in reduced phosphorylation of its target acetyl CoA carboxylase. AMPK activators metformin and AICAR partly prevented the cell cycle block, oxidative stress and apoptosis induced by compound C. The small interfering RNA (siRNA) targeting of human AMPK mimicked compound C-induced G(2)/M cell cycle arrest, but failed to induce oxidative stress and apoptosis in U251 glioma cells. In conclusion, our data indicate that AMPK inhibition is required, but not sufficient for compound C-mediated apoptotic death of glioma cells." ], "offsets": [ [ 0, 1316 ] ] } ]
[ { "id": "1282", "type": "CHEMICAL", "text": [ "AMP" ], "offsets": [ [ 220, 223 ] ], "normalized": [] }, { "id": "1283", "type": "CHEMICAL", "text": [ "phosphatidylserine" ], "offsets": [ [ 455, 473 ] ], "normalized": [] }, { "id": "1284", "type": "CHEMICAL", "text": [ "acetyl CoA" ], "offsets": [ [ 835, 845 ] ], "normalized": [] }, { "id": "1285", "type": "CHEMICAL", "text": [ "metformin" ], "offsets": [ [ 875, 884 ] ], "normalized": [] }, { "id": "1286", "type": "CHEMICAL", "text": [ "AICAR" ], "offsets": [ [ 889, 894 ] ], "normalized": [] }, { "id": "1287", "type": "CHEMICAL", "text": [ "AMP" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "1288", "type": "GENE-N", "text": [ "AMP-activated protein kinase" ], "offsets": [ [ 220, 248 ] ], "normalized": [] }, { "id": "1289", "type": "GENE-N", "text": [ "AMPK" ], "offsets": [ [ 1212, 1216 ] ], "normalized": [] }, { "id": "1290", "type": "GENE-N", "text": [ "AMPK" ], "offsets": [ [ 250, 254 ] ], "normalized": [] }, { "id": "1291", "type": "GENE-N", "text": [ "caspase" ], "offsets": [ [ 435, 442 ] ], "normalized": [] }, { "id": "1292", "type": "GENE-N", "text": [ "Bcl-2" ], "offsets": [ [ 655, 660 ] ], "normalized": [] }, { "id": "1293", "type": "GENE-N", "text": [ "Bax" ], "offsets": [ [ 699, 702 ] ], "normalized": [] }, { "id": "1294", "type": "GENE-N", "text": [ "AMPK" ], "offsets": [ [ 739, 743 ] ], "normalized": [] }, { "id": "1295", "type": "GENE-N", "text": [ "acetyl CoA carboxylase" ], "offsets": [ [ 835, 857 ] ], "normalized": [] }, { "id": "1296", "type": "GENE-N", "text": [ "AMPK" ], "offsets": [ [ 859, 863 ] ], "normalized": [] }, { "id": "1297", "type": "GENE-Y", "text": [ "human AMPK" ], "offsets": [ [ 1035, 1045 ] ], "normalized": [] }, { "id": "1298", "type": "GENE-N", "text": [ "AMP-activated protein kinase" ], "offsets": [ [ 0, 28 ] ], "normalized": [] }, { "id": "1299", "type": "CHEMICAL", "text": [ "compound C" ], "offsets": [ [ 108, 118 ] ], "normalized": [] }, { "id": "1300", "type": "CHEMICAL", "text": [ "compound C" ], "offsets": [ [ 150, 160 ] ], "normalized": [] }, { "id": "1301", "type": "CHEMICAL", "text": [ "Compound C" ], "offsets": [ [ 332, 342 ] ], "normalized": [] }, { "id": "1302", "type": "CHEMICAL", "text": [ "compound C" ], "offsets": [ [ 560, 570 ] ], "normalized": [] }, { "id": "1303", "type": "CHEMICAL", "text": [ "Compound C" ], "offsets": [ [ 717, 727 ] ], "normalized": [] }, { "id": "1304", "type": "CHEMICAL", "text": [ "compound C" ], "offsets": [ [ 976, 986 ] ], "normalized": [] }, { "id": "1305", "type": "CHEMICAL", "text": [ "compound C" ], "offsets": [ [ 1055, 1065 ] ], "normalized": [] }, { "id": "1306", "type": "CHEMICAL", "text": [ "compound C" ], "offsets": [ [ 1264, 1274 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1307", "type": "Regulator", "arg1_id": "1299", "arg2_id": "1298", "normalized": [] }, { "id": "1308", "type": "Downregulator", "arg1_id": "1300", "arg2_id": "1288", "normalized": [] }, { "id": "1309", "type": "Downregulator", "arg1_id": "1300", "arg2_id": "1290", "normalized": [] }, { "id": "1310", "type": "Upregulator", "arg1_id": "1301", "arg2_id": "1291", "normalized": [] }, { "id": "1311", "type": "Downregulator", "arg1_id": "1302", "arg2_id": "1292", "normalized": [] }, { "id": "1312", "type": "Not", "arg1_id": "1302", "arg2_id": "1293", "normalized": [] }, { "id": "1313", "type": "Downregulator", "arg1_id": "1303", "arg2_id": "1295", "normalized": [] }, { "id": "1314", "type": "Upregulator", "arg1_id": "1285", "arg2_id": "1296", "normalized": [] }, { "id": "1315", "type": "Upregulator", "arg1_id": "1286", "arg2_id": "1296", "normalized": [] }, { "id": "1316", "type": "Downregulator", "arg1_id": "1306", "arg2_id": "1289", "normalized": [] }, { "id": "1317", "type": "Downregulator", "arg1_id": "1303", "arg2_id": "1294", "normalized": [] } ]
1318
14766200
[ { "id": "1319", "type": "title and abstract", "text": [ "Expression of DDAH1 in chick and rat embryos.\nDimethylarginine dimethylaminohydrolase 1 (DDAH1) is an enzyme that metabolizes methylated arginine to citrulline and methylamine, thus working to produce nitric oxide (NO). We isolated a gene encoding chick DDAH1. In situ hybridization analysis revealed characteristic DDAH1 mRNA expression in the embryonic spinal cord, which was especially strong in the ventral horn and dorsal root ganglion (DRG). DDAH1 was also detected in the brain, kidney, digestive tract, and in other tissues. We examined the expression pattern of DDAH1 in developing rats and compared this with the expression pattern in chicks. The expression pattern in the rats was very similar to that in the chicks, but there were some differences between the chicks and rats in the amount of DDAH1 detected in the heart, liver, lung, and DRG. We also investigated neural nitric oxide synthase (nNOS) mRNA expression patterns in rat embryos. The DDAH1 expression patterns were completely different from nNOS expression patterns. Our study suggests that DDAH1 plays an important role in development." ], "offsets": [ [ 0, 1110 ] ] } ]
[ { "id": "1320", "type": "CHEMICAL", "text": [ "Dimethylarginine" ], "offsets": [ [ 46, 62 ] ], "normalized": [] }, { "id": "1321", "type": "CHEMICAL", "text": [ "citrulline" ], "offsets": [ [ 149, 159 ] ], "normalized": [] }, { "id": "1322", "type": "CHEMICAL", "text": [ "methylamine" ], "offsets": [ [ 164, 175 ] ], "normalized": [] }, { "id": "1323", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 201, 213 ] ], "normalized": [] }, { "id": "1324", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 215, 217 ] ], "normalized": [] }, { "id": "1325", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 884, 896 ] ], "normalized": [] }, { "id": "1326", "type": "GENE-N", "text": [ "Dimethylarginine dimethylaminohydrolase 1" ], "offsets": [ [ 46, 87 ] ], "normalized": [] }, { "id": "1327", "type": "GENE-N", "text": [ "DDAH1" ], "offsets": [ [ 1065, 1070 ] ], "normalized": [] }, { "id": "1328", "type": "GENE-Y", "text": [ "chick DDAH1" ], "offsets": [ [ 248, 259 ] ], "normalized": [] }, { "id": "1329", "type": "GENE-Y", "text": [ "DDAH1" ], "offsets": [ [ 316, 321 ] ], "normalized": [] }, { "id": "1330", "type": "GENE-Y", "text": [ "DDAH1" ], "offsets": [ [ 448, 453 ] ], "normalized": [] }, { "id": "1331", "type": "GENE-N", "text": [ "DDAH1" ], "offsets": [ [ 89, 94 ] ], "normalized": [] }, { "id": "1332", "type": "GENE-Y", "text": [ "DDAH1" ], "offsets": [ [ 571, 576 ] ], "normalized": [] }, { "id": "1333", "type": "GENE-N", "text": [ "DDAH1" ], "offsets": [ [ 805, 810 ] ], "normalized": [] }, { "id": "1334", "type": "GENE-Y", "text": [ "neural nitric oxide synthase" ], "offsets": [ [ 877, 905 ] ], "normalized": [] }, { "id": "1335", "type": "GENE-Y", "text": [ "nNOS" ], "offsets": [ [ 907, 911 ] ], "normalized": [] }, { "id": "1336", "type": "GENE-Y", "text": [ "DDAH1" ], "offsets": [ [ 958, 963 ] ], "normalized": [] }, { "id": "1337", "type": "GENE-Y", "text": [ "nNOS" ], "offsets": [ [ 1015, 1019 ] ], "normalized": [] }, { "id": "1338", "type": "GENE-N", "text": [ "DDAH1" ], "offsets": [ [ 14, 19 ] ], "normalized": [] }, { "id": "1339", "type": "CHEMICAL", "text": [ "methylated arginine" ], "offsets": [ [ 126, 145 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1340", "type": "Substrate", "arg1_id": "1339", "arg2_id": "1326", "normalized": [] }, { "id": "1341", "type": "Substrate", "arg1_id": "1339", "arg2_id": "1331", "normalized": [] }, { "id": "1342", "type": "Substrate", "arg1_id": "1321", "arg2_id": "1331", "normalized": [] }, { "id": "1343", "type": "Substrate", "arg1_id": "1321", "arg2_id": "1326", "normalized": [] }, { "id": "1344", "type": "Substrate", "arg1_id": "1322", "arg2_id": "1326", "normalized": [] }, { "id": "1345", "type": "Substrate", "arg1_id": "1322", "arg2_id": "1331", "normalized": [] } ]
1346
23110812
[ { "id": "1347", "type": "title and abstract", "text": [ "SPIDIA-RNA: first external quality assessment for the pre-analytical phase of blood samples used for RNA based analyses.\nThe diagnostic use of in vitro molecular assays can be limited by the lack of guidelines for collection, handling, stabilization and storage of patient specimens. One of the major goals of the EC funded project SPIDIA (www.spidia.eu) is to develop evidence-based quality guidelines for the pre-analytical phase of blood samples used for molecular testing which requires intracellular RNA analytes. To this end, a survey and a pan-European external quality assessment (EQA) were implemented. This report is the summary of the results of that trial. With the European Federation of Laboratory Medicine (EFLM) support, 124 applications for participation in the trial were received from 27 different European countries, and 102 laboratories actually participated in the trial. Each participating laboratory described their respective laboratory policies and practices as well as blood collection tubes typically used in performing this type of testing. The participating laboratories received two identical blood specimens: in an EDTA tubes (unstabilized blood; n=67) or in tubes designed specifically for the stabilization of intracellular RNA in blood (PAXgene® Blood RNA tubes; n=35). Laboratories were requested to perform RNA extraction according to the laboratory's own procedure as soon as possible upon receipt of the tubes for one tube and 24h after the first extraction for the second tube. Participants (n=93) returned the two extracted RNAs to SPIDIA facility for analysis, and provided details about the reagents and protocols they used for the extraction. At the SPIDIA facility responsible for coordinating the study, the survey data were classified, and the extracted RNA samples were evaluated for purity, yield, integrity, stability, and the presence of interfering substances affecting RT-qPCR assays. All participants received a report comparing the performance of the RNA they submitted to that of the other participants. All the results obtained by participants for each RNA quality parameter were classified as \"in control\", \"warning\", \"out of control\" and \"missing\" by consensus mean analysis. From the survey data, the most variable parameters were the volume of blood collected and the time and storage temperature between blood collection and RNA extraction. Analyzing the results of quality testing of submitted RNA samples we observed a data distribution of purity, yield, and presence of assay interference in agreement with expected values. The RNA Integrity Number (RIN) values distribution was, on the other hand, much wider than the optimal expected value, which led to an \"in control\" classification, even for partly degraded RNA samples. On the other hand, RIN values below 5 significantly correlated with a reduction of GAPDH expression levels. Furthermore, the distribution of the values of the four transcripts investigated (c-fos, IL-1β, IL-8, and GAPDH) was wide and the RNA instability between samples separated by 24h were similar. Assuming the presence of at least two quality parameters \"out of control\" as an indication of a critical performance of the laboratory, 33% of the laboratories were included in this group. The results of this study will be the basis for implementing a second pan-European EQA and the results of both EQAs will be pooled and will provide the basis for the implementation of evidence-based guidelines for the pre-analytical phase of RNA analysis of blood samples." ], "offsets": [ [ 0, 3553 ] ] } ]
[ { "id": "1348", "type": "CHEMICAL", "text": [ "EDTA" ], "offsets": [ [ 1147, 1151 ] ], "normalized": [] }, { "id": "1349", "type": "GENE-Y", "text": [ "GAPDH" ], "offsets": [ [ 2874, 2879 ] ], "normalized": [] }, { "id": "1350", "type": "GENE-Y", "text": [ "c-fos" ], "offsets": [ [ 2981, 2986 ] ], "normalized": [] }, { "id": "1351", "type": "GENE-Y", "text": [ "IL-1β" ], "offsets": [ [ 2988, 2993 ] ], "normalized": [] }, { "id": "1352", "type": "GENE-Y", "text": [ "IL-8" ], "offsets": [ [ 2995, 2999 ] ], "normalized": [] }, { "id": "1353", "type": "GENE-Y", "text": [ "GAPDH" ], "offsets": [ [ 3005, 3010 ] ], "normalized": [] } ]
[]
[]
[]
1354
17484506
[ { "id": "1355", "type": "title and abstract", "text": [ "Endometriosis: the way forward.\nEndometriosis, a common cause of morbidity, affects 10% of women of reproductive age. In this review we focus on the new developments in pathogenesis, diagnosis and treatment options, reviewing the literature published about this enigmatic disorder over the past three years. More specifically, new theories of the pathogenesis of the syndrome of Sampson and Cullen are discussed. The new era of genomics may characterize endometriosis and transform clinical management of the disease. Literature suggesting that endometriosis may have an environmental origin is reviewed. New approaches to medical therapy of endometriosis have been developed, including the levonorgestrel-releasing intrauterine device, aromatase inhibitors, immunomodulatory drugs, angiogenesis inhibitors, selective estrogen and progesterone receptor modulators, and statins. Subfertility is another well-known result of endometriosis and often complex decisions must be made regarding management of the endometriosis patient who wishes to conceive. Laparoscopic surgery and assisted reproduction--with or without gonadotropin-releasing hormone-agonist treatment--are reviewed. Finally we speculate about new developments in the field of endometriosis in the coming three years." ], "offsets": [ [ 0, 1280 ] ] } ]
[ { "id": "1356", "type": "CHEMICAL", "text": [ "levonorgestrel" ], "offsets": [ [ 691, 705 ] ], "normalized": [] }, { "id": "1357", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 818, 826 ] ], "normalized": [] }, { "id": "1358", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 831, 843 ] ], "normalized": [] }, { "id": "1359", "type": "GENE-N", "text": [ "gonadotropin-releasing hormone" ], "offsets": [ [ 1116, 1146 ] ], "normalized": [] }, { "id": "1360", "type": "GENE-Y", "text": [ "aromatase" ], "offsets": [ [ 737, 746 ] ], "normalized": [] }, { "id": "1361", "type": "GENE-N", "text": [ "estrogen and progesterone receptor" ], "offsets": [ [ 818, 852 ] ], "normalized": [] } ]
[]
[]
[]
1362
23494186
[ { "id": "1363", "type": "title and abstract", "text": [ "LDL Cholesterol Goals in High-Risk Patients: How Low Do We Go and How Do We Get There?\nIt is widely recognised that low-density lipoprotein cholesterol (LDL-C) is one of the most important and modifiable risk factors for cardiovascular disease (CVD). Statins (HMG-CoA reductase inhibitors) have consistently been shown to decrease both LDL-C and CVD risk in almost all patient categories, with the exception of heart and kidney failure as well as advanced aortic stenosis. As a consequence, statins have become the cornerstone in current prevention guidelines. In patients who do not reach the LDL-C target, combination therapy with additional LDL-C lowering drugs (e.g. ezetimibe, bile acid sequestrants or fibrates) should be considered. Guidelines provide different LDL-C levels to strive for, depending on the CVD risk. In this review, we describe the rationale for these LDL-C targets and how these goals might be reached by current and future therapies." ], "offsets": [ [ 0, 959 ] ] } ]
[ { "id": "1364", "type": "CHEMICAL", "text": [ "HMG-CoA" ], "offsets": [ [ 260, 267 ] ], "normalized": [] }, { "id": "1365", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 140, 151 ] ], "normalized": [] }, { "id": "1366", "type": "CHEMICAL", "text": [ "ezetimibe" ], "offsets": [ [ 671, 680 ] ], "normalized": [] }, { "id": "1367", "type": "CHEMICAL", "text": [ "bile acid" ], "offsets": [ [ 682, 691 ] ], "normalized": [] }, { "id": "1368", "type": "CHEMICAL", "text": [ "fibrates" ], "offsets": [ [ 708, 716 ] ], "normalized": [] }, { "id": "1369", "type": "CHEMICAL", "text": [ "Cholesterol" ], "offsets": [ [ 4, 15 ] ], "normalized": [] }, { "id": "1370", "type": "GENE-Y", "text": [ "HMG-CoA reductase" ], "offsets": [ [ 260, 277 ] ], "normalized": [] }, { "id": "1371", "type": "GENE-N", "text": [ "LDL" ], "offsets": [ [ 336, 339 ] ], "normalized": [] }, { "id": "1372", "type": "GENE-N", "text": [ "low-density lipoprotein" ], "offsets": [ [ 116, 139 ] ], "normalized": [] }, { "id": "1373", "type": "GENE-N", "text": [ "LDL" ], "offsets": [ [ 594, 597 ] ], "normalized": [] }, { "id": "1374", "type": "GENE-N", "text": [ "LDL" ], "offsets": [ [ 644, 647 ] ], "normalized": [] }, { "id": "1375", "type": "GENE-N", "text": [ "LDL" ], "offsets": [ [ 153, 156 ] ], "normalized": [] }, { "id": "1376", "type": "GENE-N", "text": [ "LDL" ], "offsets": [ [ 769, 772 ] ], "normalized": [] }, { "id": "1377", "type": "GENE-N", "text": [ "LDL" ], "offsets": [ [ 876, 879 ] ], "normalized": [] }, { "id": "1378", "type": "GENE-N", "text": [ "LDL" ], "offsets": [ [ 0, 3 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1379", "type": "Downregulator", "arg1_id": "1366", "arg2_id": "1373", "normalized": [] }, { "id": "1380", "type": "Downregulator", "arg1_id": "1367", "arg2_id": "1373", "normalized": [] }, { "id": "1381", "type": "Downregulator", "arg1_id": "1368", "arg2_id": "1373", "normalized": [] }, { "id": "1382", "type": "Downregulator", "arg1_id": "1366", "arg2_id": "1374", "normalized": [] }, { "id": "1383", "type": "Downregulator", "arg1_id": "1367", "arg2_id": "1374", "normalized": [] }, { "id": "1384", "type": "Downregulator", "arg1_id": "1368", "arg2_id": "1374", "normalized": [] } ]
1385
23195959
[ { "id": "1386", "type": "title and abstract", "text": [ "Ubiquitin-dependent regulation of phospho-AKT dynamics by the ubiquitin E3 ligase, NEDD4-1, in the insulin-like growth factor-1 response.\nAKT is a critical effector kinase downstream of the PI3K pathway that regulates a plethora of cellular processes including cell growth, death, differentiation, and migration. Mechanisms underlying activated phospho-AKT (pAKT) translocation to its action sites remain unclear. Here we show that NEDD4-1 is a novel E3 ligase that specifically regulates ubiquitin-dependent trafficking of pAKT in insulin-like growth factor (IGF)-1 signaling. NEDD4-1 physically interacts with AKT and promotes HECT domain-dependent ubiquitination of exogenous and endogenous AKT. NEDD4-1 catalyzes K63-type polyubiquitin chain formation on AKT in vitro. Plasma membrane binding is the key step for AKT ubiquitination by NEDD4-1 in vivo. Ubiquitinated pAKT translocates to perinuclear regions, where it is released into the cytoplasm, imported into the nucleus, or coupled with proteasomal degradation. IGF-1 signaling specifically stimulates NEDD4-1-mediated ubiquitination of pAKT, without altering total AKT ubiquitination. A cancer-derived plasma membrane-philic mutant AKT(E17K) is more effectively ubiquitinated by NEDD4-1 and more efficiently trafficked into the nucleus compared with wild type AKT. This study reveals a novel mechanism by which a specific E3 ligase is required for ubiquitin-dependent control of pAKT dynamics in a ligand-specific manner." ], "offsets": [ [ 0, 1481 ] ] } ]
[ { "id": "1387", "type": "CHEMICAL", "text": [ "phospho" ], "offsets": [ [ 345, 352 ] ], "normalized": [] }, { "id": "1388", "type": "CHEMICAL", "text": [ "phospho" ], "offsets": [ [ 34, 41 ] ], "normalized": [] }, { "id": "1389", "type": "GENE-N", "text": [ "AKT" ], "offsets": [ [ 138, 141 ] ], "normalized": [] }, { "id": "1390", "type": "GENE-N", "text": [ "AKT" ], "offsets": [ [ 1192, 1195 ] ], "normalized": [] }, { "id": "1391", "type": "GENE-N", "text": [ "E17K" ], "offsets": [ [ 1196, 1200 ] ], "normalized": [] }, { "id": "1392", "type": "GENE-N", "text": [ "NEDD4-1" ], "offsets": [ [ 1239, 1246 ] ], "normalized": [] }, { "id": "1393", "type": "GENE-N", "text": [ "AKT" ], "offsets": [ [ 1320, 1323 ] ], "normalized": [] }, { "id": "1394", "type": "GENE-N", "text": [ "E3 ligase" ], "offsets": [ [ 1382, 1391 ] ], "normalized": [] }, { "id": "1395", "type": "GENE-N", "text": [ "ubiquitin" ], "offsets": [ [ 1408, 1417 ] ], "normalized": [] }, { "id": "1396", "type": "GENE-N", "text": [ "pAKT" ], "offsets": [ [ 1439, 1443 ] ], "normalized": [] }, { "id": "1397", "type": "GENE-N", "text": [ "phospho-AKT" ], "offsets": [ [ 345, 356 ] ], "normalized": [] }, { "id": "1398", "type": "GENE-N", "text": [ "pAKT" ], "offsets": [ [ 358, 362 ] ], "normalized": [] }, { "id": "1399", "type": "GENE-N", "text": [ "kinase" ], "offsets": [ [ 165, 171 ] ], "normalized": [] }, { "id": "1400", "type": "GENE-N", "text": [ "NEDD4-1" ], "offsets": [ [ 432, 439 ] ], "normalized": [] }, { "id": "1401", "type": "GENE-N", "text": [ "E3 ligase" ], "offsets": [ [ 451, 460 ] ], "normalized": [] }, { "id": "1402", "type": "GENE-N", "text": [ "ubiquitin" ], "offsets": [ [ 489, 498 ] ], "normalized": [] }, { "id": "1403", "type": "GENE-N", "text": [ "pAKT" ], "offsets": [ [ 524, 528 ] ], "normalized": [] }, { "id": "1404", "type": "GENE-Y", "text": [ "insulin-like growth factor (IGF)-1" ], "offsets": [ [ 532, 566 ] ], "normalized": [] }, { "id": "1405", "type": "GENE-N", "text": [ "NEDD4-1" ], "offsets": [ [ 578, 585 ] ], "normalized": [] }, { "id": "1406", "type": "GENE-N", "text": [ "AKT" ], "offsets": [ [ 612, 615 ] ], "normalized": [] }, { "id": "1407", "type": "GENE-N", "text": [ "HECT domain" ], "offsets": [ [ 629, 640 ] ], "normalized": [] }, { "id": "1408", "type": "GENE-N", "text": [ "PI3K" ], "offsets": [ [ 190, 194 ] ], "normalized": [] }, { "id": "1409", "type": "GENE-N", "text": [ "AKT." ], "offsets": [ [ 694, 698 ] ], "normalized": [] }, { "id": "1410", "type": "GENE-N", "text": [ "NEDD4-1" ], "offsets": [ [ 699, 706 ] ], "normalized": [] }, { "id": "1411", "type": "GENE-N", "text": [ "AKT" ], "offsets": [ [ 759, 762 ] ], "normalized": [] }, { "id": "1412", "type": "GENE-N", "text": [ "AKT" ], "offsets": [ [ 817, 820 ] ], "normalized": [] }, { "id": "1413", "type": "GENE-N", "text": [ "NEDD4-1" ], "offsets": [ [ 839, 846 ] ], "normalized": [] }, { "id": "1414", "type": "GENE-N", "text": [ "pAKT" ], "offsets": [ [ 870, 874 ] ], "normalized": [] }, { "id": "1415", "type": "GENE-Y", "text": [ "IGF-1" ], "offsets": [ [ 1021, 1026 ] ], "normalized": [] }, { "id": "1416", "type": "GENE-N", "text": [ "NEDD4-1" ], "offsets": [ [ 1061, 1068 ] ], "normalized": [] }, { "id": "1417", "type": "GENE-N", "text": [ "pAKT" ], "offsets": [ [ 1096, 1100 ] ], "normalized": [] }, { "id": "1418", "type": "GENE-N", "text": [ "AKT" ], "offsets": [ [ 1125, 1128 ] ], "normalized": [] }, { "id": "1419", "type": "GENE-N", "text": [ "Ubiquitin" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "1420", "type": "GENE-N", "text": [ "phospho-AKT" ], "offsets": [ [ 34, 45 ] ], "normalized": [] }, { "id": "1421", "type": "GENE-N", "text": [ "ubiquitin E3 ligase" ], "offsets": [ [ 62, 81 ] ], "normalized": [] }, { "id": "1422", "type": "GENE-N", "text": [ "NEDD4-1" ], "offsets": [ [ 83, 90 ] ], "normalized": [] }, { "id": "1423", "type": "GENE-Y", "text": [ "insulin-like growth factor-1" ], "offsets": [ [ 99, 127 ] ], "normalized": [] } ]
[]
[]
[]
1424
23611835
[ { "id": "1425", "type": "title and abstract", "text": [ "Molecular Mechanisms of the antitumor activity of SB225002: A novel microtubule inhibitor.\nSB225002 (SB) is an IL-8 receptor B (IL-8RB) antagonist that has previously been shown to inhibit IL-8-based cancer cell invasion, and to possess in vivo anti-inflammatory and anti-nociceptive effects. The present study presented an evidence for the cell cycle-targeting activity of SB in a panel of p53-mutant human cancer cell lines of different origin, and investigated the underlying molecular mechanisms. A combination of cell cycle analysis, immunocytometry, immunoblotting, and RNA interference revealed that SB induced a BubR1-dependent mitotic arrest. Mechanistically, SB was shown to possess a microtubule destabilizing activity evidenced by hyperphosphorylation of Bcl2 and BclxL, suppression of microtubule polymerization and induction of a prometaphase arrest. Molecular docking studies suggested that SB has a good affinity towards vinblastine-binding site on β-tubulin subunit. Of note, SB265610 which is a close structural analogue of SB225002 with a potent IL-8RB antagonistic activity did not exhibit a similar antimitotic activity. Importantly, in P-glycoprotein overexpressing NCI/Adr-Res cells the antitumor activity of SB was unaffected by multidrug resistance. Interestingly, the mechanisms of SB-induced cell death were cell-line dependent, where in invasive hepatocellular carcinoma HLE cells the significant contribution of BAK-dependent mitochondrial apoptosis was demonstrated. Conversely, SB activated p38 MAPK signaling in colorectal adenocarcinoma cells SW480, and pharmacologic inhibition of p38 MAPK activity revealed its key role in mediating SB-induced caspase-independent cell death. In summary, the present study introduced SB as a promising antitumor agent which has the potential to exert its activity through dual mechanisms involving microtubules targeting and interference with IL-8-drivin cancer progression." ], "offsets": [ [ 0, 1942 ] ] } ]
[ { "id": "1426", "type": "CHEMICAL", "text": [ "SB225002" ], "offsets": [ [ 91, 99 ] ], "normalized": [] }, { "id": "1427", "type": "CHEMICAL", "text": [ "vinblastine" ], "offsets": [ [ 937, 948 ] ], "normalized": [] }, { "id": "1428", "type": "CHEMICAL", "text": [ "SB265610" ], "offsets": [ [ 993, 1001 ] ], "normalized": [] }, { "id": "1429", "type": "CHEMICAL", "text": [ "SB225002" ], "offsets": [ [ 1042, 1050 ] ], "normalized": [] }, { "id": "1430", "type": "CHEMICAL", "text": [ "SB225002" ], "offsets": [ [ 50, 58 ] ], "normalized": [] }, { "id": "1431", "type": "GENE-Y", "text": [ "P-glycoprotein" ], "offsets": [ [ 1158, 1172 ] ], "normalized": [] }, { "id": "1432", "type": "GENE-Y", "text": [ "BAK" ], "offsets": [ [ 1441, 1444 ] ], "normalized": [] }, { "id": "1433", "type": "GENE-N", "text": [ "p38" ], "offsets": [ [ 1522, 1525 ] ], "normalized": [] }, { "id": "1434", "type": "GENE-N", "text": [ "MAPK" ], "offsets": [ [ 1526, 1530 ] ], "normalized": [] }, { "id": "1435", "type": "GENE-N", "text": [ "p38" ], "offsets": [ [ 1615, 1618 ] ], "normalized": [] }, { "id": "1436", "type": "GENE-N", "text": [ "MAPK" ], "offsets": [ [ 1619, 1623 ] ], "normalized": [] }, { "id": "1437", "type": "GENE-N", "text": [ "caspase" ], "offsets": [ [ 1679, 1686 ] ], "normalized": [] }, { "id": "1438", "type": "GENE-Y", "text": [ "IL-8" ], "offsets": [ [ 1911, 1915 ] ], "normalized": [] }, { "id": "1439", "type": "GENE-Y", "text": [ "IL-8 receptor B" ], "offsets": [ [ 111, 126 ] ], "normalized": [] }, { "id": "1440", "type": "GENE-Y", "text": [ "p53" ], "offsets": [ [ 391, 394 ] ], "normalized": [] }, { "id": "1441", "type": "GENE-Y", "text": [ "IL-8RB" ], "offsets": [ [ 128, 134 ] ], "normalized": [] }, { "id": "1442", "type": "GENE-Y", "text": [ "BubR1" ], "offsets": [ [ 620, 625 ] ], "normalized": [] }, { "id": "1443", "type": "GENE-Y", "text": [ "Bcl2" ], "offsets": [ [ 767, 771 ] ], "normalized": [] }, { "id": "1444", "type": "GENE-Y", "text": [ "BclxL" ], "offsets": [ [ 776, 781 ] ], "normalized": [] }, { "id": "1445", "type": "GENE-Y", "text": [ "β-tubulin" ], "offsets": [ [ 965, 974 ] ], "normalized": [] }, { "id": "1446", "type": "GENE-Y", "text": [ "IL-8RB" ], "offsets": [ [ 1065, 1071 ] ], "normalized": [] }, { "id": "1447", "type": "GENE-Y", "text": [ "IL-8" ], "offsets": [ [ 189, 193 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1448", "type": "Antagonist", "arg1_id": "1426", "arg2_id": "1439", "normalized": [] }, { "id": "1449", "type": "Antagonist", "arg1_id": "1426", "arg2_id": "1441", "normalized": [] }, { "id": "1450", "type": "Regulator", "arg1_id": "1427", "arg2_id": "1445", "normalized": [] }, { "id": "1451", "type": "Antagonist", "arg1_id": "1428", "arg2_id": "1446", "normalized": [] }, { "id": "1452", "type": "Regulator", "arg1_id": "1426", "arg2_id": "1447", "normalized": [] } ]
1453
10403635
[ { "id": "1454", "type": "title and abstract", "text": [ "Success of pyridostigmine, physostigmine, eptastigmine and phosphotriesterase treatments in acute sarin intoxication.\nThe acute toxicity of organophosphorus (OP) compounds in mammals is due to their irreversible inhibition of acetylcholinesterase (AChE) in the nervous system, which leads to increased synaptic acetylcholine levels. The protective actions of intravenously (i.v.) administered pyridostigmine, physostigmine, eptastigmine, and an organophosphate hydrolase, phosphotriesterase, in acute sarin intoxication were studied in mice. The acute intragastric (i.g.) toxicity (LD50) of sarin with and without the pretreatments was tested by the up-and-down method. The mice received pyridostigmine (0.06 mg/kg body weight), physostigmine (0.09 mg/kg body weight), the physostigmine derivative eptastigmine (0.90 mg/kg body weight) or phosphotriesterase (104 U/g, 10.7 microg/g body weight) 10 min prior to the i.g. administration of sarin. Physostigmine was also administered with phosphotriesterase. Phosphotriesterase was the most effective antidote in sarin intoxication. The LD50 value for sarin increased 3.4-fold in mice receiving phosphotriesterase. Physostigmine was the most effective carbamate in sarin exposure. The protective ratios of physostigmine and pyridostigmine were 1.5- and 1.2-1.3-fold, respectively. Eptastigmine did not give any protection against sarin toxicity. Both the phosphotriesterase and physostigmine treatments protected the brain AChE activities measured 24 h after sarin exposure. In phosphotriesterase and physostigmine-treated mice, a 4- and 2-fold higher sarin dose, respectively, was needed to cause a 50% inhibition of brain AChE activity. Moreover, the combination of phosphotriesterase-physostigmine increased the LD50 value for sarin 4.3-fold. The animals pretreated with phosphotriesterase-ephysostigmine tolerated four times the lethal dose in control animals, furthermore their survival time was 2-3 h in comparison to 20 min in controls. In conclusion, phosphotriesterase and physostigmine were the most effective treatments against sarin intoxication. However, eptastigmine did not provide any protection against sarin toxicity." ], "offsets": [ [ 0, 2182 ] ] } ]
[ { "id": "1455", "type": "CHEMICAL", "text": [ "Physostigmine" ], "offsets": [ [ 1162, 1175 ] ], "normalized": [] }, { "id": "1456", "type": "CHEMICAL", "text": [ "carbamate" ], "offsets": [ [ 1199, 1208 ] ], "normalized": [] }, { "id": "1457", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 1212, 1217 ] ], "normalized": [] }, { "id": "1458", "type": "CHEMICAL", "text": [ "physostigmine" ], "offsets": [ [ 1253, 1266 ] ], "normalized": [] }, { "id": "1459", "type": "CHEMICAL", "text": [ "pyridostigmine" ], "offsets": [ [ 1271, 1285 ] ], "normalized": [] }, { "id": "1460", "type": "CHEMICAL", "text": [ "Eptastigmine" ], "offsets": [ [ 1328, 1340 ] ], "normalized": [] }, { "id": "1461", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 1377, 1382 ] ], "normalized": [] }, { "id": "1462", "type": "CHEMICAL", "text": [ "physostigmine" ], "offsets": [ [ 1425, 1438 ] ], "normalized": [] }, { "id": "1463", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 1506, 1511 ] ], "normalized": [] }, { "id": "1464", "type": "CHEMICAL", "text": [ "physostigmine" ], "offsets": [ [ 1548, 1561 ] ], "normalized": [] }, { "id": "1465", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 1599, 1604 ] ], "normalized": [] }, { "id": "1466", "type": "CHEMICAL", "text": [ "physostigmine" ], "offsets": [ [ 1734, 1747 ] ], "normalized": [] }, { "id": "1467", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 1777, 1782 ] ], "normalized": [] }, { "id": "1468", "type": "CHEMICAL", "text": [ "ephysostigmine" ], "offsets": [ [ 1840, 1854 ] ], "normalized": [] }, { "id": "1469", "type": "CHEMICAL", "text": [ "physostigmine" ], "offsets": [ [ 2029, 2042 ] ], "normalized": [] }, { "id": "1470", "type": "CHEMICAL", "text": [ "acetylcholine" ], "offsets": [ [ 311, 324 ] ], "normalized": [] }, { "id": "1471", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 2086, 2091 ] ], "normalized": [] }, { "id": "1472", "type": "CHEMICAL", "text": [ "eptastigmine" ], "offsets": [ [ 2115, 2127 ] ], "normalized": [] }, { "id": "1473", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 2167, 2172 ] ], "normalized": [] }, { "id": "1474", "type": "CHEMICAL", "text": [ "organophosphorus" ], "offsets": [ [ 140, 156 ] ], "normalized": [] }, { "id": "1475", "type": "CHEMICAL", "text": [ "pyridostigmine" ], "offsets": [ [ 393, 407 ] ], "normalized": [] }, { "id": "1476", "type": "CHEMICAL", "text": [ "physostigmine" ], "offsets": [ [ 409, 422 ] ], "normalized": [] }, { "id": "1477", "type": "CHEMICAL", "text": [ "eptastigmine" ], "offsets": [ [ 424, 436 ] ], "normalized": [] }, { "id": "1478", "type": "CHEMICAL", "text": [ "organophosphate" ], "offsets": [ [ 445, 460 ] ], "normalized": [] }, { "id": "1479", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 501, 506 ] ], "normalized": [] }, { "id": "1480", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 591, 596 ] ], "normalized": [] }, { "id": "1481", "type": "CHEMICAL", "text": [ "pyridostigmine" ], "offsets": [ [ 688, 702 ] ], "normalized": [] }, { "id": "1482", "type": "CHEMICAL", "text": [ "physostigmine" ], "offsets": [ [ 729, 742 ] ], "normalized": [] }, { "id": "1483", "type": "CHEMICAL", "text": [ "physostigmine" ], "offsets": [ [ 773, 786 ] ], "normalized": [] }, { "id": "1484", "type": "CHEMICAL", "text": [ "eptastigmine" ], "offsets": [ [ 798, 810 ] ], "normalized": [] }, { "id": "1485", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 938, 943 ] ], "normalized": [] }, { "id": "1486", "type": "CHEMICAL", "text": [ "Physostigmine" ], "offsets": [ [ 945, 958 ] ], "normalized": [] }, { "id": "1487", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 1060, 1065 ] ], "normalized": [] }, { "id": "1488", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 1099, 1104 ] ], "normalized": [] }, { "id": "1489", "type": "CHEMICAL", "text": [ "pyridostigmine" ], "offsets": [ [ 11, 25 ] ], "normalized": [] }, { "id": "1490", "type": "CHEMICAL", "text": [ "physostigmine" ], "offsets": [ [ 27, 40 ] ], "normalized": [] }, { "id": "1491", "type": "CHEMICAL", "text": [ "eptastigmine" ], "offsets": [ [ 42, 54 ] ], "normalized": [] }, { "id": "1492", "type": "CHEMICAL", "text": [ "sarin" ], "offsets": [ [ 98, 103 ] ], "normalized": [] }, { "id": "1493", "type": "GENE-N", "text": [ "phosphotriesterase" ], "offsets": [ [ 1142, 1160 ] ], "normalized": [] }, { "id": "1494", "type": "GENE-N", "text": [ "acetylcholinesterase" ], "offsets": [ [ 226, 246 ] ], "normalized": [] }, { "id": "1495", "type": "GENE-N", "text": [ "phosphotriesterase" ], "offsets": [ [ 1402, 1420 ] ], "normalized": [] }, { "id": "1496", "type": "GENE-N", "text": [ "AChE" ], "offsets": [ [ 248, 252 ] ], "normalized": [] }, { "id": "1497", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 1470, 1474 ] ], "normalized": [] }, { "id": "1498", "type": "GENE-N", "text": [ "phosphotriesterase" ], "offsets": [ [ 1525, 1543 ] ], "normalized": [] }, { "id": "1499", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 1671, 1675 ] ], "normalized": [] }, { "id": "1500", "type": "GENE-N", "text": [ "phosphotriesterase" ], "offsets": [ [ 1715, 1733 ] ], "normalized": [] }, { "id": "1501", "type": "GENE-N", "text": [ "phosphotriesterase" ], "offsets": [ [ 1821, 1839 ] ], "normalized": [] }, { "id": "1502", "type": "GENE-N", "text": [ "phosphotriesterase" ], "offsets": [ [ 2006, 2024 ] ], "normalized": [] }, { "id": "1503", "type": "GENE-N", "text": [ "organophosphate hydrolase" ], "offsets": [ [ 445, 470 ] ], "normalized": [] }, { "id": "1504", "type": "GENE-N", "text": [ "phosphotriesterase" ], "offsets": [ [ 472, 490 ] ], "normalized": [] }, { "id": "1505", "type": "GENE-N", "text": [ "phosphotriesterase" ], "offsets": [ [ 839, 857 ] ], "normalized": [] }, { "id": "1506", "type": "GENE-N", "text": [ "phosphotriesterase" ], "offsets": [ [ 986, 1004 ] ], "normalized": [] }, { "id": "1507", "type": "GENE-N", "text": [ "Phosphotriesterase" ], "offsets": [ [ 1006, 1024 ] ], "normalized": [] }, { "id": "1508", "type": "GENE-N", "text": [ "phosphotriesterase" ], "offsets": [ [ 59, 77 ] ], "normalized": [] }, { "id": "1509", "type": "CHEMICAL", "text": [ "OP" ], "offsets": [ [ 158, 160 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1510", "type": "Upregulator", "arg1_id": "1462", "arg2_id": "1497", "normalized": [] }, { "id": "1511", "type": "Downregulator", "arg1_id": "1465", "arg2_id": "1499", "normalized": [] }, { "id": "1512", "type": "Upregulator", "arg1_id": "1464", "arg2_id": "1499", "normalized": [] }, { "id": "1513", "type": "Downregulator", "arg1_id": "1509", "arg2_id": "1494", "normalized": [] }, { "id": "1514", "type": "Downregulator", "arg1_id": "1509", "arg2_id": "1496", "normalized": [] }, { "id": "1515", "type": "Downregulator", "arg1_id": "1474", "arg2_id": "1494", "normalized": [] }, { "id": "1516", "type": "Downregulator", "arg1_id": "1474", "arg2_id": "1496", "normalized": [] }, { "id": "1517", "type": "Downregulator", "arg1_id": "1463", "arg2_id": "1497", "normalized": [] } ]
1518
23562072
[ { "id": "1519", "type": "title and abstract", "text": [ "Altered cholesterol homeostasis in aged macrophages linked to neovascular macular degeneration.\nAbnormal lipid metabolism has been linked to age-related macular degeneration (AMD); choroidal neovascularization in late AMD commonly causes blindness. Sene et al. (2013) now demonstrate that in aged macrophages decreased ABCA1 expression, regulated by liver X receptor and miR-33, impairs export of intracellular cholesterol, which promotes neovascular AMD." ], "offsets": [ [ 0, 455 ] ] } ]
[ { "id": "1520", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 411, 422 ] ], "normalized": [] }, { "id": "1521", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 8, 19 ] ], "normalized": [] }, { "id": "1522", "type": "GENE-Y", "text": [ "ABCA1" ], "offsets": [ [ 319, 324 ] ], "normalized": [] }, { "id": "1523", "type": "GENE-N", "text": [ "liver X receptor" ], "offsets": [ [ 350, 366 ] ], "normalized": [] }, { "id": "1524", "type": "GENE-N", "text": [ "miR-33" ], "offsets": [ [ 371, 377 ] ], "normalized": [] } ]
[]
[]
[]
1525
23402744
[ { "id": "1526", "type": "title and abstract", "text": [ "Sexually dimorphic behavior after developmental exposure to characterize endocrine-mediated effects of different non-dioxin-like PCBs in rats.\nMany 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": [ [ 0, 2624 ] ] } ]
[ { "id": "1527", "type": "CHEMICAL", "text": [ "PCB180" ], "offsets": [ [ 1190, 1196 ] ], "normalized": [] }, { "id": "1528", "type": "CHEMICAL", "text": [ "PCB74" ], "offsets": [ [ 1323, 1328 ] ], "normalized": [] }, { "id": "1529", "type": "CHEMICAL", "text": [ "PCB95" ], "offsets": [ [ 1332, 1337 ] ], "normalized": [] }, { "id": "1530", "type": "CHEMICAL", "text": [ "PCB74" ], "offsets": [ [ 1428, 1433 ] ], "normalized": [] }, { "id": "1531", "type": "CHEMICAL", "text": [ "PCB95" ], "offsets": [ [ 1438, 1443 ] ], "normalized": [] }, { "id": "1532", "type": "CHEMICAL", "text": [ "saccharin" ], "offsets": [ [ 1532, 1541 ] ], "normalized": [] }, { "id": "1533", "type": "CHEMICAL", "text": [ "PCB52" ], "offsets": [ [ 1889, 1894 ] ], "normalized": [] }, { "id": "1534", "type": "CHEMICAL", "text": [ "PCB180" ], "offsets": [ [ 1924, 1930 ] ], "normalized": [] }, { "id": "1535", "type": "CHEMICAL", "text": [ "saccharin" ], "offsets": [ [ 1999, 2008 ] ], "normalized": [] }, { "id": "1536", "type": "CHEMICAL", "text": [ "PCB74" ], "offsets": [ [ 2121, 2126 ] ], "normalized": [] }, { "id": "1537", "type": "CHEMICAL", "text": [ "PCB95" ], "offsets": [ [ 2164, 2169 ] ], "normalized": [] }, { "id": "1538", "type": "CHEMICAL", "text": [ "saccharin" ], "offsets": [ [ 2180, 2189 ] ], "normalized": [] }, { "id": "1539", "type": "CHEMICAL", "text": [ "PCBs" ], "offsets": [ [ 2348, 2352 ] ], "normalized": [] }, { "id": "1540", "type": "CHEMICAL", "text": [ "PCBs" ], "offsets": [ [ 2619, 2623 ] ], "normalized": [] }, { "id": "1541", "type": "CHEMICAL", "text": [ "polychlorinated biphenyls" ], "offsets": [ [ 499, 524 ] ], "normalized": [] }, { "id": "1542", "type": "CHEMICAL", "text": [ "PCBs" ], "offsets": [ [ 526, 530 ] ], "normalized": [] }, { "id": "1543", "type": "CHEMICAL", "text": [ "dioxin" ], "offsets": [ [ 813, 819 ] ], "normalized": [] }, { "id": "1544", "type": "CHEMICAL", "text": [ "dioxin" ], "offsets": [ [ 832, 838 ] ], "normalized": [] }, { "id": "1545", "type": "CHEMICAL", "text": [ "PCBs" ], "offsets": [ [ 850, 854 ] ], "normalized": [] }, { "id": "1546", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 887, 894 ] ], "normalized": [] }, { "id": "1547", "type": "CHEMICAL", "text": [ "PCBs" ], "offsets": [ [ 992, 996 ] ], "normalized": [] }, { "id": "1548", "type": "CHEMICAL", "text": [ "PCB52" ], "offsets": [ [ 1126, 1131 ] ], "normalized": [] }, { "id": "1549", "type": "CHEMICAL", "text": [ "dioxin" ], "offsets": [ [ 117, 123 ] ], "normalized": [] }, { "id": "1550", "type": "CHEMICAL", "text": [ "PCBs" ], "offsets": [ [ 129, 133 ] ], "normalized": [] }, { "id": "1551", "type": "GENE-Y", "text": [ "Ah receptor" ], "offsets": [ [ 2459, 2470 ] ], "normalized": [] }, { "id": "1552", "type": "GENE-Y", "text": [ "aromatase" ], "offsets": [ [ 733, 742 ] ], "normalized": [] }, { "id": "1553", "type": "GENE-Y", "text": [ "Ah receptor" ], "offsets": [ [ 1008, 1019 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1554", "type": "Downregulator", "arg1_id": "1541", "arg2_id": "1552", "normalized": [] }, { "id": "1555", "type": "Downregulator", "arg1_id": "1542", "arg2_id": "1552", "normalized": [] } ]
1556
23538162
[ { "id": "1557", "type": "title and abstract", "text": [ "Activating glucocorticoid receptor-ERK signaling pathway contributes to ginsenoside Rg1 protection against β-amyloid peptide-induced human endothelial cells apoptosis.\nThe deposition of β-amyloid (Aβ) in neurons and vascular cells of the brain has been characterized in Alzheimer's disease. Ginsenoside Rg1 (Rg1) is an active components in Panax ginseng, a famous traditional Chinese medicines recorded in Compendium of Materia Medica. Present study attempted to evaluate the potential mechanisms of Aβ-mediated insult and the protective effects of Rg1 on human endothelial cells. Rg1 attenuated the Aβ25-35-associated mitochondrial apoptotic events, accompanied by inhibiting HIF-1α expression followed by intracellular reactive nitrogen species generation, and protein nitrotyrosination. These protective effects were abolished by glucocorticoid receptor (GR) antagonist RU486 or p-ERK inhibitor U0126 rather than estrogen receptor α antagonist ICI 82,780. Taken together, our results suggested that Rg1 protected against Aβ25-35-induced apoptosis at least in part by two complementary GR-dependent ERK phosphorylation pathways: (1) down-regulating HIF-1α initiated protein nitrotyrosination, and (2) inhibiting mitochondrial apoptotic cascades. These data provided a novel insight to the mechanisms of Rg1protective effects on Aβ25-35-induced endothelial cells apoptosis, suggesting that GR-ERK signaling pathway might play an important role in it." ], "offsets": [ [ 0, 1451 ] ] } ]
[ { "id": "1558", "type": "CHEMICAL", "text": [ "Rg1" ], "offsets": [ [ 1305, 1308 ] ], "normalized": [] }, { "id": "1559", "type": "CHEMICAL", "text": [ "Ginsenoside Rg1" ], "offsets": [ [ 291, 306 ] ], "normalized": [] }, { "id": "1560", "type": "CHEMICAL", "text": [ "Rg1" ], "offsets": [ [ 308, 311 ] ], "normalized": [] }, { "id": "1561", "type": "CHEMICAL", "text": [ "Rg1" ], "offsets": [ [ 549, 552 ] ], "normalized": [] }, { "id": "1562", "type": "CHEMICAL", "text": [ "Rg1" ], "offsets": [ [ 581, 584 ] ], "normalized": [] }, { "id": "1563", "type": "CHEMICAL", "text": [ "nitrogen" ], "offsets": [ [ 730, 738 ] ], "normalized": [] }, { "id": "1564", "type": "CHEMICAL", "text": [ "RU486" ], "offsets": [ [ 873, 878 ] ], "normalized": [] }, { "id": "1565", "type": "CHEMICAL", "text": [ "U0126" ], "offsets": [ [ 898, 903 ] ], "normalized": [] }, { "id": "1566", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 916, 924 ] ], "normalized": [] }, { "id": "1567", "type": "CHEMICAL", "text": [ "ICI 82,780" ], "offsets": [ [ 947, 957 ] ], "normalized": [] }, { "id": "1568", "type": "CHEMICAL", "text": [ "Rg1" ], "offsets": [ [ 1002, 1005 ] ], "normalized": [] }, { "id": "1569", "type": "CHEMICAL", "text": [ "ginsenoside Rg1" ], "offsets": [ [ 72, 87 ] ], "normalized": [] }, { "id": "1570", "type": "GENE-Y", "text": [ "Aβ25-35" ], "offsets": [ [ 1330, 1337 ] ], "normalized": [] }, { "id": "1571", "type": "GENE-Y", "text": [ "GR" ], "offsets": [ [ 1391, 1393 ] ], "normalized": [] }, { "id": "1572", "type": "GENE-N", "text": [ "ERK" ], "offsets": [ [ 1394, 1397 ] ], "normalized": [] }, { "id": "1573", "type": "GENE-Y", "text": [ "β-amyloid" ], "offsets": [ [ 186, 195 ] ], "normalized": [] }, { "id": "1574", "type": "GENE-Y", "text": [ "Aβ" ], "offsets": [ [ 197, 199 ] ], "normalized": [] }, { "id": "1575", "type": "GENE-Y", "text": [ "Aβ" ], "offsets": [ [ 500, 502 ] ], "normalized": [] }, { "id": "1576", "type": "GENE-Y", "text": [ "Aβ25-35" ], "offsets": [ [ 600, 607 ] ], "normalized": [] }, { "id": "1577", "type": "GENE-Y", "text": [ "HIF-1α" ], "offsets": [ [ 677, 683 ] ], "normalized": [] }, { "id": "1578", "type": "GENE-Y", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 833, 856 ] ], "normalized": [] }, { "id": "1579", "type": "GENE-Y", "text": [ "GR" ], "offsets": [ [ 858, 860 ] ], "normalized": [] }, { "id": "1580", "type": "GENE-N", "text": [ "p-ERK" ], "offsets": [ [ 882, 887 ] ], "normalized": [] }, { "id": "1581", "type": "GENE-Y", "text": [ "estrogen receptor α" ], "offsets": [ [ 916, 935 ] ], "normalized": [] }, { "id": "1582", "type": "GENE-Y", "text": [ "Aβ25-35" ], "offsets": [ [ 1024, 1031 ] ], "normalized": [] }, { "id": "1583", "type": "GENE-Y", "text": [ "GR" ], "offsets": [ [ 1088, 1090 ] ], "normalized": [] }, { "id": "1584", "type": "GENE-N", "text": [ "ERK" ], "offsets": [ [ 1101, 1104 ] ], "normalized": [] }, { "id": "1585", "type": "GENE-Y", "text": [ "HIF-1α" ], "offsets": [ [ 1151, 1157 ] ], "normalized": [] }, { "id": "1586", "type": "GENE-Y", "text": [ "β-amyloid peptide" ], "offsets": [ [ 107, 124 ] ], "normalized": [] }, { "id": "1587", "type": "GENE-Y", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 11, 34 ] ], "normalized": [] }, { "id": "1588", "type": "GENE-N", "text": [ "ERK" ], "offsets": [ [ 35, 38 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1589", "type": "Downregulator", "arg1_id": "1562", "arg2_id": "1576", "normalized": [] }, { "id": "1590", "type": "Downregulator", "arg1_id": "1562", "arg2_id": "1577", "normalized": [] }, { "id": "1591", "type": "Antagonist", "arg1_id": "1564", "arg2_id": "1578", "normalized": [] }, { "id": "1592", "type": "Antagonist", "arg1_id": "1564", "arg2_id": "1579", "normalized": [] }, { "id": "1593", "type": "Downregulator", "arg1_id": "1565", "arg2_id": "1580", "normalized": [] }, { "id": "1594", "type": "Antagonist", "arg1_id": "1567", "arg2_id": "1581", "normalized": [] }, { "id": "1595", "type": "Regulator", "arg1_id": "1568", "arg2_id": "1583", "normalized": [] }, { "id": "1596", "type": "Regulator", "arg1_id": "1568", "arg2_id": "1584", "normalized": [] }, { "id": "1597", "type": "Downregulator", "arg1_id": "1568", "arg2_id": "1585", "normalized": [] }, { "id": "1598", "type": "Regulator", "arg1_id": "1558", "arg2_id": "1571", "normalized": [] }, { "id": "1599", "type": "Regulator", "arg1_id": "1558", "arg2_id": "1572", "normalized": [] } ]
1600
23458420
[ { "id": "1601", "type": "title and abstract", "text": [ "Thioflavin T and its photoirradiative derivatives: exploring their spectroscopic properties in the absence and presence of amyloid fibrils.\nIn this work, we found that, during storage or after UV irradiation, ThT is demethylated or oxidized, forming three derivatives. These three derivatives were purified by high performance liquid chromatography and characterized by mass and nuclear magnetic resonance spectroscopy and the spectroscopic properties of pure ThT and the derivatives carefully compared. Our results show that the emission peak at 450 nm results from oxidized ThT and not from the monomeric form of ThT, as previously proposed. The partial conversion of ThT into oxidized and demethylated derivatives has an effect on amyloid detection using ThT assay. Irradiated ThT has the same lag time as pure ThT in the amyloidogenesis of insulin, but the intensity of the emitted fluorescence is significantly decreased." ], "offsets": [ [ 0, 926 ] ] } ]
[ { "id": "1602", "type": "CHEMICAL", "text": [ "ThT" ], "offsets": [ [ 460, 463 ] ], "normalized": [] }, { "id": "1603", "type": "CHEMICAL", "text": [ "ThT" ], "offsets": [ [ 576, 579 ] ], "normalized": [] }, { "id": "1604", "type": "CHEMICAL", "text": [ "ThT" ], "offsets": [ [ 615, 618 ] ], "normalized": [] }, { "id": "1605", "type": "CHEMICAL", "text": [ "ThT" ], "offsets": [ [ 670, 673 ] ], "normalized": [] }, { "id": "1606", "type": "CHEMICAL", "text": [ "ThT" ], "offsets": [ [ 758, 761 ] ], "normalized": [] }, { "id": "1607", "type": "CHEMICAL", "text": [ "ThT" ], "offsets": [ [ 780, 783 ] ], "normalized": [] }, { "id": "1608", "type": "CHEMICAL", "text": [ "ThT" ], "offsets": [ [ 814, 817 ] ], "normalized": [] }, { "id": "1609", "type": "CHEMICAL", "text": [ "ThT" ], "offsets": [ [ 209, 212 ] ], "normalized": [] }, { "id": "1610", "type": "CHEMICAL", "text": [ "Thioflavin T" ], "offsets": [ [ 0, 12 ] ], "normalized": [] }, { "id": "1611", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 844, 851 ] ], "normalized": [] } ]
[]
[]
[]
1612
15204055
[ { "id": "1613", "type": "title and abstract", "text": [ "Are the cognitive effects of atypical antipsychotics influenced by their affinity to 5HT-2A receptors?\nIt is well documented that atypical antipsychotics have an influence on cognitive function in patients with schizophrenia, although the neurochemical basis for this effect is not well understood. One suggestion is that the effects are exerted through action on 5HT-2A receptors, which leads to changes in the level of dopamine in the prefrontal cortex. The following study explored this hypothesis by comparing the cognitive effects of the atypical antipsychotics which have a high affinity for 5HT-2A receptors, with those that have little or no affinity to these receptors. Forty-four patients with a DSM-IV diagnosis of schizophrenia were recruited within 6 weeks of starting one of the atypical antipsychotics: clozapine, olanzapine, risperidone, quetiapine, or amisulpride. The patients were divided into two groups according to the 5HT-2A affinity of the individual medications (high 5HT-2A affinity--clozapine, olanzapine, risperidone vs. low 5HT-2A affinity--quetiapine, amisulpride). Patients were tested on a broad range of neuropsychological measures after 9 months and 18 months of treatment. The high 5HT-2A affinity group showed a decrement in performance on tests of visual recognition memory and planning ability. In contrast, the low-5HT-2A affinity group showed improvements on these measures in addition to others. The 5HT-2A affinity of the atypical antipsychotics is an important determinant of their cognitive effects." ], "offsets": [ [ 0, 1543 ] ] } ]
[ { "id": "1614", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 421, 429 ] ], "normalized": [] }, { "id": "1615", "type": "CHEMICAL", "text": [ "clozapine" ], "offsets": [ [ 818, 827 ] ], "normalized": [] }, { "id": "1616", "type": "CHEMICAL", "text": [ "olanzapine" ], "offsets": [ [ 829, 839 ] ], "normalized": [] }, { "id": "1617", "type": "CHEMICAL", "text": [ "risperidone" ], "offsets": [ [ 841, 852 ] ], "normalized": [] }, { "id": "1618", "type": "CHEMICAL", "text": [ "quetiapine" ], "offsets": [ [ 854, 864 ] ], "normalized": [] }, { "id": "1619", "type": "CHEMICAL", "text": [ "amisulpride" ], "offsets": [ [ 869, 880 ] ], "normalized": [] }, { "id": "1620", "type": "CHEMICAL", "text": [ "clozapine" ], "offsets": [ [ 1010, 1019 ] ], "normalized": [] }, { "id": "1621", "type": "CHEMICAL", "text": [ "olanzapine" ], "offsets": [ [ 1021, 1031 ] ], "normalized": [] }, { "id": "1622", "type": "CHEMICAL", "text": [ "risperidone" ], "offsets": [ [ 1033, 1044 ] ], "normalized": [] }, { "id": "1623", "type": "CHEMICAL", "text": [ "quetiapine" ], "offsets": [ [ 1070, 1080 ] ], "normalized": [] }, { "id": "1624", "type": "CHEMICAL", "text": [ "amisulpride" ], "offsets": [ [ 1082, 1093 ] ], "normalized": [] }, { "id": "1625", "type": "GENE-Y", "text": [ "5HT-2A" ], "offsets": [ [ 1217, 1223 ] ], "normalized": [] }, { "id": "1626", "type": "GENE-Y", "text": [ "5HT-2A" ], "offsets": [ [ 1354, 1360 ] ], "normalized": [] }, { "id": "1627", "type": "GENE-Y", "text": [ "5HT-2A" ], "offsets": [ [ 1441, 1447 ] ], "normalized": [] }, { "id": "1628", "type": "GENE-Y", "text": [ "5HT-2A" ], "offsets": [ [ 364, 370 ] ], "normalized": [] }, { "id": "1629", "type": "GENE-Y", "text": [ "5HT-2A" ], "offsets": [ [ 598, 604 ] ], "normalized": [] }, { "id": "1630", "type": "GENE-Y", "text": [ "5HT-2A" ], "offsets": [ [ 941, 947 ] ], "normalized": [] }, { "id": "1631", "type": "GENE-Y", "text": [ "5HT-2A" ], "offsets": [ [ 993, 999 ] ], "normalized": [] }, { "id": "1632", "type": "GENE-Y", "text": [ "5HT-2A" ], "offsets": [ [ 1053, 1059 ] ], "normalized": [] }, { "id": "1633", "type": "GENE-Y", "text": [ "5HT-2A" ], "offsets": [ [ 85, 91 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1634", "type": "Regulator", "arg1_id": "1620", "arg2_id": "1631", "normalized": [] }, { "id": "1635", "type": "Regulator", "arg1_id": "1621", "arg2_id": "1631", "normalized": [] }, { "id": "1636", "type": "Regulator", "arg1_id": "1622", "arg2_id": "1631", "normalized": [] }, { "id": "1637", "type": "Regulator", "arg1_id": "1623", "arg2_id": "1632", "normalized": [] }, { "id": "1638", "type": "Regulator", "arg1_id": "1624", "arg2_id": "1632", "normalized": [] }, { "id": "1639", "type": "Regulator", "arg1_id": "1620", "arg2_id": "1632", "normalized": [] }, { "id": "1640", "type": "Regulator", "arg1_id": "1621", "arg2_id": "1632", "normalized": [] }, { "id": "1641", "type": "Regulator", "arg1_id": "1622", "arg2_id": "1632", "normalized": [] }, { "id": "1642", "type": "Regulator", "arg1_id": "1623", "arg2_id": "1631", "normalized": [] }, { "id": "1643", "type": "Regulator", "arg1_id": "1624", "arg2_id": "1631", "normalized": [] }, { "id": "1644", "type": "Regulator", "arg1_id": "1620", "arg2_id": "1630", "normalized": [] }, { "id": "1645", "type": "Regulator", "arg1_id": "1621", "arg2_id": "1630", "normalized": [] }, { "id": "1646", "type": "Regulator", "arg1_id": "1622", "arg2_id": "1630", "normalized": [] }, { "id": "1647", "type": "Regulator", "arg1_id": "1623", "arg2_id": "1630", "normalized": [] }, { "id": "1648", "type": "Regulator", "arg1_id": "1624", "arg2_id": "1630", "normalized": [] } ]
1649
23409951
[ { "id": "1650", "type": "title and abstract", "text": [ "Acute arsenic treatment alters cytochrome P450 expression and arachidonic acid metabolism in lung, liver and kidney of C57Bl/6 mice.\nAbstract 1. Arsenic (As(III)) toxicity has received increasing attention as human exposure to arsenic is associated with pulmonary, hepatic and renal toxicities. Therefore, in the present study, we investigated the effect of acute As(III) treatment on pulmonary, hepatic and renal cytochrome (CYP) P450-mediated arachidonic acid metabolism. 2. Our results demonstrated that acute As(III) treatment (12.5 mg/kg) altered CYP epoxygenases, CYP ω-hydroxylases and EPHX2 mRNA levels that were isozyme and tissue specific. 3. Furthermore, As(III) increased the formation of epoxyeicosatrienoic acids (EETs) in the kidney without affecting their levels in the lung or liver. In addition, acute As(III) treatment increased dihydroxyeicosatrienoic acid (DHETs) formation in the lung, while it did not affect liver DHETs formation and decreased kidney DHETs formation. 4. As(III) also increased total epoxygenases activity in the lung while it decreased its levels in the kidney and had no effect on the liver. Furthermore, As(III) increased 20-hydroxyeicosatetraenoic acid formation in the liver while it decreased its formation in the kidney. 5. Lastly, As(III) increased soluble epoxide hydrolase activity in the lung, while it decreased its levels in the kidney and had no effect on the liver. In conclusion, this is the first demonstration that As(III) alters arachidonic acid metabolism in a tissue specific manner." ], "offsets": [ [ 0, 1544 ] ] } ]
[ { "id": "1651", "type": "CHEMICAL", "text": [ "As(III)" ], "offsets": [ [ 1147, 1154 ] ], "normalized": [] }, { "id": "1652", "type": "CHEMICAL", "text": [ "20-hydroxyeicosatetraenoic acid" ], "offsets": [ [ 1165, 1196 ] ], "normalized": [] }, { "id": "1653", "type": "CHEMICAL", "text": [ "As(III)" ], "offsets": [ [ 1279, 1286 ] ], "normalized": [] }, { "id": "1654", "type": "CHEMICAL", "text": [ "epoxide" ], "offsets": [ [ 1305, 1312 ] ], "normalized": [] }, { "id": "1655", "type": "CHEMICAL", "text": [ "Arsenic" ], "offsets": [ [ 145, 152 ] ], "normalized": [] }, { "id": "1656", "type": "CHEMICAL", "text": [ "As(III)" ], "offsets": [ [ 1473, 1480 ] ], "normalized": [] }, { "id": "1657", "type": "CHEMICAL", "text": [ "arachidonic acid" ], "offsets": [ [ 1488, 1504 ] ], "normalized": [] }, { "id": "1658", "type": "CHEMICAL", "text": [ "As(III)" ], "offsets": [ [ 154, 161 ] ], "normalized": [] }, { "id": "1659", "type": "CHEMICAL", "text": [ "As(III)" ], "offsets": [ [ 364, 371 ] ], "normalized": [] }, { "id": "1660", "type": "CHEMICAL", "text": [ "arachidonic acid" ], "offsets": [ [ 445, 461 ] ], "normalized": [] }, { "id": "1661", "type": "CHEMICAL", "text": [ "As(III)" ], "offsets": [ [ 513, 520 ] ], "normalized": [] }, { "id": "1662", "type": "CHEMICAL", "text": [ "As(III)" ], "offsets": [ [ 666, 673 ] ], "normalized": [] }, { "id": "1663", "type": "CHEMICAL", "text": [ "epoxyeicosatrienoic acids" ], "offsets": [ [ 701, 726 ] ], "normalized": [] }, { "id": "1664", "type": "CHEMICAL", "text": [ "EETs" ], "offsets": [ [ 728, 732 ] ], "normalized": [] }, { "id": "1665", "type": "CHEMICAL", "text": [ "As(III)" ], "offsets": [ [ 820, 827 ] ], "normalized": [] }, { "id": "1666", "type": "CHEMICAL", "text": [ "dihydroxyeicosatrienoic acid" ], "offsets": [ [ 848, 876 ] ], "normalized": [] }, { "id": "1667", "type": "CHEMICAL", "text": [ "DHETs" ], "offsets": [ [ 878, 883 ] ], "normalized": [] }, { "id": "1668", "type": "CHEMICAL", "text": [ "DHETs" ], "offsets": [ [ 938, 943 ] ], "normalized": [] }, { "id": "1669", "type": "CHEMICAL", "text": [ "DHETs" ], "offsets": [ [ 975, 980 ] ], "normalized": [] }, { "id": "1670", "type": "CHEMICAL", "text": [ "As(III)" ], "offsets": [ [ 995, 1002 ] ], "normalized": [] }, { "id": "1671", "type": "CHEMICAL", "text": [ "arsenic" ], "offsets": [ [ 227, 234 ] ], "normalized": [] }, { "id": "1672", "type": "CHEMICAL", "text": [ "arsenic" ], "offsets": [ [ 6, 13 ] ], "normalized": [] }, { "id": "1673", "type": "CHEMICAL", "text": [ "arachidonic acid" ], "offsets": [ [ 62, 78 ] ], "normalized": [] }, { "id": "1674", "type": "GENE-N", "text": [ "soluble epoxide hydrolase" ], "offsets": [ [ 1297, 1322 ] ], "normalized": [] }, { "id": "1675", "type": "GENE-N", "text": [ "cytochrome (CYP) P450" ], "offsets": [ [ 414, 435 ] ], "normalized": [] }, { "id": "1676", "type": "GENE-N", "text": [ "CYP" ], "offsets": [ [ 552, 555 ] ], "normalized": [] }, { "id": "1677", "type": "GENE-N", "text": [ "epoxygenases" ], "offsets": [ [ 556, 568 ] ], "normalized": [] }, { "id": "1678", "type": "GENE-N", "text": [ "CYP" ], "offsets": [ [ 570, 573 ] ], "normalized": [] }, { "id": "1679", "type": "GENE-N", "text": [ "ω-hydroxylases" ], "offsets": [ [ 574, 588 ] ], "normalized": [] }, { "id": "1680", "type": "GENE-Y", "text": [ "EPHX2" ], "offsets": [ [ 593, 598 ] ], "normalized": [] }, { "id": "1681", "type": "GENE-N", "text": [ "epoxygenases" ], "offsets": [ [ 1024, 1036 ] ], "normalized": [] }, { "id": "1682", "type": "GENE-N", "text": [ "cytochrome P450" ], "offsets": [ [ 31, 46 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1683", "type": "Regulator", "arg1_id": "1672", "arg2_id": "1682", "normalized": [] }, { "id": "1684", "type": "Regulator", "arg1_id": "1661", "arg2_id": "1676", "normalized": [] }, { "id": "1685", "type": "Regulator", "arg1_id": "1661", "arg2_id": "1677", "normalized": [] }, { "id": "1686", "type": "Regulator", "arg1_id": "1661", "arg2_id": "1678", "normalized": [] }, { "id": "1687", "type": "Regulator", "arg1_id": "1661", "arg2_id": "1679", "normalized": [] }, { "id": "1688", "type": "Regulator", "arg1_id": "1661", "arg2_id": "1680", "normalized": [] }, { "id": "1689", "type": "Upregulator", "arg1_id": "1670", "arg2_id": "1681", "normalized": [] }, { "id": "1690", "type": "Upregulator", "arg1_id": "1653", "arg2_id": "1674", "normalized": [] } ]
1691
23063069
[ { "id": "1692", "type": "title and abstract", "text": [ "Parental exposure to natural mixtures of POPs reduced embryo production and altered gene transcription in zebrafish embryos.\nDetermination of toxicity of complex mixtures has been proposed to be one of the most important challenges for modern toxicology. In this study we performed genome wide transcriptome profiling to assess potential toxicant induced changes in gene regulation in zebrafish embryos following parental exposure to two natural mixtures of persistent organic pollutants (POPs). The mixtures used were extracted from burbot (Lota lota) liver originating from two lakes (Lake Mjøsa and Lake Losna) belonging to the same freshwater system in Norway. The dominating groups of contaminants were polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane metabolites (DDTs). Because both mixtures used in the present study induced similar effects, it is likely that the same toxicants are involved. The Mjøsa mixture contains high levels of PBDEs while this group of pollutants is low in the Losna mixture. However, both mixtures contain substantial concentrations of PCB and DDT suggesting these contaminants as the predominant contributors to the toxicity observed. The observed effects included phenotypic traits, like embryo production and survival, and gene transcription changes corresponding with disease and biological functions such as cancer, reproductive system disease, cardiovascular disease, lipid and protein metabolism, small molecule biochemistry and cell cycle. The changes in gene transcription included genes regulated by HNF4A, insulin, LH, FSH and NF-κB which are known to be central regulators of endocrine signaling, metabolism, metabolic homeostasis, immune functions, cancer development and reproduction. The results suggest that relative low concentrations of the natural mixtures of POPs used in the present study might pose a threat to wild freshwater fish living in the lakes from which the POPs mixtures originated." ], "offsets": [ [ 0, 2008 ] ] } ]
[ { "id": "1693", "type": "CHEMICAL", "text": [ "PCB" ], "offsets": [ [ 1130, 1133 ] ], "normalized": [] }, { "id": "1694", "type": "CHEMICAL", "text": [ "DDT" ], "offsets": [ [ 1138, 1141 ] ], "normalized": [] }, { "id": "1695", "type": "CHEMICAL", "text": [ "polybrominated diphenyl ethers" ], "offsets": [ [ 708, 738 ] ], "normalized": [] }, { "id": "1696", "type": "CHEMICAL", "text": [ "PBDEs" ], "offsets": [ [ 740, 745 ] ], "normalized": [] }, { "id": "1697", "type": "CHEMICAL", "text": [ "polychlorinated biphenyls" ], "offsets": [ [ 748, 773 ] ], "normalized": [] }, { "id": "1698", "type": "CHEMICAL", "text": [ "PCBs" ], "offsets": [ [ 775, 779 ] ], "normalized": [] }, { "id": "1699", "type": "CHEMICAL", "text": [ "dichlorodiphenyltrichloroethane" ], "offsets": [ [ 785, 816 ] ], "normalized": [] }, { "id": "1700", "type": "CHEMICAL", "text": [ "PBDEs" ], "offsets": [ [ 1003, 1008 ] ], "normalized": [] }, { "id": "1701", "type": "GENE-Y", "text": [ "HNF4A" ], "offsets": [ [ 1604, 1609 ] ], "normalized": [] }, { "id": "1702", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 1611, 1618 ] ], "normalized": [] }, { "id": "1703", "type": "GENE-N", "text": [ "LH" ], "offsets": [ [ 1620, 1622 ] ], "normalized": [] }, { "id": "1704", "type": "GENE-N", "text": [ "FSH" ], "offsets": [ [ 1624, 1627 ] ], "normalized": [] }, { "id": "1705", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 1632, 1637 ] ], "normalized": [] }, { "id": "1706", "type": "CHEMICAL", "text": [ "DDTs" ], "offsets": [ [ 830, 834 ] ], "normalized": [] } ]
[]
[]
[]
1707
23620436
[ { "id": "1708", "type": "title and abstract", "text": [ "A New Proposed Rodent Model of Chemically Induced Prostate Carcinogenesis: Distinct Time-Course Prostate Cancer Progression in the Dorsolateral and Ventral Lobes.\nBACKGROUND: Characterization of novel rodent models for prostate cancer studies requires evaluation of either spontaneous and carcinogen-induced tumors as well as tumor incidence in different prostatic lobes. We propose a new short-term rodent model of chemically induced prostate carcinogenesis in which prostate cancer progression occurs differentially in the dorsolateral and ventral lobes. METHODS: Adult gerbils were treated with MNU alone or associated with testosterone for 3 or 6 months of treatment. Tumor incidence, latency, localization, and immunohistochemistry (AR, PCNA, smooth muscle α-actin, p63, MGMT, and E-cadherin) were studied in both lobes. RESULTS: Comparisons between both lobes revealed that lesions developed first in the DL while the VL presented longer tumor latency. However, after 6 months, there was a dramatic increase in tumor multiplicity in the VL, mainly in MNU-treated groups. Lesions clearly progressed from a premalignant to a malignant phenotype over time and tumor latency was decreased by MNU + testosterone administration. Three-dimensional reconstruction of the prostatic complex showed that the DL developed tumors exclusively in the periurethral area and showed intense AR, PCNA, and MGMT immunostaining. Moreover, VL lesions emerged throughout the entire lobe. MNU-induced lesions presented markers indicative of an aggressive phenotype: lack of basal cells, rupture of the smooth muscle cell layer, loss of E-cadherin, and high MGMT staining. CONCLUSIONS: There are distinct pathways involved in tumor progression in gerbil prostate lobes. This animal provides a good model for prostate cancer since it allows the investigation of advanced steps of carcinogenesis with shorter latency periods in both lobes. Prostate © 2013 Wiley Periodicals, Inc." ], "offsets": [ [ 0, 1958 ] ] } ]
[ { "id": "1709", "type": "CHEMICAL", "text": [ "MNU" ], "offsets": [ [ 1194, 1197 ] ], "normalized": [] }, { "id": "1710", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 1200, 1212 ] ], "normalized": [] }, { "id": "1711", "type": "CHEMICAL", "text": [ "MNU" ], "offsets": [ [ 1471, 1474 ] ], "normalized": [] }, { "id": "1712", "type": "CHEMICAL", "text": [ "MNU" ], "offsets": [ [ 598, 601 ] ], "normalized": [] }, { "id": "1713", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 627, 639 ] ], "normalized": [] }, { "id": "1714", "type": "CHEMICAL", "text": [ "MNU" ], "offsets": [ [ 1057, 1060 ] ], "normalized": [] }, { "id": "1715", "type": "GENE-N", "text": [ "AR" ], "offsets": [ [ 1379, 1381 ] ], "normalized": [] }, { "id": "1716", "type": "GENE-N", "text": [ "PCNA" ], "offsets": [ [ 1383, 1387 ] ], "normalized": [] }, { "id": "1717", "type": "GENE-N", "text": [ "MGMT" ], "offsets": [ [ 1393, 1397 ] ], "normalized": [] }, { "id": "1718", "type": "GENE-Y", "text": [ "E-cadherin" ], "offsets": [ [ 1618, 1628 ] ], "normalized": [] }, { "id": "1719", "type": "GENE-N", "text": [ "MGMT" ], "offsets": [ [ 1639, 1643 ] ], "normalized": [] }, { "id": "1720", "type": "GENE-N", "text": [ "AR" ], "offsets": [ [ 738, 740 ] ], "normalized": [] }, { "id": "1721", "type": "GENE-N", "text": [ "PCNA" ], "offsets": [ [ 742, 746 ] ], "normalized": [] }, { "id": "1722", "type": "GENE-N", "text": [ "smooth muscle α-actin" ], "offsets": [ [ 748, 769 ] ], "normalized": [] }, { "id": "1723", "type": "GENE-N", "text": [ "p63" ], "offsets": [ [ 771, 774 ] ], "normalized": [] }, { "id": "1724", "type": "GENE-N", "text": [ "MGMT" ], "offsets": [ [ 776, 780 ] ], "normalized": [] }, { "id": "1725", "type": "GENE-Y", "text": [ "E-cadherin" ], "offsets": [ [ 786, 796 ] ], "normalized": [] } ]
[]
[]
[ { "id": "1726", "type": "Downregulator", "arg1_id": "1711", "arg2_id": "1718", "normalized": [] }, { "id": "1727", "type": "Upregulator", "arg1_id": "1711", "arg2_id": "1719", "normalized": [] } ]