Datasets:

bigbio

/

drugprot

like 5

[ { "id": "23564645_title", "type": "title", "text": [ "Detection of Statin Cytotoxicity Is Increased in Cells Expressing the OATP1B1 Transporter." ], "offsets": [ [ 0, 90 ] ] }, { "id": "23564645_abstract", "type": "abstract", "text": [ "Cytotoxicity of a compound is determined by the intracellular concentration mediated both by passive permeability and active uptake through drug transporters. However, the major liver uptake transporters were either absent or expressed at significantly lower levels in human liver cell lines than in human liver. When comparing cytotoxicity of five statins, the organic anion transporting polypeptide 1B1 (OATP1B1) expressing HEK cells showed a significantly higher sensitivity than the wild-type HEK cells. The IC50 shifts ranged from 9- to >100-fold, and the potency shifts collapsed in the presence of rifampicin, the inhibitor for OATPs. The extent of the IC50 shift correlated with the permeability of the statins with high permeable compounds having smaller shifts and low permeable compounds having larger shifts. The changes in statin potency in transporter transfected cells reflect the active uptake of statins into the cells and the increased intracellular drug concentration lead to increased toxicity. The data suggested that uptake transporters have a significant impact on the outcomes of a cell-based assay and should be considered during the early stages of compound toxicity screening in drug discovery. For compounds with low permeability which are likely to undergo transporter-mediated uptake, it is important to test them in transporter-competent cell models." ], "offsets": [ [ 91, 1472 ] ] } ]

[ { "id": "23564645_T1", "type": "CHEMICAL", "text": [ "rifampicin" ], "offsets": [ [ 696, 706 ] ], "normalized": [] }, { "id": "23564645_T2", "type": "GENE-N", "text": [ "liver uptake transporters" ], "offsets": [ [ 269, 294 ] ], "normalized": [] }, { "id": "23564645_T3", "type": "GENE-Y", "text": [ "organic anion transporting polypeptide 1B1" ], "offsets": [ [ 453, 495 ] ], "normalized": [] }, { "id": "23564645_T4", "type": "GENE-Y", "text": [ "OATP1B1" ], "offsets": [ [ 497, 504 ] ], "normalized": [] }, { "id": "23564645_T5", "type": "GENE-N", "text": [ "OATPs" ], "offsets": [ [ 726, 731 ] ], "normalized": [] }, { "id": "23564645_T6", "type": "GENE-Y", "text": [ "OATP1B1" ], "offsets": [ [ 70, 77 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "1438284_title", "type": "title", "text": [ "Conversion of acetylcholinesterase to butyrylcholinesterase: modeling and mutagenesis." ], "offsets": [ [ 0, 86 ] ] }, { "id": "1438284_abstract", "type": "abstract", "text": [ "Torpedo acetylcholinesterase (AcChoEase, EC 3.1.1.7) and human butyrylcholinesterase (BtChoEase, EC 3.1.1.8), while clearly differing in substrate specificity and sensitivity to inhibitors, possess 53% sequence homology; this permitted modeling human BtChoEase on the basis of the three-dimensional structure of Torpedo AcChoEase. The modeled BtChoEase structure closely resembled that of AcChoEase in overall features. However, six conserved aromatic residues that line the active-site gorge, which is a prominent feature of the AcChoEase structure, are absent in BtChoEase. Modeling showed that two such residues, Phe-288 and Phe-290, replaced by leucine and valine, respectively, in BtChoEase, may prevent entrance of butyrylcholine into the acyl-binding pocket. Their mutation to leucine and valine in AcChoEase, by site-directed mutagenesis, produced a double mutant that hydrolyzed butyrylthiocholine almost as well as acetylthiocholine. The mutated enzyme was also inhibited well by the bulky, BtChoEase-selective organophosphate inhibitor (tetraisopropylpyrophosphoramide, iso-OMPA). Trp-279, at the entrance of the active-site gorge in AcChoEase, is absent in BtChoEase. Modeling designated it as part of the \"peripheral\" anionic site, which is lacking in BtChoEase. The mutant W279A displayed strongly reduced inhibition by the peripheral site-specific ligand propidium relative to wild-type Torpedo AcChoEase, whereas inhibition by the catalytic-site inhibitor edrophonium was unaffected." ], "offsets": [ [ 87, 1586 ] ] } ]

[ { "id": "1438284_T1", "type": "CHEMICAL", "text": [ "organophosphate" ], "offsets": [ [ 1108, 1123 ] ], "normalized": [] }, { "id": "1438284_T2", "type": "CHEMICAL", "text": [ "tetraisopropylpyrophosphoramide" ], "offsets": [ [ 1135, 1166 ] ], "normalized": [] }, { "id": "1438284_T3", "type": "CHEMICAL", "text": [ "iso-OMPA" ], "offsets": [ [ 1168, 1176 ] ], "normalized": [] }, { "id": "1438284_T4", "type": "CHEMICAL", "text": [ "Trp" ], "offsets": [ [ 1179, 1182 ] ], "normalized": [] }, { "id": "1438284_T5", "type": "CHEMICAL", "text": [ "propidium" ], "offsets": [ [ 1457, 1466 ] ], "normalized": [] }, { "id": "1438284_T6", "type": "CHEMICAL", "text": [ "edrophonium" ], "offsets": [ [ 1559, 1570 ] ], "normalized": [] }, { "id": "1438284_T7", "type": "CHEMICAL", "text": [ "Phe" ], "offsets": [ [ 703, 706 ] ], "normalized": [] }, { "id": "1438284_T8", "type": "CHEMICAL", "text": [ "Phe" ], "offsets": [ [ 715, 718 ] ], "normalized": [] }, { "id": "1438284_T9", "type": "CHEMICAL", "text": [ "leucine" ], "offsets": [ [ 736, 743 ] ], "normalized": [] }, { "id": "1438284_T10", "type": "CHEMICAL", "text": [ "valine" ], "offsets": [ [ 748, 754 ] ], "normalized": [] }, { "id": "1438284_T11", "type": "CHEMICAL", "text": [ "butyrylcholine" ], "offsets": [ [ 808, 822 ] ], "normalized": [] }, { "id": "1438284_T12", "type": "CHEMICAL", "text": [ "acyl" ], "offsets": [ [ 832, 836 ] ], "normalized": [] }, { "id": "1438284_T13", "type": "CHEMICAL", "text": [ "leucine" ], "offsets": [ [ 871, 878 ] ], "normalized": [] }, { "id": "1438284_T14", "type": "CHEMICAL", "text": [ "valine" ], "offsets": [ [ 883, 889 ] ], "normalized": [] }, { "id": "1438284_T15", "type": "CHEMICAL", "text": [ "butyrylthiocholine" ], "offsets": [ [ 975, 993 ] ], "normalized": [] }, { "id": "1438284_T16", "type": "CHEMICAL", "text": [ "acetylthiocholine" ], "offsets": [ [ 1012, 1029 ] ], "normalized": [] }, { "id": "1438284_T17", "type": "GENE-Y", "text": [ "Torpedo acetylcholinesterase" ], "offsets": [ [ 87, 115 ] ], "normalized": [] }, { "id": "1438284_T18", "type": "GENE-Y", "text": [ "BtChoEase" ], "offsets": [ [ 1088, 1097 ] ], "normalized": [] }, { "id": "1438284_T19", "type": "GENE-Y", "text": [ "AcChoEase" ], "offsets": [ [ 1232, 1241 ] ], "normalized": [] }, { "id": "1438284_T20", "type": "GENE-Y", "text": [ "BtChoEase" ], "offsets": [ [ 1256, 1265 ] ], "normalized": [] }, { "id": "1438284_T21", "type": "GENE-Y", "text": [ "BtChoEase" ], "offsets": [ [ 1352, 1361 ] ], "normalized": [] }, { "id": "1438284_T22", "type": "GENE-N", "text": [ "W279A" ], "offsets": [ [ 1374, 1379 ] ], "normalized": [] }, { "id": "1438284_T23", "type": "GENE-Y", "text": [ "Torpedo AcChoEase" ], "offsets": [ [ 1489, 1506 ] ], "normalized": [] }, { "id": "1438284_T24", "type": "GENE-Y", "text": [ "human BtChoEase" ], "offsets": [ [ 332, 347 ] ], "normalized": [] }, { "id": "1438284_T25", "type": "GENE-Y", "text": [ "AcChoEase" ], "offsets": [ [ 117, 126 ] ], "normalized": [] }, { "id": "1438284_T26", "type": "GENE-Y", "text": [ "Torpedo AcChoEase" ], "offsets": [ [ 399, 416 ] ], "normalized": [] }, { "id": "1438284_T27", "type": "GENE-Y", "text": [ "BtChoEase" ], "offsets": [ [ 430, 439 ] ], "normalized": [] }, { "id": "1438284_T28", "type": "GENE-Y", "text": [ "AcChoEase" ], "offsets": [ [ 476, 485 ] ], "normalized": [] }, { "id": "1438284_T29", "type": "GENE-Y", "text": [ "EC 3.1.1.7" ], "offsets": [ [ 128, 138 ] ], "normalized": [] }, { "id": "1438284_T30", "type": "GENE-Y", "text": [ "AcChoEase" ], "offsets": [ [ 617, 626 ] ], "normalized": [] }, { "id": "1438284_T31", "type": "GENE-Y", "text": [ "BtChoEase" ], "offsets": [ [ 652, 661 ] ], "normalized": [] }, { "id": "1438284_T32", "type": "GENE-Y", "text": [ "human butyrylcholinesterase" ], "offsets": [ [ 144, 171 ] ], "normalized": [] }, { "id": "1438284_T33", "type": "GENE-Y", "text": [ "BtChoEase" ], "offsets": [ [ 773, 782 ] ], "normalized": [] }, { "id": "1438284_T34", "type": "GENE-N", "text": [ "acyl-binding pocket" ], "offsets": [ [ 832, 851 ] ], "normalized": [] }, { "id": "1438284_T35", "type": "GENE-Y", "text": [ "AcChoEase" ], "offsets": [ [ 893, 902 ] ], "normalized": [] }, { "id": "1438284_T36", "type": "GENE-Y", "text": [ "BtChoEase" ], "offsets": [ [ 173, 182 ] ], "normalized": [] }, { "id": "1438284_T37", "type": "GENE-Y", "text": [ "EC 3.1.1.8" ], "offsets": [ [ 184, 194 ] ], "normalized": [] }, { "id": "1438284_T38", "type": "GENE-Y", "text": [ "acetylcholinesterase" ], "offsets": [ [ 14, 34 ] ], "normalized": [] }, { "id": "1438284_T39", "type": "GENE-Y", "text": [ "butyrylcholinesterase" ], "offsets": [ [ 38, 59 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23276728_title", "type": "title", "text": [ "Potential antipsoriatic effect of chondroitin sulfate through inhibition of NF-κB and STAT3 in human keratinocytes." ], "offsets": [ [ 0, 115 ] ] }, { "id": "23276728_abstract", "type": "abstract", "text": [ "Chondroitin sulfate (CS) is a natural glycosaminoglycan, formed by the 1-3 linkage of d-glucuronic acid to N-acetylgalactosamine, present in the extracellular matrix. It is used as a slow acting disease modifying agent in the treatment of osteoarthritis, and part of its beneficial effects are due to its antiinflammatory properties that result from an inhibitory effect on NF-κB signaling pathway. This ability raises the hypothesis that CS might be effective in other chronic inflammatory processes such as psoriasis, in which a deregulation of NF-κB is a key feature. In addition, psoriasis is characterized by an upregulation of STAT3 signaling pathway that is related to the epidermal hyperplasia. In the present study we report the pharmacological modulation of the NF-κB and STAT3 signaling pathways by CS in normal human keratinocytes. CS inhibited NF-κB activation and the release of some of the key psoriatic cytokines such as TNFα, IL-8, IL-6 and CCL27. Moreover, it impaired STAT3 translocation to the nucleus and significantly reduced STAT3 transcriptional activity by a mechanism that was independent from STAT3 phosphorylation. Our results confirm the interest of CS as a candidate for future drug research in the therapeutics of psoriasis given the need of more effective and safer oral medications for these patients." ], "offsets": [ [ 116, 1450 ] ] } ]

[ { "id": "23276728_T1", "type": "CHEMICAL", "text": [ "N-acetylgalactosamine" ], "offsets": [ [ 223, 244 ] ], "normalized": [] }, { "id": "23276728_T2", "type": "CHEMICAL", "text": [ "sulfate" ], "offsets": [ [ 128, 135 ] ], "normalized": [] }, { "id": "23276728_T3", "type": "CHEMICAL", "text": [ "d-glucuronic acid" ], "offsets": [ [ 202, 219 ] ], "normalized": [] }, { "id": "23276728_T4", "type": "CHEMICAL", "text": [ "sulfate" ], "offsets": [ [ 46, 53 ] ], "normalized": [] }, { "id": "23276728_T5", "type": "GENE-Y", "text": [ "STAT3" ], "offsets": [ [ 1164, 1169 ] ], "normalized": [] }, { "id": "23276728_T6", "type": "GENE-Y", "text": [ "STAT3" ], "offsets": [ [ 1236, 1241 ] ], "normalized": [] }, { "id": "23276728_T7", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 490, 495 ] ], "normalized": [] }, { "id": "23276728_T8", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 663, 668 ] ], "normalized": [] }, { "id": "23276728_T9", "type": "GENE-Y", "text": [ "STAT3" ], "offsets": [ [ 749, 754 ] ], "normalized": [] }, { "id": "23276728_T10", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 888, 893 ] ], "normalized": [] }, { "id": "23276728_T11", "type": "GENE-Y", "text": [ "STAT3" ], "offsets": [ [ 898, 903 ] ], "normalized": [] }, { "id": "23276728_T12", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 973, 978 ] ], "normalized": [] }, { "id": "23276728_T13", "type": "GENE-N", "text": [ "cytokines" ], "offsets": [ [ 1035, 1044 ] ], "normalized": [] }, { "id": "23276728_T14", "type": "GENE-Y", "text": [ "TNFα" ], "offsets": [ [ 1053, 1057 ] ], "normalized": [] }, { "id": "23276728_T15", "type": "GENE-Y", "text": [ "IL-8" ], "offsets": [ [ 1059, 1063 ] ], "normalized": [] }, { "id": "23276728_T16", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 1065, 1069 ] ], "normalized": [] }, { "id": "23276728_T17", "type": "GENE-Y", "text": [ "CCL27" ], "offsets": [ [ 1074, 1079 ] ], "normalized": [] }, { "id": "23276728_T18", "type": "GENE-Y", "text": [ "STAT3" ], "offsets": [ [ 1103, 1108 ] ], "normalized": [] }, { "id": "23276728_T19", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 76, 81 ] ], "normalized": [] }, { "id": "23276728_T20", "type": "GENE-Y", "text": [ "STAT3" ], "offsets": [ [ 86, 91 ] ], "normalized": [] } ]

[]

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[ { "id": "23085121_title", "type": "title", "text": [ "Cholinesterase confabs and cousins: Approaching forty years." ], "offsets": [ [ 0, 60 ] ] }, { "id": "23085121_abstract", "type": "abstract", "text": [ "In the past four decades of cholinesterase (ChE) research, we have seen substantive evolution of the field from one centered around substrate and inhibitor kinetic profiles and compound characterizations to the analysis of ChE structure, first through the gene families and then by X-ray crystallographic determinations of the free enzymes and their complexes and conjugates. Indeed, these endeavors have been facilitated by recombinant DNA technologies, structure determinations and parallel studies in related proteins in the α/β-hydrolase fold family. This approach has not only contributed to a fundamental understanding of structure and function of a large family of hydrolase-like proteins possessing functions other than catalysis, but also has been used to develop new practical strategies for scavenging and antidotal activity in cases of organophosphate insecticide or nerve agent exposure." ], "offsets": [ [ 61, 961 ] ] } ]

[ { "id": "23085121_T1", "type": "CHEMICAL", "text": [ "organophosphate" ], "offsets": [ [ 909, 924 ] ], "normalized": [] }, { "id": "23085121_T2", "type": "GENE-Y", "text": [ "ChE" ], "offsets": [ [ 284, 287 ] ], "normalized": [] }, { "id": "23085121_T3", "type": "GENE-Y", "text": [ "cholinesterase" ], "offsets": [ [ 89, 103 ] ], "normalized": [] }, { "id": "23085121_T4", "type": "GENE-Y", "text": [ "ChE" ], "offsets": [ [ 105, 108 ] ], "normalized": [] }, { "id": "23085121_T5", "type": "GENE-N", "text": [ "α/β-hydrolase" ], "offsets": [ [ 589, 602 ] ], "normalized": [] }, { "id": "23085121_T6", "type": "GENE-N", "text": [ "hydrolase" ], "offsets": [ [ 733, 742 ] ], "normalized": [] }, { "id": "23085121_T7", "type": "GENE-Y", "text": [ "Cholinesterase" ], "offsets": [ [ 0, 14 ] ], "normalized": [] } ]

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[ { "id": "23337911_title", "type": "title", "text": [ "Toxicity assessment on trophoblast cells for some environment polluting chemicals and 17β-estradiol." ], "offsets": [ [ 0, 100 ] ] }, { "id": "23337911_abstract", "type": "abstract", "text": [ "The identification of reproductive toxicants is a major scientific challenge for human health. We investigated the effects of a selected group of environmental polluting chemicals mostly provided with estrogenic activity on the human trophoblast cell lines BeWo and HTR-8/SVneo. Cells were exposed for 24h to various concentrations (from 0.1 pM to 1 mM) of atrazine (ATR), diethylstilbestrol (DES), para-nonylphenol (p-NP), resveratrol (RES) and 17 β-estradiol (E2) and assayed for cell viability and human beta-Chorionic Gonadotropin (β-hCG) secretion. Decrease of cell viability as respect to control, vehicle-treated, cultures was obtained for all chemicals in the concentration range of 1 μM-1 mM in both cell types. A parallel decrease of β-hCG secretion was observed in BeWo cells, at 1 μM-1 mM concentrations, with the only exception of ATR which caused an increase at concentrations up to 1mM. β-hCG release was also unexpectedly inhibited by ATR, DES, p-NP and RES at non-toxic (pM-nM) concentrations. These findings raise concern about the negative, potential effects of various environmental polluting chemicals on pregnancy success and fetal health." ], "offsets": [ [ 101, 1262 ] ] } ]

[ { "id": "23337911_T1", "type": "CHEMICAL", "text": [ "atrazine" ], "offsets": [ [ 458, 466 ] ], "normalized": [] }, { "id": "23337911_T2", "type": "CHEMICAL", "text": [ "ATR" ], "offsets": [ [ 468, 471 ] ], "normalized": [] }, { "id": "23337911_T3", "type": "CHEMICAL", "text": [ "diethylstilbestrol" ], "offsets": [ [ 474, 492 ] ], "normalized": [] }, { "id": "23337911_T4", "type": "CHEMICAL", "text": [ "DES" ], "offsets": [ [ 494, 497 ] ], "normalized": [] }, { "id": "23337911_T5", "type": "CHEMICAL", "text": [ "para-nonylphenol" ], "offsets": [ [ 500, 516 ] ], "normalized": [] }, { "id": "23337911_T6", "type": "CHEMICAL", "text": [ "p-NP" ], "offsets": [ [ 518, 522 ] ], "normalized": [] }, { "id": "23337911_T7", "type": "CHEMICAL", "text": [ "resveratrol" ], "offsets": [ [ 525, 536 ] ], "normalized": [] }, { "id": "23337911_T8", "type": "CHEMICAL", "text": [ "RES" ], "offsets": [ [ 538, 541 ] ], "normalized": [] }, { "id": "23337911_T9", "type": "CHEMICAL", "text": [ "17 β-estradiol" ], "offsets": [ [ 547, 561 ] ], "normalized": [] }, { "id": "23337911_T10", "type": "CHEMICAL", "text": [ "ATR" ], "offsets": [ [ 945, 948 ] ], "normalized": [] }, { "id": "23337911_T11", "type": "CHEMICAL", "text": [ "ATR" ], "offsets": [ [ 1052, 1055 ] ], "normalized": [] }, { "id": "23337911_T12", "type": "CHEMICAL", "text": [ "DES" ], "offsets": [ [ 1057, 1060 ] ], "normalized": [] }, { "id": "23337911_T13", "type": "CHEMICAL", "text": [ "p-NP" ], "offsets": [ [ 1062, 1066 ] ], "normalized": [] }, { "id": "23337911_T14", "type": "CHEMICAL", "text": [ "RES" ], "offsets": [ [ 1071, 1074 ] ], "normalized": [] }, { "id": "23337911_T15", "type": "CHEMICAL", "text": [ "17β-estradiol" ], "offsets": [ [ 86, 99 ] ], "normalized": [] }, { "id": "23337911_T16", "type": "GENE-Y", "text": [ "human beta-Chorionic Gonadotropin" ], "offsets": [ [ 602, 635 ] ], "normalized": [] }, { "id": "23337911_T17", "type": "GENE-Y", "text": [ "β-hCG" ], "offsets": [ [ 637, 642 ] ], "normalized": [] }, { "id": "23337911_T18", "type": "GENE-Y", "text": [ "β-hCG" ], "offsets": [ [ 845, 850 ] ], "normalized": [] }, { "id": "23337911_T19", "type": "GENE-Y", "text": [ "β-hCG" ], "offsets": [ [ 1003, 1008 ] ], "normalized": [] } ]

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[]

[ { "id": "23337911_0", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23337911_T10", "arg2_id": "23337911_T18", "normalized": [] }, { "id": "23337911_1", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23337911_T11", "arg2_id": "23337911_T19", "normalized": [] }, { "id": "23337911_2", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23337911_T12", "arg2_id": "23337911_T19", "normalized": [] }, { "id": "23337911_3", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23337911_T13", "arg2_id": "23337911_T19", "normalized": [] }, { "id": "23337911_4", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23337911_T14", "arg2_id": "23337911_T19", "normalized": [] } ]

[ { "id": "19610651_title", "type": "title", "text": [ "Small molecule chloropyramine hydrochloride (C4) targets the binding site of focal adhesion kinase and vascular endothelial growth factor receptor 3 and suppresses breast cancer growth in vivo." ], "offsets": [ [ 0, 193 ] ] }, { "id": "19610651_abstract", "type": "abstract", "text": [ "FAK is a tyrosine kinase that functions as a key orchestrator of signals leading to invasion and metastasis. Since FAK interacts directly with a number of critical proteins involved in survival signaling in tumor cells, we hypothesized that targeting a key protein-protein interface with druglike small molecules was a feasible strategy for inhibiting tumor growth. In this study, we targeted the protein-protein interface between FAK and VEGFR-3 and identified compound C4 (chloropyramine hydrochloride) as a drug capable of (1) inhibiting the biochemical function of VEGFR-3 and FAK, (2) inhibiting proliferation of a diverse set of cancer cell types in vitro, and (3) reducing tumor growth in vivo. Chloropyramine hydrochloride reduced tumor growth as a single agent, while concomitant administration with doxorubicin had a pronounced synergistic effect. Our data demonstrate that the FAK-VEGFR-3 interaction can be targeted by small druglike molecules and this interaction can provide the basis for highly specific novel cancer therapeutics." ], "offsets": [ [ 194, 1239 ] ] } ]

[ { "id": "19610651_T1", "type": "CHEMICAL", "text": [ "chloropyramine hydrochloride" ], "offsets": [ [ 669, 697 ] ], "normalized": [] }, { "id": "19610651_T2", "type": "CHEMICAL", "text": [ "Chloropyramine hydrochloride" ], "offsets": [ [ 896, 924 ] ], "normalized": [] }, { "id": "19610651_T3", "type": "CHEMICAL", "text": [ "doxorubicin" ], "offsets": [ [ 1003, 1014 ] ], "normalized": [] }, { "id": "19610651_T4", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 203, 211 ] ], "normalized": [] }, { "id": "19610651_T5", "type": "CHEMICAL", "text": [ "chloropyramine hydrochloride" ], "offsets": [ [ 15, 43 ] ], "normalized": [] }, { "id": "19610651_T6", "type": "GENE-Y", "text": [ "FAK" ], "offsets": [ [ 194, 197 ] ], "normalized": [] }, { "id": "19610651_T7", "type": "GENE-Y", "text": [ "FAK" ], "offsets": [ [ 309, 312 ] ], "normalized": [] }, { "id": "19610651_T8", "type": "GENE-Y", "text": [ "FAK" ], "offsets": [ [ 625, 628 ] ], "normalized": [] }, { "id": "19610651_T9", "type": "GENE-Y", "text": [ "VEGFR-3" ], "offsets": [ [ 633, 640 ] ], "normalized": [] }, { "id": "19610651_T10", "type": "GENE-Y", "text": [ "VEGFR-3" ], "offsets": [ [ 763, 770 ] ], "normalized": [] }, { "id": "19610651_T11", "type": "GENE-Y", "text": [ "FAK" ], "offsets": [ [ 775, 778 ] ], "normalized": [] }, { "id": "19610651_T12", "type": "GENE-Y", "text": [ "FAK" ], "offsets": [ [ 1082, 1085 ] ], "normalized": [] }, { "id": "19610651_T13", "type": "GENE-Y", "text": [ "VEGFR-3" ], "offsets": [ [ 1086, 1093 ] ], "normalized": [] }, { "id": "19610651_T14", "type": "GENE-N", "text": [ "tyrosine kinase" ], "offsets": [ [ 203, 218 ] ], "normalized": [] }, { "id": "19610651_T15", "type": "GENE-Y", "text": [ "vascular endothelial growth factor receptor 3" ], "offsets": [ [ 103, 148 ] ], "normalized": [] }, { "id": "19610651_T16", "type": "GENE-Y", "text": [ "focal adhesion kinase" ], "offsets": [ [ 77, 98 ] ], "normalized": [] } ]

[]

[]

[ { "id": "19610651_0", "type": "DIRECT-REGULATOR", "arg1_id": "19610651_T5", "arg2_id": "19610651_T16", "normalized": [] }, { "id": "19610651_1", "type": "DIRECT-REGULATOR", "arg1_id": "19610651_T5", "arg2_id": "19610651_T15", "normalized": [] }, { "id": "19610651_2", "type": "INHIBITOR", "arg1_id": "19610651_T1", "arg2_id": "19610651_T10", "normalized": [] }, { "id": "19610651_3", "type": "INHIBITOR", "arg1_id": "19610651_T1", "arg2_id": "19610651_T11", "normalized": [] } ]

[ { "id": "23578608_title", "type": "title", "text": [ "Role of plant stanol derivatives in the modulation of cholesterol metabolism and liver gene expression in mice." ], "offsets": [ [ 0, 111 ] ] }, { "id": "23578608_abstract", "type": "abstract", "text": [ "The present study was to evaluate the cholesterol-lowering effect of two novel plant stanol derivatives and its potential molecular mechanism in hyper-cholesterol mice induced by a high-cholesterol diet. Results showed that oral administration of plant stanyl hemisuccinate (2×, 5×) and plant stanyl sorbitol succinate (2×, 5×) effectively attenuated the serum total cholesterol and low density lipoprotein cholesterol levels, while had no effect on the serum triacylglycerol and high density lipoprotein cholesterol. And plant stanol derivatives decreased liver cholesterol concentration and increased faecal cholesterol output. Meanwhile, both plant stanyl hemisuccinate and plant stanyl sorbitol succinate could remarkably promote liver X receptor alpha (LXRα) expression, and increased cholesterol 7α-hydroxylase (CYP7A1) expression and faecal total bile acid output to varying degrees. These results suggested two novel plant stanol derivatives possessed hypocholesterolemic effect, and the cholesterol-lowering action of plant stanol derivatives may be through activating the potential LXRα-CYP7A1-bile acid excretion pathway." ], "offsets": [ [ 112, 1244 ] ] } ]

[ { "id": "23578608_T1", "type": "CHEMICAL", "text": [ "stanol" ], "offsets": [ [ 1145, 1151 ] ], "normalized": [] }, { "id": "23578608_T2", "type": "CHEMICAL", "text": [ "bile acid" ], "offsets": [ [ 1216, 1225 ] ], "normalized": [] }, { "id": "23578608_T3", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 263, 274 ] ], "normalized": [] }, { "id": "23578608_T4", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 298, 309 ] ], "normalized": [] }, { "id": "23578608_T5", "type": "CHEMICAL", "text": [ "stanyl hemisuccinate" ], "offsets": [ [ 365, 385 ] ], "normalized": [] }, { "id": "23578608_T6", "type": "CHEMICAL", "text": [ "stanyl sorbitol succinate" ], "offsets": [ [ 405, 430 ] ], "normalized": [] }, { "id": "23578608_T7", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 479, 490 ] ], "normalized": [] }, { "id": "23578608_T8", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 150, 161 ] ], "normalized": [] }, { "id": "23578608_T9", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 519, 530 ] ], "normalized": [] }, { "id": "23578608_T10", "type": "CHEMICAL", "text": [ "triacylglycerol" ], "offsets": [ [ 572, 587 ] ], "normalized": [] }, { "id": "23578608_T11", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 617, 628 ] ], "normalized": [] }, { "id": "23578608_T12", "type": "CHEMICAL", "text": [ "stanol" ], "offsets": [ [ 640, 646 ] ], "normalized": [] }, { "id": "23578608_T13", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 675, 686 ] ], "normalized": [] }, { "id": "23578608_T14", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 722, 733 ] ], "normalized": [] }, { "id": "23578608_T15", "type": "CHEMICAL", "text": [ "stanyl hemisuccinate" ], "offsets": [ [ 764, 784 ] ], "normalized": [] }, { "id": "23578608_T16", "type": "CHEMICAL", "text": [ "stanyl sorbitol succinate" ], "offsets": [ [ 795, 820 ] ], "normalized": [] }, { "id": "23578608_T17", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 902, 913 ] ], "normalized": [] }, { "id": "23578608_T18", "type": "CHEMICAL", "text": [ "bile acid" ], "offsets": [ [ 966, 975 ] ], "normalized": [] }, { "id": "23578608_T19", "type": "CHEMICAL", "text": [ "stanol" ], "offsets": [ [ 197, 203 ] ], "normalized": [] }, { "id": "23578608_T20", "type": "CHEMICAL", "text": [ "stanol" ], "offsets": [ [ 1043, 1049 ] ], "normalized": [] }, { "id": "23578608_T21", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 1108, 1119 ] ], "normalized": [] }, { "id": "23578608_T22", "type": "CHEMICAL", "text": [ "stanol" ], "offsets": [ [ 14, 20 ] ], "normalized": [] }, { "id": "23578608_T23", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 54, 65 ] ], "normalized": [] }, { "id": "23578608_T24", "type": "GENE-Y", "text": [ "LXRα" ], "offsets": [ [ 1204, 1208 ] ], "normalized": [] }, { "id": "23578608_T25", "type": "GENE-Y", "text": [ "CYP7A1" ], "offsets": [ [ 1209, 1215 ] ], "normalized": [] }, { "id": "23578608_T26", "type": "GENE-N", "text": [ "low density lipoprotein" ], "offsets": [ [ 495, 518 ] ], "normalized": [] }, { "id": "23578608_T27", "type": "GENE-N", "text": [ "high density lipoprotein" ], "offsets": [ [ 592, 616 ] ], "normalized": [] }, { "id": "23578608_T28", "type": "GENE-Y", "text": [ "liver X receptor alpha" ], "offsets": [ [ 846, 868 ] ], "normalized": [] }, { "id": "23578608_T29", "type": "GENE-Y", "text": [ "LXRα" ], "offsets": [ [ 870, 874 ] ], "normalized": [] }, { "id": "23578608_T30", "type": "GENE-Y", "text": [ "cholesterol 7α-hydroxylase" ], "offsets": [ [ 902, 928 ] ], "normalized": [] }, { "id": "23578608_T31", "type": "GENE-Y", "text": [ "CYP7A1" ], "offsets": [ [ 930, 936 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23578608_0", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23578608_T5", "arg2_id": "23578608_T26", "normalized": [] }, { "id": "23578608_1", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23578608_T6", "arg2_id": "23578608_T26", "normalized": [] }, { "id": "23578608_2", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23578608_T15", "arg2_id": "23578608_T28", "normalized": [] }, { "id": "23578608_3", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23578608_T16", "arg2_id": "23578608_T28", "normalized": [] }, { "id": "23578608_4", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23578608_T15", "arg2_id": "23578608_T29", "normalized": [] }, { "id": "23578608_5", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23578608_T16", "arg2_id": "23578608_T29", "normalized": [] }, { "id": "23578608_6", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23578608_T15", "arg2_id": "23578608_T30", "normalized": [] }, { "id": "23578608_7", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23578608_T16", "arg2_id": "23578608_T30", "normalized": [] }, { "id": "23578608_8", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23578608_T15", "arg2_id": "23578608_T31", "normalized": [] }, { "id": "23578608_9", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23578608_T16", "arg2_id": "23578608_T31", "normalized": [] }, { "id": "23578608_10", "type": "ACTIVATOR", "arg1_id": "23578608_T20", "arg2_id": "23578608_T24", "normalized": [] }, { "id": "23578608_11", "type": "ACTIVATOR", "arg1_id": "23578608_T20", "arg2_id": "23578608_T25", "normalized": [] } ]

[ { "id": "23397510_title", "type": "title", "text": [ "Prolactin and sex steroids levels in congenital lifetime isolated GH deficiency." ], "offsets": [ [ 0, 80 ] ] }, { "id": "23397510_abstract", "type": "abstract", "text": [ "Growth hormone (GH) and prolactin share similarities in structure and function. We have previously shown that women with congenital isolated GH deficiency (IGHD) caused by a homozygous mutation in the GHRH receptor gene (GHRHR) (MUT/MUT) have a short reproductive life, with anticipated climacteric. At climacteric, they have lower prolactin levels than normal controls (N/N). Because they are able to breast feed, we hypothesized that this prolactin reduction is limited to climacteric, as result of lower estradiol exposure of the lactotrophs. The purposes of this work were to assess prolactin levels in broader age adults homozygous and heterozygous (MUT/N) for the mutation and in normal controls (N/N), and to correlate them to sex steroids levels. We enrolled 24 GH-naïve MUT/MUT (12 female), 25 MUT/N (14 female), and 25 N/N (11 female) subjects, aged 25-65 years. Anthropometric data and serum prolactin, estradiol, total testosterone, and sex hormone binding globulin (SHBG) were measured. Free testosterone was calculated. Prolactin levels were similar in the three groups. In males, testosterone and SHBG levels were higher in MUT/MUT in comparison to N/N. There was no difference in free testosterone among groups. In all 74 individuals, prolactin correlated inversely with age (p < 0.0001) and directly with serum estradiol (p = 0.018). Prolactin levels in subjects with IGHD due to a homozygous GHRHR mutation are similar to heterozygous and normal homozygous, but total testosterone and SHBG are higher in male MUT/MUT, with no difference in free testosterone. The reduced prolactin level is limited to climacteric period, possibly due to reduced estrogen exposure." ], "offsets": [ [ 81, 1762 ] ] } ]

[ { "id": "23397510_T1", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 1086, 1098 ] ], "normalized": [] }, { "id": "23397510_T2", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 1176, 1188 ] ], "normalized": [] }, { "id": "23397510_T3", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 1282, 1294 ] ], "normalized": [] }, { "id": "23397510_T4", "type": "CHEMICAL", "text": [ "estradiol" ], "offsets": [ [ 1409, 1418 ] ], "normalized": [] }, { "id": "23397510_T5", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 1567, 1579 ] ], "normalized": [] }, { "id": "23397510_T6", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 1644, 1656 ] ], "normalized": [] }, { "id": "23397510_T7", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 1744, 1752 ] ], "normalized": [] }, { "id": "23397510_T8", "type": "CHEMICAL", "text": [ "estradiol" ], "offsets": [ [ 588, 597 ] ], "normalized": [] }, { "id": "23397510_T9", "type": "CHEMICAL", "text": [ "steroids" ], "offsets": [ [ 819, 827 ] ], "normalized": [] }, { "id": "23397510_T10", "type": "CHEMICAL", "text": [ "estradiol" ], "offsets": [ [ 995, 1004 ] ], "normalized": [] }, { "id": "23397510_T11", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 1012, 1024 ] ], "normalized": [] }, { "id": "23397510_T12", "type": "CHEMICAL", "text": [ "steroids" ], "offsets": [ [ 18, 26 ] ], "normalized": [] }, { "id": "23397510_T13", "type": "GENE-Y", "text": [ "Growth hormone" ], "offsets": [ [ 81, 95 ] ], "normalized": [] }, { "id": "23397510_T14", "type": "GENE-Y", "text": [ "Prolactin" ], "offsets": [ [ 1115, 1124 ] ], "normalized": [] }, { "id": "23397510_T15", "type": "GENE-Y", "text": [ "SHBG" ], "offsets": [ [ 1193, 1197 ] ], "normalized": [] }, { "id": "23397510_T16", "type": "GENE-Y", "text": [ "prolactin" ], "offsets": [ [ 1332, 1341 ] ], "normalized": [] }, { "id": "23397510_T17", "type": "GENE-Y", "text": [ "Prolactin" ], "offsets": [ [ 1432, 1441 ] ], "normalized": [] }, { "id": "23397510_T18", "type": "GENE-Y", "text": [ "GHRHR" ], "offsets": [ [ 1491, 1496 ] ], "normalized": [] }, { "id": "23397510_T19", "type": "GENE-Y", "text": [ "GH" ], "offsets": [ [ 222, 224 ] ], "normalized": [] }, { "id": "23397510_T20", "type": "GENE-Y", "text": [ "SHBG" ], "offsets": [ [ 1584, 1588 ] ], "normalized": [] }, { "id": "23397510_T21", "type": "GENE-Y", "text": [ "prolactin" ], "offsets": [ [ 1670, 1679 ] ], "normalized": [] }, { "id": "23397510_T22", "type": "GENE-Y", "text": [ "GH" ], "offsets": [ [ 97, 99 ] ], "normalized": [] }, { "id": "23397510_T23", "type": "GENE-Y", "text": [ "GHRH receptor" ], "offsets": [ [ 282, 295 ] ], "normalized": [] }, { "id": "23397510_T24", "type": "GENE-Y", "text": [ "GHRHR" ], "offsets": [ [ 302, 307 ] ], "normalized": [] }, { "id": "23397510_T25", "type": "GENE-Y", "text": [ "prolactin" ], "offsets": [ [ 105, 114 ] ], "normalized": [] }, { "id": "23397510_T26", "type": "GENE-Y", "text": [ "prolactin" ], "offsets": [ [ 413, 422 ] ], "normalized": [] }, { "id": "23397510_T27", "type": "GENE-Y", "text": [ "prolactin" ], "offsets": [ [ 522, 531 ] ], "normalized": [] }, { "id": "23397510_T28", "type": "GENE-Y", "text": [ "prolactin" ], "offsets": [ [ 668, 677 ] ], "normalized": [] }, { "id": "23397510_T29", "type": "GENE-Y", "text": [ "GH" ], "offsets": [ [ 851, 853 ] ], "normalized": [] }, { "id": "23397510_T30", "type": "GENE-Y", "text": [ "prolactin" ], "offsets": [ [ 984, 993 ] ], "normalized": [] }, { "id": "23397510_T31", "type": "GENE-Y", "text": [ "sex hormone binding globulin" ], "offsets": [ [ 1030, 1058 ] ], "normalized": [] }, { "id": "23397510_T32", "type": "GENE-Y", "text": [ "SHBG" ], "offsets": [ [ 1060, 1064 ] ], "normalized": [] }, { "id": "23397510_T33", "type": "GENE-Y", "text": [ "Prolactin" ], "offsets": [ [ 0, 9 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "17559874_title", "type": "title", "text": [ "The structure of serine palmitoyltransferase; gateway to sphingolipid biosynthesis." ], "offsets": [ [ 0, 83 ] ] }, { "id": "17559874_abstract", "type": "abstract", "text": [ "Sphingolipid biosynthesis commences with the condensation of L-serine and palmitoyl-CoA to produce 3-ketodihydrosphingosine (KDS). This reaction is catalysed by the PLP-dependent enzyme serine palmitoyltransferase (SPT; EC 2.3.1.50), which is a membrane-bound heterodimer (SPT1/SPT2) in eukaryotes such as humans and yeast and a cytoplasmic homodimer in the Gram-negative bacterium Sphingomonas paucimobilis. Unusually, the outer membrane of S. paucimobilis contains glycosphingolipid (GSL) instead of lipopolysaccharide (LPS), and SPT catalyses the first step of the GSL biosynthetic pathway in this organism. We report here the crystal structure of the holo-form of S. paucimobilis SPT at 1.3 A resolution. The enzyme is a symmetrical homodimer with two active sites and a monomeric tertiary structure consisting of three domains. The PLP cofactor is bound covalently to a lysine residue (Lys265) as an internal aldimine/Schiff base and the active site is composed of residues from both subunits, located at the bottom of a deep cleft. Models of the human SPT1/SPT2 heterodimer were generated from the bacterial structure by bioinformatics analysis. Mutations in the human SPT1-encoding subunit have been shown to cause a neuropathological disease known as hereditary sensory and autonomic neuropathy type I (HSAN1). Our models provide an understanding of how these mutations may affect the activity of the enzyme." ], "offsets": [ [ 84, 1500 ] ] } ]

[ { "id": "17559874_T1", "type": "CHEMICAL", "text": [ "KDS" ], "offsets": [ [ 209, 212 ] ], "normalized": [] }, { "id": "17559874_T2", "type": "CHEMICAL", "text": [ "PLP" ], "offsets": [ [ 249, 252 ] ], "normalized": [] }, { "id": "17559874_T3", "type": "CHEMICAL", "text": [ "serine" ], "offsets": [ [ 270, 276 ] ], "normalized": [] }, { "id": "17559874_T4", "type": "CHEMICAL", "text": [ "L-serine" ], "offsets": [ [ 145, 153 ] ], "normalized": [] }, { "id": "17559874_T5", "type": "CHEMICAL", "text": [ "palmitoyl-CoA" ], "offsets": [ [ 158, 171 ] ], "normalized": [] }, { "id": "17559874_T6", "type": "CHEMICAL", "text": [ "PLP" ], "offsets": [ [ 921, 924 ] ], "normalized": [] }, { "id": "17559874_T7", "type": "CHEMICAL", "text": [ "lysine" ], "offsets": [ [ 959, 965 ] ], "normalized": [] }, { "id": "17559874_T8", "type": "CHEMICAL", "text": [ "aldimine" ], "offsets": [ [ 998, 1006 ] ], "normalized": [] }, { "id": "17559874_T9", "type": "CHEMICAL", "text": [ "Schiff base" ], "offsets": [ [ 1007, 1018 ] ], "normalized": [] }, { "id": "17559874_T10", "type": "CHEMICAL", "text": [ "3-ketodihydrosphingosine" ], "offsets": [ [ 183, 207 ] ], "normalized": [] }, { "id": "17559874_T11", "type": "CHEMICAL", "text": [ "serine" ], "offsets": [ [ 17, 23 ] ], "normalized": [] }, { "id": "17559874_T12", "type": "GENE-Y", "text": [ "human SPT1" ], "offsets": [ [ 1136, 1146 ] ], "normalized": [] }, { "id": "17559874_T13", "type": "GENE-Y", "text": [ "SPT2" ], "offsets": [ [ 1147, 1151 ] ], "normalized": [] }, { "id": "17559874_T14", "type": "GENE-Y", "text": [ "human SPT1" ], "offsets": [ [ 1253, 1263 ] ], "normalized": [] }, { "id": "17559874_T15", "type": "GENE-N", "text": [ "serine palmitoyltransferase" ], "offsets": [ [ 270, 297 ] ], "normalized": [] }, { "id": "17559874_T16", "type": "GENE-N", "text": [ "SPT" ], "offsets": [ [ 299, 302 ] ], "normalized": [] }, { "id": "17559874_T17", "type": "GENE-Y", "text": [ "EC 2.3.1.50" ], "offsets": [ [ 304, 315 ] ], "normalized": [] }, { "id": "17559874_T18", "type": "GENE-Y", "text": [ "SPT1" ], "offsets": [ [ 357, 361 ] ], "normalized": [] }, { "id": "17559874_T19", "type": "GENE-Y", "text": [ "SPT2" ], "offsets": [ [ 362, 366 ] ], "normalized": [] }, { "id": "17559874_T20", "type": "GENE-N", "text": [ "SPT" ], "offsets": [ [ 616, 619 ] ], "normalized": [] }, { "id": "17559874_T21", "type": "GENE-Y", "text": [ "S. paucimobilis SPT" ], "offsets": [ [ 752, 771 ] ], "normalized": [] }, { "id": "17559874_T22", "type": "GENE-N", "text": [ "serine palmitoyltransferase" ], "offsets": [ [ 17, 44 ] ], "normalized": [] } ]

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[ { "id": "23298258_title", "type": "title", "text": [ "All-trans retinoic acid protects hepatocellular carcinoma cells against serum-starvation-induced cell death by upregulating collagen 8A2." ], "offsets": [ [ 0, 137 ] ] }, { "id": "23298258_abstract", "type": "abstract", "text": [ "As a therapeutic or chemopreventative agent for various cancers, all-trans retinoic acid (atRA) has been reported to inhibit growth, induce apoptosis or cause differentiation. It was found that atRA could protect hepatocellular carcinoma (HCC) cells against cell death induced by serum starvation. Furthermore, it was found that atRA could enhance cell adhesion, but had no effect on the cell cycle and apoptosis. Using an Illumina Human HT-12 v4 expression microarray, 207 upregulated and 173 downregulated genes were identified in HepG2 cells treated with atRA. The most upregulated genes are cytochrome P450 family 26 subfamily A polypeptide 1 (CYP26A1), histidine triad nucleotide binding protein 3 (HINT3), miR-1282 and cytochrome P450 family 26 subfamily B polypeptide 1 (CYP26B1), which showed more than fivefold greater expression. Using Gene Ontology analysis, the greatest significance was found in extracellular-matrix-related molecular functions and the cellular component in upregulated genes. The upregulation of collagen 8A2 (COL8A2) was further confirmed using quantitative RT-PCR and western blotting. Knockdown of COL8A2 blocked enhancement in the early stage of cell adhesion by atRA treatment. Re-expression of COL8A2 in COL8A2-knocked-down HCC cells reversed the effect of small interfering RNA-COL8A2. In addition, COL8A2 could increase HCC cell migration and invasion. Thus, COL8A2 was identified as the key protein involved in the enhancement of cell adhesion of atRA under serum-free conditions. In conclusion, atRA protects HCC cells against serum-starvation-induced cell death by enhancing cell adhesion, and COL8A2 plays an important role in HCC cell migration and invasion." ], "offsets": [ [ 138, 1840 ] ] } ]

[ { "id": "23298258_T1", "type": "CHEMICAL", "text": [ "atRA" ], "offsets": [ [ 1336, 1340 ] ], "normalized": [] }, { "id": "23298258_T2", "type": "CHEMICAL", "text": [ "atRA" ], "offsets": [ [ 1625, 1629 ] ], "normalized": [] }, { "id": "23298258_T3", "type": "CHEMICAL", "text": [ "atRA" ], "offsets": [ [ 1674, 1678 ] ], "normalized": [] }, { "id": "23298258_T4", "type": "CHEMICAL", "text": [ "atRA" ], "offsets": [ [ 332, 336 ] ], "normalized": [] }, { "id": "23298258_T5", "type": "CHEMICAL", "text": [ "atRA" ], "offsets": [ [ 467, 471 ] ], "normalized": [] }, { "id": "23298258_T6", "type": "CHEMICAL", "text": [ "atRA" ], "offsets": [ [ 696, 700 ] ], "normalized": [] }, { "id": "23298258_T7", "type": "CHEMICAL", "text": [ "histidine" ], "offsets": [ [ 796, 805 ] ], "normalized": [] }, { "id": "23298258_T8", "type": "CHEMICAL", "text": [ "all-trans retinoic acid" ], "offsets": [ [ 203, 226 ] ], "normalized": [] }, { "id": "23298258_T9", "type": "CHEMICAL", "text": [ "atRA" ], "offsets": [ [ 228, 232 ] ], "normalized": [] }, { "id": "23298258_T10", "type": "CHEMICAL", "text": [ "All-trans retinoic acid" ], "offsets": [ [ 0, 23 ] ], "normalized": [] }, { "id": "23298258_T11", "type": "GENE-Y", "text": [ "collagen 8A2" ], "offsets": [ [ 1165, 1177 ] ], "normalized": [] }, { "id": "23298258_T12", "type": "GENE-Y", "text": [ "COL8A2" ], "offsets": [ [ 1179, 1185 ] ], "normalized": [] }, { "id": "23298258_T13", "type": "GENE-Y", "text": [ "COL8A2" ], "offsets": [ [ 1270, 1276 ] ], "normalized": [] }, { "id": "23298258_T14", "type": "GENE-Y", "text": [ "COL8A2" ], "offsets": [ [ 1369, 1375 ] ], "normalized": [] }, { "id": "23298258_T15", "type": "GENE-Y", "text": [ "COL8A2" ], "offsets": [ [ 1379, 1385 ] ], "normalized": [] }, { "id": "23298258_T16", "type": "GENE-Y", "text": [ "COL8A2" ], "offsets": [ [ 1454, 1460 ] ], "normalized": [] }, { "id": "23298258_T17", "type": "GENE-Y", "text": [ "COL8A2" ], "offsets": [ [ 1475, 1481 ] ], "normalized": [] }, { "id": "23298258_T18", "type": "GENE-Y", "text": [ "COL8A2" ], "offsets": [ [ 1536, 1542 ] ], "normalized": [] }, { "id": "23298258_T19", "type": "GENE-Y", "text": [ "COL8A2" ], "offsets": [ [ 1774, 1780 ] ], "normalized": [] }, { "id": "23298258_T20", "type": "GENE-Y", "text": [ "cytochrome P450 family 26 subfamily A polypeptide 1" ], "offsets": [ [ 733, 784 ] ], "normalized": [] }, { "id": "23298258_T21", "type": "GENE-Y", "text": [ "CYP26A1" ], "offsets": [ [ 786, 793 ] ], "normalized": [] }, { "id": "23298258_T22", "type": "GENE-Y", "text": [ "histidine triad nucleotide binding protein 3" ], "offsets": [ [ 796, 840 ] ], "normalized": [] }, { "id": "23298258_T23", "type": "GENE-Y", "text": [ "HINT3" ], "offsets": [ [ 842, 847 ] ], "normalized": [] }, { "id": "23298258_T24", "type": "GENE-Y", "text": [ "miR-1282" ], "offsets": [ [ 850, 858 ] ], "normalized": [] }, { "id": "23298258_T25", "type": "GENE-Y", "text": [ "cytochrome P450 family 26 subfamily B polypeptide 1" ], "offsets": [ [ 863, 914 ] ], "normalized": [] }, { "id": "23298258_T26", "type": "GENE-Y", "text": [ "CYP26B1" ], "offsets": [ [ 916, 923 ] ], "normalized": [] }, { "id": "23298258_T27", "type": "GENE-Y", "text": [ "collagen 8A2" ], "offsets": [ [ 124, 136 ] ], "normalized": [] } ]

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[ { "id": "17600786_title", "type": "title", "text": [ "A fluorescent polymeric heparin sensor." ], "offsets": [ [ 0, 39 ] ] }, { "id": "17600786_abstract", "type": "abstract", "text": [ "Linear copolymers have been developed which carry binding sites tailored for sulfated sugars. All binding monomers are based on the methacrylamide skeleton and ensure statistical radical copolymerization. They are decorated with o-aminomethylphenylboronates for covalent ester formation and/or alkylammonium ions for noncovalent Coulomb attraction. Alcohol sidechains maintain a high water solubility; a dansyl monomer was constructed as a fluorescence label. Statistical copolymerization of comonomer mixtures with optimized ratios was started by AIBN (AIBN=2,2'-azoisobutyronitrile) and furnished water-soluble comonomers with an exceptionally high affinity for glucosaminoglucans. Heparin can be quantitatively detected with an unprecedented 30 nM sensitivity, and a neutral polymer without any ammonium cation is still able to bind the target with almost micromolar affinity. From this unexpected result, we propose a new binding scheme between the boronate and a sulfated ethylene glycol or aminoethanol unit. Although the mechanism of heparin binding involves covalent boronate ester formation, it can be completely reversed by protamine addition, similar to heparin's complex formation with antithrombin III." ], "offsets": [ [ 40, 1255 ] ] } ]

[ { "id": "17600786_T1", "type": "CHEMICAL", "text": [ "boronate ester" ], "offsets": [ [ 1115, 1129 ] ], "normalized": [] }, { "id": "17600786_T2", "type": "CHEMICAL", "text": [ "methacrylamide" ], "offsets": [ [ 172, 186 ] ], "normalized": [] }, { "id": "17600786_T3", "type": "CHEMICAL", "text": [ "o-aminomethylphenylboronates" ], "offsets": [ [ 269, 297 ] ], "normalized": [] }, { "id": "17600786_T4", "type": "CHEMICAL", "text": [ "alkylammonium" ], "offsets": [ [ 334, 347 ] ], "normalized": [] }, { "id": "17600786_T5", "type": "CHEMICAL", "text": [ "Alcohol" ], "offsets": [ [ 389, 396 ] ], "normalized": [] }, { "id": "17600786_T6", "type": "CHEMICAL", "text": [ "dansyl" ], "offsets": [ [ 444, 450 ] ], "normalized": [] }, { "id": "17600786_T7", "type": "CHEMICAL", "text": [ "AIBN" ], "offsets": [ [ 588, 592 ] ], "normalized": [] }, { "id": "17600786_T8", "type": "CHEMICAL", "text": [ "AIBN" ], "offsets": [ [ 594, 598 ] ], "normalized": [] }, { "id": "17600786_T9", "type": "CHEMICAL", "text": [ "2,2'-azoisobutyronitrile" ], "offsets": [ [ 599, 623 ] ], "normalized": [] }, { "id": "17600786_T10", "type": "CHEMICAL", "text": [ "ammonium cation" ], "offsets": [ [ 838, 853 ] ], "normalized": [] }, { "id": "17600786_T11", "type": "CHEMICAL", "text": [ "boronate" ], "offsets": [ [ 993, 1001 ] ], "normalized": [] }, { "id": "17600786_T12", "type": "CHEMICAL", "text": [ "ethylene glycol" ], "offsets": [ [ 1017, 1032 ] ], "normalized": [] }, { "id": "17600786_T13", "type": "CHEMICAL", "text": [ "aminoethanol" ], "offsets": [ [ 1036, 1048 ] ], "normalized": [] }, { "id": "17600786_T14", "type": "GENE-Y", "text": [ "antithrombin III" ], "offsets": [ [ 1238, 1254 ] ], "normalized": [] } ]

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[ { "id": "23210783_title", "type": "title", "text": [ "From traditional European medicine to discovery of new drug candidates for the treatment of dementia and Alzheimer's disease: acetylcholinesterase inhibitors." ], "offsets": [ [ 0, 158 ] ] }, { "id": "23210783_abstract", "type": "abstract", "text": [ "The leading Alzheimer's disease (AD) therapeutics to date involves inhibitors of acetylcholinesterase (AChE), which should, in principle, elevate cholinergic signaling and limit inflammation. In spite of the effectiveness in 20%-30% of AD patients, more attention has been paid to find new anti-AChE agents from medicinal plants. Galanthamine, contained in the bulbs and flowers of Galanthus and related genera like Narcissus, represents a good example. The aim of this study is to review the role of possible AChE inhibitors (AChEI) present in plants traditionally used in European medicine for improving memory. Starting from Galanthamine, properties of Melissa species, Salvia officinalis, Arnica chamissonis and Ruta graveolens are discussed to point to the role of these plants as potential sources for the development of therapeutic agents for AD." ], "offsets": [ [ 159, 1012 ] ] } ]

[ { "id": "23210783_T1", "type": "CHEMICAL", "text": [ "Galanthamine" ], "offsets": [ [ 489, 501 ] ], "normalized": [] }, { "id": "23210783_T2", "type": "CHEMICAL", "text": [ "Galanthamine" ], "offsets": [ [ 787, 799 ] ], "normalized": [] }, { "id": "23210783_T3", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 262, 266 ] ], "normalized": [] }, { "id": "23210783_T4", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 454, 458 ] ], "normalized": [] }, { "id": "23210783_T5", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 669, 673 ] ], "normalized": [] }, { "id": "23210783_T6", "type": "GENE-Y", "text": [ "acetylcholinesterase" ], "offsets": [ [ 240, 260 ] ], "normalized": [] }, { "id": "23210783_T7", "type": "GENE-Y", "text": [ "acetylcholinesterase" ], "offsets": [ [ 126, 146 ] ], "normalized": [] } ]

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[ { "id": "10381812_title", "type": "title", "text": [ "Expression of multiple alpha1-adrenoceptors on vascular smooth muscle: correlation with the regulation of contraction." ], "offsets": [ [ 0, 118 ] ] }, { "id": "10381812_abstract", "type": "abstract", "text": [ "Previous work has shown that the genes encoding each alpha1-adrenoceptor subtype are coexpressed throughout the peripheral vascular system. We have evaluated subtype-selective antibodies as tools to determine the extent of protein expression in arteries. The alpha1A-, alpha1B-, and alpha1D-adrenoceptors were detected in the medial layer of the aorta, caudal, femoral, iliac, renal, superior mesenteric, and mesenteric resistance arteries. In Rat1 fibroblasts expressing each subtype, immunoreactivity was noted both on the cell surface and in a perinuclear orientation. Intense alpha1B-adrenoceptor immunostaining was similarly localized in cultured femoral and renal vascular smooth muscle cells. Although the cellular localization appeared to be the same, immunoreactivity obtained with alpha1A- and alpha1D-adrenoceptors was much less intense than that with the alpha1B-adrenoceptor. The alpha1A-adrenoceptor selective agonist A-61603 was 22-fold more potent in activating renal artery contraction when compared with the femoral artery. The expression of each alpha1-adrenoceptor was significantly decreased by in vivo application of antisense oligonucleotides targeted against each subtype. Inhibition of the expression of only one, the alpha1A in renal and the alpha1D in femoral arteries, reduced the contractile response to naphazoline. The results show: 1) subtype-selective antibodies can be used in tissues and cell culture to localize the alpha1-adrenoceptor subtypes, 2) in addition to expression on the cell surface, the alpha1-adrenoceptors are expressed intracellularly, and 3) despite expression of all adrenoceptors, a single subtype mediates the contractile response in the femoral and renal arteries." ], "offsets": [ [ 119, 1840 ] ] } ]

[ { "id": "10381812_T1", "type": "CHEMICAL", "text": [ "oligonucleotides" ], "offsets": [ [ 1268, 1284 ] ], "normalized": [] }, { "id": "10381812_T2", "type": "CHEMICAL", "text": [ "naphazoline" ], "offsets": [ [ 1452, 1463 ] ], "normalized": [] }, { "id": "10381812_T3", "type": "CHEMICAL", "text": [ "A-61603" ], "offsets": [ [ 1051, 1058 ] ], "normalized": [] }, { "id": "10381812_T4", "type": "GENE-N", "text": [ "alpha1-adrenoceptor" ], "offsets": [ [ 1184, 1203 ] ], "normalized": [] }, { "id": "10381812_T5", "type": "GENE-N", "text": [ "alpha1-adrenoceptor" ], "offsets": [ [ 1571, 1590 ] ], "normalized": [] }, { "id": "10381812_T6", "type": "GENE-N", "text": [ "alpha1-adrenoceptors" ], "offsets": [ [ 1655, 1675 ] ], "normalized": [] }, { "id": "10381812_T7", "type": "GENE-N", "text": [ "adrenoceptors" ], "offsets": [ [ 1740, 1753 ] ], "normalized": [] }, { "id": "10381812_T8", "type": "GENE-N", "text": [ "alpha1A-, alpha1B-, and alpha1D-adrenoceptors" ], "offsets": [ [ 378, 423 ] ], "normalized": [] }, { "id": "10381812_T9", "type": "GENE-N", "text": [ "alpha1-adrenoceptor" ], "offsets": [ [ 172, 191 ] ], "normalized": [] }, { "id": "10381812_T10", "type": "GENE-Y", "text": [ "alpha1B-adrenoceptor" ], "offsets": [ [ 699, 719 ] ], "normalized": [] }, { "id": "10381812_T11", "type": "GENE-N", "text": [ "alpha1A- and alpha1D-adrenoceptors" ], "offsets": [ [ 910, 944 ] ], "normalized": [] }, { "id": "10381812_T12", "type": "GENE-Y", "text": [ "alpha1B-adrenoceptor" ], "offsets": [ [ 986, 1006 ] ], "normalized": [] }, { "id": "10381812_T13", "type": "GENE-Y", "text": [ "alpha1A-adrenoceptor" ], "offsets": [ [ 1012, 1032 ] ], "normalized": [] }, { "id": "10381812_T14", "type": "GENE-N", "text": [ "alpha1-adrenoceptors" ], "offsets": [ [ 23, 43 ] ], "normalized": [] } ]

[]

[]

[ { "id": "10381812_0", "type": "AGONIST", "arg1_id": "10381812_T3", "arg2_id": "10381812_T13", "normalized": [] }, { "id": "10381812_1", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "10381812_T1", "arg2_id": "10381812_T4", "normalized": [] } ]

[ { "id": "23229056_title", "type": "title", "text": [ "Synthesis and antibacterial evaluation of novel 11,4″-disubstituted azithromycin analogs with greatly improved activity against erythromycin-resistant bacteria." ], "offsets": [ [ 0, 160 ] ] }, { "id": "23229056_abstract", "type": "abstract", "text": [ "A series of novel 11,4″-disubstituted azithromycin analogs were synthesized and evaluated for their antibacterial activity. All the 11,4″-disubstituted analogs exhibited excellent activity (0.03-0.12 μg/ml) against erythromycin-susceptible Streptococcus pneumoniae, and significantly improved activity against three phenotypes of erythromycin-resistant S. pneumoniae compared with erythromycin A, clarithromycin or azithromycin. Among them, compounds 26-28 showed the most potent activity (0.25, 0.03 and 2 μg/ml) against S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, respectively. In addition, compound 28 was the most effective (0.03 and 0.12 μg/ml) against erythromycin-susceptible S. pneumoniae and Staphylococcus aureus as well. It is noteworthy that the most active compounds described above possess the same terminal 3,5-dinitrophenyl groups on their C-4″ bisamide side chains." ], "offsets": [ [ 161, 1078 ] ] } ]

[ { "id": "23229056_T1", "type": "CHEMICAL", "text": [ "11,4″-disubstituted azithromycin" ], "offsets": [ [ 179, 211 ] ], "normalized": [] }, { "id": "23229056_T2", "type": "CHEMICAL", "text": [ "erythromycin" ], "offsets": [ [ 376, 388 ] ], "normalized": [] }, { "id": "23229056_T3", "type": "CHEMICAL", "text": [ "erythromycin" ], "offsets": [ [ 491, 503 ] ], "normalized": [] }, { "id": "23229056_T4", "type": "CHEMICAL", "text": [ "erythromycin A" ], "offsets": [ [ 542, 556 ] ], "normalized": [] }, { "id": "23229056_T5", "type": "CHEMICAL", "text": [ "clarithromycin" ], "offsets": [ [ 558, 572 ] ], "normalized": [] }, { "id": "23229056_T6", "type": "CHEMICAL", "text": [ "azithromycin" ], "offsets": [ [ 576, 588 ] ], "normalized": [] }, { "id": "23229056_T7", "type": "CHEMICAL", "text": [ "erythromycin" ], "offsets": [ [ 854, 866 ] ], "normalized": [] }, { "id": "23229056_T8", "type": "CHEMICAL", "text": [ "3,5-dinitrophenyl" ], "offsets": [ [ 1018, 1035 ] ], "normalized": [] }, { "id": "23229056_T9", "type": "CHEMICAL", "text": [ "bisamide" ], "offsets": [ [ 1057, 1065 ] ], "normalized": [] }, { "id": "23229056_T10", "type": "CHEMICAL", "text": [ "erythromycin" ], "offsets": [ [ 128, 140 ] ], "normalized": [] }, { "id": "23229056_T11", "type": "CHEMICAL", "text": [ "11,4″-disubstituted azithromycin" ], "offsets": [ [ 48, 80 ] ], "normalized": [] }, { "id": "23229056_T12", "type": "GENE-N", "text": [ "erm" ], "offsets": [ [ 712, 715 ] ], "normalized": [] }, { "id": "23229056_T13", "type": "GENE-N", "text": [ "mef" ], "offsets": [ [ 726, 729 ] ], "normalized": [] }, { "id": "23229056_T14", "type": "GENE-N", "text": [ "erm" ], "offsets": [ [ 743, 746 ] ], "normalized": [] }, { "id": "23229056_T15", "type": "GENE-N", "text": [ "mef" ], "offsets": [ [ 751, 754 ] ], "normalized": [] } ]

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[ { "id": "23429263_title", "type": "title", "text": [ "Intracellular localization of the BCL-2 family member BOK and functional implications." ], "offsets": [ [ 0, 86 ] ] }, { "id": "23429263_abstract", "type": "abstract", "text": [ "The pro-apoptotic BCL-2 family member BOK is widely expressed and resembles the multi-BH domain proteins BAX and BAK based on its amino acid sequence. The genomic region encoding BOK was reported to be frequently deleted in human cancer and it has therefore been hypothesized that BOK functions as a tumor suppressor. However, little is known about the molecular functions of BOK. We show that enforced expression of BOK activates the intrinsic (mitochondrial) apoptotic pathway in BAX/BAK-proficient cells but fails to kill cells lacking both BAX and BAK or sensitize them to cytotoxic insults. Interestingly, major portions of endogenous BOK are localized to and partially inserted into the membranes of the Golgi apparatus as well as the endoplasmic reticulum (ER) and associated membranes. The C-terminal transmembrane domain of BOK thereby constitutes a 'tail-anchor' specific for targeting to the Golgi and ER. Overexpression of full-length BOK causes early fragmentation of ER and Golgi compartments. A role for BOK on the Golgi apparatus and the ER is supported by an abnormal response of Bok-deficient cells to the Golgi/ER stressor brefeldin A. Based on these results, we propose that major functions of BOK are exerted at the Golgi and ER membranes and that BOK induces apoptosis in a manner dependent on BAX and BAK." ], "offsets": [ [ 87, 1415 ] ] } ]

[ { "id": "23429263_T1", "type": "CHEMICAL", "text": [ "brefeldin A" ], "offsets": [ [ 1229, 1240 ] ], "normalized": [] }, { "id": "23429263_T2", "type": "CHEMICAL", "text": [ "amino acid" ], "offsets": [ [ 217, 227 ] ], "normalized": [] }, { "id": "23429263_T3", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 885, 886 ] ], "normalized": [] }, { "id": "23429263_T4", "type": "GENE-Y", "text": [ "BOK" ], "offsets": [ [ 1106, 1109 ] ], "normalized": [] }, { "id": "23429263_T5", "type": "GENE-Y", "text": [ "BAX" ], "offsets": [ [ 192, 195 ] ], "normalized": [] }, { "id": "23429263_T6", "type": "GENE-Y", "text": [ "Bok" ], "offsets": [ [ 1184, 1187 ] ], "normalized": [] }, { "id": "23429263_T7", "type": "GENE-Y", "text": [ "BAK" ], "offsets": [ [ 200, 203 ] ], "normalized": [] }, { "id": "23429263_T8", "type": "GENE-Y", "text": [ "BOK" ], "offsets": [ [ 1301, 1304 ] ], "normalized": [] }, { "id": "23429263_T9", "type": "GENE-Y", "text": [ "BOK" ], "offsets": [ [ 1356, 1359 ] ], "normalized": [] }, { "id": "23429263_T10", "type": "GENE-Y", "text": [ "BAX" ], "offsets": [ [ 1403, 1406 ] ], "normalized": [] }, { "id": "23429263_T11", "type": "GENE-Y", "text": [ "BAK" ], "offsets": [ [ 1411, 1414 ] ], "normalized": [] }, { "id": "23429263_T12", "type": "GENE-Y", "text": [ "BOK" ], "offsets": [ [ 266, 269 ] ], "normalized": [] }, { "id": "23429263_T13", "type": "GENE-Y", "text": [ "BCL-2" ], "offsets": [ [ 105, 110 ] ], "normalized": [] }, { "id": "23429263_T14", "type": "GENE-Y", "text": [ "BOK" ], "offsets": [ [ 368, 371 ] ], "normalized": [] }, { "id": "23429263_T15", "type": "GENE-N", "text": [ "BOK" ], "offsets": [ [ 463, 466 ] ], "normalized": [] }, { "id": "23429263_T16", "type": "GENE-Y", "text": [ "BOK" ], "offsets": [ [ 125, 128 ] ], "normalized": [] }, { "id": "23429263_T17", "type": "GENE-N", "text": [ "BOK" ], "offsets": [ [ 504, 507 ] ], "normalized": [] }, { "id": "23429263_T18", "type": "GENE-Y", "text": [ "BAX" ], "offsets": [ [ 569, 572 ] ], "normalized": [] }, { "id": "23429263_T19", "type": "GENE-Y", "text": [ "BAK" ], "offsets": [ [ 573, 576 ] ], "normalized": [] }, { "id": "23429263_T20", "type": "GENE-Y", "text": [ "BAX" ], "offsets": [ [ 631, 634 ] ], "normalized": [] }, { "id": "23429263_T21", "type": "GENE-Y", "text": [ "BAK" ], "offsets": [ [ 639, 642 ] ], "normalized": [] }, { "id": "23429263_T22", "type": "GENE-Y", "text": [ "BOK" ], "offsets": [ [ 727, 730 ] ], "normalized": [] }, { "id": "23429263_T23", "type": "GENE-Y", "text": [ "BOK" ], "offsets": [ [ 920, 923 ] ], "normalized": [] }, { "id": "23429263_T24", "type": "GENE-N", "text": [ "BH domain" ], "offsets": [ [ 173, 182 ] ], "normalized": [] }, { "id": "23429263_T25", "type": "GENE-Y", "text": [ "BOK" ], "offsets": [ [ 1034, 1037 ] ], "normalized": [] }, { "id": "23429263_T26", "type": "GENE-Y", "text": [ "BCL-2" ], "offsets": [ [ 34, 39 ] ], "normalized": [] }, { "id": "23429263_T27", "type": "GENE-Y", "text": [ "BOK" ], "offsets": [ [ 54, 57 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23429263_0", "type": "PART-OF", "arg1_id": "23429263_T3", "arg2_id": "23429263_T23", "normalized": [] }, { "id": "23429263_1", "type": "PART-OF", "arg1_id": "23429263_T2", "arg2_id": "23429263_T5", "normalized": [] }, { "id": "23429263_2", "type": "PART-OF", "arg1_id": "23429263_T2", "arg2_id": "23429263_T7", "normalized": [] }, { "id": "23429263_3", "type": "PART-OF", "arg1_id": "23429263_T2", "arg2_id": "23429263_T24", "normalized": [] } ]

[ { "id": "17513393_title", "type": "title", "text": [ "Copper deficiency decreases plasma homocysteine in rats." ], "offsets": [ [ 0, 56 ] ] }, { "id": "17513393_abstract", "type": "abstract", "text": [ "The purpose of this study was to determine the effects of copper deficiency on key aspects of homocysteine metabolism that involve methionine recycling and transsulfuration. Male weanling Sprague-Dawley rats were fed AIN-93G-based diets containing <1 or approximately 6 mg Cu/kg. After 6 wk (Expt. 1) and 4 wk (Expt. 2) we found that plasma homocysteine was significantly decreased, and plasma glutathione significantly increased, in rats fed the low-Cu diet. Real-time RT-PCR was used to determine the expression of the subunits of glutamate-cysteine ligase (Gcl) in liver that catalyzes the rate-limiting step in glutathione biosynthesis. The expression of Gclc, the catalytic subunit of Gcl, was upregulated by Cu deficiency; Gclm, the modifier subunit, was not affected. Hepatic betaine-homocysteine methyltransferase (Bhmt), which catalyzes one of the two ways that homocysteine can be remethylated to methionine, was downregulated by Cu deficiency. Because Cu deficiency results in upregulation of Gclc and an increase in the biosynthesis of glutathione, it is plausible that the net flux of homocysteine through the transsulfuration pathway is increased. Furthermore, if Bhmt is downregulated, less homocysteine is available for remethylation (methionine recycling) and more is then available to irreversibly enter the transsulfuration pathway where it is lost. The net effect of increased Gclc and decreased Bhmt would be a decrease in homocysteine as a result of Cu deficiency." ], "offsets": [ [ 57, 1543 ] ] } ]

[ { "id": "17513393_T1", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 1105, 1116 ] ], "normalized": [] }, { "id": "17513393_T2", "type": "CHEMICAL", "text": [ "homocysteine" ], "offsets": [ [ 1155, 1167 ] ], "normalized": [] }, { "id": "17513393_T3", "type": "CHEMICAL", "text": [ "homocysteine" ], "offsets": [ [ 1263, 1275 ] ], "normalized": [] }, { "id": "17513393_T4", "type": "CHEMICAL", "text": [ "methionine" ], "offsets": [ [ 1308, 1318 ] ], "normalized": [] }, { "id": "17513393_T5", "type": "CHEMICAL", "text": [ "methionine" ], "offsets": [ [ 188, 198 ] ], "normalized": [] }, { "id": "17513393_T6", "type": "CHEMICAL", "text": [ "homocysteine" ], "offsets": [ [ 1501, 1513 ] ], "normalized": [] }, { "id": "17513393_T7", "type": "CHEMICAL", "text": [ "Cu" ], "offsets": [ [ 1529, 1531 ] ], "normalized": [] }, { "id": "17513393_T8", "type": "CHEMICAL", "text": [ "Cu" ], "offsets": [ [ 330, 332 ] ], "normalized": [] }, { "id": "17513393_T9", "type": "CHEMICAL", "text": [ "homocysteine" ], "offsets": [ [ 398, 410 ] ], "normalized": [] }, { "id": "17513393_T10", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 451, 462 ] ], "normalized": [] }, { "id": "17513393_T11", "type": "CHEMICAL", "text": [ "Cu" ], "offsets": [ [ 508, 510 ] ], "normalized": [] }, { "id": "17513393_T12", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 590, 599 ] ], "normalized": [] }, { "id": "17513393_T13", "type": "CHEMICAL", "text": [ "cysteine" ], "offsets": [ [ 600, 608 ] ], "normalized": [] }, { "id": "17513393_T14", "type": "CHEMICAL", "text": [ "copper" ], "offsets": [ [ 115, 121 ] ], "normalized": [] }, { "id": "17513393_T15", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 672, 683 ] ], "normalized": [] }, { "id": "17513393_T16", "type": "CHEMICAL", "text": [ "Cu" ], "offsets": [ [ 771, 773 ] ], "normalized": [] }, { "id": "17513393_T17", "type": "CHEMICAL", "text": [ "betaine" ], "offsets": [ [ 840, 847 ] ], "normalized": [] }, { "id": "17513393_T18", "type": "CHEMICAL", "text": [ "homocysteine" ], "offsets": [ [ 848, 860 ] ], "normalized": [] }, { "id": "17513393_T19", "type": "CHEMICAL", "text": [ "homocysteine" ], "offsets": [ [ 928, 940 ] ], "normalized": [] }, { "id": "17513393_T20", "type": "CHEMICAL", "text": [ "methionine" ], "offsets": [ [ 964, 974 ] ], "normalized": [] }, { "id": "17513393_T21", "type": "CHEMICAL", "text": [ "Cu" ], "offsets": [ [ 997, 999 ] ], "normalized": [] }, { "id": "17513393_T22", "type": "CHEMICAL", "text": [ "homocysteine" ], "offsets": [ [ 151, 163 ] ], "normalized": [] }, { "id": "17513393_T23", "type": "CHEMICAL", "text": [ "Cu" ], "offsets": [ [ 1020, 1022 ] ], "normalized": [] }, { "id": "17513393_T24", "type": "CHEMICAL", "text": [ "Copper" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "17513393_T25", "type": "CHEMICAL", "text": [ "homocysteine" ], "offsets": [ [ 35, 47 ] ], "normalized": [] }, { "id": "17513393_T26", "type": "GENE-Y", "text": [ "Gclc" ], "offsets": [ [ 1061, 1065 ] ], "normalized": [] }, { "id": "17513393_T27", "type": "GENE-Y", "text": [ "Bhmt" ], "offsets": [ [ 1235, 1239 ] ], "normalized": [] }, { "id": "17513393_T28", "type": "GENE-Y", "text": [ "Gclc" ], "offsets": [ [ 1454, 1458 ] ], "normalized": [] }, { "id": "17513393_T29", "type": "GENE-Y", "text": [ "Bhmt" ], "offsets": [ [ 1473, 1477 ] ], "normalized": [] }, { "id": "17513393_T30", "type": "GENE-N", "text": [ "glutamate-cysteine ligase" ], "offsets": [ [ 590, 615 ] ], "normalized": [] }, { "id": "17513393_T31", "type": "GENE-N", "text": [ "Gcl" ], "offsets": [ [ 617, 620 ] ], "normalized": [] }, { "id": "17513393_T32", "type": "GENE-Y", "text": [ "Gclc" ], "offsets": [ [ 716, 720 ] ], "normalized": [] }, { "id": "17513393_T33", "type": "GENE-N", "text": [ "Gcl" ], "offsets": [ [ 747, 750 ] ], "normalized": [] }, { "id": "17513393_T34", "type": "GENE-Y", "text": [ "Gclm" ], "offsets": [ [ 786, 790 ] ], "normalized": [] }, { "id": "17513393_T35", "type": "GENE-Y", "text": [ "betaine-homocysteine methyltransferase" ], "offsets": [ [ 840, 878 ] ], "normalized": [] }, { "id": "17513393_T36", "type": "GENE-Y", "text": [ "Bhmt" ], "offsets": [ [ 880, 884 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23561191_title", "type": "title", "text": [ "Hepatic biotransformation of alkylresorcinols is mediated via cytochrome P450 and β-oxidation: A proof of concept study." ], "offsets": [ [ 0, 120 ] ] }, { "id": "23561191_abstract", "type": "abstract", "text": [ "Alkylresorcinols (AR) are phenolic lipids present in the bran of some cereals. AR may serve as a biomarker for whole grain wheat and rye intake. While AR pharmacokinetics and two major metabolites have been reported, the metabolic pathways contributing to their relatively rapid elimination from the circulation remain to be speculative. In this study, we investigated if ω- and β-oxidation mediate catabolism of the AR homologue C19:0 to form 3,5-dihydroxybenzoic acid and 3-(3,5-dihydroxyphenyl)-1-propanoic acid (DHPPA), using 3 in vitro platforms, human cytochrome P450 4F2 (CYP4F2), human liver S9, and HepG2 cells. One hydroxylated C19:0 metabolite was formed by CYP4F2 and one hydroxylated and one carboxylated C19:0 were tentatively identified after incubation of AR with S9. The formation of DHPPA was quantifiable when HepG2 cells were treated with C19:0 for 48h. Our results are consistent with a metabolic pathway by which AR are degraded to phenolic acids via CYP4F2-mediated ω-oxidation and subsequent β-oxidation." ], "offsets": [ [ 121, 1149 ] ] } ]

[ { "id": "23561191_T1", "type": "CHEMICAL", "text": [ "Alkylresorcinols" ], "offsets": [ [ 121, 137 ] ], "normalized": [] }, { "id": "23561191_T2", "type": "CHEMICAL", "text": [ "phenolic" ], "offsets": [ [ 147, 155 ] ], "normalized": [] }, { "id": "23561191_T3", "type": "CHEMICAL", "text": [ "3,5-dihydroxybenzoic acid" ], "offsets": [ [ 565, 590 ] ], "normalized": [] }, { "id": "23561191_T4", "type": "CHEMICAL", "text": [ "3-(3,5-dihydroxyphenyl)-1-propanoic acid" ], "offsets": [ [ 595, 635 ] ], "normalized": [] }, { "id": "23561191_T5", "type": "CHEMICAL", "text": [ "DHPPA" ], "offsets": [ [ 637, 642 ] ], "normalized": [] }, { "id": "23561191_T6", "type": "CHEMICAL", "text": [ "DHPPA" ], "offsets": [ [ 922, 927 ] ], "normalized": [] }, { "id": "23561191_T7", "type": "CHEMICAL", "text": [ "alkylresorcinols" ], "offsets": [ [ 29, 45 ] ], "normalized": [] }, { "id": "23561191_T8", "type": "GENE-Y", "text": [ "human cytochrome P450 4F2" ], "offsets": [ [ 673, 698 ] ], "normalized": [] }, { "id": "23561191_T9", "type": "GENE-Y", "text": [ "CYP4F2" ], "offsets": [ [ 700, 706 ] ], "normalized": [] }, { "id": "23561191_T10", "type": "GENE-N", "text": [ "CYP4F2" ], "offsets": [ [ 790, 796 ] ], "normalized": [] }, { "id": "23561191_T11", "type": "GENE-N", "text": [ "CYP4F2" ], "offsets": [ [ 1094, 1100 ] ], "normalized": [] }, { "id": "23561191_T12", "type": "GENE-N", "text": [ "cytochrome P450" ], "offsets": [ [ 62, 77 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23561191_0", "type": "SUBSTRATE", "arg1_id": "23561191_T7", "arg2_id": "23561191_T12", "normalized": [] }, { "id": "23561191_1", "type": "PRODUCT-OF", "arg1_id": "23561191_T3", "arg2_id": "23561191_T8", "normalized": [] }, { "id": "23561191_2", "type": "PRODUCT-OF", "arg1_id": "23561191_T3", "arg2_id": "23561191_T9", "normalized": [] }, { "id": "23561191_3", "type": "PRODUCT-OF", "arg1_id": "23561191_T4", "arg2_id": "23561191_T8", "normalized": [] }, { "id": "23561191_4", "type": "PRODUCT-OF", "arg1_id": "23561191_T4", "arg2_id": "23561191_T9", "normalized": [] }, { "id": "23561191_5", "type": "PRODUCT-OF", "arg1_id": "23561191_T5", "arg2_id": "23561191_T8", "normalized": [] }, { "id": "23561191_6", "type": "PRODUCT-OF", "arg1_id": "23561191_T5", "arg2_id": "23561191_T9", "normalized": [] } ]

[ { "id": "23265465_title", "type": "title", "text": [ "Effect of the genistein metabolite on leptin secretion in murine adipocytes in vitro." ], "offsets": [ [ 0, 85 ] ] }, { "id": "23265465_abstract", "type": "abstract", "text": [ "Soy isoflavonoids have many useful properties. However, they are metabolized in vivo, including in humans. The effect of the metabolism of soy isoflavonoids on their properties is not fully understood. We have isolated the bacterial strain SY8519, which has been shown to metabolize daidzein to O-desmethylangolensin and to produce 2-(4-hydroxyphenyl)propionic acid from genistein. According to chiral HPLC analysis, the 2-(4-hydroxyphenyl)propionic acid obtained from the bacterium was optically active. To determine the absolute stereochemistry of the microbial product, we prepared (S)-2-(4-hydroxyphenyl)propionic acid from (S)-2-phenylpropionic and concluded that the microbial product had an R-configuration by chiral HPLC analysis. We also applied the metabolite to mouse adipocytes and found that 2-HPPA was less effective at reducing leptin secretion than the parent compound genistein. Our results suggested that 'O-desmethylangolensin-production' attenuates the effect of soy isoflavonoids by reducing not only the activity of daidzein but also that of genistein." ], "offsets": [ [ 86, 1160 ] ] } ]

[ { "id": "23265465_T1", "type": "CHEMICAL", "text": [ "daidzein" ], "offsets": [ [ 1124, 1132 ] ], "normalized": [] }, { "id": "23265465_T2", "type": "CHEMICAL", "text": [ "genistein" ], "offsets": [ [ 1150, 1159 ] ], "normalized": [] }, { "id": "23265465_T3", "type": "CHEMICAL", "text": [ "isoflavonoids" ], "offsets": [ [ 229, 242 ] ], "normalized": [] }, { "id": "23265465_T4", "type": "CHEMICAL", "text": [ "daidzein" ], "offsets": [ [ 369, 377 ] ], "normalized": [] }, { "id": "23265465_T5", "type": "CHEMICAL", "text": [ "O-desmethylangolensin" ], "offsets": [ [ 381, 402 ] ], "normalized": [] }, { "id": "23265465_T6", "type": "CHEMICAL", "text": [ "2-(4-hydroxyphenyl)propionic acid" ], "offsets": [ [ 418, 451 ] ], "normalized": [] }, { "id": "23265465_T7", "type": "CHEMICAL", "text": [ "genistein" ], "offsets": [ [ 457, 466 ] ], "normalized": [] }, { "id": "23265465_T8", "type": "CHEMICAL", "text": [ "isoflavonoids" ], "offsets": [ [ 90, 103 ] ], "normalized": [] }, { "id": "23265465_T9", "type": "CHEMICAL", "text": [ "2-(4-hydroxyphenyl)propionic acid" ], "offsets": [ [ 507, 540 ] ], "normalized": [] }, { "id": "23265465_T10", "type": "CHEMICAL", "text": [ "(S)-2-(4-hydroxyphenyl)propionic acid" ], "offsets": [ [ 671, 708 ] ], "normalized": [] }, { "id": "23265465_T11", "type": "CHEMICAL", "text": [ "(S)-2-phenylpropionic" ], "offsets": [ [ 714, 735 ] ], "normalized": [] }, { "id": "23265465_T12", "type": "CHEMICAL", "text": [ "2-HPPA" ], "offsets": [ [ 891, 897 ] ], "normalized": [] }, { "id": "23265465_T13", "type": "CHEMICAL", "text": [ "genistein" ], "offsets": [ [ 971, 980 ] ], "normalized": [] }, { "id": "23265465_T14", "type": "CHEMICAL", "text": [ "O-desmethylangolensin" ], "offsets": [ [ 1010, 1031 ] ], "normalized": [] }, { "id": "23265465_T15", "type": "CHEMICAL", "text": [ "isoflavonoids" ], "offsets": [ [ 1073, 1086 ] ], "normalized": [] }, { "id": "23265465_T16", "type": "CHEMICAL", "text": [ "genistein" ], "offsets": [ [ 14, 23 ] ], "normalized": [] }, { "id": "23265465_T17", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 929, 935 ] ], "normalized": [] }, { "id": "23265465_T18", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 38, 44 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23265465_0", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23265465_T12", "arg2_id": "23265465_T17", "normalized": [] }, { "id": "23265465_1", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23265465_T13", "arg2_id": "23265465_T17", "normalized": [] } ]

[ { "id": "22898132_title", "type": "title", "text": [ "Assessment of developmental delay in the zebrafish embryo teratogenicity assay." ], "offsets": [ [ 0, 79 ] ] }, { "id": "22898132_abstract", "type": "abstract", "text": [ "In this study we analyzed some aspects of the assessment of developmental delay in the zebrafish embryotoxicity/teratogenicity test and explored the suitability of acetylcholinesterase (AChE) activity as a biochemical marker and as a higher throughput alternative to morphological endpoints such as head-trunk angle, tail length and morphological score. Embryos were exposed from 4 to 52 h post-fertilization (hpf) to a selection of known embryotoxic/teratogen compounds (valproic acid, retinoic acid, caffeine, sodium salicylate, glucose, hydroxyurea, methoxyacetic acid, boric acid and paraoxon-methyl) over a concentration range. They were evaluated for AChE activity, head-trunk angle, tail length and several qualitative parameters integrated in a morphological score. In general, the different patterns of the concentration-response curves allowed distinguishing between chemicals that produced growth retardation (valproic and methoxyacetic acid) and chemicals that produced non-growth-delay related malformations. An acceptable correlation between the morphological score, AChE activity and head-trunk angle as markers of developmental delay was observed, being AChE activity particularly sensitive to detect delay in the absence of malformations." ], "offsets": [ [ 80, 1335 ] ] } ]

[ { "id": "22898132_T1", "type": "CHEMICAL", "text": [ "valproic acid" ], "offsets": [ [ 552, 565 ] ], "normalized": [] }, { "id": "22898132_T2", "type": "CHEMICAL", "text": [ "retinoic acid" ], "offsets": [ [ 567, 580 ] ], "normalized": [] }, { "id": "22898132_T3", "type": "CHEMICAL", "text": [ "caffeine" ], "offsets": [ [ 582, 590 ] ], "normalized": [] }, { "id": "22898132_T4", "type": "CHEMICAL", "text": [ "sodium salicylate" ], "offsets": [ [ 592, 609 ] ], "normalized": [] }, { "id": "22898132_T5", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 611, 618 ] ], "normalized": [] }, { "id": "22898132_T6", "type": "CHEMICAL", "text": [ "hydroxyurea" ], "offsets": [ [ 620, 631 ] ], "normalized": [] }, { "id": "22898132_T7", "type": "CHEMICAL", "text": [ "methoxyacetic acid" ], "offsets": [ [ 633, 651 ] ], "normalized": [] }, { "id": "22898132_T8", "type": "CHEMICAL", "text": [ "boric acid" ], "offsets": [ [ 653, 663 ] ], "normalized": [] }, { "id": "22898132_T9", "type": "CHEMICAL", "text": [ "paraoxon-methyl" ], "offsets": [ [ 668, 683 ] ], "normalized": [] }, { "id": "22898132_T10", "type": "CHEMICAL", "text": [ "valproic and methoxyacetic acid" ], "offsets": [ [ 1001, 1032 ] ], "normalized": [] }, { "id": "22898132_T11", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 1161, 1165 ] ], "normalized": [] }, { "id": "22898132_T12", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 1250, 1254 ] ], "normalized": [] }, { "id": "22898132_T13", "type": "GENE-Y", "text": [ "acetylcholinesterase" ], "offsets": [ [ 244, 264 ] ], "normalized": [] }, { "id": "22898132_T14", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 266, 270 ] ], "normalized": [] }, { "id": "22898132_T15", "type": "GENE-Y", "text": [ "AChE" ], "offsets": [ [ 737, 741 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "23500058_title", "type": "title", "text": [ "Gene silencing of TNF-alpha in a murine model of acute colitis using a modified cyclodextrin delivery system." ], "offsets": [ [ 0, 109 ] ] }, { "id": "23500058_abstract", "type": "abstract", "text": [ "Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the gastrointestinal tract. The cytokine TNF-alpha (TNF-α) plays a pivotal role in mediating this inflammatory response. RNA interference (RNAi) holds great promise for the specific and selective silencing of aberrantly expressed genes, such as TNF-α in IBD. The aim of this study was to investigate the efficacy of an amphiphilic cationic cyclodextrin (CD) vector for effective TNF-α siRNA delivery to macrophage cells and to mice with induced acute-colitis. The stability of CD.siRNA was examined by gel electrophoresis in biorelevant media reflecting colonic fluids. RAW264.7 cells were transfected with CD.TNF-α siRNA, stimulated with lipopolysaccharide (LPS) and TNF-α and IL-6 responses were measured by PCR and ELISA. Female C57BL/6 mice were exposed to dextran sodium sulphate (DSS) and treated by intrarectal administration with either CD.siRNA TNF-α or a control solution. In vitro, siRNA in CD nanocomplexes remained intact and stable in both fed and fasted simulated colonic fluids. RAW264.7 cells transfected with CD.TNF-α siRNA and stimulated with LPS displayed a significant reduction in both gene and protein levels of TNF-α and IL-6. CD.TNF-α siRNA-treated mice revealed a mild amelioration in clinical signs of colitis, but significant reductions in total colon weight and colonic mRNA expression of TNF-α and IL-6 compared to DSS-control mice were detected. This data indicates the clinical potential of a local CD-based TNF-α siRNA delivery system for the treatment of IBD." ], "offsets": [ [ 110, 1675 ] ] } ]

[ { "id": "23500058_T1", "type": "CHEMICAL", "text": [ "sodium sulphate" ], "offsets": [ [ 951, 966 ] ], "normalized": [] }, { "id": "23500058_T2", "type": "GENE-N", "text": [ "cytokine" ], "offsets": [ [ 214, 222 ] ], "normalized": [] }, { "id": "23500058_T3", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 1212, 1217 ] ], "normalized": [] }, { "id": "23500058_T4", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 223, 232 ] ], "normalized": [] }, { "id": "23500058_T5", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 1317, 1322 ] ], "normalized": [] }, { "id": "23500058_T6", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 1327, 1331 ] ], "normalized": [] }, { "id": "23500058_T7", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 1336, 1341 ] ], "normalized": [] }, { "id": "23500058_T8", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 234, 239 ] ], "normalized": [] }, { "id": "23500058_T9", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 1500, 1505 ] ], "normalized": [] }, { "id": "23500058_T10", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 1510, 1514 ] ], "normalized": [] }, { "id": "23500058_T11", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 1622, 1627 ] ], "normalized": [] }, { "id": "23500058_T12", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 427, 432 ] ], "normalized": [] }, { "id": "23500058_T13", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 561, 566 ] ], "normalized": [] }, { "id": "23500058_T14", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 792, 797 ] ], "normalized": [] }, { "id": "23500058_T15", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 850, 855 ] ], "normalized": [] }, { "id": "23500058_T16", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 860, 864 ] ], "normalized": [] }, { "id": "23500058_T17", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 1036, 1041 ] ], "normalized": [] }, { "id": "23500058_T18", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 18, 27 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "23466342_title", "type": "title", "text": [ "Reversal of P-glycoprotein-mediated multidrug resistance is induced by mollugin in MCF-7/adriamycin cells." ], "offsets": [ [ 0, 106 ] ] }, { "id": "23466342_abstract", "type": "abstract", "text": [ "P-glycoprotein (P-gp), an important efflux transporter, is encoded by the MDR1 class of genes and is a central element of the multidrug resistance (MDR) phenomenon in cancer cells. In the present study, we investigated whether mollugin, purified from roots of Rubica cordifolia L., down-regulated MDR1 expression in MCF-7/adriamycin (MCF-7/adr) cells, a human breast multidrug-resistant cancer cell line. Mollugin treatment significantly inhibited MDR1 expression by blocking MDR1 transcription. Mollugin treatment also significantly increased intracellular accumulation of the fluorescently-tagged P-gp substrate, rhodamine-123. The suppression of MDR1 promoter activity and protein expression was mediated through mollugin-induced activation of AMP-activated protein kinase (AMPK). Furthermore, mollugin inhibited MDR1 expression through the suppression of NF-κB and CREB activation. Interestingly, mollugin also inhibited COX-2 expression. These results suggest that mollugin treatment enhanced suppression of P-gp expression by inhibiting the NF-κB signaling pathway and COX-2 expression, as well as attenuating CRE transcriptional activity through AMPK activation." ], "offsets": [ [ 107, 1276 ] ] } ]

[ { "id": "23466342_T1", "type": "CHEMICAL", "text": [ "mollugin" ], "offsets": [ [ 334, 342 ] ], "normalized": [] }, { "id": "23466342_T2", "type": "CHEMICAL", "text": [ "adriamycin" ], "offsets": [ [ 429, 439 ] ], "normalized": [] }, { "id": "23466342_T3", "type": "CHEMICAL", "text": [ "Mollugin" ], "offsets": [ [ 512, 520 ] ], "normalized": [] }, { "id": "23466342_T4", "type": "CHEMICAL", "text": [ "Mollugin" ], "offsets": [ [ 603, 611 ] ], "normalized": [] }, { "id": "23466342_T5", "type": "CHEMICAL", "text": [ "rhodamine-123" ], "offsets": [ [ 722, 735 ] ], "normalized": [] }, { "id": "23466342_T6", "type": "CHEMICAL", "text": [ "mollugin" ], "offsets": [ [ 823, 831 ] ], "normalized": [] }, { "id": "23466342_T7", "type": "CHEMICAL", "text": [ "AMP" ], "offsets": [ [ 854, 857 ] ], "normalized": [] }, { "id": "23466342_T8", "type": "CHEMICAL", "text": [ "mollugin" ], "offsets": [ [ 904, 912 ] ], "normalized": [] }, { "id": "23466342_T9", "type": "CHEMICAL", "text": [ "mollugin" ], "offsets": [ [ 1008, 1016 ] ], "normalized": [] }, { "id": "23466342_T10", "type": "CHEMICAL", "text": [ "mollugin" ], "offsets": [ [ 1077, 1085 ] ], "normalized": [] }, { "id": "23466342_T11", "type": "CHEMICAL", "text": [ "mollugin" ], "offsets": [ [ 71, 79 ] ], "normalized": [] }, { "id": "23466342_T12", "type": "GENE-N", "text": [ "P-glycoprotein" ], "offsets": [ [ 107, 121 ] ], "normalized": [] }, { "id": "23466342_T13", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 1120, 1124 ] ], "normalized": [] }, { "id": "23466342_T14", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 1154, 1159 ] ], "normalized": [] }, { "id": "23466342_T15", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1182, 1187 ] ], "normalized": [] }, { "id": "23466342_T16", "type": "GENE-N", "text": [ "CRE" ], "offsets": [ [ 1223, 1226 ] ], "normalized": [] }, { "id": "23466342_T17", "type": "GENE-Y", "text": [ "AMPK" ], "offsets": [ [ 1260, 1264 ] ], "normalized": [] }, { "id": "23466342_T18", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 123, 127 ] ], "normalized": [] }, { "id": "23466342_T19", "type": "GENE-Y", "text": [ "MDR1" ], "offsets": [ [ 404, 408 ] ], "normalized": [] }, { "id": "23466342_T20", "type": "GENE-Y", "text": [ "MDR1" ], "offsets": [ [ 555, 559 ] ], "normalized": [] }, { "id": "23466342_T21", "type": "GENE-Y", "text": [ "MDR1" ], "offsets": [ [ 583, 587 ] ], "normalized": [] }, { "id": "23466342_T22", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 706, 710 ] ], "normalized": [] }, { "id": "23466342_T23", "type": "GENE-N", "text": [ "MDR1 promoter" ], "offsets": [ [ 756, 769 ] ], "normalized": [] }, { "id": "23466342_T24", "type": "GENE-Y", "text": [ "AMP-activated protein kinase" ], "offsets": [ [ 854, 882 ] ], "normalized": [] }, { "id": "23466342_T25", "type": "GENE-Y", "text": [ "MDR1" ], "offsets": [ [ 181, 185 ] ], "normalized": [] }, { "id": "23466342_T26", "type": "GENE-Y", "text": [ "AMPK" ], "offsets": [ [ 884, 888 ] ], "normalized": [] }, { "id": "23466342_T27", "type": "GENE-Y", "text": [ "MDR1" ], "offsets": [ [ 923, 927 ] ], "normalized": [] }, { "id": "23466342_T28", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 966, 971 ] ], "normalized": [] }, { "id": "23466342_T29", "type": "GENE-N", "text": [ "CREB" ], "offsets": [ [ 976, 980 ] ], "normalized": [] }, { "id": "23466342_T30", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1032, 1037 ] ], "normalized": [] }, { "id": "23466342_T31", "type": "GENE-N", "text": [ "P-glycoprotein" ], "offsets": [ [ 12, 26 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23466342_0", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23466342_T3", "arg2_id": "23466342_T20", "normalized": [] }, { "id": "23466342_1", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23466342_T3", "arg2_id": "23466342_T21", "normalized": [] }, { "id": "23466342_2", "type": "SUBSTRATE", "arg1_id": "23466342_T5", "arg2_id": "23466342_T22", "normalized": [] }, { "id": "23466342_3", "type": "ACTIVATOR", "arg1_id": "23466342_T6", "arg2_id": "23466342_T24", "normalized": [] }, { "id": "23466342_4", "type": "ACTIVATOR", "arg1_id": "23466342_T6", "arg2_id": "23466342_T26", "normalized": [] }, { "id": "23466342_5", "type": "INHIBITOR", "arg1_id": "23466342_T6", "arg2_id": "23466342_T23", "normalized": [] }, { "id": "23466342_6", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23466342_T6", "arg2_id": "23466342_T23", "normalized": [] }, { "id": "23466342_7", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23466342_T8", "arg2_id": "23466342_T27", "normalized": [] }, { "id": "23466342_8", "type": "INHIBITOR", "arg1_id": "23466342_T8", "arg2_id": "23466342_T28", "normalized": [] }, { "id": "23466342_9", "type": "INHIBITOR", "arg1_id": "23466342_T8", "arg2_id": "23466342_T29", "normalized": [] }, { "id": "23466342_10", "type": "INHIBITOR", "arg1_id": "23466342_T9", "arg2_id": "23466342_T30", "normalized": [] }, { "id": "23466342_11", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23466342_T10", "arg2_id": "23466342_T13", "normalized": [] }, { "id": "23466342_12", "type": "INHIBITOR", "arg1_id": "23466342_T10", "arg2_id": "23466342_T14", "normalized": [] }, { "id": "23466342_13", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23466342_T10", "arg2_id": "23466342_T15", "normalized": [] }, { "id": "23466342_14", "type": "INHIBITOR", "arg1_id": "23466342_T10", "arg2_id": "23466342_T16", "normalized": [] }, { "id": "23466342_15", "type": "ACTIVATOR", "arg1_id": "23466342_T10", "arg2_id": "23466342_T17", "normalized": [] }, { "id": "23466342_16", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23466342_T11", "arg2_id": "23466342_T31", "normalized": [] } ]

[ { "id": "23040268_title", "type": "title", "text": [ "Lipoprotein(a) metabolism: potential sites for therapeutic targets." ], "offsets": [ [ 0, 67 ] ] }, { "id": "23040268_abstract", "type": "abstract", "text": [ "Lipoprotein(a) [Lp(a)] resembles low-density lipoprotein (LDL), with an LDL lipid core and apolipoprotein B (apoB), but contains a unique apolipoprotein, apo(a). Elevated Lp(a) is an independent risk factor for coronary and peripheral vascular diseases. The size and concentration of plasma Lp(a) are related to the synthetic rate, not the catabolic rate, and are highly variable with small isoforms associated with high concentrations and pathogenic risk. Apo(a) is synthesized in the liver, although assembly of apo(a) and LDL may occur in the hepatocytes or plasma. While the uptake and clearance site of Lp(a) is poorly delineated, the kidney is the site of apo(a) fragment excretion. The structure of apo(a) has high homology to plasminogen, the zymogen for plasmin and the primary clot lysis enzyme. Apo(a) interferes with plasminogen binding to C-terminal lysines of cell surface and extracellular matrix proteins. Lp(a) and apo(a) inhibit fibrinolysis and accumulate in the vascular wall in atherosclerotic lesions. The pathogenic role of Lp(a) is not known. Small isoforms and high concentrations of Lp(a) are found in healthy octogenarians that suggest Lp(a) may also have a physiological role. Studies of Lp(a) function have been limited since it is not found in commonly studied small mammals. An important aspect of Lp(a) metabolism is the modification of circulating Lp(a), which has the potential to alter the functions of Lp(a). There are no therapeutic drugs that selectively target elevated Lp(a), but a number of possible agents are being considered. Recently, new modifiers of apo(a) synthesis have been identified. This review reports the regulation of Lp(a) metabolism and potential sites for therapeutic targets." ], "offsets": [ [ 68, 1803 ] ] } ]

[ { "id": "23040268_T1", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 920, 921 ] ], "normalized": [] }, { "id": "23040268_T2", "type": "GENE-Y", "text": [ "Lipoprotein(a)" ], "offsets": [ [ 68, 82 ] ], "normalized": [] }, { "id": "23040268_T3", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 1115, 1120 ] ], "normalized": [] }, { "id": "23040268_T4", "type": "GENE-Y", "text": [ "apoB" ], "offsets": [ [ 177, 181 ] ], "normalized": [] }, { "id": "23040268_T5", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 1177, 1182 ] ], "normalized": [] }, { "id": "23040268_T6", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 1231, 1236 ] ], "normalized": [] }, { "id": "23040268_T7", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 1284, 1289 ] ], "normalized": [] }, { "id": "23040268_T8", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 1397, 1402 ] ], "normalized": [] }, { "id": "23040268_T9", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 1449, 1454 ] ], "normalized": [] }, { "id": "23040268_T10", "type": "GENE-N", "text": [ "apolipoprotein" ], "offsets": [ [ 206, 220 ] ], "normalized": [] }, { "id": "23040268_T11", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 1506, 1511 ] ], "normalized": [] }, { "id": "23040268_T12", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 1577, 1582 ] ], "normalized": [] }, { "id": "23040268_T13", "type": "GENE-Y", "text": [ "apo(a)" ], "offsets": [ [ 222, 228 ] ], "normalized": [] }, { "id": "23040268_T14", "type": "GENE-Y", "text": [ "apo(a)" ], "offsets": [ [ 1665, 1671 ] ], "normalized": [] }, { "id": "23040268_T15", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 84, 89 ] ], "normalized": [] }, { "id": "23040268_T16", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 1742, 1747 ] ], "normalized": [] }, { "id": "23040268_T17", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 239, 244 ] ], "normalized": [] }, { "id": "23040268_T18", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 359, 364 ] ], "normalized": [] }, { "id": "23040268_T19", "type": "GENE-N", "text": [ "low-density lipoprotein" ], "offsets": [ [ 101, 124 ] ], "normalized": [] }, { "id": "23040268_T20", "type": "GENE-Y", "text": [ "Apo(a)" ], "offsets": [ [ 525, 531 ] ], "normalized": [] }, { "id": "23040268_T21", "type": "GENE-Y", "text": [ "apo(a)" ], "offsets": [ [ 582, 588 ] ], "normalized": [] }, { "id": "23040268_T22", "type": "GENE-N", "text": [ "LDL" ], "offsets": [ [ 593, 596 ] ], "normalized": [] }, { "id": "23040268_T23", "type": "GENE-N", "text": [ "LDL" ], "offsets": [ [ 126, 129 ] ], "normalized": [] }, { "id": "23040268_T24", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 676, 681 ] ], "normalized": [] }, { "id": "23040268_T25", "type": "GENE-Y", "text": [ "apo(a)" ], "offsets": [ [ 730, 736 ] ], "normalized": [] }, { "id": "23040268_T26", "type": "GENE-Y", "text": [ "apo(a)" ], "offsets": [ [ 774, 780 ] ], "normalized": [] }, { "id": "23040268_T27", "type": "GENE-N", "text": [ "LDL" ], "offsets": [ [ 140, 143 ] ], "normalized": [] }, { "id": "23040268_T28", "type": "GENE-Y", "text": [ "plasminogen" ], "offsets": [ [ 802, 813 ] ], "normalized": [] }, { "id": "23040268_T29", "type": "GENE-Y", "text": [ "plasmin" ], "offsets": [ [ 831, 838 ] ], "normalized": [] }, { "id": "23040268_T30", "type": "GENE-Y", "text": [ "Apo(a)" ], "offsets": [ [ 874, 880 ] ], "normalized": [] }, { "id": "23040268_T31", "type": "GENE-Y", "text": [ "plasminogen" ], "offsets": [ [ 897, 908 ] ], "normalized": [] }, { "id": "23040268_T32", "type": "GENE-N", "text": [ "cell surface and extracellular matrix proteins" ], "offsets": [ [ 942, 988 ] ], "normalized": [] }, { "id": "23040268_T33", "type": "GENE-Y", "text": [ "apolipoprotein B" ], "offsets": [ [ 159, 175 ] ], "normalized": [] }, { "id": "23040268_T34", "type": "GENE-Y", "text": [ "Lp(a)" ], "offsets": [ [ 990, 995 ] ], "normalized": [] }, { "id": "23040268_T35", "type": "GENE-Y", "text": [ "apo(a)" ], "offsets": [ [ 1000, 1006 ] ], "normalized": [] }, { "id": "23040268_T36", "type": "GENE-Y", "text": [ "Lipoprotein(a)" ], "offsets": [ [ 0, 14 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23040268_0", "type": "PART-OF", "arg1_id": "23040268_T1", "arg2_id": "23040268_T32", "normalized": [] } ]

[ { "id": "17182172_title", "type": "title", "text": [ "The growth plate sparing effects of the selective glucocorticoid receptor modulator, AL-438." ], "offsets": [ [ 0, 92 ] ] }, { "id": "17182172_abstract", "type": "abstract", "text": [ "Long-term use of glucocorticoids (GC) can cause growth retardation in children due to their actions on growth plate chondrocytes. AL-438, a non-steroidal anti-inflammatory agent that acts through the glucocorticoid receptor (GR) retains full anti-inflammatory efficacy but has reduced negative effects on osteoblasts compared to those elicited by prednisolone (Pred) or dexamethasone (Dex). We have used the murine chondrogenic ATDC5 cell line to compare the effects of AL-438 with those of Dex and Pred on chondrocyte dynamics. Dex and Pred caused a reduction in cell proliferation and proteoglycan synthesis, whereas exposure to AL-438 had no effect. LPS-induced IL-6 production in ATDC5 cells was reduced by Dex or AL-438, showing that AL-438 has similar anti-inflammatory efficacy to Dex in these cells. Fetal mouse metatarsals grown in the presence of Dex were shorter than control bones whereas AL-438 treated metatarsals paralleled control bone growth. These results indicate that the adverse effects Dex or Pred have on chondrocyte proliferation and bone growth were attenuated following AL-438 exposure, suggesting that AL-438 has a reduced side effect profile on chondrocytes compared to other GCs. This could prove important in the search for new anti-inflammatory treatments for children." ], "offsets": [ [ 93, 1393 ] ] } ]

[ { "id": "17182172_T1", "type": "CHEMICAL", "text": [ "Dex" ], "offsets": [ [ 1101, 1104 ] ], "normalized": [] }, { "id": "17182172_T2", "type": "CHEMICAL", "text": [ "Pred" ], "offsets": [ [ 1108, 1112 ] ], "normalized": [] }, { "id": "17182172_T3", "type": "CHEMICAL", "text": [ "AL-438" ], "offsets": [ [ 1189, 1195 ] ], "normalized": [] }, { "id": "17182172_T4", "type": "CHEMICAL", "text": [ "AL-438" ], "offsets": [ [ 1222, 1228 ] ], "normalized": [] }, { "id": "17182172_T5", "type": "CHEMICAL", "text": [ "AL-438" ], "offsets": [ [ 223, 229 ] ], "normalized": [] }, { "id": "17182172_T6", "type": "CHEMICAL", "text": [ "prednisolone" ], "offsets": [ [ 440, 452 ] ], "normalized": [] }, { "id": "17182172_T7", "type": "CHEMICAL", "text": [ "Pred" ], "offsets": [ [ 454, 458 ] ], "normalized": [] }, { "id": "17182172_T8", "type": "CHEMICAL", "text": [ "dexamethasone" ], "offsets": [ [ 463, 476 ] ], "normalized": [] }, { "id": "17182172_T9", "type": "CHEMICAL", "text": [ "Dex" ], "offsets": [ [ 478, 481 ] ], "normalized": [] }, { "id": "17182172_T10", "type": "CHEMICAL", "text": [ "AL-438" ], "offsets": [ [ 563, 569 ] ], "normalized": [] }, { "id": "17182172_T11", "type": "CHEMICAL", "text": [ "Dex" ], "offsets": [ [ 584, 587 ] ], "normalized": [] }, { "id": "17182172_T12", "type": "CHEMICAL", "text": [ "Pred" ], "offsets": [ [ 592, 596 ] ], "normalized": [] }, { "id": "17182172_T13", "type": "CHEMICAL", "text": [ "Dex" ], "offsets": [ [ 622, 625 ] ], "normalized": [] }, { "id": "17182172_T14", "type": "CHEMICAL", "text": [ "Pred" ], "offsets": [ [ 630, 634 ] ], "normalized": [] }, { "id": "17182172_T15", "type": "CHEMICAL", "text": [ "AL-438" ], "offsets": [ [ 724, 730 ] ], "normalized": [] }, { "id": "17182172_T16", "type": "CHEMICAL", "text": [ "Dex" ], "offsets": [ [ 804, 807 ] ], "normalized": [] }, { "id": "17182172_T17", "type": "CHEMICAL", "text": [ "AL-438" ], "offsets": [ [ 811, 817 ] ], "normalized": [] }, { "id": "17182172_T18", "type": "CHEMICAL", "text": [ "AL-438" ], "offsets": [ [ 832, 838 ] ], "normalized": [] }, { "id": "17182172_T19", "type": "CHEMICAL", "text": [ "Dex" ], "offsets": [ [ 881, 884 ] ], "normalized": [] }, { "id": "17182172_T20", "type": "CHEMICAL", "text": [ "AL-438" ], "offsets": [ [ 994, 1000 ] ], "normalized": [] }, { "id": "17182172_T21", "type": "CHEMICAL", "text": [ "AL-438" ], "offsets": [ [ 85, 91 ] ], "normalized": [] }, { "id": "17182172_T22", "type": "GENE-Y", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 293, 316 ] ], "normalized": [] }, { "id": "17182172_T23", "type": "GENE-Y", "text": [ "GR" ], "offsets": [ [ 318, 320 ] ], "normalized": [] }, { "id": "17182172_T24", "type": "GENE-N", "text": [ "proteoglycan" ], "offsets": [ [ 680, 692 ] ], "normalized": [] }, { "id": "17182172_T25", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 758, 762 ] ], "normalized": [] }, { "id": "17182172_T26", "type": "GENE-Y", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 50, 73 ] ], "normalized": [] } ]

[]

[]

[ { "id": "17182172_0", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "17182172_T13", "arg2_id": "17182172_T24", "normalized": [] }, { "id": "17182172_1", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "17182172_T14", "arg2_id": "17182172_T24", "normalized": [] }, { "id": "17182172_2", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "17182172_T16", "arg2_id": "17182172_T25", "normalized": [] }, { "id": "17182172_3", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "17182172_T17", "arg2_id": "17182172_T25", "normalized": [] } ]

[ { "id": "15837316_title", "type": "title", "text": [ "Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cytosolic isozyme II and mitochondrial isozyme V: solution and X-ray crystallographic studies." ], "offsets": [ [ 0, 169 ] ] }, { "id": "15837316_abstract", "type": "abstract", "text": [ "The antiepileptic drug zonisamide was considered to act as a weak inhibitor of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) (with a K(I) of 4.3 microM against the cytosolic isozyme II). Here we prove that this is not true. Indeed, testing zonisamide in the classical assay conditions of the CO2 hydrase activity of hCA II, with incubation times of enzyme and inhibitor solution of 15 min, a K(I) of 10.3 microM has been obtained. However, when the incubation between enzyme and inhibitor was prolonged to 1 h, the obtained K(I) was of 35.2 nM, of the same order of magnitude as that of the clinically used sulfonamides/sulfamates acetazolamide, methazolamide, ethoxzolamide and topiramate (K(I)s in the range of 5.4-15.4 nM). The inhibition of the human mitochondrial isozyme hCA V with these compounds has been also tested by means of a dansylamide competition binding assay, which showed zonisamide and topiramate to be effective inhibitors, with K(I)s in the range of 20.6-25.4 nM. The X-ray crystal structure of the adduct of hCA II with zonisamide has also been solved at a resolution of 1.70 A, showing that the sulfonamide moiety participates in the classical interactions with the Zn(II) ion and the residues Thr199 and Glu106, whereas the benzisoxazole ring is oriented toward the hydrophobic half of the active site, establishing a large number of strong van der Waals interactions (<4.5 A) with residues Gln92, Val121, Phe131, Leu198, Thr200, Pro202." ], "offsets": [ [ 170, 1638 ] ] } ]

[ { "id": "15837316_T1", "type": "CHEMICAL", "text": [ "zonisamide" ], "offsets": [ [ 1219, 1229 ] ], "normalized": [] }, { "id": "15837316_T2", "type": "CHEMICAL", "text": [ "sulfonamide" ], "offsets": [ [ 1295, 1306 ] ], "normalized": [] }, { "id": "15837316_T3", "type": "CHEMICAL", "text": [ "Zn(II)" ], "offsets": [ [ 1366, 1372 ] ], "normalized": [] }, { "id": "15837316_T4", "type": "CHEMICAL", "text": [ "zonisamide" ], "offsets": [ [ 193, 203 ] ], "normalized": [] }, { "id": "15837316_T5", "type": "CHEMICAL", "text": [ "zonisamide" ], "offsets": [ [ 416, 426 ] ], "normalized": [] }, { "id": "15837316_T6", "type": "CHEMICAL", "text": [ "CO2" ], "offsets": [ [ 468, 471 ] ], "normalized": [] }, { "id": "15837316_T7", "type": "CHEMICAL", "text": [ "sulfonamides" ], "offsets": [ [ 783, 795 ] ], "normalized": [] }, { "id": "15837316_T8", "type": "CHEMICAL", "text": [ "sulfamates" ], "offsets": [ [ 796, 806 ] ], "normalized": [] }, { "id": "15837316_T9", "type": "CHEMICAL", "text": [ "acetazolamide" ], "offsets": [ [ 807, 820 ] ], "normalized": [] }, { "id": "15837316_T10", "type": "CHEMICAL", "text": [ "methazolamide" ], "offsets": [ [ 822, 835 ] ], "normalized": [] }, { "id": "15837316_T11", "type": "CHEMICAL", "text": [ "ethoxzolamide" ], "offsets": [ [ 837, 850 ] ], "normalized": [] }, { "id": "15837316_T12", "type": "CHEMICAL", "text": [ "topiramate" ], "offsets": [ [ 855, 865 ] ], "normalized": [] }, { "id": "15837316_T13", "type": "CHEMICAL", "text": [ "zinc" ], "offsets": [ [ 253, 257 ] ], "normalized": [] }, { "id": "15837316_T14", "type": "CHEMICAL", "text": [ "dansylamide" ], "offsets": [ [ 1015, 1026 ] ], "normalized": [] }, { "id": "15837316_T15", "type": "CHEMICAL", "text": [ "zonisamide" ], "offsets": [ [ 1067, 1077 ] ], "normalized": [] }, { "id": "15837316_T16", "type": "CHEMICAL", "text": [ "topiramate" ], "offsets": [ [ 1082, 1092 ] ], "normalized": [] }, { "id": "15837316_T17", "type": "CHEMICAL", "text": [ "Zonisamide" ], "offsets": [ [ 31, 41 ] ], "normalized": [] }, { "id": "15837316_T18", "type": "GENE-Y", "text": [ "hCA II" ], "offsets": [ [ 1207, 1213 ] ], "normalized": [] }, { "id": "15837316_T19", "type": "GENE-N", "text": [ "CA" ], "offsets": [ [ 285, 287 ] ], "normalized": [] }, { "id": "15837316_T20", "type": "GENE-Y", "text": [ "EC 4.2.1.1" ], "offsets": [ [ 289, 299 ] ], "normalized": [] }, { "id": "15837316_T21", "type": "GENE-Y", "text": [ "cytosolic isozyme II" ], "offsets": [ [ 340, 360 ] ], "normalized": [] }, { "id": "15837316_T22", "type": "GENE-Y", "text": [ "hCA II" ], "offsets": [ [ 492, 498 ] ], "normalized": [] }, { "id": "15837316_T23", "type": "GENE-N", "text": [ "hCA V" ], "offsets": [ [ 953, 958 ] ], "normalized": [] }, { "id": "15837316_T24", "type": "GENE-N", "text": [ "carbonic anhydrase" ], "offsets": [ [ 265, 283 ] ], "normalized": [] }, { "id": "15837316_T25", "type": "GENE-N", "text": [ "mitochondrial isozyme V" ], "offsets": [ [ 100, 123 ] ], "normalized": [] }, { "id": "15837316_T26", "type": "GENE-Y", "text": [ "cytosolic isozyme II" ], "offsets": [ [ 75, 95 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "23616352_title", "type": "title", "text": [ "Selective Bisubstrate Inhibitors with Sub-nanomolar Affinity for Protein Kinase Pim-1." ], "offsets": [ [ 0, 86 ] ] }, { "id": "23616352_abstract", "type": "abstract", "text": [ "Potent and selective: The unique nature of the ATP binding pocket structure of Pim family protein kinases (PKs) was used for the development of bisubstrate inhibitors and a fluorescent probe with sub-nanomolar affinity. Conjugates of arginine-rich peptides with two ATP mimetic scaffolds were synthesized and tested as inhibitors of Pim-1. Against a panel of 124 protein kinases, a novel ARC-PIM conjugate selectively inhibited PKs of the Pim family." ], "offsets": [ [ 87, 537 ] ] } ]

[ { "id": "23616352_T1", "type": "CHEMICAL", "text": [ "arginine" ], "offsets": [ [ 321, 329 ] ], "normalized": [] }, { "id": "23616352_T2", "type": "CHEMICAL", "text": [ "ATP" ], "offsets": [ [ 353, 356 ] ], "normalized": [] }, { "id": "23616352_T3", "type": "CHEMICAL", "text": [ "ATP" ], "offsets": [ [ 134, 137 ] ], "normalized": [] }, { "id": "23616352_T4", "type": "GENE-N", "text": [ "PKs" ], "offsets": [ [ 194, 197 ] ], "normalized": [] }, { "id": "23616352_T5", "type": "GENE-Y", "text": [ "Pim-1" ], "offsets": [ [ 420, 425 ] ], "normalized": [] }, { "id": "23616352_T6", "type": "GENE-N", "text": [ "protein kinases" ], "offsets": [ [ 450, 465 ] ], "normalized": [] }, { "id": "23616352_T7", "type": "GENE-N", "text": [ "PIM" ], "offsets": [ [ 479, 482 ] ], "normalized": [] }, { "id": "23616352_T8", "type": "GENE-N", "text": [ "PKs" ], "offsets": [ [ 515, 518 ] ], "normalized": [] }, { "id": "23616352_T9", "type": "GENE-N", "text": [ "Pim" ], "offsets": [ [ 526, 529 ] ], "normalized": [] }, { "id": "23616352_T10", "type": "GENE-N", "text": [ "Pim" ], "offsets": [ [ 166, 169 ] ], "normalized": [] }, { "id": "23616352_T11", "type": "GENE-N", "text": [ "protein kinases" ], "offsets": [ [ 177, 192 ] ], "normalized": [] }, { "id": "23616352_T12", "type": "GENE-N", "text": [ "Protein Kinase" ], "offsets": [ [ 65, 79 ] ], "normalized": [] }, { "id": "23616352_T13", "type": "GENE-Y", "text": [ "Pim-1" ], "offsets": [ [ 80, 85 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23616352_0", "type": "DIRECT-REGULATOR", "arg1_id": "23616352_T3", "arg2_id": "23616352_T10", "normalized": [] }, { "id": "23616352_1", "type": "DIRECT-REGULATOR", "arg1_id": "23616352_T3", "arg2_id": "23616352_T11", "normalized": [] }, { "id": "23616352_2", "type": "DIRECT-REGULATOR", "arg1_id": "23616352_T3", "arg2_id": "23616352_T4", "normalized": [] } ]

[ { "id": "23529824_title", "type": "title", "text": [ "Everolimus in Combination with Exemestane: A Review of its Use in the Treatment of Patients with Postmenopausal Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer." ], "offsets": [ [ 0, 176 ] ] }, { "id": "23529824_abstract", "type": "abstract", "text": [ "Oral everolimus (Afinitor(®)) in combination with exemestane is indicated for the treatment of hormone receptor-positive, human epidermal growth factor receptor (HER) 2-negative advanced breast cancer in postmenopausal women after failure of treatment with letrozole or anastrozole (in the USA) or after recurrence of progression following a nonsteroidal aromatase inhibitor (AI) in women without symptomatic visceral disease (in the EU). Everolimus, a selective inhibitor of mammalian target of rapamycin (mTOR), inhibits the downstream signalling events of the mTOR pathway. This review summarizes the pharmacology of everolimus and reviews its efficacy and tolerability when administered in combination with exemestane in postmenopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer refractory to nonsteroidal AIs. In the well-designed BOLERO-2 study, the addition of everolimus to exemestane was shown to significantly prolong progression-free survival in this patient population. However, treatment-emergent adverse events and treatment discontinuations occurred more frequently with combination therapy than with exemestane alone, suggesting a need for careful benefit/risk assessment prior to initiating therapy. Mature survival data from this study are awaited and additional studies would help to further demonstrate the benefit of combination therapy. Nevertheless, current evidence suggests that everolimus plus exemestane combination therapy may be a useful treatment option in patients with postmenopausal hormone receptor-positive, HER2-negative, advanced breast cancer refractory to nonsteroidal AIs." ], "offsets": [ [ 177, 1823 ] ] } ]

[ { "id": "23529824_T1", "type": "CHEMICAL", "text": [ "exemestane" ], "offsets": [ [ 1327, 1337 ] ], "normalized": [] }, { "id": "23529824_T2", "type": "CHEMICAL", "text": [ "everolimus" ], "offsets": [ [ 1615, 1625 ] ], "normalized": [] }, { "id": "23529824_T3", "type": "CHEMICAL", "text": [ "exemestane" ], "offsets": [ [ 1631, 1641 ] ], "normalized": [] }, { "id": "23529824_T4", "type": "CHEMICAL", "text": [ "Afinitor" ], "offsets": [ [ 194, 202 ] ], "normalized": [] }, { "id": "23529824_T5", "type": "CHEMICAL", "text": [ "letrozole" ], "offsets": [ [ 434, 443 ] ], "normalized": [] }, { "id": "23529824_T6", "type": "CHEMICAL", "text": [ "anastrozole" ], "offsets": [ [ 447, 458 ] ], "normalized": [] }, { "id": "23529824_T7", "type": "CHEMICAL", "text": [ "Everolimus" ], "offsets": [ [ 616, 626 ] ], "normalized": [] }, { "id": "23529824_T8", "type": "CHEMICAL", "text": [ "rapamycin" ], "offsets": [ [ 673, 682 ] ], "normalized": [] }, { "id": "23529824_T9", "type": "CHEMICAL", "text": [ "exemestane" ], "offsets": [ [ 227, 237 ] ], "normalized": [] }, { "id": "23529824_T10", "type": "CHEMICAL", "text": [ "everolimus" ], "offsets": [ [ 182, 192 ] ], "normalized": [] }, { "id": "23529824_T11", "type": "CHEMICAL", "text": [ "everolimus" ], "offsets": [ [ 797, 807 ] ], "normalized": [] }, { "id": "23529824_T12", "type": "CHEMICAL", "text": [ "exemestane" ], "offsets": [ [ 888, 898 ] ], "normalized": [] }, { "id": "23529824_T13", "type": "CHEMICAL", "text": [ "oestrogen" ], "offsets": [ [ 928, 937 ] ], "normalized": [] }, { "id": "23529824_T14", "type": "CHEMICAL", "text": [ "everolimus" ], "offsets": [ [ 1079, 1089 ] ], "normalized": [] }, { "id": "23529824_T15", "type": "CHEMICAL", "text": [ "exemestane" ], "offsets": [ [ 1093, 1103 ] ], "normalized": [] }, { "id": "23529824_T16", "type": "CHEMICAL", "text": [ "Everolimus" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "23529824_T17", "type": "CHEMICAL", "text": [ "Exemestane" ], "offsets": [ [ 31, 41 ] ], "normalized": [] }, { "id": "23529824_T18", "type": "GENE-Y", "text": [ "human epidermal growth factor receptor (HER) 2" ], "offsets": [ [ 299, 345 ] ], "normalized": [] }, { "id": "23529824_T19", "type": "GENE-N", "text": [ "hormone receptor" ], "offsets": [ [ 1727, 1743 ] ], "normalized": [] }, { "id": "23529824_T20", "type": "GENE-Y", "text": [ "HER2" ], "offsets": [ [ 1754, 1758 ] ], "normalized": [] }, { "id": "23529824_T21", "type": "GENE-Y", "text": [ "aromatase" ], "offsets": [ [ 532, 541 ] ], "normalized": [] }, { "id": "23529824_T22", "type": "GENE-Y", "text": [ "mammalian target of rapamycin" ], "offsets": [ [ 653, 682 ] ], "normalized": [] }, { "id": "23529824_T23", "type": "GENE-Y", "text": [ "mTOR" ], "offsets": [ [ 684, 688 ] ], "normalized": [] }, { "id": "23529824_T24", "type": "GENE-Y", "text": [ "mTOR" ], "offsets": [ [ 740, 744 ] ], "normalized": [] }, { "id": "23529824_T25", "type": "GENE-Y", "text": [ "HER2" ], "offsets": [ [ 957, 961 ] ], "normalized": [] }, { "id": "23529824_T26", "type": "GENE-N", "text": [ "hormone receptor" ], "offsets": [ [ 272, 288 ] ], "normalized": [] }, { "id": "23529824_T27", "type": "GENE-N", "text": [ "Hormone Receptor" ], "offsets": [ [ 112, 128 ] ], "normalized": [] }, { "id": "23529824_T28", "type": "GENE-Y", "text": [ "HER2" ], "offsets": [ [ 139, 143 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23529824_0", "type": "INHIBITOR", "arg1_id": "23529824_T7", "arg2_id": "23529824_T22", "normalized": [] }, { "id": "23529824_1", "type": "INHIBITOR", "arg1_id": "23529824_T7", "arg2_id": "23529824_T23", "normalized": [] }, { "id": "23529824_2", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23529824_T7", "arg2_id": "23529824_T24", "normalized": [] } ]

[ { "id": "11736858_title", "type": "title", "text": [ "Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): a comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine." ], "offsets": [ [ 0, 222 ] ] }, { "id": "11736858_abstract", "type": "abstract", "text": [ "AIMS: Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood-brain-barrier and the consequent occupation of brain histamine H1-receptors. We previously studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second-generation antihistamine, with cognitive performance tests. In the present study, H1-receptor occupation by ebastine was examined in the human brain using PET. METHODS: Ebastine 10 mg and (+)-chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with [11C]-doxepin, a potent H1-receptor antagonist, were conducted near tmax of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP = Bmax/Kd) for available brain H1-receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H1-receptor occupancy of drugs was calculated in several H1-receptor rich regions. RESULTS: Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)-chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that H1-receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BPs after ebastine were significantly higher than after (+)-chlorpheniramine (2 mg). H1-receptor occupancies in cortex were approximately 10% by ebastine and > or = 50% by either dose of (+)-chlorpheniramine (95% confidence interval for difference in the mean receptor occupancies: 27%, 54% for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)-chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine. CONCLUSIONS: Ebastine (10 mg orally) causes brain histamine H1-receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)-chlorpheniramine occupied about 50% of brain H1-receptors even at a low but sedative dose of 2 mg; occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration." ], "offsets": [ [ 223, 2615 ] ] } ]

[ { "id": "11736858_T1", "type": "CHEMICAL", "text": [ "(+)-chlorpheniramine" ], "offsets": [ [ 1462, 1482 ] ], "normalized": [] }, { "id": "11736858_T2", "type": "CHEMICAL", "text": [ "ebastine" ], "offsets": [ [ 1515, 1523 ] ], "normalized": [] }, { "id": "11736858_T3", "type": "CHEMICAL", "text": [ "(+)-chlorpheniramine" ], "offsets": [ [ 1783, 1803 ] ], "normalized": [] }, { "id": "11736858_T4", "type": "CHEMICAL", "text": [ "ebastine" ], "offsets": [ [ 1872, 1880 ] ], "normalized": [] }, { "id": "11736858_T5", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 390, 399 ] ], "normalized": [] }, { "id": "11736858_T6", "type": "CHEMICAL", "text": [ "(+)-chlorpheniramine" ], "offsets": [ [ 1914, 1934 ] ], "normalized": [] }, { "id": "11736858_T7", "type": "CHEMICAL", "text": [ "(+)-chlorpheniramine" ], "offsets": [ [ 2148, 2168 ] ], "normalized": [] }, { "id": "11736858_T8", "type": "CHEMICAL", "text": [ "carebastine" ], "offsets": [ [ 2200, 2211 ] ], "normalized": [] }, { "id": "11736858_T9", "type": "CHEMICAL", "text": [ "ebastine" ], "offsets": [ [ 2237, 2245 ] ], "normalized": [] }, { "id": "11736858_T10", "type": "CHEMICAL", "text": [ "Ebastine" ], "offsets": [ [ 2260, 2268 ] ], "normalized": [] }, { "id": "11736858_T11", "type": "CHEMICAL", "text": [ "(+)-chlorpheniramine" ], "offsets": [ [ 2416, 2436 ] ], "normalized": [] }, { "id": "11736858_T12", "type": "CHEMICAL", "text": [ "(+)-chlorpheniramine" ], "offsets": [ [ 2532, 2552 ] ], "normalized": [] }, { "id": "11736858_T13", "type": "CHEMICAL", "text": [ "(+)-chlorpheniramine" ], "offsets": [ [ 2580, 2600 ] ], "normalized": [] }, { "id": "11736858_T14", "type": "CHEMICAL", "text": [ "Ebastine" ], "offsets": [ [ 773, 781 ] ], "normalized": [] }, { "id": "11736858_T15", "type": "CHEMICAL", "text": [ "(+)-chlorpheniramine" ], "offsets": [ [ 792, 812 ] ], "normalized": [] }, { "id": "11736858_T16", "type": "CHEMICAL", "text": [ "[11C]-doxepin" ], "offsets": [ [ 884, 897 ] ], "normalized": [] }, { "id": "11736858_T17", "type": "CHEMICAL", "text": [ "doxepin" ], "offsets": [ [ 1066, 1073 ] ], "normalized": [] }, { "id": "11736858_T18", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 16, 25 ] ], "normalized": [] }, { "id": "11736858_T19", "type": "CHEMICAL", "text": [ "(+)-chlorpheniramine" ], "offsets": [ [ 174, 194 ] ], "normalized": [] }, { "id": "11736858_T20", "type": "GENE-Y", "text": [ "H1-receptor" ], "offsets": [ [ 1223, 1234 ] ], "normalized": [] }, { "id": "11736858_T21", "type": "GENE-Y", "text": [ "H1-receptor" ], "offsets": [ [ 1280, 1291 ] ], "normalized": [] }, { "id": "11736858_T22", "type": "GENE-Y", "text": [ "H1-receptor" ], "offsets": [ [ 1632, 1643 ] ], "normalized": [] }, { "id": "11736858_T23", "type": "GENE-Y", "text": [ "H1-receptor" ], "offsets": [ [ 1812, 1823 ] ], "normalized": [] }, { "id": "11736858_T24", "type": "GENE-Y", "text": [ "histamine H1-receptors" ], "offsets": [ [ 390, 412 ] ], "normalized": [] }, { "id": "11736858_T25", "type": "GENE-Y", "text": [ "histamine H1-receptor" ], "offsets": [ [ 2297, 2318 ] ], "normalized": [] }, { "id": "11736858_T26", "type": "GENE-Y", "text": [ "H1-receptors" ], "offsets": [ [ 2465, 2477 ] ], "normalized": [] }, { "id": "11736858_T27", "type": "GENE-Y", "text": [ "H1-receptor" ], "offsets": [ [ 686, 697 ] ], "normalized": [] }, { "id": "11736858_T28", "type": "GENE-Y", "text": [ "H1-receptor" ], "offsets": [ [ 908, 919 ] ], "normalized": [] }, { "id": "11736858_T29", "type": "GENE-Y", "text": [ "H1-receptors" ], "offsets": [ [ 1109, 1121 ] ], "normalized": [] }, { "id": "11736858_T30", "type": "GENE-Y", "text": [ "histamine H1-receptor" ], "offsets": [ [ 16, 37 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11736858_0", "type": "ANTAGONIST", "arg1_id": "11736858_T16", "arg2_id": "11736858_T28", "normalized": [] }, { "id": "11736858_1", "type": "DIRECT-REGULATOR", "arg1_id": "11736858_T17", "arg2_id": "11736858_T29", "normalized": [] }, { "id": "11736858_2", "type": "DIRECT-REGULATOR", "arg1_id": "11736858_T4", "arg2_id": "11736858_T23", "normalized": [] }, { "id": "11736858_3", "type": "DIRECT-REGULATOR", "arg1_id": "11736858_T6", "arg2_id": "11736858_T23", "normalized": [] }, { "id": "11736858_4", "type": "DIRECT-REGULATOR", "arg1_id": "11736858_T10", "arg2_id": "11736858_T25", "normalized": [] }, { "id": "11736858_5", "type": "DIRECT-REGULATOR", "arg1_id": "11736858_T11", "arg2_id": "11736858_T26", "normalized": [] }, { "id": "11736858_6", "type": "DIRECT-REGULATOR", "arg1_id": "11736858_T12", "arg2_id": "11736858_T26", "normalized": [] } ]

[ { "id": "11972287_title", "type": "title", "text": [ "Central 5-HT3 receptor stimulation by m-CPBG increases blood glucose in rats." ], "offsets": [ [ 0, 77 ] ] }, { "id": "11972287_abstract", "type": "abstract", "text": [ "The aim of the present study was to investigate the role of central 5-HT3 receptors on the control of blood glucose in stressed and non-stressed rats in both fasted and fed states. Adult Wistar male rats had each their third ventricle cannulated 7 days before the experiments. Injections of m-CPBG, a selective 5-HT3 receptor agonist, induced a significant increase in blood glucose in non-stressed rats in both fasted and in fed states. The same procedure was unable to modify stress-induced hyperglycemia. The hyperglycemic effect of m-CPBG central administration was blocked by pretreatment with ondansetron, a specific 5-HT3 receptor antagonist, indicating that the effects here obtained with m-CPBG were a result of its interaction with 5-HT3 receptors. Third ventricle injections of ondansetron alone were not able to modify blood glucose in non-stressed animals and did not change the hyperglycemic responses observed after immobilization stress. We conclude that pharmacological activation of the central 5-HT3 receptor induces a hyperglycemic effect in non-stressed animals." ], "offsets": [ [ 78, 1161 ] ] } ]

[ { "id": "11972287_T1", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 186, 193 ] ], "normalized": [] }, { "id": "11972287_T2", "type": "CHEMICAL", "text": [ "m-CPBG" ], "offsets": [ [ 369, 375 ] ], "normalized": [] }, { "id": "11972287_T3", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 453, 460 ] ], "normalized": [] }, { "id": "11972287_T4", "type": "CHEMICAL", "text": [ "m-CPBG" ], "offsets": [ [ 614, 620 ] ], "normalized": [] }, { "id": "11972287_T5", "type": "CHEMICAL", "text": [ "m-CPBG" ], "offsets": [ [ 775, 781 ] ], "normalized": [] }, { "id": "11972287_T6", "type": "CHEMICAL", "text": [ "ondansetron" ], "offsets": [ [ 867, 878 ] ], "normalized": [] }, { "id": "11972287_T7", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 915, 922 ] ], "normalized": [] }, { "id": "11972287_T8", "type": "CHEMICAL", "text": [ "m-CPBG" ], "offsets": [ [ 38, 44 ] ], "normalized": [] }, { "id": "11972287_T9", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 61, 68 ] ], "normalized": [] }, { "id": "11972287_T10", "type": "GENE-Y", "text": [ "5-HT3" ], "offsets": [ [ 1091, 1096 ] ], "normalized": [] }, { "id": "11972287_T11", "type": "GENE-Y", "text": [ "5-HT3" ], "offsets": [ [ 389, 394 ] ], "normalized": [] }, { "id": "11972287_T12", "type": "GENE-Y", "text": [ "5-HT3" ], "offsets": [ [ 701, 706 ] ], "normalized": [] }, { "id": "11972287_T13", "type": "GENE-Y", "text": [ "5-HT3" ], "offsets": [ [ 146, 151 ] ], "normalized": [] }, { "id": "11972287_T14", "type": "GENE-Y", "text": [ "5-HT3" ], "offsets": [ [ 820, 825 ] ], "normalized": [] }, { "id": "11972287_T15", "type": "GENE-Y", "text": [ "5-HT3" ], "offsets": [ [ 8, 13 ] ], "normalized": [] } ]

[]

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[ { "id": "11972287_0", "type": "ACTIVATOR", "arg1_id": "11972287_T8", "arg2_id": "11972287_T15", "normalized": [] }, { "id": "11972287_1", "type": "AGONIST", "arg1_id": "11972287_T2", "arg2_id": "11972287_T11", "normalized": [] }, { "id": "11972287_2", "type": "AGONIST", "arg1_id": "11972287_T4", "arg2_id": "11972287_T12", "normalized": [] }, { "id": "11972287_3", "type": "DIRECT-REGULATOR", "arg1_id": "11972287_T5", "arg2_id": "11972287_T14", "normalized": [] } ]

[ { "id": "11060293_title", "type": "title", "text": [ "The reactive oxygen species--and Michael acceptor-inducible human aldo-keto reductase AKR1C1 reduces the alpha,beta-unsaturated aldehyde 4-hydroxy-2-nonenal to 1,4-dihydroxy-2-nonene." ], "offsets": [ [ 0, 183 ] ] }, { "id": "11060293_abstract", "type": "abstract", "text": [ "The human aldo-keto reductase AKR1C1 (20alpha(3alpha)-hydroxysteroid dehydrogenase) is induced by electrophilic Michael acceptors and reactive oxygen species (ROS) via a presumptive antioxidant response element (Burczynski, M. E., Lin, H. K., and Penning, T. M. (1999) Cancer Res. 59, 607-614). Physiologically, AKR1C1 regulates progesterone action by converting the hormone into its inactive metabolite 20alpha-hydroxyprogesterone, and toxicologically this enzyme activates polycyclic aromatic hydrocarbon trans-dihydrodiols to redox-cycling o-quinones. However, the significance of its potent induction by Michael acceptors and oxidative stress is unknown. 4-Hydroxy-2-nonenal (HNE) and other alpha,beta-unsaturated aldehydes produced during lipid peroxidation were reduced by AKR1C1 with high catalytic efficiency. Kinetic studies revealed that AKR1C1 reduced HNE (K(m) = 34 microm, k(cat) = 8.8 min(-1)) with a k(cat)/K(m) similar to that for 20alpha-hydroxysteroids. Six other homogeneous recombinant AKRs were examined for their ability to reduce HNE. Of these, AKR1C1 possessed one of the highest specific activities and was the only isoform induced by oxidative stress and by agents that deplete glutathione (ethacrynic acid). Several hydroxysteroid dehydrogenases of the AKR1C subfamily catalyzed the reduction of HNE with higher activity than aldehyde reductase (AKR1A1). NMR spectroscopy identified the product of the NADPH-dependent reduction of HNE as 1,4-dihydroxy-2-nonene. The K(m) of recombinant AKR1C1 for nicotinamide cofactors (K(m) NADPH approximately 6 microm, K(m)(app) NADH >6 mm) suggested that it is primed for reductive metabolism of HNE. Isoform-specific reverse transcription-polymerase chain reaction showed that exposure of HepG2 cells to HNE resulted in elevated levels of AKR1C1 mRNA. Thus, HNE induces its own metabolism via AKR1C1, and this enzyme may play a hitherto unrecognized role in a response mounted to counter oxidative stress. AKRs represent alternative GSH-independent/NADPH-dependent routes for the reductive elimination of HNE. Of these, AKR1C1 provides an inducible cytosolic barrier to HNE following ROS exposure." ], "offsets": [ [ 184, 2347 ] ] } ]

[ { "id": "11060293_T1", "type": "CHEMICAL", "text": [ "aldo" ], "offsets": [ [ 194, 198 ] ], "normalized": [] }, { "id": "11060293_T2", "type": "CHEMICAL", "text": [ "HNE" ], "offsets": [ [ 1237, 1240 ] ], "normalized": [] }, { "id": "11060293_T3", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 1388, 1399 ] ], "normalized": [] }, { "id": "11060293_T4", "type": "CHEMICAL", "text": [ "ethacrynic acid" ], "offsets": [ [ 1401, 1416 ] ], "normalized": [] }, { "id": "11060293_T5", "type": "CHEMICAL", "text": [ "hydroxysteroid" ], "offsets": [ [ 1427, 1441 ] ], "normalized": [] }, { "id": "11060293_T6", "type": "CHEMICAL", "text": [ "HNE" ], "offsets": [ [ 1507, 1510 ] ], "normalized": [] }, { "id": "11060293_T7", "type": "CHEMICAL", "text": [ "aldehyde" ], "offsets": [ [ 1537, 1545 ] ], "normalized": [] }, { "id": "11060293_T8", "type": "CHEMICAL", "text": [ "oxygen" ], "offsets": [ [ 327, 333 ] ], "normalized": [] }, { "id": "11060293_T9", "type": "CHEMICAL", "text": [ "HNE" ], "offsets": [ [ 1642, 1645 ] ], "normalized": [] }, { "id": "11060293_T10", "type": "CHEMICAL", "text": [ "1,4-dihydroxy-2-nonene" ], "offsets": [ [ 1649, 1671 ] ], "normalized": [] }, { "id": "11060293_T11", "type": "CHEMICAL", "text": [ "keto" ], "offsets": [ [ 199, 203 ] ], "normalized": [] }, { "id": "11060293_T12", "type": "CHEMICAL", "text": [ "NADPH" ], "offsets": [ [ 1737, 1742 ] ], "normalized": [] }, { "id": "11060293_T13", "type": "CHEMICAL", "text": [ "NADH" ], "offsets": [ [ 1777, 1781 ] ], "normalized": [] }, { "id": "11060293_T14", "type": "CHEMICAL", "text": [ "HNE" ], "offsets": [ [ 1845, 1848 ] ], "normalized": [] }, { "id": "11060293_T15", "type": "CHEMICAL", "text": [ "HNE" ], "offsets": [ [ 1954, 1957 ] ], "normalized": [] }, { "id": "11060293_T16", "type": "CHEMICAL", "text": [ "HNE" ], "offsets": [ [ 2008, 2011 ] ], "normalized": [] }, { "id": "11060293_T17", "type": "CHEMICAL", "text": [ "GSH" ], "offsets": [ [ 2183, 2186 ] ], "normalized": [] }, { "id": "11060293_T18", "type": "CHEMICAL", "text": [ "NADPH" ], "offsets": [ [ 2199, 2204 ] ], "normalized": [] }, { "id": "11060293_T19", "type": "CHEMICAL", "text": [ "HNE" ], "offsets": [ [ 2255, 2258 ] ], "normalized": [] }, { "id": "11060293_T20", "type": "CHEMICAL", "text": [ "HNE" ], "offsets": [ [ 2320, 2323 ] ], "normalized": [] }, { "id": "11060293_T21", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 513, 525 ] ], "normalized": [] }, { "id": "11060293_T22", "type": "CHEMICAL", "text": [ "20alpha(3alpha)-hydroxysteroid" ], "offsets": [ [ 222, 252 ] ], "normalized": [] }, { "id": "11060293_T23", "type": "CHEMICAL", "text": [ "20alpha-hydroxyprogesterone" ], "offsets": [ [ 588, 615 ] ], "normalized": [] }, { "id": "11060293_T24", "type": "CHEMICAL", "text": [ "polycyclic aromatic hydrocarbon" ], "offsets": [ [ 659, 690 ] ], "normalized": [] }, { "id": "11060293_T25", "type": "CHEMICAL", "text": [ "trans-dihydrodiols" ], "offsets": [ [ 691, 709 ] ], "normalized": [] }, { "id": "11060293_T26", "type": "CHEMICAL", "text": [ "o-quinones" ], "offsets": [ [ 727, 737 ] ], "normalized": [] }, { "id": "11060293_T27", "type": "CHEMICAL", "text": [ "4-Hydroxy-2-nonenal" ], "offsets": [ [ 843, 862 ] ], "normalized": [] }, { "id": "11060293_T28", "type": "CHEMICAL", "text": [ "HNE" ], "offsets": [ [ 864, 867 ] ], "normalized": [] }, { "id": "11060293_T29", "type": "CHEMICAL", "text": [ "alpha,beta-unsaturated aldehydes" ], "offsets": [ [ 879, 911 ] ], "normalized": [] }, { "id": "11060293_T30", "type": "CHEMICAL", "text": [ "HNE" ], "offsets": [ [ 1047, 1050 ] ], "normalized": [] }, { "id": "11060293_T31", "type": "CHEMICAL", "text": [ "20alpha-hydroxysteroids" ], "offsets": [ [ 1131, 1154 ] ], "normalized": [] }, { "id": "11060293_T32", "type": "CHEMICAL", "text": [ "alpha,beta-unsaturated aldehyde" ], "offsets": [ [ 105, 136 ] ], "normalized": [] }, { "id": "11060293_T33", "type": "CHEMICAL", "text": [ "oxygen" ], "offsets": [ [ 13, 19 ] ], "normalized": [] }, { "id": "11060293_T34", "type": "CHEMICAL", "text": [ "4-hydroxy-2-nonenal" ], "offsets": [ [ 137, 156 ] ], "normalized": [] }, { "id": "11060293_T35", "type": "CHEMICAL", "text": [ "1,4-dihydroxy-2-nonene" ], "offsets": [ [ 160, 182 ] ], "normalized": [] }, { "id": "11060293_T36", "type": "CHEMICAL", "text": [ "aldo" ], "offsets": [ [ 66, 70 ] ], "normalized": [] }, { "id": "11060293_T37", "type": "CHEMICAL", "text": [ "keto" ], "offsets": [ [ 71, 75 ] ], "normalized": [] }, { "id": "11060293_T38", "type": "GENE-N", "text": [ "AKRs" ], "offsets": [ [ 1190, 1194 ] ], "normalized": [] }, { "id": "11060293_T39", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 1252, 1258 ] ], "normalized": [] }, { "id": "11060293_T40", "type": "GENE-N", "text": [ "hydroxysteroid dehydrogenases" ], "offsets": [ [ 1427, 1456 ] ], "normalized": [] }, { "id": "11060293_T41", "type": "GENE-Y", "text": [ "AKR1C" ], "offsets": [ [ 1464, 1469 ] ], "normalized": [] }, { "id": "11060293_T42", "type": "GENE-N", "text": [ "aldehyde reductase" ], "offsets": [ [ 1537, 1555 ] ], "normalized": [] }, { "id": "11060293_T43", "type": "GENE-Y", "text": [ "AKR1A1" ], "offsets": [ [ 1557, 1563 ] ], "normalized": [] }, { "id": "11060293_T44", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 1697, 1703 ] ], "normalized": [] }, { "id": "11060293_T45", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 1989, 1995 ] ], "normalized": [] }, { "id": "11060293_T46", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 2043, 2049 ] ], "normalized": [] }, { "id": "11060293_T47", "type": "GENE-N", "text": [ "AKRs" ], "offsets": [ [ 2156, 2160 ] ], "normalized": [] }, { "id": "11060293_T48", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 2270, 2276 ] ], "normalized": [] }, { "id": "11060293_T49", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 214, 220 ] ], "normalized": [] }, { "id": "11060293_T50", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 496, 502 ] ], "normalized": [] }, { "id": "11060293_T51", "type": "GENE-Y", "text": [ "20alpha(3alpha)-hydroxysteroid dehydrogenase" ], "offsets": [ [ 222, 266 ] ], "normalized": [] }, { "id": "11060293_T52", "type": "GENE-N", "text": [ "human aldo-keto reductase" ], "offsets": [ [ 188, 213 ] ], "normalized": [] }, { "id": "11060293_T53", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 963, 969 ] ], "normalized": [] }, { "id": "11060293_T54", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 1032, 1038 ] ], "normalized": [] }, { "id": "11060293_T55", "type": "GENE-N", "text": [ "human aldo-keto reductase" ], "offsets": [ [ 60, 85 ] ], "normalized": [] }, { "id": "11060293_T56", "type": "GENE-Y", "text": [ "AKR1C1" ], "offsets": [ [ 86, 92 ] ], "normalized": [] } ]

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[ { "id": "23503460_title", "type": "title", "text": [ "The regulatory roles of phosphatases in cancer." ], "offsets": [ [ 0, 47 ] ] }, { "id": "23503460_abstract", "type": "abstract", "text": [ "The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology. Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied. Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3--kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking. In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies.Oncogene advance online publication, 18 March 2013; doi:10.1038/onc.2013.80." ], "offsets": [ [ 48, 976 ] ] } ]

[ { "id": "23503460_T1", "type": "CHEMICAL", "text": [ "phosphatidylinositol" ], "offsets": [ [ 650, 670 ] ], "normalized": [] }, { "id": "23503460_T2", "type": "GENE-N", "text": [ "kinases" ], "offsets": [ [ 296, 303 ] ], "normalized": [] }, { "id": "23503460_T3", "type": "GENE-N", "text": [ "phosphatases" ], "offsets": [ [ 308, 320 ] ], "normalized": [] }, { "id": "23503460_T4", "type": "GENE-Y", "text": [ "PTEN" ], "offsets": [ [ 500, 504 ] ], "normalized": [] }, { "id": "23503460_T5", "type": "GENE-N", "text": [ "phosphatase" ], "offsets": [ [ 506, 517 ] ], "normalized": [] }, { "id": "23503460_T6", "type": "GENE-N", "text": [ "tensin" ], "offsets": [ [ 522, 528 ] ], "normalized": [] }, { "id": "23503460_T7", "type": "GENE-N", "text": [ "phosphatidylinositol 3--kinase" ], "offsets": [ [ 650, 680 ] ], "normalized": [] }, { "id": "23503460_T8", "type": "GENE-N", "text": [ "phosphatase" ], "offsets": [ [ 836, 847 ] ], "normalized": [] }, { "id": "23503460_T9", "type": "GENE-N", "text": [ "phosphatases" ], "offsets": [ [ 24, 36 ] ], "normalized": [] } ]

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[]

[ { "id": "23639248_title", "type": "title", "text": [ "Bone Morphogenetic Protein-7 inhibits silica-induced pulmonary fibrosis in rats." ], "offsets": [ [ 0, 80 ] ] }, { "id": "23639248_abstract", "type": "abstract", "text": [ "Bone morphogenetic protein-7 (BMP-7) has been shown to inhibit liver and renal fibrosis in in vivo and in vitro studies. There is no study to investigate BMP-7's role in the development of pulmonary fibrosis induced by silica. In the current study, we used the rat model to explore the potential antifibrotic role of BMP-7 and its underlying mechanism in silica-induced pulmonary fibrosis. Sixty Wistar rats were randomly assigned into three groups. Control group received saline, silica group received silica and BMP-7 treated group received silica and BMP-7. BMP-7 was administered to silica-treated rats intraperitoneally at a dose of 300μg/kg/injection from day 8 to day 30 every other day. After the animals were sacrificed on day 15 and 30, hydroxyproline levels, the protein expressions of BMP/Smad and TGF-β/Smad signaling, and histopathology in lung tissues were analyzed. The hydroxyproline contents in BMP-7 treated groups were significantly lower than the silica groups (P<0.05). Histopathological results showed BMP-7 could reduce the progression of silica induced fibrosis. Furthermore, the expression of p-Smad1/5/8, a marker of BMP/Smad signaling, was significantly up-regulated in BMP-7 treated groups (P<0.05) compared with the silica groups. On the contrary, the expression of p-Smad2/3, a marker for TGF-β/Smad signaling, reduced significantly in BMP-7-treated groups compared with silica groups (P<0.05). In conclusion, the pulmonary fibrosis induced by silica in rats was significantly reduced with the therapeutic treatment of BMP-7. The antifibrotic effect of BMP-7 could be related to the activation of BMP/Smad signaling and inhibition of TGF-β/Smad pathways." ], "offsets": [ [ 81, 1766 ] ] } ]

[ { "id": "23639248_T1", "type": "CHEMICAL", "text": [ "silica" ], "offsets": [ [ 1144, 1150 ] ], "normalized": [] }, { "id": "23639248_T2", "type": "CHEMICAL", "text": [ "silica" ], "offsets": [ [ 1327, 1333 ] ], "normalized": [] }, { "id": "23639248_T3", "type": "CHEMICAL", "text": [ "silica" ], "offsets": [ [ 1483, 1489 ] ], "normalized": [] }, { "id": "23639248_T4", "type": "CHEMICAL", "text": [ "silica" ], "offsets": [ [ 1556, 1562 ] ], "normalized": [] }, { "id": "23639248_T5", "type": "CHEMICAL", "text": [ "silica" ], "offsets": [ [ 300, 306 ] ], "normalized": [] }, { "id": "23639248_T6", "type": "CHEMICAL", "text": [ "silica" ], "offsets": [ [ 436, 442 ] ], "normalized": [] }, { "id": "23639248_T7", "type": "CHEMICAL", "text": [ "silica" ], "offsets": [ [ 562, 568 ] ], "normalized": [] }, { "id": "23639248_T8", "type": "CHEMICAL", "text": [ "silica" ], "offsets": [ [ 584, 590 ] ], "normalized": [] }, { "id": "23639248_T9", "type": "CHEMICAL", "text": [ "silica" ], "offsets": [ [ 624, 630 ] ], "normalized": [] }, { "id": "23639248_T10", "type": "CHEMICAL", "text": [ "silica" ], "offsets": [ [ 668, 674 ] ], "normalized": [] }, { "id": "23639248_T11", "type": "CHEMICAL", "text": [ "hydroxyproline" ], "offsets": [ [ 828, 842 ] ], "normalized": [] }, { "id": "23639248_T12", "type": "CHEMICAL", "text": [ "hydroxyproline" ], "offsets": [ [ 967, 981 ] ], "normalized": [] }, { "id": "23639248_T13", "type": "CHEMICAL", "text": [ "silica" ], "offsets": [ [ 1049, 1055 ] ], "normalized": [] }, { "id": "23639248_T14", "type": "CHEMICAL", "text": [ "silica" ], "offsets": [ [ 38, 44 ] ], "normalized": [] }, { "id": "23639248_T15", "type": "GENE-Y", "text": [ "Bone morphogenetic protein-7" ], "offsets": [ [ 81, 109 ] ], "normalized": [] }, { "id": "23639248_T16", "type": "GENE-Y", "text": [ "BMP-7" ], "offsets": [ [ 1106, 1111 ] ], "normalized": [] }, { "id": "23639248_T17", "type": "GENE-N", "text": [ "p-Smad1/5/8" ], "offsets": [ [ 1200, 1211 ] ], "normalized": [] }, { "id": "23639248_T18", "type": "GENE-N", "text": [ "BMP" ], "offsets": [ [ 1225, 1228 ] ], "normalized": [] }, { "id": "23639248_T19", "type": "GENE-N", "text": [ "Smad" ], "offsets": [ [ 1229, 1233 ] ], "normalized": [] }, { "id": "23639248_T20", "type": "GENE-Y", "text": [ "BMP-7" ], "offsets": [ [ 1279, 1284 ] ], "normalized": [] }, { "id": "23639248_T21", "type": "GENE-N", "text": [ "p-Smad2/3" ], "offsets": [ [ 1377, 1386 ] ], "normalized": [] }, { "id": "23639248_T22", "type": "GENE-Y", "text": [ "TGF-β" ], "offsets": [ [ 1401, 1406 ] ], "normalized": [] }, { "id": "23639248_T23", "type": "GENE-N", "text": [ "Smad" ], "offsets": [ [ 1407, 1411 ] ], "normalized": [] }, { "id": "23639248_T24", "type": "GENE-Y", "text": [ "BMP-7" ], "offsets": [ [ 1448, 1453 ] ], "normalized": [] }, { "id": "23639248_T25", "type": "GENE-Y", "text": [ "BMP-7" ], "offsets": [ [ 235, 240 ] ], "normalized": [] }, { "id": "23639248_T26", "type": "GENE-Y", "text": [ "BMP-7" ], "offsets": [ [ 1631, 1636 ] ], "normalized": [] }, { "id": "23639248_T27", "type": "GENE-Y", "text": [ "BMP-7" ], "offsets": [ [ 1665, 1670 ] ], "normalized": [] }, { "id": "23639248_T28", "type": "GENE-N", "text": [ "BMP" ], "offsets": [ [ 1709, 1712 ] ], "normalized": [] }, { "id": "23639248_T29", "type": "GENE-N", "text": [ "Smad" ], "offsets": [ [ 1713, 1717 ] ], "normalized": [] }, { "id": "23639248_T30", "type": "GENE-Y", "text": [ "TGF-β" ], "offsets": [ [ 1746, 1751 ] ], "normalized": [] }, { "id": "23639248_T31", "type": "GENE-N", "text": [ "Smad" ], "offsets": [ [ 1752, 1756 ] ], "normalized": [] }, { "id": "23639248_T32", "type": "GENE-Y", "text": [ "BMP-7" ], "offsets": [ [ 111, 116 ] ], "normalized": [] }, { "id": "23639248_T33", "type": "GENE-Y", "text": [ "BMP-7" ], "offsets": [ [ 398, 403 ] ], "normalized": [] }, { "id": "23639248_T34", "type": "GENE-Y", "text": [ "BMP-7" ], "offsets": [ [ 595, 600 ] ], "normalized": [] }, { "id": "23639248_T35", "type": "GENE-Y", "text": [ "BMP-7" ], "offsets": [ [ 635, 640 ] ], "normalized": [] }, { "id": "23639248_T36", "type": "GENE-Y", "text": [ "BMP-7" ], "offsets": [ [ 642, 647 ] ], "normalized": [] }, { "id": "23639248_T37", "type": "GENE-N", "text": [ "BMP" ], "offsets": [ [ 878, 881 ] ], "normalized": [] }, { "id": "23639248_T38", "type": "GENE-N", "text": [ "Smad" ], "offsets": [ [ 882, 886 ] ], "normalized": [] }, { "id": "23639248_T39", "type": "GENE-Y", "text": [ "TGF-β" ], "offsets": [ [ 891, 896 ] ], "normalized": [] }, { "id": "23639248_T40", "type": "GENE-N", "text": [ "Smad" ], "offsets": [ [ 897, 901 ] ], "normalized": [] }, { "id": "23639248_T41", "type": "GENE-Y", "text": [ "BMP-7" ], "offsets": [ [ 994, 999 ] ], "normalized": [] }, { "id": "23639248_T42", "type": "GENE-Y", "text": [ "Bone Morphogenetic Protein-7" ], "offsets": [ [ 0, 28 ] ], "normalized": [] } ]

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[ { "id": "23614367_title", "type": "title", "text": [ "Grb10-mediated Negative Regulation of IGF1R-Activated Signalling Pathway Results in Cognitive Disorder in Diabetic Rats." ], "offsets": [ [ 0, 120 ] ] }, { "id": "23614367_abstract", "type": "abstract", "text": [ "Growth factor receptor-bound protein 10(Grb10)is a Src homology 2 (SH2) domain-containing protein and one of the binding partners for several trans-membrane tyrosine-kinase receptors, including insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1-R). The hippocampus, which is critical for cognitive functions, is one of the main distribution areas of Grb10 in the central nervous system. In recent years, diabetic encephalopathy has been defined as a third type of diabetes and the IGF1-IR pathway has been shown to be critical for the neuropathogenic process of cognitive disorder in diabetes. However, the role of endogenous Grb10 in regulating the IGF1-IR pathway and neurobehavioral changes is not explicit. The objective of this study was to determine the in vivo function of endogenous Grb10 in diabetic encephalopathy and the underlying mechanisms. Using stereotaxic surgical techniques and lentiviral vectors expressing specific short hairpin RNA (shRNA), we could steadily knock down Grb10 expression in the hippocampus. More importantly, we demonstrated that hippocampus-specific modulation of Grb10 protein levels led to a prominent remission of cognitive disorder, including improvements in both ultrastructural pathology and abnormal neurobehavioural changes. Our findings indicate that endogenous overexpression of Grb10 functions as a suppressor of the IGF1-IR pathway, which may represent an important mechanism that regulates cognitive disorder in diabetes. This article is protected by copyright. All rights reserved." ], "offsets": [ [ 121, 1674 ] ] } ]

[ { "id": "23614367_T1", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 278, 286 ] ], "normalized": [] }, { "id": "23614367_T2", "type": "GENE-Y", "text": [ "Growth factor receptor-bound protein 10" ], "offsets": [ [ 121, 160 ] ], "normalized": [] }, { "id": "23614367_T3", "type": "GENE-Y", "text": [ "Grb10" ], "offsets": [ [ 1132, 1137 ] ], "normalized": [] }, { "id": "23614367_T4", "type": "GENE-Y", "text": [ "Grb10" ], "offsets": [ [ 1243, 1248 ] ], "normalized": [] }, { "id": "23614367_T5", "type": "GENE-Y", "text": [ "Grb10" ], "offsets": [ [ 1468, 1473 ] ], "normalized": [] }, { "id": "23614367_T6", "type": "GENE-Y", "text": [ "IGF1-IR" ], "offsets": [ [ 1507, 1514 ] ], "normalized": [] }, { "id": "23614367_T7", "type": "GENE-N", "text": [ "tyrosine-kinase receptors" ], "offsets": [ [ 278, 303 ] ], "normalized": [] }, { "id": "23614367_T8", "type": "GENE-Y", "text": [ "insulin receptor" ], "offsets": [ [ 315, 331 ] ], "normalized": [] }, { "id": "23614367_T9", "type": "GENE-Y", "text": [ "IR" ], "offsets": [ [ 333, 335 ] ], "normalized": [] }, { "id": "23614367_T10", "type": "GENE-Y", "text": [ "insulin-like growth factor-1 receptor" ], "offsets": [ [ 341, 378 ] ], "normalized": [] }, { "id": "23614367_T11", "type": "GENE-Y", "text": [ "IGF1-R" ], "offsets": [ [ 380, 386 ] ], "normalized": [] }, { "id": "23614367_T12", "type": "GENE-Y", "text": [ "Grb10" ], "offsets": [ [ 490, 495 ] ], "normalized": [] }, { "id": "23614367_T13", "type": "GENE-Y", "text": [ "Grb10" ], "offsets": [ [ 161, 166 ] ], "normalized": [] }, { "id": "23614367_T14", "type": "GENE-Y", "text": [ "IGF1-IR" ], "offsets": [ [ 621, 628 ] ], "normalized": [] }, { "id": "23614367_T15", "type": "GENE-N", "text": [ "Src homology 2 (SH2) domain" ], "offsets": [ [ 172, 199 ] ], "normalized": [] }, { "id": "23614367_T16", "type": "GENE-Y", "text": [ "Grb10" ], "offsets": [ [ 766, 771 ] ], "normalized": [] }, { "id": "23614367_T17", "type": "GENE-Y", "text": [ "IGF1-IR" ], "offsets": [ [ 790, 797 ] ], "normalized": [] }, { "id": "23614367_T18", "type": "GENE-Y", "text": [ "Grb10" ], "offsets": [ [ 931, 936 ] ], "normalized": [] }, { "id": "23614367_T19", "type": "GENE-Y", "text": [ "Grb10" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "23614367_T20", "type": "GENE-Y", "text": [ "IGF1R" ], "offsets": [ [ 38, 43 ] ], "normalized": [] } ]

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[ { "id": "23586436_title", "type": "title", "text": [ "Using in Situ X-ray Reflectivity to Study Protein Adsorption on Hydrophilic and Hydrophobic Surfaces: Benefits and Limitations." ], "offsets": [ [ 0, 127 ] ] }, { "id": "23586436_abstract", "type": "abstract", "text": [ "We have employed in situ X-ray reflectivity (IXRR) to study the adsorption of a variety of proteins (lysozyme, cytochrome c, myoglobin, hemoglobin, serum albumin, and immunoglobulin G) on model hydrophilic (silicon oxide) and hydrophobic surfaces (octadecyltrichlorosilane self-assembled monolayers), evaluating this recently developed technique for its applicability in the area of biomolecular studies. We report herein the highest resolution depiction of adsorbed protein films, greatly improving on the precision of previous neutron reflectivity (NR) results and previous IXRR studies. We were able to perform complete scans in 5 min or less with the maximum momentum transfer of at least 0.52 Å(-1), allowing for some time-resolved information about the evolution of the protein film structure. The three smallest proteins (lysozyme, cytochrome c, and myoglobin) were seen to deposit as fully hydrated, nondenatured molecules onto hydrophilic surfaces, with indications of particular preferential orientations. Time evolution was observed for both lysozyme and myoglobin films. The larger proteins were not observed to deposit on the hydrophilic substrates, perhaps because of contrast limitations. On hydrophobic surfaces, all proteins were seen to denature extensively in a qualitatively similar way but with a rough trend that the larger proteins resulted in lower coverage. We have generated high-resolution electron density profiles of these denatured films, including capturing the growth of a lysozyme film. Because the solution interface of these denatured films is diffuse, IXRR cannot unambiguously determine the film extent and coverage, a drawback compared to NR. X-ray radiation damage was systematically evaluated, including the controlled exposure of protein films to high-intensity X-rays and exposure of the hydrophobic surface to X-rays before adsorption. Our analysis showed that standard measuring procedures used for XRR studies may lead to altered protein films; therefore, we used modified procedures to limit the influence of X-ray damage." ], "offsets": [ [ 128, 2196 ] ] } ]

[ { "id": "23586436_T1", "type": "CHEMICAL", "text": [ "silicon oxide" ], "offsets": [ [ 335, 348 ] ], "normalized": [] }, { "id": "23586436_T2", "type": "CHEMICAL", "text": [ "octadecyltrichlorosilane" ], "offsets": [ [ 376, 400 ] ], "normalized": [] }, { "id": "23586436_T3", "type": "GENE-Y", "text": [ "lysozyme" ], "offsets": [ [ 229, 237 ] ], "normalized": [] }, { "id": "23586436_T4", "type": "GENE-Y", "text": [ "lysozyme" ], "offsets": [ [ 1181, 1189 ] ], "normalized": [] }, { "id": "23586436_T5", "type": "GENE-Y", "text": [ "myoglobin" ], "offsets": [ [ 1194, 1203 ] ], "normalized": [] }, { "id": "23586436_T6", "type": "GENE-Y", "text": [ "cytochrome c" ], "offsets": [ [ 239, 251 ] ], "normalized": [] }, { "id": "23586436_T7", "type": "GENE-Y", "text": [ "myoglobin" ], "offsets": [ [ 253, 262 ] ], "normalized": [] }, { "id": "23586436_T8", "type": "GENE-N", "text": [ "hemoglobin" ], "offsets": [ [ 264, 274 ] ], "normalized": [] }, { "id": "23586436_T9", "type": "GENE-Y", "text": [ "serum albumin" ], "offsets": [ [ 276, 289 ] ], "normalized": [] }, { "id": "23586436_T10", "type": "GENE-Y", "text": [ "lysozyme" ], "offsets": [ [ 1633, 1641 ] ], "normalized": [] }, { "id": "23586436_T11", "type": "GENE-N", "text": [ "immunoglobulin G" ], "offsets": [ [ 295, 311 ] ], "normalized": [] }, { "id": "23586436_T12", "type": "GENE-Y", "text": [ "lysozyme" ], "offsets": [ [ 957, 965 ] ], "normalized": [] }, { "id": "23586436_T13", "type": "GENE-Y", "text": [ "cytochrome c" ], "offsets": [ [ 967, 979 ] ], "normalized": [] }, { "id": "23586436_T14", "type": "GENE-Y", "text": [ "myoglobin" ], "offsets": [ [ 985, 994 ] ], "normalized": [] } ]

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[ { "id": "12654248_title", "type": "title", "text": [ "ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures." ], "offsets": [ [ 0, 95 ] ] }, { "id": "12654248_abstract", "type": "abstract", "text": [ "Mammals detect temperature with specialized neurons in the peripheral nervous system. Four TRPV-class channels have been implicated in sensing heat, and one TRPM-class channel in sensing cold. The combined range of temperatures that activate these channels covers a majority of the relevant physiological spectrum sensed by most mammals, with a significant gap in the noxious cold range. Here, we describe the characterization of ANKTM1, a cold-activated channel with a lower activation temperature compared to the cold and menthol receptor, TRPM8. ANKTM1 is a distant family member of TRP channels with very little amino acid similarity to TRPM8. It is found in a subset of nociceptive sensory neurons where it is coexpressed with TRPV1/VR1 (the capsaicin/heat receptor) but not TRPM8. Consistent with the expression of ANKTM1, we identify noxious cold-sensitive sensory neurons that also respond to capsaicin but not to menthol." ], "offsets": [ [ 96, 1026 ] ] } ]

[ { "id": "12654248_T1", "type": "CHEMICAL", "text": [ "menthol" ], "offsets": [ [ 620, 627 ] ], "normalized": [] }, { "id": "12654248_T2", "type": "CHEMICAL", "text": [ "capsaicin" ], "offsets": [ [ 843, 852 ] ], "normalized": [] }, { "id": "12654248_T3", "type": "CHEMICAL", "text": [ "capsaicin" ], "offsets": [ [ 997, 1006 ] ], "normalized": [] }, { "id": "12654248_T4", "type": "CHEMICAL", "text": [ "menthol" ], "offsets": [ [ 1018, 1025 ] ], "normalized": [] }, { "id": "12654248_T5", "type": "GENE-N", "text": [ "TRPM-class channel" ], "offsets": [ [ 253, 271 ] ], "normalized": [] }, { "id": "12654248_T6", "type": "GENE-Y", "text": [ "ANKTM1" ], "offsets": [ [ 526, 532 ] ], "normalized": [] }, { "id": "12654248_T7", "type": "GENE-N", "text": [ "cold-activated channel" ], "offsets": [ [ 536, 558 ] ], "normalized": [] }, { "id": "12654248_T8", "type": "GENE-N", "text": [ "cold and menthol receptor" ], "offsets": [ [ 611, 636 ] ], "normalized": [] }, { "id": "12654248_T9", "type": "GENE-Y", "text": [ "TRPM8" ], "offsets": [ [ 638, 643 ] ], "normalized": [] }, { "id": "12654248_T10", "type": "GENE-Y", "text": [ "ANKTM1" ], "offsets": [ [ 645, 651 ] ], "normalized": [] }, { "id": "12654248_T11", "type": "GENE-N", "text": [ "TRP channels" ], "offsets": [ [ 682, 694 ] ], "normalized": [] }, { "id": "12654248_T12", "type": "GENE-Y", "text": [ "TRPM8" ], "offsets": [ [ 737, 742 ] ], "normalized": [] }, { "id": "12654248_T13", "type": "GENE-Y", "text": [ "TRPV1" ], "offsets": [ [ 828, 833 ] ], "normalized": [] }, { "id": "12654248_T14", "type": "GENE-Y", "text": [ "VR1" ], "offsets": [ [ 834, 837 ] ], "normalized": [] }, { "id": "12654248_T15", "type": "GENE-Y", "text": [ "capsaicin/heat receptor" ], "offsets": [ [ 843, 866 ] ], "normalized": [] }, { "id": "12654248_T16", "type": "GENE-Y", "text": [ "TRPM8" ], "offsets": [ [ 876, 881 ] ], "normalized": [] }, { "id": "12654248_T17", "type": "GENE-Y", "text": [ "ANKTM1" ], "offsets": [ [ 917, 923 ] ], "normalized": [] }, { "id": "12654248_T18", "type": "GENE-N", "text": [ "TRPV-class channels" ], "offsets": [ [ 187, 206 ] ], "normalized": [] }, { "id": "12654248_T19", "type": "GENE-Y", "text": [ "ANKTM1" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "12654248_T20", "type": "GENE-N", "text": [ "TRP-like channel" ], "offsets": [ [ 10, 26 ] ], "normalized": [] } ]

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[ { "id": "9537821_title", "type": "title", "text": [ "Pharmacological profile of antidepressants and related compounds at human monoamine transporters." ], "offsets": [ [ 0, 97 ] ] }, { "id": "9537821_abstract", "type": "abstract", "text": [ "Using radioligand binding assays, we determined the equilibrium dissociation constants (KD's) for 37 antidepressants, three of their metabolites (desmethylcitalopram, desmethylsertraline, and norfluoxetine), some mood stabilizers, and assorted other compounds (some antiepileptics, Ca2+ channel antagonists, benzodiazepines, psychostimulants, antihistamines, and monoamines) for the human serotonin, norepinephrine, and dopamine transporters. Among the compounds that we tested, mazindol was the most potent at the human norepinephrine and dopamine transporters with KD's of 0.45 +/- 0.03 nM and 8.1 +/- 0.4 nM, respectively. Sertraline (KD = 25 +/- 2 nM) and nomifensine (56 +/- 3 nM) were the two most potent antidepressants at the human dopamine transporter. We showed significant correlations for antidepressant affinities at binding to serotonin (R = 0.93), norepinephrine (R = 0.97), and dopamine (R = 0.87) transporters in comparison to their respective values for inhibiting uptake of monoamines into rat brain synaptosomes. These data are useful in predicting some possible adverse effects and drug-drug interactions of antidepressants and related compounds." ], "offsets": [ [ 98, 1265 ] ] } ]

[ { "id": "9537821_T1", "type": "CHEMICAL", "text": [ "desmethylcitalopram" ], "offsets": [ [ 244, 263 ] ], "normalized": [] }, { "id": "9537821_T2", "type": "CHEMICAL", "text": [ "desmethylsertraline" ], "offsets": [ [ 265, 284 ] ], "normalized": [] }, { "id": "9537821_T3", "type": "CHEMICAL", "text": [ "norfluoxetine" ], "offsets": [ [ 290, 303 ] ], "normalized": [] }, { "id": "9537821_T4", "type": "CHEMICAL", "text": [ "Ca2+" ], "offsets": [ [ 380, 384 ] ], "normalized": [] }, { "id": "9537821_T5", "type": "CHEMICAL", "text": [ "benzodiazepines" ], "offsets": [ [ 406, 421 ] ], "normalized": [] }, { "id": "9537821_T6", "type": "CHEMICAL", "text": [ "antihistamines" ], "offsets": [ [ 441, 455 ] ], "normalized": [] }, { "id": "9537821_T7", "type": "CHEMICAL", "text": [ "monoamines" ], "offsets": [ [ 461, 471 ] ], "normalized": [] }, { "id": "9537821_T8", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 487, 496 ] ], "normalized": [] }, { "id": "9537821_T9", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 498, 512 ] ], "normalized": [] }, { "id": "9537821_T10", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 518, 526 ] ], "normalized": [] }, { "id": "9537821_T11", "type": "CHEMICAL", "text": [ "mazindol" ], "offsets": [ [ 577, 585 ] ], "normalized": [] }, { "id": "9537821_T12", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 619, 633 ] ], "normalized": [] }, { "id": "9537821_T13", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 638, 646 ] ], "normalized": [] }, { "id": "9537821_T14", "type": "CHEMICAL", "text": [ "Sertraline" ], "offsets": [ [ 724, 734 ] ], "normalized": [] }, { "id": "9537821_T15", "type": "CHEMICAL", "text": [ "nomifensine" ], "offsets": [ [ 758, 769 ] ], "normalized": [] }, { "id": "9537821_T16", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 838, 846 ] ], "normalized": [] }, { "id": "9537821_T17", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 939, 948 ] ], "normalized": [] }, { "id": "9537821_T18", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 961, 975 ] ], "normalized": [] }, { "id": "9537821_T19", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 992, 1000 ] ], "normalized": [] }, { "id": "9537821_T20", "type": "CHEMICAL", "text": [ "monoamines" ], "offsets": [ [ 1091, 1101 ] ], "normalized": [] }, { "id": "9537821_T21", "type": "CHEMICAL", "text": [ "monoamine" ], "offsets": [ [ 74, 83 ] ], "normalized": [] }, { "id": "9537821_T22", "type": "GENE-N", "text": [ "human serotonin, norepinephrine, and dopamine transporters" ], "offsets": [ [ 481, 539 ] ], "normalized": [] }, { "id": "9537821_T23", "type": "GENE-N", "text": [ "human norepinephrine and dopamine transporters" ], "offsets": [ [ 613, 659 ] ], "normalized": [] }, { "id": "9537821_T24", "type": "GENE-Y", "text": [ "human dopamine transporter" ], "offsets": [ [ 832, 858 ] ], "normalized": [] }, { "id": "9537821_T25", "type": "GENE-N", "text": [ "human monoamine transporters" ], "offsets": [ [ 68, 96 ] ], "normalized": [] } ]

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[ { "id": "16010412_title", "type": "title", "text": [ "Potential of endogenous estrogen receptor beta to influence the selective ER modulator ERbeta complex." ], "offsets": [ [ 0, 102 ] ] }, { "id": "16010412_abstract", "type": "abstract", "text": [ "The ratio of estrogen receptor beta (ERbeta) to ERalpha can alter the estrogen-like properties of tamoxifen. Transient transfection of ERbeta cDNA into cells can decrease the estrogen-like properties of the ERalpha:tamoxifen complex, whereas an increase in the amount of ERbeta is associated with tamoxifen-resistant breast cancer. We have addressed each of these hypotheses by examining well characterized laboratory models. We determined whether changes in endogenous ERbeta are responsible for the estrogen-like or antiestrogenic properties of tamoxifen or raloxifene in MDA-MB-231 cells transfected with cDNAs for ERalpha or mutants D351G, D351Y. We found that the amount of ERbeta mRNA in separate, stable transfectants of mutant ERalpha cDNA was always < 2% of ERalpha. Since at least a 50:50 mixture of ERalpha:ERbeta is needed to silence the tamoxifen:ERalpha complex, we conclude that insufficient ERbeta mRNA is available for selective ER modulation in stable transfectants of D351G and D351Y ERalpha. Similarly, to test the hypothesis that ERbeta is up-regulated and plays an important role during the development of tamoxifen-stimulated tumor growth, we quantitatively analyzed ERbeta and ERalpha mRNA in tamoxifen-naive (MCF-7:E2, ECC1:E2) and tamoxifen-stimulated tumors (MCF-7:TAM, EnCa 101:TAM). We found that ERbeta mRNA levels were not significantly elevated in tamoxifen-stimulated tumors and the ERalpha mRNA remained over 99% out of all ER species for all the tumors tested. The same results were also obtained when mRNA levels of ERbeta and ERalpha in a series of tamoxifen-naive and tamoxifen-resistant breast cancer was analyzed. We conclude that endogenous ERbeta may not play a dominant role in the modulation of the tamoxifen ERalpha complex, or in the development of tamoxifen-stimulated resistant tumor growth." ], "offsets": [ [ 103, 1942 ] ] } ]

[ { "id": "16010412_T1", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1231, 1240 ] ], "normalized": [] }, { "id": "16010412_T2", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1320, 1329 ] ], "normalized": [] }, { "id": "16010412_T3", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1360, 1369 ] ], "normalized": [] }, { "id": "16010412_T4", "type": "CHEMICAL", "text": [ "TAM" ], "offsets": [ [ 1395, 1398 ] ], "normalized": [] }, { "id": "16010412_T5", "type": "CHEMICAL", "text": [ "TAM" ], "offsets": [ [ 1409, 1412 ] ], "normalized": [] }, { "id": "16010412_T6", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 116, 124 ] ], "normalized": [] }, { "id": "16010412_T7", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1483, 1492 ] ], "normalized": [] }, { "id": "16010412_T8", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1689, 1698 ] ], "normalized": [] }, { "id": "16010412_T9", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1709, 1718 ] ], "normalized": [] }, { "id": "16010412_T10", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1846, 1855 ] ], "normalized": [] }, { "id": "16010412_T11", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 278, 286 ] ], "normalized": [] }, { "id": "16010412_T12", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1898, 1907 ] ], "normalized": [] }, { "id": "16010412_T13", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 318, 327 ] ], "normalized": [] }, { "id": "16010412_T14", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 400, 409 ] ], "normalized": [] }, { "id": "16010412_T15", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 604, 612 ] ], "normalized": [] }, { "id": "16010412_T16", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 650, 659 ] ], "normalized": [] }, { "id": "16010412_T17", "type": "CHEMICAL", "text": [ "raloxifene" ], "offsets": [ [ 663, 673 ] ], "normalized": [] }, { "id": "16010412_T18", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 173, 181 ] ], "normalized": [] }, { "id": "16010412_T19", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 953, 962 ] ], "normalized": [] }, { "id": "16010412_T20", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 201, 210 ] ], "normalized": [] }, { "id": "16010412_T21", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 24, 32 ] ], "normalized": [] }, { "id": "16010412_T22", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 1106, 1113 ] ], "normalized": [] }, { "id": "16010412_T23", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 1154, 1160 ] ], "normalized": [] }, { "id": "16010412_T24", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 1293, 1299 ] ], "normalized": [] }, { "id": "16010412_T25", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 1304, 1311 ] ], "normalized": [] }, { "id": "16010412_T26", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 1429, 1435 ] ], "normalized": [] }, { "id": "16010412_T27", "type": "GENE-Y", "text": [ "estrogen receptor beta" ], "offsets": [ [ 116, 138 ] ], "normalized": [] }, { "id": "16010412_T28", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 238, 244 ] ], "normalized": [] }, { "id": "16010412_T29", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 1519, 1526 ] ], "normalized": [] }, { "id": "16010412_T30", "type": "GENE-Y", "text": [ "ER" ], "offsets": [ [ 1561, 1563 ] ], "normalized": [] }, { "id": "16010412_T31", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 1655, 1661 ] ], "normalized": [] }, { "id": "16010412_T32", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 1666, 1673 ] ], "normalized": [] }, { "id": "16010412_T33", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 1785, 1791 ] ], "normalized": [] }, { "id": "16010412_T34", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 1856, 1863 ] ], "normalized": [] }, { "id": "16010412_T35", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 310, 317 ] ], "normalized": [] }, { "id": "16010412_T36", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 374, 380 ] ], "normalized": [] }, { "id": "16010412_T37", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 140, 146 ] ], "normalized": [] }, { "id": "16010412_T38", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 573, 579 ] ], "normalized": [] }, { "id": "16010412_T39", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 151, 158 ] ], "normalized": [] }, { "id": "16010412_T40", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 721, 728 ] ], "normalized": [] }, { "id": "16010412_T41", "type": "GENE-N", "text": [ "D351G" ], "offsets": [ [ 740, 745 ] ], "normalized": [] }, { "id": "16010412_T42", "type": "GENE-N", "text": [ "D351Y" ], "offsets": [ [ 747, 752 ] ], "normalized": [] }, { "id": "16010412_T43", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 782, 788 ] ], "normalized": [] }, { "id": "16010412_T44", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 838, 845 ] ], "normalized": [] }, { "id": "16010412_T45", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 870, 877 ] ], "normalized": [] }, { "id": "16010412_T46", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 913, 920 ] ], "normalized": [] }, { "id": "16010412_T47", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 921, 927 ] ], "normalized": [] }, { "id": "16010412_T48", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 963, 970 ] ], "normalized": [] }, { "id": "16010412_T49", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 1010, 1016 ] ], "normalized": [] }, { "id": "16010412_T50", "type": "GENE-Y", "text": [ "ER" ], "offsets": [ [ 1049, 1051 ] ], "normalized": [] }, { "id": "16010412_T51", "type": "GENE-N", "text": [ "D351G" ], "offsets": [ [ 1090, 1095 ] ], "normalized": [] }, { "id": "16010412_T52", "type": "GENE-N", "text": [ "D351Y" ], "offsets": [ [ 1100, 1105 ] ], "normalized": [] }, { "id": "16010412_T53", "type": "GENE-Y", "text": [ "estrogen receptor beta" ], "offsets": [ [ 24, 46 ] ], "normalized": [] }, { "id": "16010412_T54", "type": "GENE-Y", "text": [ "ER" ], "offsets": [ [ 74, 76 ] ], "normalized": [] }, { "id": "16010412_T55", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 87, 93 ] ], "normalized": [] } ]

[]

[]

[ { "id": "16010412_0", "type": "DIRECT-REGULATOR", "arg1_id": "16010412_T10", "arg2_id": "16010412_T34", "normalized": [] } ]

[ { "id": "23440956_title", "type": "title", "text": [ "Graphene-Bonded and -Encapsulated Si Nanoparticles for Lithium Ion Battery Anodes." ], "offsets": [ [ 0, 82 ] ] }, { "id": "23440956_abstract", "type": "abstract", "text": [ "Silicon (Si) has been considered a very promising anode material for lithium ion batteries due to its high theoretical capacity. However, high-capacity Si nanoparticles usually suffer from low electronic conductivity, large volume change, and severe aggregation problems during lithiation and delithiation. In this paper, a unique nanostructured anode with Si nanoparticles bonded and wrapped by graphene is synthesized by a one-step aerosol spraying of surface-modified Si nanoparticles and graphene oxide suspension. The functional groups on the surface of Si nanoparticles (50-100 nm) not only react with graphene oxide and bind Si nanoparticles to the graphene oxide shell, but also prevent Si nanoparticles from aggregation, thus contributing to a uniform Si suspension. A homogeneous graphene-encapsulated Si nanoparticle morphology forms during the aerosol spraying process. The open-ended graphene shell with defects allows fast electrochemical lithiation/delithiation, and the void space inside the graphene shell accompanied by its strong mechanical strength can effectively accommodate the volume expansion of Si upon lithiation. The graphene shell provides good electronic conductivity for Si nanoparticles and prevents them from aggregating during charge/discharge cycles. The functionalized Si encapsulated by graphene sample exhibits a capacity of 2250 mAh g(-1) (based on the total mass of graphene and Si) at 0.1C and 1000 mAh g(-1) at 10C, and retains 85% of its initial capacity even after 120 charge/discharge cycles. The exceptional performance of graphene-encapsulated Si anodes combined with the scalable and one-step aerosol synthesis technique makes this material very promising for lithium ion batteries." ], "offsets": [ [ 83, 1813 ] ] } ]

[ { "id": "23440956_T1", "type": "CHEMICAL", "text": [ "Silicon" ], "offsets": [ [ 83, 90 ] ], "normalized": [] }, { "id": "23440956_T2", "type": "CHEMICAL", "text": [ "graphene" ], "offsets": [ [ 1091, 1099 ] ], "normalized": [] }, { "id": "23440956_T3", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 1204, 1206 ] ], "normalized": [] }, { "id": "23440956_T4", "type": "CHEMICAL", "text": [ "graphene" ], "offsets": [ [ 1228, 1236 ] ], "normalized": [] }, { "id": "23440956_T5", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 1285, 1287 ] ], "normalized": [] }, { "id": "23440956_T6", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 1388, 1390 ] ], "normalized": [] }, { "id": "23440956_T7", "type": "CHEMICAL", "text": [ "graphene" ], "offsets": [ [ 1407, 1415 ] ], "normalized": [] }, { "id": "23440956_T8", "type": "CHEMICAL", "text": [ "graphene" ], "offsets": [ [ 1489, 1497 ] ], "normalized": [] }, { "id": "23440956_T9", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 1502, 1504 ] ], "normalized": [] }, { "id": "23440956_T10", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 235, 237 ] ], "normalized": [] }, { "id": "23440956_T11", "type": "CHEMICAL", "text": [ "graphene" ], "offsets": [ [ 1652, 1660 ] ], "normalized": [] }, { "id": "23440956_T12", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 1674, 1676 ] ], "normalized": [] }, { "id": "23440956_T13", "type": "CHEMICAL", "text": [ "lithium" ], "offsets": [ [ 1791, 1798 ] ], "normalized": [] }, { "id": "23440956_T14", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 440, 442 ] ], "normalized": [] }, { "id": "23440956_T15", "type": "CHEMICAL", "text": [ "graphene" ], "offsets": [ [ 479, 487 ] ], "normalized": [] }, { "id": "23440956_T16", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 554, 556 ] ], "normalized": [] }, { "id": "23440956_T17", "type": "CHEMICAL", "text": [ "graphene oxide" ], "offsets": [ [ 575, 589 ] ], "normalized": [] }, { "id": "23440956_T18", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 642, 644 ] ], "normalized": [] }, { "id": "23440956_T19", "type": "CHEMICAL", "text": [ "graphene oxide" ], "offsets": [ [ 691, 705 ] ], "normalized": [] }, { "id": "23440956_T20", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 715, 717 ] ], "normalized": [] }, { "id": "23440956_T21", "type": "CHEMICAL", "text": [ "graphene oxide" ], "offsets": [ [ 739, 753 ] ], "normalized": [] }, { "id": "23440956_T22", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 778, 780 ] ], "normalized": [] }, { "id": "23440956_T23", "type": "CHEMICAL", "text": [ "lithium" ], "offsets": [ [ 152, 159 ] ], "normalized": [] }, { "id": "23440956_T24", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 844, 846 ] ], "normalized": [] }, { "id": "23440956_T25", "type": "CHEMICAL", "text": [ "graphene" ], "offsets": [ [ 873, 881 ] ], "normalized": [] }, { "id": "23440956_T26", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 895, 897 ] ], "normalized": [] }, { "id": "23440956_T27", "type": "CHEMICAL", "text": [ "graphene" ], "offsets": [ [ 980, 988 ] ], "normalized": [] }, { "id": "23440956_T28", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 92, 94 ] ], "normalized": [] }, { "id": "23440956_T29", "type": "CHEMICAL", "text": [ "Graphene" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "23440956_T30", "type": "CHEMICAL", "text": [ "Si" ], "offsets": [ [ 34, 36 ] ], "normalized": [] }, { "id": "23440956_T31", "type": "CHEMICAL", "text": [ "Lithium" ], "offsets": [ [ 55, 62 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "14642426_title", "type": "title", "text": [ "The inhibitory effect of ginseng saponins on the stress-induced plasma interleukin-6 level in mice." ], "offsets": [ [ 0, 99 ] ] }, { "id": "14642426_abstract", "type": "abstract", "text": [ "The effect of ginseng saponins on plasma interleukin-6 (IL-6) in non-stressed and immobilization-stressed mice were investigated. Ginseng total saponins, ginsenosides Rb2, Rg1 and Rd administered intraperitoneally attenuated the immobilization stress-induced increase in plasma IL-6 level. But, intracerebroventricular injection of each ginsenoside did not affect plasma IL-6 level induced by immobilization stress. Ginsenosides Rb2, Rd and Rg1 significantly decreased norepinephrine and/or epinephrine-induced increase of IL-6 level in macrophage cell line (RAW 264.7). Thus, it can be suggested that the inhibitory action of ginseng saponins against the immobilization stress-induced increase of plasma IL-6 level would be in periphery; at least in part, mediated by blocking norepinephrine- and/or epinephrine-induced increase of IL-6 level in macrophage rather than in the brain. Ginseng saponins might be proposed as a possible candidate in the research or therapeutic modulation of stress-related disorders." ], "offsets": [ [ 100, 1113 ] ] } ]

[ { "id": "14642426_T1", "type": "CHEMICAL", "text": [ "ginseng saponins" ], "offsets": [ [ 114, 130 ] ], "normalized": [] }, { "id": "14642426_T2", "type": "CHEMICAL", "text": [ "saponins" ], "offsets": [ [ 244, 252 ] ], "normalized": [] }, { "id": "14642426_T3", "type": "CHEMICAL", "text": [ "ginsenosides Rb2, Rg1 and Rd" ], "offsets": [ [ 254, 282 ] ], "normalized": [] }, { "id": "14642426_T4", "type": "CHEMICAL", "text": [ "ginsenoside" ], "offsets": [ [ 437, 448 ] ], "normalized": [] }, { "id": "14642426_T5", "type": "CHEMICAL", "text": [ "Ginsenosides Rb2, Rd and Rg1" ], "offsets": [ [ 516, 544 ] ], "normalized": [] }, { "id": "14642426_T6", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 569, 583 ] ], "normalized": [] }, { "id": "14642426_T7", "type": "CHEMICAL", "text": [ "epinephrine" ], "offsets": [ [ 591, 602 ] ], "normalized": [] }, { "id": "14642426_T8", "type": "CHEMICAL", "text": [ "ginseng saponins" ], "offsets": [ [ 727, 743 ] ], "normalized": [] }, { "id": "14642426_T9", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 878, 892 ] ], "normalized": [] }, { "id": "14642426_T10", "type": "CHEMICAL", "text": [ "epinephrine" ], "offsets": [ [ 901, 912 ] ], "normalized": [] }, { "id": "14642426_T11", "type": "CHEMICAL", "text": [ "Ginseng saponins" ], "offsets": [ [ 984, 1000 ] ], "normalized": [] }, { "id": "14642426_T12", "type": "CHEMICAL", "text": [ "ginseng saponins" ], "offsets": [ [ 25, 41 ] ], "normalized": [] }, { "id": "14642426_T13", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 378, 382 ] ], "normalized": [] }, { "id": "14642426_T14", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 471, 475 ] ], "normalized": [] }, { "id": "14642426_T15", "type": "GENE-Y", "text": [ "interleukin-6" ], "offsets": [ [ 141, 154 ] ], "normalized": [] }, { "id": "14642426_T16", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 623, 627 ] ], "normalized": [] }, { "id": "14642426_T17", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 156, 160 ] ], "normalized": [] }, { "id": "14642426_T18", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 805, 809 ] ], "normalized": [] }, { "id": "14642426_T19", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 933, 937 ] ], "normalized": [] }, { "id": "14642426_T20", "type": "GENE-Y", "text": [ "interleukin-6" ], "offsets": [ [ 71, 84 ] ], "normalized": [] } ]

[]

[]

[ { "id": "14642426_0", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "14642426_T12", "arg2_id": "14642426_T20", "normalized": [] }, { "id": "14642426_1", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "14642426_T2", "arg2_id": "14642426_T13", "normalized": [] }, { "id": "14642426_2", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "14642426_T3", "arg2_id": "14642426_T13", "normalized": [] }, { "id": "14642426_3", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "14642426_T5", "arg2_id": "14642426_T16", "normalized": [] }, { "id": "14642426_4", "type": "INDIRECT-UPREGULATOR", "arg1_id": "14642426_T6", "arg2_id": "14642426_T16", "normalized": [] }, { "id": "14642426_5", "type": "INDIRECT-UPREGULATOR", "arg1_id": "14642426_T7", "arg2_id": "14642426_T16", "normalized": [] }, { "id": "14642426_6", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "14642426_T8", "arg2_id": "14642426_T18", "normalized": [] }, { "id": "14642426_7", "type": "INDIRECT-UPREGULATOR", "arg1_id": "14642426_T9", "arg2_id": "14642426_T19", "normalized": [] }, { "id": "14642426_8", "type": "INDIRECT-UPREGULATOR", "arg1_id": "14642426_T10", "arg2_id": "14642426_T19", "normalized": [] }, { "id": "14642426_9", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "14642426_T8", "arg2_id": "14642426_T19", "normalized": [] } ]

[ { "id": "12213053_title", "type": "title", "text": [ "Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter." ], "offsets": [ [ 0, 99 ] ] }, { "id": "12213053_abstract", "type": "abstract", "text": [ "A series of mazindol (2) and homomazindol (3) analogues with a variety of electron-donating and electron-withdrawing groups in the pendant aryl group and the benzo ring C, as well as H, methoxy, and alkyl groups replacing the hydroxyl group were synthesized, and their binding affinities at the dopamine transporter (DAT) on rat or guinea pig striatal membranes were determined. Several active analogues were also evaluated for their ability to block uptake of DA, 5-HT, and NE and inhibit binding of [(125)I] RTI-55 at HEK-hDAT, HEK-hSERT, and HEK-hNET cells. Mazindane (26) was found to be a pro-drug, oxidizing (5-H --> 5-OH) to mazindol on rat striatal membranes and HEK-hDAT cells. The 4',7,8-trichloro analogue (38) of mazindol was the most potent and selective ligand for HEK-hDAT cells (DAT K(i) = 1.1 nM; SERT/DAT = 1283 and NET/DAT = 38). Experimental results strongly favor the cyclic or ol tautomers of 2 and 3 to bind more tightly at the DAT than the corresponding keto tautomers." ], "offsets": [ [ 100, 1093 ] ] } ]

[ { "id": "12213053_T1", "type": "CHEMICAL", "text": [ "mazindol" ], "offsets": [ [ 112, 120 ] ], "normalized": [] }, { "id": "12213053_T2", "type": "CHEMICAL", "text": [ "aryl" ], "offsets": [ [ 239, 243 ] ], "normalized": [] }, { "id": "12213053_T3", "type": "CHEMICAL", "text": [ "benzo" ], "offsets": [ [ 258, 263 ] ], "normalized": [] }, { "id": "12213053_T4", "type": "CHEMICAL", "text": [ "methoxy" ], "offsets": [ [ 286, 293 ] ], "normalized": [] }, { "id": "12213053_T5", "type": "CHEMICAL", "text": [ "alkyl" ], "offsets": [ [ 299, 304 ] ], "normalized": [] }, { "id": "12213053_T6", "type": "CHEMICAL", "text": [ "hydroxyl" ], "offsets": [ [ 326, 334 ] ], "normalized": [] }, { "id": "12213053_T7", "type": "CHEMICAL", "text": [ "homomazindol" ], "offsets": [ [ 129, 141 ] ], "normalized": [] }, { "id": "12213053_T8", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 395, 403 ] ], "normalized": [] }, { "id": "12213053_T9", "type": "CHEMICAL", "text": [ "DA" ], "offsets": [ [ 561, 563 ] ], "normalized": [] }, { "id": "12213053_T10", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 565, 569 ] ], "normalized": [] }, { "id": "12213053_T11", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 575, 577 ] ], "normalized": [] }, { "id": "12213053_T12", "type": "CHEMICAL", "text": [ "[(125)I] RTI-55" ], "offsets": [ [ 601, 616 ] ], "normalized": [] }, { "id": "12213053_T13", "type": "CHEMICAL", "text": [ "Mazindane" ], "offsets": [ [ 661, 670 ] ], "normalized": [] }, { "id": "12213053_T14", "type": "CHEMICAL", "text": [ "5-H" ], "offsets": [ [ 715, 718 ] ], "normalized": [] }, { "id": "12213053_T15", "type": "CHEMICAL", "text": [ "5-OH" ], "offsets": [ [ 723, 727 ] ], "normalized": [] }, { "id": "12213053_T16", "type": "CHEMICAL", "text": [ "mazindol" ], "offsets": [ [ 732, 740 ] ], "normalized": [] }, { "id": "12213053_T17", "type": "CHEMICAL", "text": [ "4',7,8-trichloro" ], "offsets": [ [ 791, 807 ] ], "normalized": [] }, { "id": "12213053_T18", "type": "CHEMICAL", "text": [ "mazindol" ], "offsets": [ [ 825, 833 ] ], "normalized": [] }, { "id": "12213053_T19", "type": "CHEMICAL", "text": [ "Mazindol" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "12213053_T20", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 50, 57 ] ], "normalized": [] }, { "id": "12213053_T21", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 78, 86 ] ], "normalized": [] }, { "id": "12213053_T22", "type": "GENE-N", "text": [ "dopamine transporter" ], "offsets": [ [ 395, 415 ] ], "normalized": [] }, { "id": "12213053_T23", "type": "GENE-N", "text": [ "DAT" ], "offsets": [ [ 417, 420 ] ], "normalized": [] }, { "id": "12213053_T24", "type": "GENE-Y", "text": [ "hDAT" ], "offsets": [ [ 624, 628 ] ], "normalized": [] }, { "id": "12213053_T25", "type": "GENE-Y", "text": [ "hSERT" ], "offsets": [ [ 634, 639 ] ], "normalized": [] }, { "id": "12213053_T26", "type": "GENE-Y", "text": [ "hNET" ], "offsets": [ [ 649, 653 ] ], "normalized": [] }, { "id": "12213053_T27", "type": "GENE-Y", "text": [ "hDAT" ], "offsets": [ [ 775, 779 ] ], "normalized": [] }, { "id": "12213053_T28", "type": "GENE-Y", "text": [ "hDAT" ], "offsets": [ [ 883, 887 ] ], "normalized": [] }, { "id": "12213053_T29", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 895, 898 ] ], "normalized": [] }, { "id": "12213053_T30", "type": "GENE-Y", "text": [ "SERT" ], "offsets": [ [ 914, 918 ] ], "normalized": [] }, { "id": "12213053_T31", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 919, 922 ] ], "normalized": [] }, { "id": "12213053_T32", "type": "GENE-Y", "text": [ "NET" ], "offsets": [ [ 934, 937 ] ], "normalized": [] }, { "id": "12213053_T33", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 938, 941 ] ], "normalized": [] }, { "id": "12213053_T34", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 1051, 1054 ] ], "normalized": [] }, { "id": "12213053_T35", "type": "GENE-N", "text": [ "cocaine binding site" ], "offsets": [ [ 50, 70 ] ], "normalized": [] }, { "id": "12213053_T36", "type": "GENE-Y", "text": [ "dopamine transporter" ], "offsets": [ [ 78, 98 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23621521_title", "type": "title", "text": [ "Small molecule mediated proliferation of primary retinal pigment epithelial cells." ], "offsets": [ [ 0, 82 ] ] }, { "id": "23621521_abstract", "type": "abstract", "text": [ "Retinal pigment epithelial (RPE) cells form a monolayer adjacent to the retina and play a critical role in the visual light cycle. Degeneration of this layer results in vision loss, causing retinal disorders such as age-related macular degeneration. Cell transplant therapies exist to restore vision loss; however, risks associated with and an inadequate supply of donor cells have limited their therapeutic success. The identification of factors that proliferate RPE cells ex vivo could provide a renewable source of cells for the treatment of such disorders. We show that a small molecule (WS3) can reversibly proliferate primary RPE cells isolated from fetal and adult human donors. Following withdrawal of WS3, RPE cells differentiate into a functional monolayer, as exhibited by their expression of mature RPE genes and phagocytosis of photoreceptor outer segments. Furthermore, chemically expanded RPE cells preserve vision when transplanted into dystrophic Royal College of Surgeons (RCS) rats, a well-established model of retinal degeneration." ], "offsets": [ [ 83, 1134 ] ] } ]

[ { "id": "23621521_T1", "type": "CHEMICAL", "text": [ "Retinal" ], "offsets": [ [ 83, 90 ] ], "normalized": [] }, { "id": "23621521_T2", "type": "CHEMICAL", "text": [ "retinal" ], "offsets": [ [ 49, 56 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "23344822_title", "type": "title", "text": [ "Interleukin-10 involvement in exposure to low dose of benzene." ], "offsets": [ [ 0, 62 ] ] }, { "id": "23344822_abstract", "type": "abstract", "text": [ "OBJECTIVE: To establish if serum levels of interleukin-10 (IL-10) in subjects exposed to benzene are connected with age, working years, and employment age. METHODS: We evaluated serum levels of IL-10 in 51 employees working in oil refinery (group A) and in 16 office workers who resided in the same area (group B). RESULTS: There was no statistically significant difference between serum concentrations of IL-10 in groups A and B. There was a statistically significant dependent relationship in group A between age, working years, and serum concentration of IL-10. There was a statistically significant and positive dependent relationship in group A between serum concentration of IL-10 and employment age. CONCLUSIONS: The role played by IL-10 in benzene immune suppression may be relevant and attention should be directed toward assessment of age, working years, and employment age in benzene-exposed populations." ], "offsets": [ [ 63, 978 ] ] } ]

[ { "id": "23344822_T1", "type": "CHEMICAL", "text": [ "benzene" ], "offsets": [ [ 811, 818 ] ], "normalized": [] }, { "id": "23344822_T2", "type": "CHEMICAL", "text": [ "benzene" ], "offsets": [ [ 950, 957 ] ], "normalized": [] }, { "id": "23344822_T3", "type": "CHEMICAL", "text": [ "benzene" ], "offsets": [ [ 152, 159 ] ], "normalized": [] }, { "id": "23344822_T4", "type": "CHEMICAL", "text": [ "benzene" ], "offsets": [ [ 54, 61 ] ], "normalized": [] }, { "id": "23344822_T5", "type": "GENE-Y", "text": [ "IL-10" ], "offsets": [ [ 257, 262 ] ], "normalized": [] }, { "id": "23344822_T6", "type": "GENE-Y", "text": [ "IL-10" ], "offsets": [ [ 469, 474 ] ], "normalized": [] }, { "id": "23344822_T7", "type": "GENE-Y", "text": [ "interleukin-10" ], "offsets": [ [ 106, 120 ] ], "normalized": [] }, { "id": "23344822_T8", "type": "GENE-Y", "text": [ "IL-10" ], "offsets": [ [ 621, 626 ] ], "normalized": [] }, { "id": "23344822_T9", "type": "GENE-Y", "text": [ "IL-10" ], "offsets": [ [ 122, 127 ] ], "normalized": [] }, { "id": "23344822_T10", "type": "GENE-Y", "text": [ "IL-10" ], "offsets": [ [ 744, 749 ] ], "normalized": [] }, { "id": "23344822_T11", "type": "GENE-Y", "text": [ "IL-10" ], "offsets": [ [ 802, 807 ] ], "normalized": [] }, { "id": "23344822_T12", "type": "GENE-Y", "text": [ "Interleukin-10" ], "offsets": [ [ 0, 14 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "15369444_title", "type": "title", "text": [ "A review of adjuvant hormonal therapy in breast cancer." ], "offsets": [ [ 0, 55 ] ] }, { "id": "15369444_abstract", "type": "abstract", "text": [ "Breast cancer is the most common carcinoma diagnosed in women today excluding non-melanoma skin cancers. It has been well documented that estrogen plays a critical role in its development and is a major target for treatment. For many years, tamoxifen has been the gold standard for adjuvant hormonal therapy in breast cancer patients. With newer products targeting different mechanisms to suppress estrogen production, patients now have many decisions regarding their care. Agents such as luteinizing hormone releasing hormone (LHRH) agonists can suppress ovarian function in premenopausal patients and have been shown to be as effective and even better than chemotherapy (CMF--cyclophosphamide, methotrexate, fluorouracil-containing regimens) in certain patient populations. Tamoxifen continues to be an option as well as toremifene, a similar selective estrogen receptor modulator. With the advent of newer third generation aromatase inhibitors (anastrozole, letrozole and exemestane) toxicities have been documented to be less and in some cases they are more efficacious than the standard, tamoxifen. This article reviews the current data regarding ovarian suppression, ovarian suppression plus tamoxifen, tamoxifen, toremifene, anastrozole, letrozole, and exemestane in the treatment of adjuvant hormonal-sensitive breast cancer." ], "offsets": [ [ 56, 1389 ] ] } ]

[ { "id": "15369444_T1", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1149, 1158 ] ], "normalized": [] }, { "id": "15369444_T2", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1254, 1263 ] ], "normalized": [] }, { "id": "15369444_T3", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1265, 1274 ] ], "normalized": [] }, { "id": "15369444_T4", "type": "CHEMICAL", "text": [ "toremifene" ], "offsets": [ [ 1276, 1286 ] ], "normalized": [] }, { "id": "15369444_T5", "type": "CHEMICAL", "text": [ "anastrozole" ], "offsets": [ [ 1288, 1299 ] ], "normalized": [] }, { "id": "15369444_T6", "type": "CHEMICAL", "text": [ "letrozole" ], "offsets": [ [ 1301, 1310 ] ], "normalized": [] }, { "id": "15369444_T7", "type": "CHEMICAL", "text": [ "exemestane" ], "offsets": [ [ 1316, 1326 ] ], "normalized": [] }, { "id": "15369444_T8", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 194, 202 ] ], "normalized": [] }, { "id": "15369444_T9", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 297, 306 ] ], "normalized": [] }, { "id": "15369444_T10", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 454, 462 ] ], "normalized": [] }, { "id": "15369444_T11", "type": "CHEMICAL", "text": [ "cyclophosphamide" ], "offsets": [ [ 734, 750 ] ], "normalized": [] }, { "id": "15369444_T12", "type": "CHEMICAL", "text": [ "methotrexate" ], "offsets": [ [ 752, 764 ] ], "normalized": [] }, { "id": "15369444_T13", "type": "CHEMICAL", "text": [ "fluorouracil" ], "offsets": [ [ 766, 778 ] ], "normalized": [] }, { "id": "15369444_T14", "type": "CHEMICAL", "text": [ "Tamoxifen" ], "offsets": [ [ 832, 841 ] ], "normalized": [] }, { "id": "15369444_T15", "type": "CHEMICAL", "text": [ "toremifene" ], "offsets": [ [ 879, 889 ] ], "normalized": [] }, { "id": "15369444_T16", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 911, 919 ] ], "normalized": [] }, { "id": "15369444_T17", "type": "CHEMICAL", "text": [ "anastrozole" ], "offsets": [ [ 1004, 1015 ] ], "normalized": [] }, { "id": "15369444_T18", "type": "CHEMICAL", "text": [ "letrozole" ], "offsets": [ [ 1017, 1026 ] ], "normalized": [] }, { "id": "15369444_T19", "type": "CHEMICAL", "text": [ "exemestane" ], "offsets": [ [ 1031, 1041 ] ], "normalized": [] }, { "id": "15369444_T20", "type": "GENE-Y", "text": [ "luteinizing hormone releasing hormone" ], "offsets": [ [ 545, 582 ] ], "normalized": [] }, { "id": "15369444_T21", "type": "GENE-Y", "text": [ "LHRH" ], "offsets": [ [ 584, 588 ] ], "normalized": [] }, { "id": "15369444_T22", "type": "GENE-Y", "text": [ "estrogen receptor" ], "offsets": [ [ 911, 928 ] ], "normalized": [] }, { "id": "15369444_T23", "type": "GENE-Y", "text": [ "aromatase" ], "offsets": [ [ 982, 991 ] ], "normalized": [] } ]

[]

[]

[ { "id": "15369444_0", "type": "INHIBITOR", "arg1_id": "15369444_T17", "arg2_id": "15369444_T23", "normalized": [] }, { "id": "15369444_1", "type": "INHIBITOR", "arg1_id": "15369444_T18", "arg2_id": "15369444_T23", "normalized": [] }, { "id": "15369444_2", "type": "INHIBITOR", "arg1_id": "15369444_T19", "arg2_id": "15369444_T23", "normalized": [] } ]

[ { "id": "11578145_title", "type": "title", "text": [ "Contribution of enzymic alpha, gamma-elimination reaction in detoxification pathway of selenomethionine in mouse liver." ], "offsets": [ [ 0, 119 ] ] }, { "id": "11578145_abstract", "type": "abstract", "text": [ "The objective of this study was to clarify the detoxification pathways of selenomethionine (SeMet) in mouse liver. It has been postulated that SeMet may be metabolized to selenocysteine (SeCyH) via a pathway similar to methionine (Met). CySeH may be decomposed to H(2)Se, which is consequently methylated to CH(3)SeH, (CH(3))(2)Se, and (CH(3))(3)Se(+). In this study, we estimated that the median lethal single oral dose (LD(50)) was 67.0 mg/kg. We also found that (CH(3))(3)Se(+) was quickly produced in mouse liver after single oral administration of SeMet. This result suggested the existence of a quick alpha,gamma-elimination pathway. We measured the amounts of alpha-ketobutyrate, NH(3), and CH(3)SeH produced by enzymic alpha,gamma-elimination reaction of SeMet in the liver of periodate-oxidized adenosine (PAD) or D,L-propargylglycine (PPG)-treated mice in order to verify the existence of alpha,gamma-elimination enzyme. PAD is an inhibitor of S-adenosylhomocysteinase (EC 3.3.1.1), which is necessary for conversion of SeMet to SeCyH. PPG is an effective inhibitor of the pyridoxal 5'-phosphate (PLP)-containing enzyme bacterial L-methionine gamma-lyase (EC 4.4.1.11) contributing to the alpha,gamma-elimination reaction of SeMet and cystathionine gamma-lyase (EC 4.4.1.1) relating to conversion of SeMet to SeCyH. When SeMet was incubated with the S9 fraction from liver of PAD-treated mice, the formation of alpha-ketobutyrate was much the same as that from nontreated mouse liver. However, the amount of alpha-ketobutyrate formed significantly decreased in the reaction of SeMet with S9 fraction from the liver of PPG-treated mice. In an in vivo experiment using mice treated with PAD before a toxic dosage of SeMet, the amount of SeMet in the liver decreased and the amount of acid-volatile Se derived from CH(3)SeH increased gradually. This phenomenon was not observed in the PPG-pretreated group. Furthermore, the protein fraction that had the alpha,gamma-elimination enzyme activity was found in mouse liver cytosol by gel chromatographic technique. The results of this study indicated that SeMet was directly metabolized to CH(3)SeH by an alpha,gamma-elimination enzyme analogous to bacterial L-methionine gamma-lyase, in addition to the generally acceptable pathway via SeCyH." ], "offsets": [ [ 120, 2416 ] ] } ]

[ { "id": "11578145_T1", "type": "CHEMICAL", "text": [ "SeMet" ], "offsets": [ [ 1150, 1155 ] ], "normalized": [] }, { "id": "11578145_T2", "type": "CHEMICAL", "text": [ "SeCyH" ], "offsets": [ [ 1159, 1164 ] ], "normalized": [] }, { "id": "11578145_T3", "type": "CHEMICAL", "text": [ "PPG" ], "offsets": [ [ 1166, 1169 ] ], "normalized": [] }, { "id": "11578145_T4", "type": "CHEMICAL", "text": [ "pyridoxal 5'-phosphate" ], "offsets": [ [ 1203, 1225 ] ], "normalized": [] }, { "id": "11578145_T5", "type": "CHEMICAL", "text": [ "PLP" ], "offsets": [ [ 1227, 1230 ] ], "normalized": [] }, { "id": "11578145_T6", "type": "CHEMICAL", "text": [ "L-methionine" ], "offsets": [ [ 1260, 1272 ] ], "normalized": [] }, { "id": "11578145_T7", "type": "CHEMICAL", "text": [ "SeMet" ], "offsets": [ [ 1355, 1360 ] ], "normalized": [] }, { "id": "11578145_T8", "type": "CHEMICAL", "text": [ "cystathionine" ], "offsets": [ [ 1365, 1378 ] ], "normalized": [] }, { "id": "11578145_T9", "type": "CHEMICAL", "text": [ "SeMet" ], "offsets": [ [ 1430, 1435 ] ], "normalized": [] }, { "id": "11578145_T10", "type": "CHEMICAL", "text": [ "SeCyH" ], "offsets": [ [ 1439, 1444 ] ], "normalized": [] }, { "id": "11578145_T11", "type": "CHEMICAL", "text": [ "SeMet" ], "offsets": [ [ 1451, 1456 ] ], "normalized": [] }, { "id": "11578145_T12", "type": "CHEMICAL", "text": [ "alpha-ketobutyrate" ], "offsets": [ [ 1541, 1559 ] ], "normalized": [] }, { "id": "11578145_T13", "type": "CHEMICAL", "text": [ "SeMet" ], "offsets": [ [ 263, 268 ] ], "normalized": [] }, { "id": "11578145_T14", "type": "CHEMICAL", "text": [ "alpha-ketobutyrate" ], "offsets": [ [ 1638, 1656 ] ], "normalized": [] }, { "id": "11578145_T15", "type": "CHEMICAL", "text": [ "SeMet" ], "offsets": [ [ 1707, 1712 ] ], "normalized": [] }, { "id": "11578145_T16", "type": "CHEMICAL", "text": [ "PPG" ], "offsets": [ [ 1748, 1751 ] ], "normalized": [] }, { "id": "11578145_T17", "type": "CHEMICAL", "text": [ "selenocysteine" ], "offsets": [ [ 291, 305 ] ], "normalized": [] }, { "id": "11578145_T18", "type": "CHEMICAL", "text": [ "SeMet" ], "offsets": [ [ 1844, 1849 ] ], "normalized": [] }, { "id": "11578145_T19", "type": "CHEMICAL", "text": [ "SeMet" ], "offsets": [ [ 1865, 1870 ] ], "normalized": [] }, { "id": "11578145_T20", "type": "CHEMICAL", "text": [ "Se" ], "offsets": [ [ 1926, 1928 ] ], "normalized": [] }, { "id": "11578145_T21", "type": "CHEMICAL", "text": [ "CH(3)SeH" ], "offsets": [ [ 1942, 1950 ] ], "normalized": [] }, { "id": "11578145_T22", "type": "CHEMICAL", "text": [ "SeCyH" ], "offsets": [ [ 307, 312 ] ], "normalized": [] }, { "id": "11578145_T23", "type": "CHEMICAL", "text": [ "PPG" ], "offsets": [ [ 2012, 2015 ] ], "normalized": [] }, { "id": "11578145_T24", "type": "CHEMICAL", "text": [ "SeMet" ], "offsets": [ [ 2229, 2234 ] ], "normalized": [] }, { "id": "11578145_T25", "type": "CHEMICAL", "text": [ "CH(3)SeH" ], "offsets": [ [ 2263, 2271 ] ], "normalized": [] }, { "id": "11578145_T26", "type": "CHEMICAL", "text": [ "methionine" ], "offsets": [ [ 339, 349 ] ], "normalized": [] }, { "id": "11578145_T27", "type": "CHEMICAL", "text": [ "L-methionine" ], "offsets": [ [ 2332, 2344 ] ], "normalized": [] }, { "id": "11578145_T28", "type": "CHEMICAL", "text": [ "SeCyH" ], "offsets": [ [ 2410, 2415 ] ], "normalized": [] }, { "id": "11578145_T29", "type": "CHEMICAL", "text": [ "Met" ], "offsets": [ [ 351, 354 ] ], "normalized": [] }, { "id": "11578145_T30", "type": "CHEMICAL", "text": [ "CySeH" ], "offsets": [ [ 357, 362 ] ], "normalized": [] }, { "id": "11578145_T31", "type": "CHEMICAL", "text": [ "H(2)Se" ], "offsets": [ [ 384, 390 ] ], "normalized": [] }, { "id": "11578145_T32", "type": "CHEMICAL", "text": [ "CH(3)SeH" ], "offsets": [ [ 428, 436 ] ], "normalized": [] }, { "id": "11578145_T33", "type": "CHEMICAL", "text": [ "(CH(3))(2)Se" ], "offsets": [ [ 438, 450 ] ], "normalized": [] }, { "id": "11578145_T34", "type": "CHEMICAL", "text": [ "(CH(3))(3)Se(+)" ], "offsets": [ [ 456, 471 ] ], "normalized": [] }, { "id": "11578145_T35", "type": "CHEMICAL", "text": [ "(CH(3))(3)Se(+)" ], "offsets": [ [ 585, 600 ] ], "normalized": [] }, { "id": "11578145_T36", "type": "CHEMICAL", "text": [ "SeMet" ], "offsets": [ [ 673, 678 ] ], "normalized": [] }, { "id": "11578145_T37", "type": "CHEMICAL", "text": [ "alpha-ketobutyrate" ], "offsets": [ [ 787, 805 ] ], "normalized": [] }, { "id": "11578145_T38", "type": "CHEMICAL", "text": [ "NH(3)" ], "offsets": [ [ 807, 812 ] ], "normalized": [] }, { "id": "11578145_T39", "type": "CHEMICAL", "text": [ "CH(3)SeH" ], "offsets": [ [ 818, 826 ] ], "normalized": [] }, { "id": "11578145_T40", "type": "CHEMICAL", "text": [ "selenomethionine" ], "offsets": [ [ 194, 210 ] ], "normalized": [] }, { "id": "11578145_T41", "type": "CHEMICAL", "text": [ "SeMet" ], "offsets": [ [ 883, 888 ] ], "normalized": [] }, { "id": "11578145_T42", "type": "CHEMICAL", "text": [ "periodate" ], "offsets": [ [ 905, 914 ] ], "normalized": [] }, { "id": "11578145_T43", "type": "CHEMICAL", "text": [ "adenosine" ], "offsets": [ [ 924, 933 ] ], "normalized": [] }, { "id": "11578145_T44", "type": "CHEMICAL", "text": [ "D,L-propargylglycine" ], "offsets": [ [ 943, 963 ] ], "normalized": [] }, { "id": "11578145_T45", "type": "CHEMICAL", "text": [ "PPG" ], "offsets": [ [ 965, 968 ] ], "normalized": [] }, { "id": "11578145_T46", "type": "CHEMICAL", "text": [ "SeMet" ], "offsets": [ [ 212, 217 ] ], "normalized": [] }, { "id": "11578145_T47", "type": "CHEMICAL", "text": [ "selenomethionine" ], "offsets": [ [ 87, 103 ] ], "normalized": [] }, { "id": "11578145_T48", "type": "GENE-N", "text": [ "bacterial L-methionine gamma-lyase" ], "offsets": [ [ 1250, 1284 ] ], "normalized": [] }, { "id": "11578145_T49", "type": "GENE-N", "text": [ "EC 4.4.1.11" ], "offsets": [ [ 1286, 1297 ] ], "normalized": [] }, { "id": "11578145_T50", "type": "GENE-Y", "text": [ "cystathionine gamma-lyase" ], "offsets": [ [ 1365, 1390 ] ], "normalized": [] }, { "id": "11578145_T51", "type": "GENE-Y", "text": [ "EC 4.4.1.1" ], "offsets": [ [ 1392, 1402 ] ], "normalized": [] }, { "id": "11578145_T52", "type": "GENE-N", "text": [ "bacterial L-methionine gamma-lyase" ], "offsets": [ [ 2322, 2356 ] ], "normalized": [] }, { "id": "11578145_T53", "type": "GENE-Y", "text": [ "S-adenosylhomocysteinase" ], "offsets": [ [ 1074, 1098 ] ], "normalized": [] }, { "id": "11578145_T54", "type": "GENE-Y", "text": [ "EC 3.3.1.1" ], "offsets": [ [ 1100, 1110 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11578145_0", "type": "SUBSTRATE", "arg1_id": "11578145_T1", "arg2_id": "11578145_T53", "normalized": [] }, { "id": "11578145_1", "type": "SUBSTRATE", "arg1_id": "11578145_T1", "arg2_id": "11578145_T54", "normalized": [] }, { "id": "11578145_2", "type": "SUBSTRATE", "arg1_id": "11578145_T2", "arg2_id": "11578145_T53", "normalized": [] }, { "id": "11578145_3", "type": "SUBSTRATE", "arg1_id": "11578145_T2", "arg2_id": "11578145_T54", "normalized": [] }, { "id": "11578145_4", "type": "INHIBITOR", "arg1_id": "11578145_T3", "arg2_id": "11578145_T48", "normalized": [] }, { "id": "11578145_5", "type": "INHIBITOR", "arg1_id": "11578145_T3", "arg2_id": "11578145_T49", "normalized": [] }, { "id": "11578145_6", "type": "SUBSTRATE", "arg1_id": "11578145_T7", "arg2_id": "11578145_T48", "normalized": [] }, { "id": "11578145_7", "type": "SUBSTRATE", "arg1_id": "11578145_T7", "arg2_id": "11578145_T49", "normalized": [] }, { "id": "11578145_8", "type": "SUBSTRATE", "arg1_id": "11578145_T9", "arg2_id": "11578145_T50", "normalized": [] }, { "id": "11578145_9", "type": "SUBSTRATE", "arg1_id": "11578145_T9", "arg2_id": "11578145_T51", "normalized": [] }, { "id": "11578145_10", "type": "PRODUCT-OF", "arg1_id": "11578145_T10", "arg2_id": "11578145_T50", "normalized": [] }, { "id": "11578145_11", "type": "PRODUCT-OF", "arg1_id": "11578145_T10", "arg2_id": "11578145_T51", "normalized": [] }, { "id": "11578145_12", "type": "SUBSTRATE", "arg1_id": "11578145_T24", "arg2_id": "11578145_T52", "normalized": [] }, { "id": "11578145_13", "type": "PRODUCT-OF", "arg1_id": "11578145_T25", "arg2_id": "11578145_T52", "normalized": [] }, { "id": "11578145_14", "type": "SUBSTRATE", "arg1_id": "11578145_T28", "arg2_id": "11578145_T52", "normalized": [] } ]

[ { "id": "16702880_title", "type": "title", "text": [ "Comparison of maltose and acarbose as inhibitors of maltase-glucoamylase activity in assaying acid alpha-glucosidase activity in dried blood spots for the diagnosis of infantile Pompe disease." ], "offsets": [ [ 0, 192 ] ] }, { "id": "16702880_abstract", "type": "abstract", "text": [ "PURPOSE: The study's purpose was to compare acarbose and maltose as inhibitors of maltase-glucoamylase activity for determining acid alpha-glucosidase activity in dried blood spot specimens for early identification of patients with infantile Pompe disease, a severe form of acid alpha-glucosidase deficiency. METHODS: Acid alpha-glucosidase activities in dried blood spot extracts were determined fluorometrically using the artificial substrate 4-methylumbelliferyl-alpha-D-pyranoside. Acarbose or maltose was used to inhibit maltase-glucoamylase, an enzyme present in polymorphonuclear neutrophils that contributes to the total alpha-glucosidase activity at acidic pH. RESULTS: Complete discrimination between patients with proven infantile Pompe disease (n = 20), obligate heterozygotes (n = 16), and controls (n = 150) was achieved using 8 micromol/L acarbose as the inhibitor. Higher acarbose concentration (80 micromol/L) did not improve the assay. By using 4 mM maltose as the inhibitor, heterozygotes and patients were not completely separated. The results using acarbose compared well with those using the skin fibroblast assay in the same group of patients with proven infantile Pompe disease. CONCLUSION: Acid alpha-glucosidase activity measurements in dried blood spot extracts can reliably detect infantile Pompe disease in patients. The convenience of collecting and shipping dried blood specimens plus rapid turnaround time makes this assay an attractive alternative to established methods." ], "offsets": [ [ 193, 1697 ] ] } ]

[ { "id": "16702880_T1", "type": "CHEMICAL", "text": [ "acarbose" ], "offsets": [ [ 1263, 1271 ] ], "normalized": [] }, { "id": "16702880_T2", "type": "CHEMICAL", "text": [ "acarbose" ], "offsets": [ [ 237, 245 ] ], "normalized": [] }, { "id": "16702880_T3", "type": "CHEMICAL", "text": [ "4-methylumbelliferyl-alpha-D-pyranoside" ], "offsets": [ [ 638, 677 ] ], "normalized": [] }, { "id": "16702880_T4", "type": "CHEMICAL", "text": [ "Acarbose" ], "offsets": [ [ 679, 687 ] ], "normalized": [] }, { "id": "16702880_T5", "type": "CHEMICAL", "text": [ "maltose" ], "offsets": [ [ 691, 698 ] ], "normalized": [] }, { "id": "16702880_T6", "type": "CHEMICAL", "text": [ "maltose" ], "offsets": [ [ 250, 257 ] ], "normalized": [] }, { "id": "16702880_T7", "type": "CHEMICAL", "text": [ "acarbose" ], "offsets": [ [ 1047, 1055 ] ], "normalized": [] }, { "id": "16702880_T8", "type": "CHEMICAL", "text": [ "acarbose" ], "offsets": [ [ 1081, 1089 ] ], "normalized": [] }, { "id": "16702880_T9", "type": "CHEMICAL", "text": [ "maltose" ], "offsets": [ [ 1161, 1168 ] ], "normalized": [] }, { "id": "16702880_T10", "type": "CHEMICAL", "text": [ "maltose" ], "offsets": [ [ 14, 21 ] ], "normalized": [] }, { "id": "16702880_T11", "type": "CHEMICAL", "text": [ "acarbose" ], "offsets": [ [ 26, 34 ] ], "normalized": [] }, { "id": "16702880_T12", "type": "GENE-Y", "text": [ "Acid alpha-glucosidase" ], "offsets": [ [ 1408, 1430 ] ], "normalized": [] }, { "id": "16702880_T13", "type": "GENE-Y", "text": [ "acid alpha-glucosidase" ], "offsets": [ [ 321, 343 ] ], "normalized": [] }, { "id": "16702880_T14", "type": "GENE-Y", "text": [ "acid alpha-glucosidase" ], "offsets": [ [ 467, 489 ] ], "normalized": [] }, { "id": "16702880_T15", "type": "GENE-Y", "text": [ "Acid alpha-glucosidase" ], "offsets": [ [ 511, 533 ] ], "normalized": [] }, { "id": "16702880_T16", "type": "GENE-Y", "text": [ "maltase-glucoamylase" ], "offsets": [ [ 719, 739 ] ], "normalized": [] }, { "id": "16702880_T17", "type": "GENE-Y", "text": [ "alpha-glucosidase" ], "offsets": [ [ 822, 839 ] ], "normalized": [] }, { "id": "16702880_T18", "type": "GENE-Y", "text": [ "maltase-glucoamylase" ], "offsets": [ [ 275, 295 ] ], "normalized": [] }, { "id": "16702880_T19", "type": "GENE-Y", "text": [ "maltase-glucoamylase" ], "offsets": [ [ 52, 72 ] ], "normalized": [] }, { "id": "16702880_T20", "type": "GENE-Y", "text": [ "acid alpha-glucosidase" ], "offsets": [ [ 94, 116 ] ], "normalized": [] } ]

[]

[]

[ { "id": "16702880_0", "type": "INHIBITOR", "arg1_id": "16702880_T11", "arg2_id": "16702880_T19", "normalized": [] }, { "id": "16702880_1", "type": "INHIBITOR", "arg1_id": "16702880_T10", "arg2_id": "16702880_T19", "normalized": [] }, { "id": "16702880_2", "type": "INHIBITOR", "arg1_id": "16702880_T2", "arg2_id": "16702880_T18", "normalized": [] }, { "id": "16702880_3", "type": "INHIBITOR", "arg1_id": "16702880_T6", "arg2_id": "16702880_T18", "normalized": [] }, { "id": "16702880_4", "type": "SUBSTRATE", "arg1_id": "16702880_T3", "arg2_id": "16702880_T15", "normalized": [] }, { "id": "16702880_5", "type": "INHIBITOR", "arg1_id": "16702880_T4", "arg2_id": "16702880_T16", "normalized": [] }, { "id": "16702880_6", "type": "INHIBITOR", "arg1_id": "16702880_T5", "arg2_id": "16702880_T16", "normalized": [] }, { "id": "16702880_7", "type": "INHIBITOR", "arg1_id": "16702880_T4", "arg2_id": "16702880_T17", "normalized": [] }, { "id": "16702880_8", "type": "INHIBITOR", "arg1_id": "16702880_T5", "arg2_id": "16702880_T17", "normalized": [] } ]

[ { "id": "15655528_title", "type": "title", "text": [ "The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors." ], "offsets": [ [ 0, 99 ] ] }, { "id": "15655528_abstract", "type": "abstract", "text": [ "Beta-adrenoceptor antagonists (\"beta-blockers\") are one of the most widely used classes of drugs in cardiovascular medicine (hypertension, ischaemic heart disease and increasingly in heart failure) as well as in the management of anxiety, migraine and glaucoma. Where known, the mode of action in cardiovascular disease is from antagonism of endogenous catecholamine responses in the heart (mainly at beta1-adrenoceptors), while the worrisome side effects of bronchospasm result from airway beta2-adrenoceptor blockade. The aim of this study was to determine the selectivity of beta-antagonists for the human beta-adrenoceptor subtypes. (3)H-CGP 12177 whole cell-binding studies were undertaken in CHO cell lines stably expressing either the human beta1-, beta2- or the beta3-adrenoceptor in order to determine the affinity of ligands for each receptor subtype in the same cell background. In this study, the selectivity of well-known subtype-selective ligands was clearly demonstrated: thus, the selective beta1 antagonist CGP 20712A was 501-fold selective over beta2 and 4169-fold selective over beta3; the beta2-selective antagonist ICI 118551 was 550- and 661-fold selective over beta1 and beta3, respectively, and the selective beta3 compound CL 316243 was 10-fold selective over beta2 and more than 129-fold selective over beta1. Those beta2-adrenoceptor agonists used clinically for the treatment of asthma and COPD were beta2 selective: 29-, 61- and 2818-fold for salbutamol, terbutaline and salmeterol over beta1, respectively. There was little difference in the affinity of these ligands between beta1 and beta3 adrenoceptors. The clinically used beta-antagonists studied ranged from bisoprolol (14-fold beta1-selective) to timolol (26-fold beta2-selective). However, the majority showed little selectivity for the beta1- over the beta2-adrenoceptor, with many actually being more beta2-selective. This study shows that the beta1/beta2 selectivity of most clinically used beta-blockers is poor in intact cells, and that some compounds that are traditionally classed as \"beta1-selective\" actually have higher affinity for the beta2-adrenoceptor. There is therefore considerable potential for developing more selective beta-antagonists for clinical use and thereby reducing the side-effect profile of beta-blockers." ], "offsets": [ [ 100, 2423 ] ] } ]

[ { "id": "15655528_T1", "type": "CHEMICAL", "text": [ "CGP 20712A" ], "offsets": [ [ 1124, 1134 ] ], "normalized": [] }, { "id": "15655528_T2", "type": "CHEMICAL", "text": [ "ICI 118551" ], "offsets": [ [ 1236, 1246 ] ], "normalized": [] }, { "id": "15655528_T3", "type": "CHEMICAL", "text": [ "CL 316243" ], "offsets": [ [ 1348, 1357 ] ], "normalized": [] }, { "id": "15655528_T4", "type": "CHEMICAL", "text": [ "salbutamol" ], "offsets": [ [ 1572, 1582 ] ], "normalized": [] }, { "id": "15655528_T5", "type": "CHEMICAL", "text": [ "terbutaline" ], "offsets": [ [ 1584, 1595 ] ], "normalized": [] }, { "id": "15655528_T6", "type": "CHEMICAL", "text": [ "salmeterol" ], "offsets": [ [ 1600, 1610 ] ], "normalized": [] }, { "id": "15655528_T7", "type": "CHEMICAL", "text": [ "bisoprolol" ], "offsets": [ [ 1794, 1804 ] ], "normalized": [] }, { "id": "15655528_T8", "type": "CHEMICAL", "text": [ "timolol" ], "offsets": [ [ 1834, 1841 ] ], "normalized": [] }, { "id": "15655528_T9", "type": "CHEMICAL", "text": [ "catecholamine" ], "offsets": [ [ 453, 466 ] ], "normalized": [] }, { "id": "15655528_T10", "type": "CHEMICAL", "text": [ "(3)H-CGP 12177" ], "offsets": [ [ 737, 751 ] ], "normalized": [] }, { "id": "15655528_T11", "type": "GENE-N", "text": [ "Beta-adrenoceptor" ], "offsets": [ [ 100, 117 ] ], "normalized": [] }, { "id": "15655528_T12", "type": "GENE-Y", "text": [ "beta2-adrenoceptor" ], "offsets": [ [ 1442, 1460 ] ], "normalized": [] }, { "id": "15655528_T13", "type": "GENE-N", "text": [ "beta1 and beta3 adrenoceptors" ], "offsets": [ [ 1706, 1735 ] ], "normalized": [] }, { "id": "15655528_T14", "type": "GENE-Y", "text": [ "beta2-adrenoceptor" ], "offsets": [ [ 1941, 1959 ] ], "normalized": [] }, { "id": "15655528_T15", "type": "GENE-Y", "text": [ "beta2-adrenoceptor" ], "offsets": [ [ 2235, 2253 ] ], "normalized": [] }, { "id": "15655528_T16", "type": "GENE-Y", "text": [ "beta1-adrenoceptors" ], "offsets": [ [ 501, 520 ] ], "normalized": [] }, { "id": "15655528_T17", "type": "GENE-Y", "text": [ "beta2-adrenoceptor" ], "offsets": [ [ 591, 609 ] ], "normalized": [] }, { "id": "15655528_T18", "type": "GENE-N", "text": [ "human beta-adrenoceptor" ], "offsets": [ [ 703, 726 ] ], "normalized": [] }, { "id": "15655528_T19", "type": "GENE-N", "text": [ "human beta1-, beta2- or the beta3-adrenoceptor" ], "offsets": [ [ 842, 888 ] ], "normalized": [] }, { "id": "15655528_T20", "type": "GENE-N", "text": [ "beta-adrenoceptor" ], "offsets": [ [ 19, 36 ] ], "normalized": [] }, { "id": "15655528_T21", "type": "GENE-N", "text": [ "human beta1, beta2 and beta3 adrenoceptors" ], "offsets": [ [ 56, 98 ] ], "normalized": [] } ]

[]

[]

[ { "id": "15655528_0", "type": "AGONIST", "arg1_id": "15655528_T4", "arg2_id": "15655528_T12", "normalized": [] }, { "id": "15655528_1", "type": "AGONIST", "arg1_id": "15655528_T5", "arg2_id": "15655528_T12", "normalized": [] }, { "id": "15655528_2", "type": "AGONIST", "arg1_id": "15655528_T6", "arg2_id": "15655528_T12", "normalized": [] }, { "id": "15655528_3", "type": "ANTAGONIST", "arg1_id": "15655528_T9", "arg2_id": "15655528_T16", "normalized": [] }, { "id": "15655528_4", "type": "INHIBITOR", "arg1_id": "15655528_T9", "arg2_id": "15655528_T17", "normalized": [] } ]

[ { "id": "23421930_title", "type": "title", "text": [ "Bioactive phenolics from Seriphidium stenocephalum." ], "offsets": [ [ 0, 51 ] ] }, { "id": "23421930_abstract", "type": "abstract", "text": [ "Chromatographic separation of the ethyl acetate soluble part of the methanolic extract from Seriphidium stenocephalum yielded three new compounds: stenocepflavone (1), stenocepflavan (2), and stenocephol (3), together with cirsimaritin (4), 5,7,5'-trihydroxy-3',4',6-trimethoxyflavone (5), 5,6,7,5'-tetrahydroxy-4'-methoxyflavone (6), and axillaroside (7). All isolates were characterized with the help of spectroscopic data including 1D, 2D NMR, and high resolution mass spectrometry and/or in comparison with the related compounds in literature. All compounds were tested for in vitro enzyme inhibitory activities against acetylcholinesterase, butyrylcholinesterase, and lipoxygenase. Compounds 1 and 4-7 exhibited significant activity against all the tested enzymes, whereas compounds 2 and 3 were found inactive." ], "offsets": [ [ 52, 868 ] ] } ]

[ { "id": "23421930_T1", "type": "CHEMICAL", "text": [ "stenocepflavone" ], "offsets": [ [ 199, 214 ] ], "normalized": [] }, { "id": "23421930_T2", "type": "CHEMICAL", "text": [ "stenocepflavan" ], "offsets": [ [ 220, 234 ] ], "normalized": [] }, { "id": "23421930_T3", "type": "CHEMICAL", "text": [ "stenocephol" ], "offsets": [ [ 244, 255 ] ], "normalized": [] }, { "id": "23421930_T4", "type": "CHEMICAL", "text": [ "cirsimaritin" ], "offsets": [ [ 275, 287 ] ], "normalized": [] }, { "id": "23421930_T5", "type": "CHEMICAL", "text": [ "5,7,5'-trihydroxy-3',4',6-trimethoxyflavone" ], "offsets": [ [ 293, 336 ] ], "normalized": [] }, { "id": "23421930_T6", "type": "CHEMICAL", "text": [ "5,6,7,5'-tetrahydroxy-4'-methoxyflavone" ], "offsets": [ [ 342, 381 ] ], "normalized": [] }, { "id": "23421930_T7", "type": "CHEMICAL", "text": [ "axillaroside" ], "offsets": [ [ 391, 403 ] ], "normalized": [] }, { "id": "23421930_T8", "type": "CHEMICAL", "text": [ "ethyl acetate" ], "offsets": [ [ 86, 99 ] ], "normalized": [] }, { "id": "23421930_T9", "type": "CHEMICAL", "text": [ "phenolics" ], "offsets": [ [ 10, 19 ] ], "normalized": [] }, { "id": "23421930_T10", "type": "GENE-Y", "text": [ "acetylcholinesterase" ], "offsets": [ [ 676, 696 ] ], "normalized": [] }, { "id": "23421930_T11", "type": "GENE-Y", "text": [ "butyrylcholinesterase" ], "offsets": [ [ 698, 719 ] ], "normalized": [] }, { "id": "23421930_T12", "type": "GENE-N", "text": [ "lipoxygenase" ], "offsets": [ [ 725, 737 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "18056711_title", "type": "title", "text": [ "Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin." ], "offsets": [ [ 0, 103 ] ] }, { "id": "18056711_abstract", "type": "abstract", "text": [ "DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. Top1p is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. Top1p clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the Top1p clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this alpha-helix extends to include Gly and the preceding Leu. We report that mutation of this conserved Gly in yeast Top1p alters enzyme sensitivity to CPT. Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the Top1p catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate." ], "offsets": [ [ 104, 1839 ] ] } ]

[ { "id": "18056711_T1", "type": "CHEMICAL", "text": [ "Gly" ], "offsets": [ [ 1104, 1107 ] ], "normalized": [] }, { "id": "18056711_T2", "type": "CHEMICAL", "text": [ "CPT" ], "offsets": [ [ 1152, 1155 ] ], "normalized": [] }, { "id": "18056711_T3", "type": "CHEMICAL", "text": [ "Gly" ], "offsets": [ [ 1166, 1169 ] ], "normalized": [] }, { "id": "18056711_T4", "type": "CHEMICAL", "text": [ "Asp" ], "offsets": [ [ 1173, 1176 ] ], "normalized": [] }, { "id": "18056711_T5", "type": "CHEMICAL", "text": [ "Glu" ], "offsets": [ [ 1178, 1181 ] ], "normalized": [] }, { "id": "18056711_T6", "type": "CHEMICAL", "text": [ "Asn" ], "offsets": [ [ 1183, 1186 ] ], "normalized": [] }, { "id": "18056711_T7", "type": "CHEMICAL", "text": [ "Gln" ], "offsets": [ [ 1188, 1191 ] ], "normalized": [] }, { "id": "18056711_T8", "type": "CHEMICAL", "text": [ "Leu" ], "offsets": [ [ 1193, 1196 ] ], "normalized": [] }, { "id": "18056711_T9", "type": "CHEMICAL", "text": [ "Ala" ], "offsets": [ [ 1201, 1204 ] ], "normalized": [] }, { "id": "18056711_T10", "type": "CHEMICAL", "text": [ "CPT" ], "offsets": [ [ 1221, 1224 ] ], "normalized": [] }, { "id": "18056711_T11", "type": "CHEMICAL", "text": [ "Val" ], "offsets": [ [ 1349, 1352 ] ], "normalized": [] }, { "id": "18056711_T12", "type": "CHEMICAL", "text": [ "Phe" ], "offsets": [ [ 1356, 1359 ] ], "normalized": [] }, { "id": "18056711_T13", "type": "CHEMICAL", "text": [ "CPT" ], "offsets": [ [ 1393, 1396 ] ], "normalized": [] }, { "id": "18056711_T14", "type": "CHEMICAL", "text": [ "Tyr" ], "offsets": [ [ 1486, 1489 ] ], "normalized": [] }, { "id": "18056711_T15", "type": "CHEMICAL", "text": [ "CPT" ], "offsets": [ [ 1558, 1561 ] ], "normalized": [] }, { "id": "18056711_T16", "type": "CHEMICAL", "text": [ "Gly" ], "offsets": [ [ 1638, 1641 ] ], "normalized": [] }, { "id": "18056711_T17", "type": "CHEMICAL", "text": [ "camptothecin" ], "offsets": [ [ 294, 306 ] ], "normalized": [] }, { "id": "18056711_T18", "type": "CHEMICAL", "text": [ "CPT" ], "offsets": [ [ 308, 311 ] ], "normalized": [] }, { "id": "18056711_T19", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 431, 432 ] ], "normalized": [] }, { "id": "18056711_T20", "type": "CHEMICAL", "text": [ "Tyr" ], "offsets": [ [ 538, 541 ] ], "normalized": [] }, { "id": "18056711_T21", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 549, 550 ] ], "normalized": [] }, { "id": "18056711_T22", "type": "CHEMICAL", "text": [ "CPT" ], "offsets": [ [ 714, 717 ] ], "normalized": [] }, { "id": "18056711_T23", "type": "CHEMICAL", "text": [ "Gly" ], "offsets": [ [ 765, 768 ] ], "normalized": [] }, { "id": "18056711_T24", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 825, 826 ] ], "normalized": [] }, { "id": "18056711_T25", "type": "CHEMICAL", "text": [ "Tyr" ], "offsets": [ [ 916, 919 ] ], "normalized": [] }, { "id": "18056711_T26", "type": "CHEMICAL", "text": [ "Gly" ], "offsets": [ [ 1035, 1038 ] ], "normalized": [] }, { "id": "18056711_T27", "type": "CHEMICAL", "text": [ "Leu" ], "offsets": [ [ 1057, 1060 ] ], "normalized": [] }, { "id": "18056711_T28", "type": "CHEMICAL", "text": [ "camptothecin" ], "offsets": [ [ 90, 102 ] ], "normalized": [] }, { "id": "18056711_T29", "type": "GENE-Y", "text": [ "DNA topoisomerase I" ], "offsets": [ [ 104, 123 ] ], "normalized": [] }, { "id": "18056711_T30", "type": "GENE-Y", "text": [ "yeast Top1p" ], "offsets": [ [ 1111, 1122 ] ], "normalized": [] }, { "id": "18056711_T31", "type": "GENE-Y", "text": [ "Top1p" ], "offsets": [ [ 241, 246 ] ], "normalized": [] }, { "id": "18056711_T32", "type": "GENE-Y", "text": [ "Top1p" ], "offsets": [ [ 1687, 1692 ] ], "normalized": [] }, { "id": "18056711_T33", "type": "GENE-Y", "text": [ "Top1p" ], "offsets": [ [ 125, 130 ] ], "normalized": [] }, { "id": "18056711_T34", "type": "GENE-Y", "text": [ "Top1p" ], "offsets": [ [ 378, 383 ] ], "normalized": [] }, { "id": "18056711_T35", "type": "GENE-N", "text": [ "alpha-helices" ], "offsets": [ [ 476, 489 ] ], "normalized": [] }, { "id": "18056711_T36", "type": "GENE-N", "text": [ "linker domain" ], "offsets": [ [ 491, 504 ] ], "normalized": [] }, { "id": "18056711_T37", "type": "GENE-Y", "text": [ "Top1p" ], "offsets": [ [ 643, 648 ] ], "normalized": [] }, { "id": "18056711_T38", "type": "GENE-N", "text": [ "alpha-helix" ], "offsets": [ [ 870, 881 ] ], "normalized": [] }, { "id": "18056711_T39", "type": "GENE-N", "text": [ "alpha-helix" ], "offsets": [ [ 1004, 1015 ] ], "normalized": [] }, { "id": "18056711_T40", "type": "GENE-Y", "text": [ "DNA topoisomerase I" ], "offsets": [ [ 26, 45 ] ], "normalized": [] } ]

[]

[]

[ { "id": "18056711_0", "type": "PART-OF", "arg1_id": "18056711_T19", "arg2_id": "18056711_T34", "normalized": [] }, { "id": "18056711_1", "type": "PART-OF", "arg1_id": "18056711_T20", "arg2_id": "18056711_T34", "normalized": [] }, { "id": "18056711_2", "type": "PART-OF", "arg1_id": "18056711_T21", "arg2_id": "18056711_T34", "normalized": [] }, { "id": "18056711_3", "type": "PART-OF", "arg1_id": "18056711_T19", "arg2_id": "18056711_T35", "normalized": [] }, { "id": "18056711_4", "type": "PART-OF", "arg1_id": "18056711_T19", "arg2_id": "18056711_T36", "normalized": [] }, { "id": "18056711_5", "type": "PART-OF", "arg1_id": "18056711_T20", "arg2_id": "18056711_T35", "normalized": [] }, { "id": "18056711_6", "type": "PART-OF", "arg1_id": "18056711_T21", "arg2_id": "18056711_T36", "normalized": [] }, { "id": "18056711_7", "type": "PART-OF", "arg1_id": "18056711_T24", "arg2_id": "18056711_T38", "normalized": [] }, { "id": "18056711_8", "type": "PART-OF", "arg1_id": "18056711_T23", "arg2_id": "18056711_T38", "normalized": [] }, { "id": "18056711_9", "type": "PART-OF", "arg1_id": "18056711_T25", "arg2_id": "18056711_T38", "normalized": [] }, { "id": "18056711_10", "type": "PART-OF", "arg1_id": "18056711_T26", "arg2_id": "18056711_T39", "normalized": [] }, { "id": "18056711_11", "type": "PART-OF", "arg1_id": "18056711_T27", "arg2_id": "18056711_T39", "normalized": [] }, { "id": "18056711_12", "type": "PART-OF", "arg1_id": "18056711_T1", "arg2_id": "18056711_T30", "normalized": [] }, { "id": "18056711_13", "type": "PART-OF", "arg1_id": "18056711_T16", "arg2_id": "18056711_T32", "normalized": [] } ]

[ { "id": "17334413_title", "type": "title", "text": [ "H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway." ], "offsets": [ [ 0, 131 ] ] }, { "id": "17334413_abstract", "type": "abstract", "text": [ "Histamine regulates many functions by binding to four histamine G-coupled receptor proteins (H1R, H2R, H3R and H4R). As H3R exerts their effects by coupling to Galpha(i/o) proteins reducing adenosine 3', 5'-monophosphate (cAMP) levels (a key player in the modulation of cholangiocyte hyperplasia/damage), we evaluated the role of H3R in the regulation of biliary growth. We posed the following questions: (1) Do cholangiocytes express H3R? (2) Does in vivo administration of (R)-(alpha)-(-)-methylhistamine dihydrobromide (RAMH) (H3R agonist), thioperamide maleate (H3R antagonist) or histamine, in the absence/presence of thioperamide maleate, to bile duct ligated (BDL) rats regulate cholangiocyte proliferation? and (3) Does RAMH inhibit cholangiocyte proliferation by downregulation of cAMP-dependent phosphorylation of protein kinase A (PKA)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ets-like gene-1 (Elk-1)? The expression of H3R was evaluated in liver sections by immunohistochemistry and immunofluorescence, and by real-time PCR in cholangiocyte RNA from normal and BDL rats. BDL rats (immediately after BDL) were treated daily with RAMH, thioperamide maleate or histamine in the absence/presence of thioperamide maleate for 1 week. Following in vivo treatment of BDL rats with RAMH for 1 week, and in vitro stimulation of BDL cholangiocytes with RAMH, we evaluated cholangiocyte proliferation, cAMP levels and PKA, ERK1/2 and Elk-1 phosphorylation. Cholangiocytes from normal and BDL rats express H3R. The expression of H3R mRNA increased in BDL compared to normal cholangiocytes. Histamine decreased cholangiocyte growth of BDL rats to a lower extent than that observed in BDL RAMH-treated rats; histamine-induced inhibition of cholangiocyte growth was partly blocked by thioperamide maleate. In BDL rats treated with thioperamide maleate, cholangiocyte hyperplasia was slightly higher than that of BDL rats. In vitro, RAMH inhibited the proliferation of BDL cholangiocytes. RAMH inhibition of cholangiocyte growth was associated with decreased cAMP levels and PKA/ERK1/2/Elk-1 phosphorylation. Downregulation of cAMP-dependent PKA/ERK1/2/Elk-1 phosphorylation (by activation of H3R) is important in the inhibition of cholangiocyte growth in liver diseases." ], "offsets": [ [ 132, 2408 ] ] } ]

[ { "id": "17334413_T1", "type": "CHEMICAL", "text": [ "Histamine" ], "offsets": [ [ 132, 141 ] ], "normalized": [] }, { "id": "17334413_T2", "type": "CHEMICAL", "text": [ "RAMH" ], "offsets": [ [ 1282, 1286 ] ], "normalized": [] }, { "id": "17334413_T3", "type": "CHEMICAL", "text": [ "thioperamide maleate" ], "offsets": [ [ 1288, 1308 ] ], "normalized": [] }, { "id": "17334413_T4", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 1312, 1321 ] ], "normalized": [] }, { "id": "17334413_T5", "type": "CHEMICAL", "text": [ "thioperamide maleate" ], "offsets": [ [ 1349, 1369 ] ], "normalized": [] }, { "id": "17334413_T6", "type": "CHEMICAL", "text": [ "RAMH" ], "offsets": [ [ 1427, 1431 ] ], "normalized": [] }, { "id": "17334413_T7", "type": "CHEMICAL", "text": [ "RAMH" ], "offsets": [ [ 1496, 1500 ] ], "normalized": [] }, { "id": "17334413_T8", "type": "CHEMICAL", "text": [ "cAMP" ], "offsets": [ [ 1544, 1548 ] ], "normalized": [] }, { "id": "17334413_T9", "type": "CHEMICAL", "text": [ "Histamine" ], "offsets": [ [ 1731, 1740 ] ], "normalized": [] }, { "id": "17334413_T10", "type": "CHEMICAL", "text": [ "RAMH" ], "offsets": [ [ 1828, 1832 ] ], "normalized": [] }, { "id": "17334413_T11", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 1847, 1856 ] ], "normalized": [] }, { "id": "17334413_T12", "type": "CHEMICAL", "text": [ "thioperamide maleate" ], "offsets": [ [ 1922, 1942 ] ], "normalized": [] }, { "id": "17334413_T13", "type": "CHEMICAL", "text": [ "thioperamide maleate" ], "offsets": [ [ 1969, 1989 ] ], "normalized": [] }, { "id": "17334413_T14", "type": "CHEMICAL", "text": [ "adenosine 3', 5'-monophosphate" ], "offsets": [ [ 322, 352 ] ], "normalized": [] }, { "id": "17334413_T15", "type": "CHEMICAL", "text": [ "RAMH" ], "offsets": [ [ 2070, 2074 ] ], "normalized": [] }, { "id": "17334413_T16", "type": "CHEMICAL", "text": [ "RAMH" ], "offsets": [ [ 2126, 2130 ] ], "normalized": [] }, { "id": "17334413_T17", "type": "CHEMICAL", "text": [ "cAMP" ], "offsets": [ [ 2196, 2200 ] ], "normalized": [] }, { "id": "17334413_T18", "type": "CHEMICAL", "text": [ "cAMP" ], "offsets": [ [ 2264, 2268 ] ], "normalized": [] }, { "id": "17334413_T19", "type": "CHEMICAL", "text": [ "cAMP" ], "offsets": [ [ 354, 358 ] ], "normalized": [] }, { "id": "17334413_T20", "type": "CHEMICAL", "text": [ "(R)-(alpha)-(-)-methylhistamine dihydrobromide" ], "offsets": [ [ 607, 653 ] ], "normalized": [] }, { "id": "17334413_T21", "type": "CHEMICAL", "text": [ "RAMH" ], "offsets": [ [ 655, 659 ] ], "normalized": [] }, { "id": "17334413_T22", "type": "CHEMICAL", "text": [ "thioperamide maleate" ], "offsets": [ [ 676, 696 ] ], "normalized": [] }, { "id": "17334413_T23", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 186, 195 ] ], "normalized": [] }, { "id": "17334413_T24", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 717, 726 ] ], "normalized": [] }, { "id": "17334413_T25", "type": "CHEMICAL", "text": [ "thioperamide maleate" ], "offsets": [ [ 755, 775 ] ], "normalized": [] }, { "id": "17334413_T26", "type": "CHEMICAL", "text": [ "RAMH" ], "offsets": [ [ 860, 864 ] ], "normalized": [] }, { "id": "17334413_T27", "type": "CHEMICAL", "text": [ "cAMP" ], "offsets": [ [ 922, 926 ] ], "normalized": [] }, { "id": "17334413_T28", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 3, 12 ] ], "normalized": [] }, { "id": "17334413_T29", "type": "CHEMICAL", "text": [ "cAMP" ], "offsets": [ [ 91, 95 ] ], "normalized": [] }, { "id": "17334413_T30", "type": "GENE-Y", "text": [ "H3R" ], "offsets": [ [ 235, 238 ] ], "normalized": [] }, { "id": "17334413_T31", "type": "GENE-Y", "text": [ "H4R" ], "offsets": [ [ 243, 246 ] ], "normalized": [] }, { "id": "17334413_T32", "type": "GENE-N", "text": [ "H3R" ], "offsets": [ [ 252, 255 ] ], "normalized": [] }, { "id": "17334413_T33", "type": "GENE-N", "text": [ "PKA" ], "offsets": [ [ 1560, 1563 ] ], "normalized": [] }, { "id": "17334413_T34", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 1565, 1571 ] ], "normalized": [] }, { "id": "17334413_T35", "type": "GENE-Y", "text": [ "Elk-1" ], "offsets": [ [ 1576, 1581 ] ], "normalized": [] }, { "id": "17334413_T36", "type": "GENE-Y", "text": [ "H3R" ], "offsets": [ [ 1647, 1650 ] ], "normalized": [] }, { "id": "17334413_T37", "type": "GENE-Y", "text": [ "H3R" ], "offsets": [ [ 1670, 1673 ] ], "normalized": [] }, { "id": "17334413_T38", "type": "GENE-N", "text": [ "Galpha(i/o)" ], "offsets": [ [ 292, 303 ] ], "normalized": [] }, { "id": "17334413_T39", "type": "GENE-N", "text": [ "PKA" ], "offsets": [ [ 2212, 2215 ] ], "normalized": [] }, { "id": "17334413_T40", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 2216, 2222 ] ], "normalized": [] }, { "id": "17334413_T41", "type": "GENE-Y", "text": [ "Elk-1" ], "offsets": [ [ 2223, 2228 ] ], "normalized": [] }, { "id": "17334413_T42", "type": "GENE-N", "text": [ "PKA" ], "offsets": [ [ 2279, 2282 ] ], "normalized": [] }, { "id": "17334413_T43", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 2283, 2289 ] ], "normalized": [] }, { "id": "17334413_T44", "type": "GENE-Y", "text": [ "Elk-1" ], "offsets": [ [ 2290, 2295 ] ], "normalized": [] }, { "id": "17334413_T45", "type": "GENE-Y", "text": [ "H3R" ], "offsets": [ [ 2330, 2333 ] ], "normalized": [] }, { "id": "17334413_T46", "type": "GENE-Y", "text": [ "H3R" ], "offsets": [ [ 462, 465 ] ], "normalized": [] }, { "id": "17334413_T47", "type": "GENE-N", "text": [ "H3R" ], "offsets": [ [ 567, 570 ] ], "normalized": [] }, { "id": "17334413_T48", "type": "GENE-Y", "text": [ "H3R" ], "offsets": [ [ 662, 665 ] ], "normalized": [] }, { "id": "17334413_T49", "type": "GENE-N", "text": [ "histamine G-coupled receptor proteins" ], "offsets": [ [ 186, 223 ] ], "normalized": [] }, { "id": "17334413_T50", "type": "GENE-Y", "text": [ "H3R" ], "offsets": [ [ 698, 701 ] ], "normalized": [] }, { "id": "17334413_T51", "type": "GENE-N", "text": [ "protein kinase A" ], "offsets": [ [ 956, 972 ] ], "normalized": [] }, { "id": "17334413_T52", "type": "GENE-N", "text": [ "PKA" ], "offsets": [ [ 974, 977 ] ], "normalized": [] }, { "id": "17334413_T53", "type": "GENE-N", "text": [ "extracellular signal-regulated kinase 1/2" ], "offsets": [ [ 979, 1020 ] ], "normalized": [] }, { "id": "17334413_T54", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 1022, 1028 ] ], "normalized": [] }, { "id": "17334413_T55", "type": "GENE-Y", "text": [ "ets-like gene-1" ], "offsets": [ [ 1030, 1045 ] ], "normalized": [] }, { "id": "17334413_T56", "type": "GENE-Y", "text": [ "Elk-1" ], "offsets": [ [ 1047, 1052 ] ], "normalized": [] }, { "id": "17334413_T57", "type": "GENE-Y", "text": [ "H1R" ], "offsets": [ [ 225, 228 ] ], "normalized": [] }, { "id": "17334413_T58", "type": "GENE-Y", "text": [ "H3R" ], "offsets": [ [ 1073, 1076 ] ], "normalized": [] }, { "id": "17334413_T59", "type": "GENE-Y", "text": [ "H2R" ], "offsets": [ [ 230, 233 ] ], "normalized": [] }, { "id": "17334413_T60", "type": "GENE-Y", "text": [ "H3 histamine receptor" ], "offsets": [ [ 0, 21 ] ], "normalized": [] }, { "id": "17334413_T61", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 110, 116 ] ], "normalized": [] }, { "id": "17334413_T62", "type": "GENE-Y", "text": [ "ELK-1" ], "offsets": [ [ 117, 122 ] ], "normalized": [] }, { "id": "17334413_T63", "type": "GENE-N", "text": [ "cAMP-dependent PKA" ], "offsets": [ [ 91, 109 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23550028_title", "type": "title", "text": [ "2-Hydroxy-3-methylanthraquinone from Hedyotis diffusa Willd induces apoptosis in human leukemic U937 cells through modulation of MAPK pathways." ], "offsets": [ [ 0, 143 ] ] }, { "id": "23550028_abstract", "type": "abstract", "text": [ "The herb of Hedyotis diffusa Willd (H. diffusa Willd), an annual herb distributed in northeastern Asia, has been known as a traditional oriental medicine for the treatment of cancer. Recently, Chinese researchers have discovered that two anthraquinones isolated from a water extract of H. diffusa Willd showed apoptosis-inducing effects against cancer cells. However, the cellular and molecular mechanisms responsible for this phenomenon are poorly understood. The current study determines the role of mitogen-activated protein kinases (MAPK) in human leukemic U937 cells apoptosis induced by 2-hydroxy-3-methylanthraquinone from H. diffusa. Our results showed that 2-hydroxy-3-methylanthraquinone decreased phosphorylation-ERK1/2 (p-ERK1/2), and increased p-p38MAPK, but did not affect expressions of p-JNK1/2 in U937 cells. Moreover, treatment of U937 cells with 2-hydroxy-3-methylanthraquinone resulted in activation of caspase-3. Furthermore, PD98059 (ERK1/2 inhibitor) significantly enhanced 2-hydroxy-3-methylanthraquinone-induced apoptosis in U937 cells, whereas caspase-3 inhibitor or SB203580 (p-p38MAPK inhibitor), decreased apoptosis in U937 cells. Taken together, our study for the first time suggests that 2-hydroxy-3-methylanthraquinone is able to enhance apoptosis of U937 cells, at least in part, through activation of p-p38MAPK and downregulation of p-ERK1/2. Moreover, the triggering of caspase-3 activation mediated apoptotic induction." ], "offsets": [ [ 144, 1599 ] ] } ]

[ { "id": "23550028_T1", "type": "CHEMICAL", "text": [ "SB203580" ], "offsets": [ [ 1237, 1245 ] ], "normalized": [] }, { "id": "23550028_T2", "type": "CHEMICAL", "text": [ "2-hydroxy-3-methylanthraquinone" ], "offsets": [ [ 1363, 1394 ] ], "normalized": [] }, { "id": "23550028_T3", "type": "CHEMICAL", "text": [ "anthraquinones" ], "offsets": [ [ 382, 396 ] ], "normalized": [] }, { "id": "23550028_T4", "type": "CHEMICAL", "text": [ "2-hydroxy-3-methylanthraquinone" ], "offsets": [ [ 737, 768 ] ], "normalized": [] }, { "id": "23550028_T5", "type": "CHEMICAL", "text": [ "2-hydroxy-3-methylanthraquinone" ], "offsets": [ [ 810, 841 ] ], "normalized": [] }, { "id": "23550028_T6", "type": "CHEMICAL", "text": [ "2-hydroxy-3-methylanthraquinone" ], "offsets": [ [ 1009, 1040 ] ], "normalized": [] }, { "id": "23550028_T7", "type": "CHEMICAL", "text": [ "PD98059" ], "offsets": [ [ 1091, 1098 ] ], "normalized": [] }, { "id": "23550028_T8", "type": "CHEMICAL", "text": [ "2-hydroxy-3-methylanthraquinone" ], "offsets": [ [ 1141, 1172 ] ], "normalized": [] }, { "id": "23550028_T9", "type": "CHEMICAL", "text": [ "2-Hydroxy-3-methylanthraquinone" ], "offsets": [ [ 0, 31 ] ], "normalized": [] }, { "id": "23550028_T10", "type": "GENE-Y", "text": [ "caspase-3" ], "offsets": [ [ 1214, 1223 ] ], "normalized": [] }, { "id": "23550028_T11", "type": "GENE-N", "text": [ "p-p38MAPK" ], "offsets": [ [ 1247, 1256 ] ], "normalized": [] }, { "id": "23550028_T12", "type": "GENE-N", "text": [ "p-p38MAPK" ], "offsets": [ [ 1479, 1488 ] ], "normalized": [] }, { "id": "23550028_T13", "type": "GENE-N", "text": [ "p-ERK1/2" ], "offsets": [ [ 1511, 1519 ] ], "normalized": [] }, { "id": "23550028_T14", "type": "GENE-Y", "text": [ "caspase-3" ], "offsets": [ [ 1549, 1558 ] ], "normalized": [] }, { "id": "23550028_T15", "type": "GENE-N", "text": [ "mitogen-activated protein kinases" ], "offsets": [ [ 646, 679 ] ], "normalized": [] }, { "id": "23550028_T16", "type": "GENE-N", "text": [ "MAPK" ], "offsets": [ [ 681, 685 ] ], "normalized": [] }, { "id": "23550028_T17", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 868, 874 ] ], "normalized": [] }, { "id": "23550028_T18", "type": "GENE-N", "text": [ "p-ERK1/2" ], "offsets": [ [ 876, 884 ] ], "normalized": [] }, { "id": "23550028_T19", "type": "GENE-N", "text": [ "p-p38MAPK" ], "offsets": [ [ 901, 910 ] ], "normalized": [] }, { "id": "23550028_T20", "type": "GENE-N", "text": [ "p-JNK1/2" ], "offsets": [ [ 946, 954 ] ], "normalized": [] }, { "id": "23550028_T21", "type": "GENE-Y", "text": [ "caspase-3" ], "offsets": [ [ 1067, 1076 ] ], "normalized": [] }, { "id": "23550028_T22", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 1100, 1106 ] ], "normalized": [] }, { "id": "23550028_T23", "type": "GENE-N", "text": [ "MAPK" ], "offsets": [ [ 129, 133 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23523950_title", "type": "title", "text": [ "Avermectin induces P-glycoprotein expression in S2 cells via the calcium/calmodulin/NF-κB pathway." ], "offsets": [ [ 0, 98 ] ] }, { "id": "23523950_abstract", "type": "abstract", "text": [ "Avermectin (AVM) is a macrocyclic lactone agent widely used as a nematicide, acaricide and insecticide in veterinary medicine and plant protection. P-glycoprotein (P-gp) is an ATP-dependent drug efflux pump for xenobiotic compounds, and is involved in multidrug resistance. To understand the development of AVM resistance in invertebrates, we investigated the mechanisms by which AVM affected P-gp expression in Drosophila S2 cells. We found that AVM induced upregulation of P-gp protein expression, increased P-gp ATPase activity and enhanced cellular efflux of the P-gp substrate rhodamine 123 from cells. Furthermore, we observed that AVM-induced expression of P-gp was due to elevation of intracellular calcium concentration ([Ca(2+)]i). This occurred both directly, by activating calcium ion channels, and indirectly, by activating chloride ion channels. These results are supported by our observations that verapamil, a Ca(2+) channel blocker, and niflumic acid, a chloride channel antagonist, significantly attenuated AVM-induced [Ca(2+)]i elevation, thereby reducing P-gp expression. Inhibition of P-gp with anti-P-gp antibody or cyclosporine A (a P-gp inhibitor) reduced the AVM-induced elevation of [Ca(2+)]i, implying that P-gp and [Ca(2+)]i regulate each other. Finally, we found that trifluoperazine, a calmodulin inhibitor, and pyrrolidine dithiocarbamic acid, an NF-κB inhibitor, attenuated the AVM-induced expression of P-gp, suggesting that AVM induces P-gp protein expression via the calmodulin/Relish (NF-κB) signaling pathway." ], "offsets": [ [ 99, 1645 ] ] } ]

[ { "id": "23523950_T1", "type": "CHEMICAL", "text": [ "Avermectin" ], "offsets": [ [ 99, 109 ] ], "normalized": [] }, { "id": "23523950_T2", "type": "CHEMICAL", "text": [ "AVM" ], "offsets": [ [ 1124, 1127 ] ], "normalized": [] }, { "id": "23523950_T3", "type": "CHEMICAL", "text": [ "Ca(2+)" ], "offsets": [ [ 1137, 1143 ] ], "normalized": [] }, { "id": "23523950_T4", "type": "CHEMICAL", "text": [ "cyclosporine A" ], "offsets": [ [ 1237, 1251 ] ], "normalized": [] }, { "id": "23523950_T5", "type": "CHEMICAL", "text": [ "AVM" ], "offsets": [ [ 1283, 1286 ] ], "normalized": [] }, { "id": "23523950_T6", "type": "CHEMICAL", "text": [ "Ca(2+)" ], "offsets": [ [ 1309, 1315 ] ], "normalized": [] }, { "id": "23523950_T7", "type": "CHEMICAL", "text": [ "AVM" ], "offsets": [ [ 111, 114 ] ], "normalized": [] }, { "id": "23523950_T8", "type": "CHEMICAL", "text": [ "Ca(2+)" ], "offsets": [ [ 1343, 1349 ] ], "normalized": [] }, { "id": "23523950_T9", "type": "CHEMICAL", "text": [ "trifluoperazine" ], "offsets": [ [ 1396, 1411 ] ], "normalized": [] }, { "id": "23523950_T10", "type": "CHEMICAL", "text": [ "pyrrolidine dithiocarbamic acid" ], "offsets": [ [ 1441, 1472 ] ], "normalized": [] }, { "id": "23523950_T11", "type": "CHEMICAL", "text": [ "AVM" ], "offsets": [ [ 1509, 1512 ] ], "normalized": [] }, { "id": "23523950_T12", "type": "CHEMICAL", "text": [ "AVM" ], "offsets": [ [ 1557, 1560 ] ], "normalized": [] }, { "id": "23523950_T13", "type": "CHEMICAL", "text": [ "ATP" ], "offsets": [ [ 275, 278 ] ], "normalized": [] }, { "id": "23523950_T14", "type": "CHEMICAL", "text": [ "AVM" ], "offsets": [ [ 406, 409 ] ], "normalized": [] }, { "id": "23523950_T15", "type": "CHEMICAL", "text": [ "lactone" ], "offsets": [ [ 133, 140 ] ], "normalized": [] }, { "id": "23523950_T16", "type": "CHEMICAL", "text": [ "AVM" ], "offsets": [ [ 479, 482 ] ], "normalized": [] }, { "id": "23523950_T17", "type": "CHEMICAL", "text": [ "AVM" ], "offsets": [ [ 546, 549 ] ], "normalized": [] }, { "id": "23523950_T18", "type": "CHEMICAL", "text": [ "rhodamine 123" ], "offsets": [ [ 681, 694 ] ], "normalized": [] }, { "id": "23523950_T19", "type": "CHEMICAL", "text": [ "AVM" ], "offsets": [ [ 737, 740 ] ], "normalized": [] }, { "id": "23523950_T20", "type": "CHEMICAL", "text": [ "calcium" ], "offsets": [ [ 806, 813 ] ], "normalized": [] }, { "id": "23523950_T21", "type": "CHEMICAL", "text": [ "Ca(2+)" ], "offsets": [ [ 830, 836 ] ], "normalized": [] }, { "id": "23523950_T22", "type": "CHEMICAL", "text": [ "calcium" ], "offsets": [ [ 884, 891 ] ], "normalized": [] }, { "id": "23523950_T23", "type": "CHEMICAL", "text": [ "chloride" ], "offsets": [ [ 936, 944 ] ], "normalized": [] }, { "id": "23523950_T24", "type": "CHEMICAL", "text": [ "verapamil" ], "offsets": [ [ 1012, 1021 ] ], "normalized": [] }, { "id": "23523950_T25", "type": "CHEMICAL", "text": [ "Ca(2+)" ], "offsets": [ [ 1025, 1031 ] ], "normalized": [] }, { "id": "23523950_T26", "type": "CHEMICAL", "text": [ "niflumic acid" ], "offsets": [ [ 1053, 1066 ] ], "normalized": [] }, { "id": "23523950_T27", "type": "CHEMICAL", "text": [ "chloride" ], "offsets": [ [ 1070, 1078 ] ], "normalized": [] }, { "id": "23523950_T28", "type": "CHEMICAL", "text": [ "Avermectin" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "23523950_T29", "type": "CHEMICAL", "text": [ "calcium" ], "offsets": [ [ 65, 72 ] ], "normalized": [] }, { "id": "23523950_T30", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 1174, 1178 ] ], "normalized": [] }, { "id": "23523950_T31", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 1205, 1209 ] ], "normalized": [] }, { "id": "23523950_T32", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 1220, 1224 ] ], "normalized": [] }, { "id": "23523950_T33", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 1255, 1259 ] ], "normalized": [] }, { "id": "23523950_T34", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 1333, 1337 ] ], "normalized": [] }, { "id": "23523950_T35", "type": "GENE-Y", "text": [ "calmodulin" ], "offsets": [ [ 1415, 1425 ] ], "normalized": [] }, { "id": "23523950_T36", "type": "GENE-Y", "text": [ "NF-κB" ], "offsets": [ [ 1477, 1482 ] ], "normalized": [] }, { "id": "23523950_T37", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 1535, 1539 ] ], "normalized": [] }, { "id": "23523950_T38", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 1569, 1573 ] ], "normalized": [] }, { "id": "23523950_T39", "type": "GENE-N", "text": [ "P-glycoprotein" ], "offsets": [ [ 247, 261 ] ], "normalized": [] }, { "id": "23523950_T40", "type": "GENE-Y", "text": [ "calmodulin" ], "offsets": [ [ 1601, 1611 ] ], "normalized": [] }, { "id": "23523950_T41", "type": "GENE-Y", "text": [ "Relish" ], "offsets": [ [ 1612, 1618 ] ], "normalized": [] }, { "id": "23523950_T42", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 1620, 1625 ] ], "normalized": [] }, { "id": "23523950_T43", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 263, 267 ] ], "normalized": [] }, { "id": "23523950_T44", "type": "GENE-N", "text": [ "ATP-dependent drug efflux pump" ], "offsets": [ [ 275, 305 ] ], "normalized": [] }, { "id": "23523950_T45", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 492, 496 ] ], "normalized": [] }, { "id": "23523950_T46", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 574, 578 ] ], "normalized": [] }, { "id": "23523950_T47", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 609, 613 ] ], "normalized": [] }, { "id": "23523950_T48", "type": "GENE-N", "text": [ "ATPase" ], "offsets": [ [ 614, 620 ] ], "normalized": [] }, { "id": "23523950_T49", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 666, 670 ] ], "normalized": [] }, { "id": "23523950_T50", "type": "GENE-N", "text": [ "P-gp" ], "offsets": [ [ 763, 767 ] ], "normalized": [] }, { "id": "23523950_T51", "type": "GENE-N", "text": [ "calcium ion channels" ], "offsets": [ [ 884, 904 ] ], "normalized": [] }, { "id": "23523950_T52", "type": "GENE-N", "text": [ "chloride ion channels" ], "offsets": [ [ 936, 957 ] ], "normalized": [] }, { "id": "23523950_T53", "type": "GENE-N", "text": [ "Ca(2+) channel" ], "offsets": [ [ 1025, 1039 ] ], "normalized": [] }, { "id": "23523950_T54", "type": "GENE-N", "text": [ "chloride channel" ], "offsets": [ [ 1070, 1086 ] ], "normalized": [] }, { "id": "23523950_T55", "type": "GENE-N", "text": [ "P-glycoprotein" ], "offsets": [ [ 19, 33 ] ], "normalized": [] }, { "id": "23523950_T56", "type": "GENE-Y", "text": [ "calmodulin" ], "offsets": [ [ 73, 83 ] ], "normalized": [] }, { "id": "23523950_T57", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 84, 89 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23523950_0", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23523950_T28", "arg2_id": "23523950_T55", "normalized": [] }, { "id": "23523950_1", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23523950_T17", "arg2_id": "23523950_T46", "normalized": [] }, { "id": "23523950_2", "type": "ACTIVATOR", "arg1_id": "23523950_T17", "arg2_id": "23523950_T47", "normalized": [] }, { "id": "23523950_3", "type": "ACTIVATOR", "arg1_id": "23523950_T17", "arg2_id": "23523950_T48", "normalized": [] }, { "id": "23523950_4", "type": "SUBSTRATE", "arg1_id": "23523950_T18", "arg2_id": "23523950_T49", "normalized": [] }, { "id": "23523950_5", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23523950_T19", "arg2_id": "23523950_T50", "normalized": [] }, { "id": "23523950_6", "type": "INHIBITOR", "arg1_id": "23523950_T24", "arg2_id": "23523950_T53", "normalized": [] }, { "id": "23523950_7", "type": "ANTAGONIST", "arg1_id": "23523950_T26", "arg2_id": "23523950_T54", "normalized": [] }, { "id": "23523950_8", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23523950_T24", "arg2_id": "23523950_T30", "normalized": [] }, { "id": "23523950_9", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23523950_T26", "arg2_id": "23523950_T30", "normalized": [] }, { "id": "23523950_10", "type": "INHIBITOR", "arg1_id": "23523950_T4", "arg2_id": "23523950_T33", "normalized": [] }, { "id": "23523950_11", "type": "INHIBITOR", "arg1_id": "23523950_T4", "arg2_id": "23523950_T31", "normalized": [] }, { "id": "23523950_12", "type": "INHIBITOR", "arg1_id": "23523950_T9", "arg2_id": "23523950_T35", "normalized": [] }, { "id": "23523950_13", "type": "INHIBITOR", "arg1_id": "23523950_T10", "arg2_id": "23523950_T36", "normalized": [] }, { "id": "23523950_14", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23523950_T11", "arg2_id": "23523950_T37", "normalized": [] }, { "id": "23523950_15", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23523950_T12", "arg2_id": "23523950_T38", "normalized": [] }, { "id": "23523950_16", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23523950_T9", "arg2_id": "23523950_T37", "normalized": [] }, { "id": "23523950_17", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23523950_T10", "arg2_id": "23523950_T37", "normalized": [] }, { "id": "23523950_18", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23523950_T9", "arg2_id": "23523950_T38", "normalized": [] }, { "id": "23523950_19", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23523950_T10", "arg2_id": "23523950_T38", "normalized": [] } ]

[ { "id": "17340133_title", "type": "title", "text": [ "Limited availability of L-arginine increases DNA-binding activity of NF-kappaB and contributes to regulation of iNOS expression." ], "offsets": [ [ 0, 128 ] ] }, { "id": "17340133_abstract", "type": "abstract", "text": [ "The impact of nutrients on gene expression can be mediated by the availability of amino acids. The aim of this study is to examine the effect of limited availability of L: -arginine on the DNA-binding activity of NF-kappaB, a dominant transcription factor in inflammation, and the consequence for the expression pattern of inducible nitric oxide synthase (iNOS) in murine keratinocytes. Low availability of L: -arginine leads to activation and increased DNA-binding activity of NF-kappaB and induction of iNOS messenger RNA (mRNA) in the absence of cytokines, but not to translation into iNOS protein. Cytokine challenge at low L: -arginine also enhances iNOS mRNA expression, but translation into iNOS protein is diminished, leading to lowered nitric oxide production. The decrease in iNOS protein expression is mediated by the phosphorylation of the translation initiation factor eIF2alpha subunit, a key regulator of cellular translation. In contrast, the mRNA expression of the NF-kappaB-dependent genes IL-1alpha and cationic amino acid transporter-2 (CAT-2) are not affected by the availability of L-arginine. These results demonstrate that the availability of L: -arginine can play a role in the control of gene expression by augmenting the DNA-binding activity of NF-kappaB, which can affect the initiation and progression of dermal inflammation." ], "offsets": [ [ 129, 1483 ] ] } ]

[ { "id": "17340133_T1", "type": "CHEMICAL", "text": [ "amino acid" ], "offsets": [ [ 1160, 1170 ] ], "normalized": [] }, { "id": "17340133_T2", "type": "CHEMICAL", "text": [ "L-arginine" ], "offsets": [ [ 1233, 1243 ] ], "normalized": [] }, { "id": "17340133_T3", "type": "CHEMICAL", "text": [ "L: -arginine" ], "offsets": [ [ 1296, 1308 ] ], "normalized": [] }, { "id": "17340133_T4", "type": "CHEMICAL", "text": [ "L: -arginine" ], "offsets": [ [ 298, 310 ] ], "normalized": [] }, { "id": "17340133_T5", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 462, 474 ] ], "normalized": [] }, { "id": "17340133_T6", "type": "CHEMICAL", "text": [ "L: -arginine" ], "offsets": [ [ 536, 548 ] ], "normalized": [] }, { "id": "17340133_T7", "type": "CHEMICAL", "text": [ "L: -arginine" ], "offsets": [ [ 757, 769 ] ], "normalized": [] }, { "id": "17340133_T8", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 874, 886 ] ], "normalized": [] }, { "id": "17340133_T9", "type": "CHEMICAL", "text": [ "amino acids" ], "offsets": [ [ 211, 222 ] ], "normalized": [] }, { "id": "17340133_T10", "type": "CHEMICAL", "text": [ "L-arginine" ], "offsets": [ [ 24, 34 ] ], "normalized": [] }, { "id": "17340133_T11", "type": "GENE-Y", "text": [ "IL-1alpha" ], "offsets": [ [ 1137, 1146 ] ], "normalized": [] }, { "id": "17340133_T12", "type": "GENE-Y", "text": [ "cationic amino acid transporter-2" ], "offsets": [ [ 1151, 1184 ] ], "normalized": [] }, { "id": "17340133_T13", "type": "GENE-Y", "text": [ "CAT-2" ], "offsets": [ [ 1186, 1191 ] ], "normalized": [] }, { "id": "17340133_T14", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 1401, 1410 ] ], "normalized": [] }, { "id": "17340133_T15", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 342, 351 ] ], "normalized": [] }, { "id": "17340133_T16", "type": "GENE-Y", "text": [ "inducible nitric oxide synthase" ], "offsets": [ [ 452, 483 ] ], "normalized": [] }, { "id": "17340133_T17", "type": "GENE-Y", "text": [ "iNOS" ], "offsets": [ [ 485, 489 ] ], "normalized": [] }, { "id": "17340133_T18", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 607, 616 ] ], "normalized": [] }, { "id": "17340133_T19", "type": "GENE-Y", "text": [ "iNOS" ], "offsets": [ [ 634, 638 ] ], "normalized": [] }, { "id": "17340133_T20", "type": "GENE-N", "text": [ "cytokines" ], "offsets": [ [ 678, 687 ] ], "normalized": [] }, { "id": "17340133_T21", "type": "GENE-Y", "text": [ "iNOS" ], "offsets": [ [ 717, 721 ] ], "normalized": [] }, { "id": "17340133_T22", "type": "GENE-N", "text": [ "Cytokine" ], "offsets": [ [ 731, 739 ] ], "normalized": [] }, { "id": "17340133_T23", "type": "GENE-Y", "text": [ "iNOS" ], "offsets": [ [ 784, 788 ] ], "normalized": [] }, { "id": "17340133_T24", "type": "GENE-Y", "text": [ "iNOS" ], "offsets": [ [ 827, 831 ] ], "normalized": [] }, { "id": "17340133_T25", "type": "GENE-Y", "text": [ "iNOS" ], "offsets": [ [ 915, 919 ] ], "normalized": [] }, { "id": "17340133_T26", "type": "GENE-Y", "text": [ "translation initiation factor eIF2alpha" ], "offsets": [ [ 981, 1020 ] ], "normalized": [] }, { "id": "17340133_T27", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 1111, 1120 ] ], "normalized": [] }, { "id": "17340133_T28", "type": "GENE-Y", "text": [ "iNOS" ], "offsets": [ [ 112, 116 ] ], "normalized": [] }, { "id": "17340133_T29", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 69, 78 ] ], "normalized": [] } ]

[]

[]

[ { "id": "17340133_0", "type": "ACTIVATOR", "arg1_id": "17340133_T10", "arg2_id": "17340133_T29", "normalized": [] }, { "id": "17340133_1", "type": "INDIRECT-UPREGULATOR", "arg1_id": "17340133_T10", "arg2_id": "17340133_T28", "normalized": [] }, { "id": "17340133_2", "type": "ACTIVATOR", "arg1_id": "17340133_T6", "arg2_id": "17340133_T18", "normalized": [] }, { "id": "17340133_3", "type": "INDIRECT-UPREGULATOR", "arg1_id": "17340133_T6", "arg2_id": "17340133_T19", "normalized": [] }, { "id": "17340133_4", "type": "INDIRECT-UPREGULATOR", "arg1_id": "17340133_T7", "arg2_id": "17340133_T23", "normalized": [] }, { "id": "17340133_5", "type": "PRODUCT-OF", "arg1_id": "17340133_T8", "arg2_id": "17340133_T24", "normalized": [] }, { "id": "17340133_6", "type": "ACTIVATOR", "arg1_id": "17340133_T3", "arg2_id": "17340133_T14", "normalized": [] } ]

[ { "id": "23412922_title", "type": "title", "text": [ "Differential gene expression in ERα-positive and ERα-negative breast cancer cells upon leptin stimulation." ], "offsets": [ [ 0, 106 ] ] }, { "id": "23412922_abstract", "type": "abstract", "text": [ "In postmenopausal women, adipositas represents a serious risk factor for cancer development and progression. White adipose tissue secretes the 16 kDa hormone leptin which plays a key role in the regulation of appetite and metabolism. An increasing number of reports indicate that leptin also interferes with signal transduction pathways implicated in the development of breast cancer. In our previous study, we identified the estrogen receptor alpha (ERα) as a relevant enhancer of leptin-induced signal transduction leading to transactivation of signal transducer and activator of transcription 3 (Stat3). The purpose of this study is the investigation of specific target gene expression in response to leptin-mediated Stat3 signaling. We performed a comprehensive microarray analysis of ERα-positive and ERα-negative MDA-MB-231 cells upon leptin treatment and identified 49 genes which showed a significant ERα-dependent regulation in leptin-treated MDA-MB-231 cells. There was no intersection with genes which were merely up- or downregulated by ERα expression and only 9 and 11 genes overlapping targets which were regulated by leptin stimulation either in ERα-expressing or ERα-negative MDA-MB-231 cells, respectively. To demonstrate the specificity, expression of three target genes was validated by quantitative real-time PCR. In conclusion, these data imply that leptin can induce a different set of target genes dependent on ERα expression, which might contribute to the development and progression of cancer diseases." ], "offsets": [ [ 107, 1634 ] ] } ]

[ { "id": "23412922_T1", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 533, 541 ] ], "normalized": [] }, { "id": "23412922_T2", "type": "GENE-Y", "text": [ "ERα" ], "offsets": [ [ 1156, 1159 ] ], "normalized": [] }, { "id": "23412922_T3", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 1239, 1245 ] ], "normalized": [] }, { "id": "23412922_T4", "type": "GENE-Y", "text": [ "ERα" ], "offsets": [ [ 1268, 1271 ] ], "normalized": [] }, { "id": "23412922_T5", "type": "GENE-Y", "text": [ "ERα" ], "offsets": [ [ 1286, 1289 ] ], "normalized": [] }, { "id": "23412922_T6", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 1478, 1484 ] ], "normalized": [] }, { "id": "23412922_T7", "type": "GENE-Y", "text": [ "ERα" ], "offsets": [ [ 1541, 1544 ] ], "normalized": [] }, { "id": "23412922_T8", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 265, 271 ] ], "normalized": [] }, { "id": "23412922_T9", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 387, 393 ] ], "normalized": [] }, { "id": "23412922_T10", "type": "GENE-Y", "text": [ "estrogen receptor alpha" ], "offsets": [ [ 533, 556 ] ], "normalized": [] }, { "id": "23412922_T11", "type": "GENE-Y", "text": [ "ERα" ], "offsets": [ [ 558, 561 ] ], "normalized": [] }, { "id": "23412922_T12", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 589, 595 ] ], "normalized": [] }, { "id": "23412922_T13", "type": "GENE-Y", "text": [ "signal transducer and activator of transcription 3" ], "offsets": [ [ 654, 704 ] ], "normalized": [] }, { "id": "23412922_T14", "type": "GENE-Y", "text": [ "Stat3" ], "offsets": [ [ 706, 711 ] ], "normalized": [] }, { "id": "23412922_T15", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 811, 817 ] ], "normalized": [] }, { "id": "23412922_T16", "type": "GENE-N", "text": [ "Stat3" ], "offsets": [ [ 827, 832 ] ], "normalized": [] }, { "id": "23412922_T17", "type": "GENE-Y", "text": [ "ERα" ], "offsets": [ [ 896, 899 ] ], "normalized": [] }, { "id": "23412922_T18", "type": "GENE-Y", "text": [ "ERα" ], "offsets": [ [ 913, 916 ] ], "normalized": [] }, { "id": "23412922_T19", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 948, 954 ] ], "normalized": [] }, { "id": "23412922_T20", "type": "GENE-Y", "text": [ "ERα" ], "offsets": [ [ 1016, 1019 ] ], "normalized": [] }, { "id": "23412922_T21", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 1044, 1050 ] ], "normalized": [] }, { "id": "23412922_T22", "type": "GENE-Y", "text": [ "ERα" ], "offsets": [ [ 32, 35 ] ], "normalized": [] }, { "id": "23412922_T23", "type": "GENE-Y", "text": [ "ERα" ], "offsets": [ [ 49, 52 ] ], "normalized": [] }, { "id": "23412922_T24", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 87, 93 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "17321471_title", "type": "title", "text": [ "The role of adenosine A(2) receptors in the regulation of TNF-alpha production and PGE(2) release in mouse peritoneal macrophages." ], "offsets": [ [ 0, 130 ] ] }, { "id": "17321471_abstract", "type": "abstract", "text": [ "The adenosine A(2) receptors are known to mediate most of the anti-inflammatory activities of adenosine. In lipopolysaccharides (LPS)-stimulated macrophages adenosine strongly inhibits TNF-alpha release, but may also enhance PGE(2) generation. The aims of this study were to determine the relative contributions of the A(2A) and A(2B) receptor subclasses in these two effects and to determine whether the enhanced release of PGE(2) contributes to the inhibition of TNF-alpha release. In LPS-stimulated mouse macrophages, adenosine potently inhibited TNF-alpha production and also potentiated PGE(2) release, though less potently (IC(50)=250 nM vs EC(50) approximately 8 microM, respectively). The non-selective adenosine receptor agonist NECA, and the selective A(2A) receptor agonist CGS21680 also inhibited TNF-alpha production even more potently (IC(50)=4.8 and 2.3 nM, respectively). NECA, but not CGS21680, also enhanced PGE(2) production. The selective A(2A) receptor antagonist ZM241385 (30 nM), but not the selective A(2B) receptor antagonist MRS1754 (30 nM), blocked the inhibitory effect of NECA and CGS21680 on TNF-alpha release. On the other hand, MRS1754, but not ZM241385, abolished the PGE(2) potentiating effect of NECA. Pre-treatment with indomethacin (1 microM) abolished adenosine-induced PGE(2) release enhancement but did not prevent the inhibition of TNF-alpha release. These results show that in this system, the inhibition of TNF-alpha release by adenosine is mediated by the A(2A) receptors whereas the enhancement of PGE(2) release appears to be mediated by the A(2B) receptors. The results also show that while exogenous PGE(2) is a potent inhibitor of TNF-alpha release, the enhanced PGE(2) release induced by adenosine does not appear to contribute to the inhibition of TNF-alpha release." ], "offsets": [ [ 131, 1948 ] ] } ]

[ { "id": "17321471_T1", "type": "CHEMICAL", "text": [ "MRS1754" ], "offsets": [ [ 1182, 1189 ] ], "normalized": [] }, { "id": "17321471_T2", "type": "CHEMICAL", "text": [ "NECA" ], "offsets": [ [ 1232, 1236 ] ], "normalized": [] }, { "id": "17321471_T3", "type": "CHEMICAL", "text": [ "CGS21680" ], "offsets": [ [ 1241, 1249 ] ], "normalized": [] }, { "id": "17321471_T4", "type": "CHEMICAL", "text": [ "MRS1754" ], "offsets": [ [ 1291, 1298 ] ], "normalized": [] }, { "id": "17321471_T5", "type": "CHEMICAL", "text": [ "ZM241385" ], "offsets": [ [ 1308, 1316 ] ], "normalized": [] }, { "id": "17321471_T6", "type": "CHEMICAL", "text": [ "PGE(2)" ], "offsets": [ [ 1332, 1338 ] ], "normalized": [] }, { "id": "17321471_T7", "type": "CHEMICAL", "text": [ "NECA" ], "offsets": [ [ 1362, 1366 ] ], "normalized": [] }, { "id": "17321471_T8", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 1387, 1399 ] ], "normalized": [] }, { "id": "17321471_T9", "type": "CHEMICAL", "text": [ "adenosine" ], "offsets": [ [ 1421, 1430 ] ], "normalized": [] }, { "id": "17321471_T10", "type": "CHEMICAL", "text": [ "PGE(2)" ], "offsets": [ [ 1439, 1445 ] ], "normalized": [] }, { "id": "17321471_T11", "type": "CHEMICAL", "text": [ "adenosine" ], "offsets": [ [ 1602, 1611 ] ], "normalized": [] }, { "id": "17321471_T12", "type": "CHEMICAL", "text": [ "PGE(2)" ], "offsets": [ [ 1674, 1680 ] ], "normalized": [] }, { "id": "17321471_T13", "type": "CHEMICAL", "text": [ "adenosine" ], "offsets": [ [ 288, 297 ] ], "normalized": [] }, { "id": "17321471_T14", "type": "CHEMICAL", "text": [ "PGE(2)" ], "offsets": [ [ 1779, 1785 ] ], "normalized": [] }, { "id": "17321471_T15", "type": "CHEMICAL", "text": [ "PGE(2)" ], "offsets": [ [ 1843, 1849 ] ], "normalized": [] }, { "id": "17321471_T16", "type": "CHEMICAL", "text": [ "adenosine" ], "offsets": [ [ 1869, 1878 ] ], "normalized": [] }, { "id": "17321471_T17", "type": "CHEMICAL", "text": [ "PGE(2)" ], "offsets": [ [ 356, 362 ] ], "normalized": [] }, { "id": "17321471_T18", "type": "CHEMICAL", "text": [ "adenosine" ], "offsets": [ [ 135, 144 ] ], "normalized": [] }, { "id": "17321471_T19", "type": "CHEMICAL", "text": [ "PGE(2)" ], "offsets": [ [ 556, 562 ] ], "normalized": [] }, { "id": "17321471_T20", "type": "CHEMICAL", "text": [ "adenosine" ], "offsets": [ [ 652, 661 ] ], "normalized": [] }, { "id": "17321471_T21", "type": "CHEMICAL", "text": [ "PGE(2)" ], "offsets": [ [ 723, 729 ] ], "normalized": [] }, { "id": "17321471_T22", "type": "CHEMICAL", "text": [ "adenosine" ], "offsets": [ [ 842, 851 ] ], "normalized": [] }, { "id": "17321471_T23", "type": "CHEMICAL", "text": [ "NECA" ], "offsets": [ [ 869, 873 ] ], "normalized": [] }, { "id": "17321471_T24", "type": "CHEMICAL", "text": [ "CGS21680" ], "offsets": [ [ 916, 924 ] ], "normalized": [] }, { "id": "17321471_T25", "type": "CHEMICAL", "text": [ "NECA" ], "offsets": [ [ 1019, 1023 ] ], "normalized": [] }, { "id": "17321471_T26", "type": "CHEMICAL", "text": [ "CGS21680" ], "offsets": [ [ 1033, 1041 ] ], "normalized": [] }, { "id": "17321471_T27", "type": "CHEMICAL", "text": [ "PGE(2)" ], "offsets": [ [ 1057, 1063 ] ], "normalized": [] }, { "id": "17321471_T28", "type": "CHEMICAL", "text": [ "adenosine" ], "offsets": [ [ 225, 234 ] ], "normalized": [] }, { "id": "17321471_T29", "type": "CHEMICAL", "text": [ "ZM241385" ], "offsets": [ [ 1116, 1124 ] ], "normalized": [] }, { "id": "17321471_T30", "type": "CHEMICAL", "text": [ "adenosine" ], "offsets": [ [ 12, 21 ] ], "normalized": [] }, { "id": "17321471_T31", "type": "CHEMICAL", "text": [ "PGE(2)" ], "offsets": [ [ 83, 89 ] ], "normalized": [] }, { "id": "17321471_T32", "type": "GENE-Y", "text": [ "A(2B) receptor" ], "offsets": [ [ 1156, 1170 ] ], "normalized": [] }, { "id": "17321471_T33", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 1253, 1262 ] ], "normalized": [] }, { "id": "17321471_T34", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 1504, 1513 ] ], "normalized": [] }, { "id": "17321471_T35", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 1581, 1590 ] ], "normalized": [] }, { "id": "17321471_T36", "type": "GENE-Y", "text": [ "A(2A) receptors" ], "offsets": [ [ 1631, 1646 ] ], "normalized": [] }, { "id": "17321471_T37", "type": "GENE-Y", "text": [ "A(2B) receptors" ], "offsets": [ [ 1719, 1734 ] ], "normalized": [] }, { "id": "17321471_T38", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 1811, 1820 ] ], "normalized": [] }, { "id": "17321471_T39", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 1930, 1939 ] ], "normalized": [] }, { "id": "17321471_T40", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 316, 325 ] ], "normalized": [] }, { "id": "17321471_T41", "type": "GENE-N", "text": [ "A(2A) and A(2B) receptor" ], "offsets": [ [ 450, 474 ] ], "normalized": [] }, { "id": "17321471_T42", "type": "GENE-N", "text": [ "adenosine A(2) receptors" ], "offsets": [ [ 135, 159 ] ], "normalized": [] }, { "id": "17321471_T43", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 596, 605 ] ], "normalized": [] }, { "id": "17321471_T44", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 681, 690 ] ], "normalized": [] }, { "id": "17321471_T45", "type": "GENE-N", "text": [ "adenosine receptor" ], "offsets": [ [ 842, 860 ] ], "normalized": [] }, { "id": "17321471_T46", "type": "GENE-Y", "text": [ "A(2A) receptor" ], "offsets": [ [ 893, 907 ] ], "normalized": [] }, { "id": "17321471_T47", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 940, 949 ] ], "normalized": [] }, { "id": "17321471_T48", "type": "GENE-Y", "text": [ "A(2A) receptor" ], "offsets": [ [ 1090, 1104 ] ], "normalized": [] }, { "id": "17321471_T49", "type": "GENE-N", "text": [ "adenosine A(2) receptors" ], "offsets": [ [ 12, 36 ] ], "normalized": [] }, { "id": "17321471_T50", "type": "GENE-Y", "text": [ "TNF-alpha" ], "offsets": [ [ 58, 67 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23212742_title", "type": "title", "text": [ "Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia." ], "offsets": [ [ 0, 153 ] ] }, { "id": "23212742_abstract", "type": "abstract", "text": [ "Long-term therapy with certain drugs, especially cytochrome P450 (P450; CYP)-inducing agents, confers an increased risk of osteomalacia that is attributed to vitamin D deficiency. Human CYP24A1, CYP3A4, and CYP27B1 catalyze the inactivation and activation of vitamin D and have been implicated in the adverse drug response. In this study, the inducibility of these enzymes and monohydroxylation of 25-hydroxyvitamin D3 (25OHD3 ) were evaluated after exposure to P450-inducing drugs. With human hepatocytes, treatment with phenobarbital, hyperforin, carbamazepine, and rifampin significantly increased the levels of CYP3A4, but not CYP24A1 or CYP27B1 mRNA. In addition, rifampin pretreatment resulted in an 8-fold increase in formation of the major metabolite of 25OHD3 , 4β,25(OH)2 D3 . This inductive effect was blocked by the addition of 6',7'-dihydroxybergamottin, a selective CYP3A4 inhibitor. With human renal proximal tubular HK-2 cells, treatment with the same inducers did not alter CYP3A4, CYP24A1, or CYP27B1 expression. 24R,25(OH)2 D3 was the predominant monohydroxy metabolite produced from 25OHD3 , but its formation was unaffected by the inducers. With healthy volunteers, the mean plasma concentration of 4β,25(OH)2 D3 was increased 60% (p < 0.01) after short-term rifampin administration. This was accompanied by a statistically significant reduction in plasma 1α,25(OH)2 D3 (-10%; p = 0.03), and a nonsignificant change in 24R,25(OH)2 D3 (-8%; p = 0.09) levels. Further analysis revealed a negative correlation between the increase in 4β,25(OH)2 D3 and decrease in 1α,25(OH)2 D3 levels. Examination of the plasma monohydroxy metabolite/25OHD3 ratios indicated selective induction of the CYP3A4-dependent 4β-hydroxylation pathway of 25OHD3 elimination. These results suggest that induction of hepatic CYP3A4 may be important in the etiology of drug-induced osteomalacia. © 2013 American Society for Bone and Mineral Research." ], "offsets": [ [ 154, 2095 ] ] } ]

[ { "id": "23212742_T1", "type": "CHEMICAL", "text": [ "24R,25(OH)2 D3" ], "offsets": [ [ 1185, 1199 ] ], "normalized": [] }, { "id": "23212742_T2", "type": "CHEMICAL", "text": [ "monohydroxy" ], "offsets": [ [ 1220, 1231 ] ], "normalized": [] }, { "id": "23212742_T3", "type": "CHEMICAL", "text": [ "25OHD3" ], "offsets": [ [ 1257, 1263 ] ], "normalized": [] }, { "id": "23212742_T4", "type": "CHEMICAL", "text": [ "4β,25(OH)2 D3" ], "offsets": [ [ 1374, 1387 ] ], "normalized": [] }, { "id": "23212742_T5", "type": "CHEMICAL", "text": [ "rifampin" ], "offsets": [ [ 1434, 1442 ] ], "normalized": [] }, { "id": "23212742_T6", "type": "CHEMICAL", "text": [ "1α,25(OH)2 D3" ], "offsets": [ [ 1531, 1544 ] ], "normalized": [] }, { "id": "23212742_T7", "type": "CHEMICAL", "text": [ "24R,25(OH)2 D3" ], "offsets": [ [ 1594, 1608 ] ], "normalized": [] }, { "id": "23212742_T8", "type": "CHEMICAL", "text": [ "4β,25(OH)2 D3" ], "offsets": [ [ 1706, 1719 ] ], "normalized": [] }, { "id": "23212742_T9", "type": "CHEMICAL", "text": [ "vitamin D" ], "offsets": [ [ 312, 321 ] ], "normalized": [] }, { "id": "23212742_T10", "type": "CHEMICAL", "text": [ "1α,25(OH)2 D3" ], "offsets": [ [ 1736, 1749 ] ], "normalized": [] }, { "id": "23212742_T11", "type": "CHEMICAL", "text": [ "monohydroxy" ], "offsets": [ [ 1784, 1795 ] ], "normalized": [] }, { "id": "23212742_T12", "type": "CHEMICAL", "text": [ "25OHD3" ], "offsets": [ [ 1807, 1813 ] ], "normalized": [] }, { "id": "23212742_T13", "type": "CHEMICAL", "text": [ "25OHD3" ], "offsets": [ [ 1903, 1909 ] ], "normalized": [] }, { "id": "23212742_T14", "type": "CHEMICAL", "text": [ "vitamin D" ], "offsets": [ [ 413, 422 ] ], "normalized": [] }, { "id": "23212742_T15", "type": "CHEMICAL", "text": [ "25-hydroxyvitamin D3" ], "offsets": [ [ 552, 572 ] ], "normalized": [] }, { "id": "23212742_T16", "type": "CHEMICAL", "text": [ "25OHD3" ], "offsets": [ [ 574, 580 ] ], "normalized": [] }, { "id": "23212742_T17", "type": "CHEMICAL", "text": [ "phenobarbital" ], "offsets": [ [ 676, 689 ] ], "normalized": [] }, { "id": "23212742_T18", "type": "CHEMICAL", "text": [ "hyperforin" ], "offsets": [ [ 691, 701 ] ], "normalized": [] }, { "id": "23212742_T19", "type": "CHEMICAL", "text": [ "carbamazepine" ], "offsets": [ [ 703, 716 ] ], "normalized": [] }, { "id": "23212742_T20", "type": "CHEMICAL", "text": [ "rifampin" ], "offsets": [ [ 722, 730 ] ], "normalized": [] }, { "id": "23212742_T21", "type": "CHEMICAL", "text": [ "rifampin" ], "offsets": [ [ 823, 831 ] ], "normalized": [] }, { "id": "23212742_T22", "type": "CHEMICAL", "text": [ "25OHD3" ], "offsets": [ [ 916, 922 ] ], "normalized": [] }, { "id": "23212742_T23", "type": "CHEMICAL", "text": [ "4β,25(OH)2 D3" ], "offsets": [ [ 925, 938 ] ], "normalized": [] }, { "id": "23212742_T24", "type": "CHEMICAL", "text": [ "6',7'-dihydroxybergamottin" ], "offsets": [ [ 994, 1020 ] ], "normalized": [] }, { "id": "23212742_T25", "type": "CHEMICAL", "text": [ "25-hydroxyvitamin D3" ], "offsets": [ [ 42, 62 ] ], "normalized": [] }, { "id": "23212742_T26", "type": "GENE-Y", "text": [ "CYP27B1" ], "offsets": [ [ 1165, 1172 ] ], "normalized": [] }, { "id": "23212742_T27", "type": "GENE-Y", "text": [ "CYP3A4" ], "offsets": [ [ 1858, 1864 ] ], "normalized": [] }, { "id": "23212742_T28", "type": "GENE-Y", "text": [ "Human CYP24A1" ], "offsets": [ [ 334, 347 ] ], "normalized": [] }, { "id": "23212742_T29", "type": "GENE-Y", "text": [ "CYP3A4" ], "offsets": [ [ 1971, 1977 ] ], "normalized": [] }, { "id": "23212742_T30", "type": "GENE-Y", "text": [ "CYP3A4" ], "offsets": [ [ 349, 355 ] ], "normalized": [] }, { "id": "23212742_T31", "type": "GENE-Y", "text": [ "CYP27B1" ], "offsets": [ [ 361, 368 ] ], "normalized": [] }, { "id": "23212742_T32", "type": "GENE-N", "text": [ "cytochrome P450" ], "offsets": [ [ 203, 218 ] ], "normalized": [] }, { "id": "23212742_T33", "type": "GENE-Y", "text": [ "CYP3A4" ], "offsets": [ [ 769, 775 ] ], "normalized": [] }, { "id": "23212742_T34", "type": "GENE-Y", "text": [ "CYP24A1" ], "offsets": [ [ 785, 792 ] ], "normalized": [] }, { "id": "23212742_T35", "type": "GENE-Y", "text": [ "CYP27B1" ], "offsets": [ [ 796, 803 ] ], "normalized": [] }, { "id": "23212742_T36", "type": "GENE-N", "text": [ "P450" ], "offsets": [ [ 220, 224 ] ], "normalized": [] }, { "id": "23212742_T37", "type": "GENE-N", "text": [ "CYP" ], "offsets": [ [ 226, 229 ] ], "normalized": [] }, { "id": "23212742_T38", "type": "GENE-Y", "text": [ "CYP3A4" ], "offsets": [ [ 1034, 1040 ] ], "normalized": [] }, { "id": "23212742_T39", "type": "GENE-Y", "text": [ "CYP3A4" ], "offsets": [ [ 1145, 1151 ] ], "normalized": [] }, { "id": "23212742_T40", "type": "GENE-Y", "text": [ "CYP24A1" ], "offsets": [ [ 1153, 1160 ] ], "normalized": [] }, { "id": "23212742_T41", "type": "GENE-Y", "text": [ "CYP3A4" ], "offsets": [ [ 71, 77 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23212742_0", "type": "SUBSTRATE", "arg1_id": "23212742_T25", "arg2_id": "23212742_T41", "normalized": [] }, { "id": "23212742_1", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23212742_T17", "arg2_id": "23212742_T33", "normalized": [] }, { "id": "23212742_2", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23212742_T18", "arg2_id": "23212742_T33", "normalized": [] }, { "id": "23212742_3", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23212742_T19", "arg2_id": "23212742_T33", "normalized": [] }, { "id": "23212742_4", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23212742_T20", "arg2_id": "23212742_T33", "normalized": [] }, { "id": "23212742_5", "type": "INHIBITOR", "arg1_id": "23212742_T24", "arg2_id": "23212742_T38", "normalized": [] }, { "id": "23212742_6", "type": "ACTIVATOR", "arg1_id": "23212742_T11", "arg2_id": "23212742_T27", "normalized": [] }, { "id": "23212742_7", "type": "ACTIVATOR", "arg1_id": "23212742_T12", "arg2_id": "23212742_T27", "normalized": [] }, { "id": "23212742_8", "type": "SUBSTRATE", "arg1_id": "23212742_T14", "arg2_id": "23212742_T28", "normalized": [] }, { "id": "23212742_9", "type": "SUBSTRATE", "arg1_id": "23212742_T14", "arg2_id": "23212742_T30", "normalized": [] }, { "id": "23212742_10", "type": "SUBSTRATE", "arg1_id": "23212742_T14", "arg2_id": "23212742_T31", "normalized": [] } ]

[ { "id": "23086198_title", "type": "title", "text": [ "Importance of UDP-glucuronosyltransferases 2A2 and 2A3 in tobacco carcinogen metabolism." ], "offsets": [ [ 0, 88 ] ] }, { "id": "23086198_abstract", "type": "abstract", "text": [ "UDP-glucuronosyltransferase A1 (UGT2A1) is expressed in the lung and exhibits activity against polycyclic aromatic hydrocarbons (PAHs), suggesting UGT2A1 involvement in the local metabolism of PAH tobacco carcinogens. The goal of the present study was to investigate the importance of two additional UGT2A enzymes, UGT2A2 and UGT2A3, in tobacco carcinogen metabolism. Real-time polymerase chain reaction suggested that wild-type UGT2A2 had the highest expression in the breast, followed by trachea > larynx > kidney. A novel splice variant of UGT2A2 lacking exon 3 (termed UGT2A2Δexon3) was investigated, with UGT2A2Δexon3 expression determined to be 25-50% that of wild-type UGT2A2 in all tissues examined. UGT2A3 was determined to be well expressed in the liver and colon, followed by pancreas > kidney > lung > tonsil > trachea > larynx. Cell homogenates prepared from human embryonic kidney (HEK)293 cells overexpressing wild-type UGT2A2 (termed UGT2A2_i1) exhibited glucuronidation activity, as observed by reverse-phase ultra-pressure liquid chromatography, against 1-hydroxy-(OH)-pyrene, 1-naphthol, and hydroxylated benzo(a)pyrene metabolites, whereas homogenates prepared from HEK293 cells overexpressing UGT2A3 only showed activity against simple PAHs like 1-OH-pyrene and 1-naphthol. Activity assays showed the UGT2A2Δexon3 protein (termed UGT2A2_i2) exhibited no detectable glucuronidation activity against all substrates examined; however, coexpression studies suggested that UGT2A2_i2 negatively modulates UGT2A2_i1 activity. Both UGT2A2 and UGT2A3 exhibited no detectable activity against complex PAH proximate carcinogens, tobacco-specific nitrosamines, or heterocyclic amines. These data suggest that, although UGT2A1 is the only UGT2A enzyme active against PAH proximate carcinogens (including PAH diols), both UGTs 2A1 and 2A2 play an important role in the local detoxification of procarcinogenic monohydroxylated PAH metabolites." ], "offsets": [ [ 89, 2038 ] ] } ]

[ { "id": "23086198_T1", "type": "CHEMICAL", "text": [ "UDP" ], "offsets": [ [ 89, 92 ] ], "normalized": [] }, { "id": "23086198_T2", "type": "CHEMICAL", "text": [ "1-hydroxy-(OH)-pyrene" ], "offsets": [ [ 1161, 1182 ] ], "normalized": [] }, { "id": "23086198_T3", "type": "CHEMICAL", "text": [ "1-naphthol" ], "offsets": [ [ 1184, 1194 ] ], "normalized": [] }, { "id": "23086198_T4", "type": "CHEMICAL", "text": [ "hydroxylated benzo(a)pyrene" ], "offsets": [ [ 1200, 1227 ] ], "normalized": [] }, { "id": "23086198_T5", "type": "CHEMICAL", "text": [ "PAHs" ], "offsets": [ [ 1346, 1350 ] ], "normalized": [] }, { "id": "23086198_T6", "type": "CHEMICAL", "text": [ "1-OH-pyrene" ], "offsets": [ [ 1356, 1367 ] ], "normalized": [] }, { "id": "23086198_T7", "type": "CHEMICAL", "text": [ "1-naphthol" ], "offsets": [ [ 1372, 1382 ] ], "normalized": [] }, { "id": "23086198_T8", "type": "CHEMICAL", "text": [ "PAHs" ], "offsets": [ [ 218, 222 ] ], "normalized": [] }, { "id": "23086198_T9", "type": "CHEMICAL", "text": [ "PAH" ], "offsets": [ [ 1701, 1704 ] ], "normalized": [] }, { "id": "23086198_T10", "type": "CHEMICAL", "text": [ "nitrosamines" ], "offsets": [ [ 1745, 1757 ] ], "normalized": [] }, { "id": "23086198_T11", "type": "CHEMICAL", "text": [ "heterocyclic amines" ], "offsets": [ [ 1762, 1781 ] ], "normalized": [] }, { "id": "23086198_T12", "type": "CHEMICAL", "text": [ "PAH" ], "offsets": [ [ 1864, 1867 ] ], "normalized": [] }, { "id": "23086198_T13", "type": "CHEMICAL", "text": [ "PAH" ], "offsets": [ [ 1901, 1904 ] ], "normalized": [] }, { "id": "23086198_T14", "type": "CHEMICAL", "text": [ "diols" ], "offsets": [ [ 1905, 1910 ] ], "normalized": [] }, { "id": "23086198_T15", "type": "CHEMICAL", "text": [ "monohydroxylated PAH" ], "offsets": [ [ 2005, 2025 ] ], "normalized": [] }, { "id": "23086198_T16", "type": "CHEMICAL", "text": [ "PAH" ], "offsets": [ [ 282, 285 ] ], "normalized": [] }, { "id": "23086198_T17", "type": "CHEMICAL", "text": [ "polycyclic aromatic hydrocarbons" ], "offsets": [ [ 184, 216 ] ], "normalized": [] }, { "id": "23086198_T18", "type": "CHEMICAL", "text": [ "UDP" ], "offsets": [ [ 14, 17 ] ], "normalized": [] }, { "id": "23086198_T19", "type": "GENE-Y", "text": [ "UDP-glucuronosyltransferase A1" ], "offsets": [ [ 89, 119 ] ], "normalized": [] }, { "id": "23086198_T20", "type": "GENE-Y", "text": [ "UGT2A3" ], "offsets": [ [ 1303, 1309 ] ], "normalized": [] }, { "id": "23086198_T21", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 1411, 1417 ] ], "normalized": [] }, { "id": "23086198_T22", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 1440, 1446 ] ], "normalized": [] }, { "id": "23086198_T23", "type": "GENE-Y", "text": [ "UGT2A1" ], "offsets": [ [ 236, 242 ] ], "normalized": [] }, { "id": "23086198_T24", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 1578, 1584 ] ], "normalized": [] }, { "id": "23086198_T25", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 1609, 1615 ] ], "normalized": [] }, { "id": "23086198_T26", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 1634, 1640 ] ], "normalized": [] }, { "id": "23086198_T27", "type": "GENE-Y", "text": [ "UGT2A3" ], "offsets": [ [ 1645, 1651 ] ], "normalized": [] }, { "id": "23086198_T28", "type": "GENE-Y", "text": [ "UGT2A1" ], "offsets": [ [ 1817, 1823 ] ], "normalized": [] }, { "id": "23086198_T29", "type": "GENE-N", "text": [ "UGT2A" ], "offsets": [ [ 1836, 1841 ] ], "normalized": [] }, { "id": "23086198_T30", "type": "GENE-N", "text": [ "UGTs 2A1 and 2A2" ], "offsets": [ [ 1918, 1934 ] ], "normalized": [] }, { "id": "23086198_T31", "type": "GENE-N", "text": [ "UGT2A" ], "offsets": [ [ 389, 394 ] ], "normalized": [] }, { "id": "23086198_T32", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 404, 410 ] ], "normalized": [] }, { "id": "23086198_T33", "type": "GENE-Y", "text": [ "UGT2A1" ], "offsets": [ [ 121, 127 ] ], "normalized": [] }, { "id": "23086198_T34", "type": "GENE-Y", "text": [ "UGT2A3" ], "offsets": [ [ 415, 421 ] ], "normalized": [] }, { "id": "23086198_T35", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 518, 524 ] ], "normalized": [] }, { "id": "23086198_T36", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 632, 638 ] ], "normalized": [] }, { "id": "23086198_T37", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 662, 668 ] ], "normalized": [] }, { "id": "23086198_T38", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 699, 705 ] ], "normalized": [] }, { "id": "23086198_T39", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 765, 771 ] ], "normalized": [] }, { "id": "23086198_T40", "type": "GENE-Y", "text": [ "UGT2A3" ], "offsets": [ [ 797, 803 ] ], "normalized": [] }, { "id": "23086198_T41", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 1024, 1030 ] ], "normalized": [] }, { "id": "23086198_T42", "type": "GENE-Y", "text": [ "UGT2A2" ], "offsets": [ [ 1039, 1045 ] ], "normalized": [] }, { "id": "23086198_T43", "type": "GENE-N", "text": [ "UDP-glucuronosyltransferases 2A2 and 2A3" ], "offsets": [ [ 14, 54 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23261528_title", "type": "title", "text": [ "Inhibition of Th1/Th17 responses via suppression of STAT1 and STAT3 activation contributes to the amelioration of murine experimental colitis by a natural flavonoid glucoside icariin." ], "offsets": [ [ 0, 183 ] ] }, { "id": "23261528_abstract", "type": "abstract", "text": [ "Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestine which involves overproduction of pro-inflammatory cytokines and excessive functions of inflammatory cells. However, current treatments for IBD may have potential adverse effects including steroid dependence, infections and lymphoma. Therefore new therapies or drug candidates for the treatment of IBD are desperately needed. In the present study we found that icariin, a major bioactive compound from plants in Epimedium family, exerted protective effect on intestinal inflammation in mice induced by dextran sulfate sodium. Oral administration of icariin significantly attenuated the disease progression and alleviated the pathological changes of colitis. It also inhibited the production of pro-inflammatory cytokines and expression of p-p65, p-STAT1 and p-STAT3 in colon tissues. Further study showed that icariin dose-dependently inhibited the proliferation and activation of T lymphocytes, and suppressed pro-inflammatory cytokine levels of activated T cells. Moreover, icariin treatment inhibited the phosphorylations of STAT1 and STAT3 in CD4(+) T cells, which were the crucial transcription factors for Th1 and Th17 respectively. Taken together, these results indicate that icariin is a potential therapeutic agent for IBD." ], "offsets": [ [ 184, 1500 ] ] } ]

[ { "id": "23261528_T1", "type": "CHEMICAL", "text": [ "icariin" ], "offsets": [ [ 1244, 1251 ] ], "normalized": [] }, { "id": "23261528_T2", "type": "CHEMICAL", "text": [ "icariin" ], "offsets": [ [ 1451, 1458 ] ], "normalized": [] }, { "id": "23261528_T3", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 457, 464 ] ], "normalized": [] }, { "id": "23261528_T4", "type": "CHEMICAL", "text": [ "icariin" ], "offsets": [ [ 629, 636 ] ], "normalized": [] }, { "id": "23261528_T5", "type": "CHEMICAL", "text": [ "sulfate" ], "offsets": [ [ 778, 785 ] ], "normalized": [] }, { "id": "23261528_T6", "type": "CHEMICAL", "text": [ "sodium" ], "offsets": [ [ 786, 792 ] ], "normalized": [] }, { "id": "23261528_T7", "type": "CHEMICAL", "text": [ "icariin" ], "offsets": [ [ 817, 824 ] ], "normalized": [] }, { "id": "23261528_T8", "type": "CHEMICAL", "text": [ "icariin" ], "offsets": [ [ 1078, 1085 ] ], "normalized": [] }, { "id": "23261528_T9", "type": "CHEMICAL", "text": [ "flavonoid" ], "offsets": [ [ 155, 164 ] ], "normalized": [] }, { "id": "23261528_T10", "type": "CHEMICAL", "text": [ "icariin" ], "offsets": [ [ 175, 182 ] ], "normalized": [] }, { "id": "23261528_T11", "type": "GENE-N", "text": [ "cytokine" ], "offsets": [ [ 1196, 1204 ] ], "normalized": [] }, { "id": "23261528_T12", "type": "GENE-Y", "text": [ "STAT1" ], "offsets": [ [ 1296, 1301 ] ], "normalized": [] }, { "id": "23261528_T13", "type": "GENE-Y", "text": [ "STAT3" ], "offsets": [ [ 1306, 1311 ] ], "normalized": [] }, { "id": "23261528_T14", "type": "GENE-N", "text": [ "cytokines" ], "offsets": [ [ 319, 328 ] ], "normalized": [] }, { "id": "23261528_T15", "type": "GENE-N", "text": [ "cytokines" ], "offsets": [ [ 979, 988 ] ], "normalized": [] }, { "id": "23261528_T16", "type": "GENE-Y", "text": [ "p-p65" ], "offsets": [ [ 1007, 1012 ] ], "normalized": [] }, { "id": "23261528_T17", "type": "GENE-Y", "text": [ "p-STAT1" ], "offsets": [ [ 1014, 1021 ] ], "normalized": [] }, { "id": "23261528_T18", "type": "GENE-Y", "text": [ "p-STAT3" ], "offsets": [ [ 1026, 1033 ] ], "normalized": [] }, { "id": "23261528_T19", "type": "GENE-Y", "text": [ "STAT1" ], "offsets": [ [ 52, 57 ] ], "normalized": [] }, { "id": "23261528_T20", "type": "GENE-Y", "text": [ "STAT3" ], "offsets": [ [ 62, 67 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "3146348_title", "type": "title", "text": [ "Effectors of the activation of human [Glu1]plasminogen by human tissue plasminogen activator." ], "offsets": [ [ 0, 93 ] ] }, { "id": "3146348_abstract", "type": "abstract", "text": [ "The activation of human [Glu1]plasminogen [( Glu1]Pg) by human recombinant (rec) two-chain tissue plasminogen activator (t-PA) is inhibited by Cl-, at physiological concentrations, and stimulated by epsilon-aminocaproic acid (EACA), as well as fibrin(ogen). Chloride functions as a result of its binding to [Glu1]Pg, with a Ki of approximately 9.0 mM, thereby rendering [Glu1]Pg a less effective substrate for two-chain rec-t-PA. EACA stimulates the activation in Cl-(-)containing solutions, with a Ka of approximately 4.0 mM, primarily by reversal of the Cl-(-)inhibitory effect. Fibrinogen appears to exert its stimulatory properties mainly through effects on the enzyme, two-chain rec-t-PA, with a Ka of approximately 3.7 microM in activation systems containing physiological levels of Cl-. Analysis of the results of this paper reveals that normal plasma components, Cl- and fibrinogen, exert major regulatory roles on the ability of [Glu1]Pg to be activated by two-chain rec-t-PA, in in vitro systems. The presence of Cl- inhibits the stimulation of [Glu1]Pg activation that would normally occur in the presence of fibrinogen, a result of possible importance to the observation that some degree of systemic fibrinogenolysis accompanies therapeutic use of tissue plasminogen activator." ], "offsets": [ [ 94, 1383 ] ] } ]

[ { "id": "3146348_T1", "type": "CHEMICAL", "text": [ "Cl-" ], "offsets": [ [ 1117, 1120 ] ], "normalized": [] }, { "id": "3146348_T2", "type": "CHEMICAL", "text": [ "Cl-" ], "offsets": [ [ 237, 240 ] ], "normalized": [] }, { "id": "3146348_T3", "type": "CHEMICAL", "text": [ "epsilon-aminocaproic acid" ], "offsets": [ [ 293, 318 ] ], "normalized": [] }, { "id": "3146348_T4", "type": "CHEMICAL", "text": [ "EACA" ], "offsets": [ [ 320, 324 ] ], "normalized": [] }, { "id": "3146348_T5", "type": "CHEMICAL", "text": [ "Chloride" ], "offsets": [ [ 352, 360 ] ], "normalized": [] }, { "id": "3146348_T6", "type": "CHEMICAL", "text": [ "EACA" ], "offsets": [ [ 524, 528 ] ], "normalized": [] }, { "id": "3146348_T7", "type": "CHEMICAL", "text": [ "Cl-(-)" ], "offsets": [ [ 558, 564 ] ], "normalized": [] }, { "id": "3146348_T8", "type": "CHEMICAL", "text": [ "Cl-(-)" ], "offsets": [ [ 650, 656 ] ], "normalized": [] }, { "id": "3146348_T9", "type": "CHEMICAL", "text": [ "Cl-" ], "offsets": [ [ 883, 886 ] ], "normalized": [] }, { "id": "3146348_T10", "type": "CHEMICAL", "text": [ "Cl-" ], "offsets": [ [ 965, 968 ] ], "normalized": [] }, { "id": "3146348_T11", "type": "GENE-Y", "text": [ "[Glu1]Pg" ], "offsets": [ [ 1149, 1157 ] ], "normalized": [] }, { "id": "3146348_T12", "type": "GENE-N", "text": [ "fibrinogen" ], "offsets": [ [ 1214, 1224 ] ], "normalized": [] }, { "id": "3146348_T13", "type": "GENE-Y", "text": [ "t-PA" ], "offsets": [ [ 215, 219 ] ], "normalized": [] }, { "id": "3146348_T14", "type": "GENE-Y", "text": [ "tissue plasminogen activator" ], "offsets": [ [ 1354, 1382 ] ], "normalized": [] }, { "id": "3146348_T15", "type": "GENE-Y", "text": [ "human [Glu1]plasminogen" ], "offsets": [ [ 112, 135 ] ], "normalized": [] }, { "id": "3146348_T16", "type": "GENE-Y", "text": [ "[Glu1]Pg" ], "offsets": [ [ 401, 409 ] ], "normalized": [] }, { "id": "3146348_T17", "type": "GENE-Y", "text": [ "[Glu1]Pg" ], "offsets": [ [ 464, 472 ] ], "normalized": [] }, { "id": "3146348_T18", "type": "GENE-Y", "text": [ "t-PA" ], "offsets": [ [ 518, 522 ] ], "normalized": [] }, { "id": "3146348_T19", "type": "GENE-Y", "text": [ "( Glu1]Pg" ], "offsets": [ [ 137, 146 ] ], "normalized": [] }, { "id": "3146348_T20", "type": "GENE-N", "text": [ "Fibrinogen" ], "offsets": [ [ 675, 685 ] ], "normalized": [] }, { "id": "3146348_T21", "type": "GENE-Y", "text": [ "t-PA" ], "offsets": [ [ 782, 786 ] ], "normalized": [] }, { "id": "3146348_T22", "type": "GENE-N", "text": [ "fibrinogen" ], "offsets": [ [ 973, 983 ] ], "normalized": [] }, { "id": "3146348_T23", "type": "GENE-Y", "text": [ "tissue plasminogen activator" ], "offsets": [ [ 185, 213 ] ], "normalized": [] }, { "id": "3146348_T24", "type": "GENE-Y", "text": [ "[Glu1]Pg" ], "offsets": [ [ 1032, 1040 ] ], "normalized": [] }, { "id": "3146348_T25", "type": "GENE-Y", "text": [ "t-PA" ], "offsets": [ [ 1074, 1078 ] ], "normalized": [] }, { "id": "3146348_T26", "type": "GENE-Y", "text": [ "human [Glu1]plasminogen" ], "offsets": [ [ 31, 54 ] ], "normalized": [] }, { "id": "3146348_T27", "type": "GENE-Y", "text": [ "human tissue plasminogen activator" ], "offsets": [ [ 58, 92 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "20089905_title", "type": "title", "text": [ "A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons." ], "offsets": [ [ 0, 72 ] ] }, { "id": "20089905_abstract", "type": "abstract", "text": [ "Ibuprofen is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of cyclooxygenases. Recently, we have demonstrated that ibuprofen inhibits intracellular signaling of RhoA and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents. In addition, another study suggests that ibuprofen reduces generation of amyloid-beta42 peptide via inactivation of RhoA signaling, although it may also regulate amyloid-beta42 formation by direct inhibition of the gamma-secretase complex. The molecular mechanisms by which ibuprofen inhibits the RhoA signal in neurons, however, remain unclear. Here, we report that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for coupling ibuprofen to RhoA inhibition and subsequent neurite growth promotion in neurons. Ibuprofen activates PPARgamma in neuron-like PC12 and B104 cells. Activation of PPARgamma with traditional agonists mimics the RhoA-inhibiting properties of ibuprofen in PC12 cells and, like ibuprofen, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors. Protein knockdown with small interfering RNA specific for PPARgamma blocks RhoA suppression of PPARgamma agonists in PC12 cells. Moreover, the effect of ibuprofen on RhoA activity and neurite growth in neuronal cultures is prevented by selective PPARgamma inhibition. These findings support that PPARgamma plays an essential role in mediating the RhoA-inhibiting effect of ibuprofen. Elucidation of the novel molecular mechanisms linking ibuprofen to RhoA inhibition may provide additional therapeutic targets to the disorders characterized by RhoA activation, including spinal cord injuries and Alzheimer's disease." ], "offsets": [ [ 73, 1885 ] ] } ]

[ { "id": "20089905_T1", "type": "CHEMICAL", "text": [ "Ibuprofen" ], "offsets": [ [ 73, 82 ] ], "normalized": [] }, { "id": "20089905_T2", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 1131, 1140 ] ], "normalized": [] }, { "id": "20089905_T3", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 1165, 1174 ] ], "normalized": [] }, { "id": "20089905_T4", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 1422, 1431 ] ], "normalized": [] }, { "id": "20089905_T5", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 1642, 1651 ] ], "normalized": [] }, { "id": "20089905_T6", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 1707, 1716 ] ], "normalized": [] }, { "id": "20089905_T7", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 258, 267 ] ], "normalized": [] }, { "id": "20089905_T8", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 455, 464 ] ], "normalized": [] }, { "id": "20089905_T9", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 688, 697 ] ], "normalized": [] }, { "id": "20089905_T10", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 893, 902 ] ], "normalized": [] }, { "id": "20089905_T11", "type": "CHEMICAL", "text": [ "Ibuprofen" ], "offsets": [ [ 974, 983 ] ], "normalized": [] }, { "id": "20089905_T12", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 26, 35 ] ], "normalized": [] }, { "id": "20089905_T13", "type": "GENE-Y", "text": [ "RhoA" ], "offsets": [ [ 1101, 1105 ] ], "normalized": [] }, { "id": "20089905_T14", "type": "GENE-Y", "text": [ "PPARgamma" ], "offsets": [ [ 1327, 1336 ] ], "normalized": [] }, { "id": "20089905_T15", "type": "GENE-Y", "text": [ "RhoA" ], "offsets": [ [ 1344, 1348 ] ], "normalized": [] }, { "id": "20089905_T16", "type": "GENE-Y", "text": [ "PPARgamma" ], "offsets": [ [ 1364, 1373 ] ], "normalized": [] }, { "id": "20089905_T17", "type": "GENE-N", "text": [ "cyclooxygenases" ], "offsets": [ [ 205, 220 ] ], "normalized": [] }, { "id": "20089905_T18", "type": "GENE-Y", "text": [ "RhoA" ], "offsets": [ [ 1435, 1439 ] ], "normalized": [] }, { "id": "20089905_T19", "type": "GENE-Y", "text": [ "PPARgamma" ], "offsets": [ [ 1515, 1524 ] ], "normalized": [] }, { "id": "20089905_T20", "type": "GENE-Y", "text": [ "PPARgamma" ], "offsets": [ [ 1565, 1574 ] ], "normalized": [] }, { "id": "20089905_T21", "type": "GENE-Y", "text": [ "RhoA" ], "offsets": [ [ 1616, 1620 ] ], "normalized": [] }, { "id": "20089905_T22", "type": "GENE-Y", "text": [ "RhoA" ], "offsets": [ [ 1720, 1724 ] ], "normalized": [] }, { "id": "20089905_T23", "type": "GENE-Y", "text": [ "RhoA" ], "offsets": [ [ 1813, 1817 ] ], "normalized": [] }, { "id": "20089905_T24", "type": "GENE-Y", "text": [ "RhoA" ], "offsets": [ [ 304, 308 ] ], "normalized": [] }, { "id": "20089905_T25", "type": "GENE-Y", "text": [ "amyloid-beta42" ], "offsets": [ [ 487, 501 ] ], "normalized": [] }, { "id": "20089905_T26", "type": "GENE-Y", "text": [ "RhoA" ], "offsets": [ [ 530, 534 ] ], "normalized": [] }, { "id": "20089905_T27", "type": "GENE-Y", "text": [ "amyloid-beta42" ], "offsets": [ [ 576, 590 ] ], "normalized": [] }, { "id": "20089905_T28", "type": "GENE-N", "text": [ "gamma-secretase complex" ], "offsets": [ [ 629, 652 ] ], "normalized": [] }, { "id": "20089905_T29", "type": "GENE-Y", "text": [ "RhoA" ], "offsets": [ [ 711, 715 ] ], "normalized": [] }, { "id": "20089905_T30", "type": "GENE-Y", "text": [ "peroxisome proliferator-activated receptor gamma" ], "offsets": [ [ 806, 854 ] ], "normalized": [] }, { "id": "20089905_T31", "type": "GENE-Y", "text": [ "PPARgamma" ], "offsets": [ [ 856, 865 ] ], "normalized": [] }, { "id": "20089905_T32", "type": "GENE-Y", "text": [ "RhoA" ], "offsets": [ [ 906, 910 ] ], "normalized": [] }, { "id": "20089905_T33", "type": "GENE-Y", "text": [ "PPARgamma" ], "offsets": [ [ 994, 1003 ] ], "normalized": [] }, { "id": "20089905_T34", "type": "GENE-Y", "text": [ "PPARgamma" ], "offsets": [ [ 1054, 1063 ] ], "normalized": [] }, { "id": "20089905_T35", "type": "GENE-Y", "text": [ "RhoA" ], "offsets": [ [ 45, 49 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "11430635_title", "type": "title", "text": [ "Indomethacin activates carbonic anhydrase and antagonizes the effect of the specific carbonic anhydrase inhibitor acetazolamide, by a direct mechanism of action." ], "offsets": [ [ 0, 161 ] ] }, { "id": "11430635_abstract", "type": "abstract", "text": [ "OBJECTIVES: In this paper we investigated the effect of indomethacin, acetazolamide and their combination in vitro and in vivo on carbonic anhydrase (CA) isozymes. METHOD: In vitro experiments followed the effect of the two substances at concentrations between 10(-8)-10(-4) M on purified human red cell CA I and II as well as on human gastric mucosa CA IV using dose-response relationships. Kinetic studies were also performed. The effects of single and combined administration of indomethacin and acetazolamide on red cell CA and on gastric acid secretion were studied in vivo. RESULTS: Indomethacin, in vitro and in vivo. induces an increase in erythorcyte CA I and CA II activity. Acetazolamide, a specific inhibitor of CA, reduces the activity of CA I and CA II from red cells. Indomethacin completely antagonizes CA activity, i.e. abolishes the inhibitory effect of acetazolamide on CA. In humans, an increase or decrease in erythrocyte CA II activity is correlated with an increase or decrease in gastric acid secretion. CONCLUSIONS: Our results show that indomethacin, a known cyclooxygenase (COX) inhibitor, is also an activator of CA. Our data also prove that indomethacin is not only an activator of CA but also antagonizes the effect of acetazolamide, a specific inhibitor of this enzyme. In view of the role of CA in acid-base balance as well as the fact that an increase or decrease in its activity is accompanied by an increase or decrease in intra- and extracellular pH, our results suggest that: firstly, CA activation induced by indomethacin might cause changes in COX activity; secondly, PGs are synthetized as a consequence of the changes in COX activity, a hypothesis that requires further study." ], "offsets": [ [ 162, 1879 ] ] } ]

[ { "id": "11430635_T1", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 1225, 1237 ] ], "normalized": [] }, { "id": "11430635_T2", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 1332, 1344 ] ], "normalized": [] }, { "id": "11430635_T3", "type": "CHEMICAL", "text": [ "acetazolamide" ], "offsets": [ [ 1411, 1424 ] ], "normalized": [] }, { "id": "11430635_T4", "type": "CHEMICAL", "text": [ "carbonic" ], "offsets": [ [ 292, 300 ] ], "normalized": [] }, { "id": "11430635_T5", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 1709, 1721 ] ], "normalized": [] }, { "id": "11430635_T6", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 644, 656 ] ], "normalized": [] }, { "id": "11430635_T7", "type": "CHEMICAL", "text": [ "acetazolamide" ], "offsets": [ [ 661, 674 ] ], "normalized": [] }, { "id": "11430635_T8", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 218, 230 ] ], "normalized": [] }, { "id": "11430635_T9", "type": "CHEMICAL", "text": [ "Indomethacin" ], "offsets": [ [ 751, 763 ] ], "normalized": [] }, { "id": "11430635_T10", "type": "CHEMICAL", "text": [ "Acetazolamide" ], "offsets": [ [ 847, 860 ] ], "normalized": [] }, { "id": "11430635_T11", "type": "CHEMICAL", "text": [ "acetazolamide" ], "offsets": [ [ 232, 245 ] ], "normalized": [] }, { "id": "11430635_T12", "type": "CHEMICAL", "text": [ "Indomethacin" ], "offsets": [ [ 945, 957 ] ], "normalized": [] }, { "id": "11430635_T13", "type": "CHEMICAL", "text": [ "acetazolamide" ], "offsets": [ [ 1034, 1047 ] ], "normalized": [] }, { "id": "11430635_T14", "type": "CHEMICAL", "text": [ "Indomethacin" ], "offsets": [ [ 0, 12 ] ], "normalized": [] }, { "id": "11430635_T15", "type": "CHEMICAL", "text": [ "acetazolamide" ], "offsets": [ [ 114, 127 ] ], "normalized": [] }, { "id": "11430635_T16", "type": "CHEMICAL", "text": [ "carbonic" ], "offsets": [ [ 23, 31 ] ], "normalized": [] }, { "id": "11430635_T17", "type": "CHEMICAL", "text": [ "carbonic" ], "offsets": [ [ 85, 93 ] ], "normalized": [] }, { "id": "11430635_T18", "type": "GENE-N", "text": [ "cyclooxygenase" ], "offsets": [ [ 1247, 1261 ] ], "normalized": [] }, { "id": "11430635_T19", "type": "GENE-N", "text": [ "COX" ], "offsets": [ [ 1263, 1266 ] ], "normalized": [] }, { "id": "11430635_T20", "type": "GENE-N", "text": [ "CA" ], "offsets": [ [ 1303, 1305 ] ], "normalized": [] }, { "id": "11430635_T21", "type": "GENE-N", "text": [ "CA" ], "offsets": [ [ 1373, 1375 ] ], "normalized": [] }, { "id": "11430635_T22", "type": "GENE-N", "text": [ "carbonic anhydrase" ], "offsets": [ [ 292, 310 ] ], "normalized": [] }, { "id": "11430635_T23", "type": "GENE-N", "text": [ "CA" ], "offsets": [ [ 1486, 1488 ] ], "normalized": [] }, { "id": "11430635_T24", "type": "GENE-N", "text": [ "CA" ], "offsets": [ [ 312, 314 ] ], "normalized": [] }, { "id": "11430635_T25", "type": "GENE-N", "text": [ "CA" ], "offsets": [ [ 1684, 1686 ] ], "normalized": [] }, { "id": "11430635_T26", "type": "GENE-N", "text": [ "COX" ], "offsets": [ [ 1745, 1748 ] ], "normalized": [] }, { "id": "11430635_T27", "type": "GENE-N", "text": [ "COX" ], "offsets": [ [ 1824, 1827 ] ], "normalized": [] }, { "id": "11430635_T28", "type": "GENE-N", "text": [ "human red cell CA I and II" ], "offsets": [ [ 451, 477 ] ], "normalized": [] }, { "id": "11430635_T29", "type": "GENE-Y", "text": [ "human gastric mucosa CA IV" ], "offsets": [ [ 492, 518 ] ], "normalized": [] }, { "id": "11430635_T30", "type": "GENE-N", "text": [ "CA" ], "offsets": [ [ 687, 689 ] ], "normalized": [] }, { "id": "11430635_T31", "type": "GENE-Y", "text": [ "CA I" ], "offsets": [ [ 822, 826 ] ], "normalized": [] }, { "id": "11430635_T32", "type": "GENE-Y", "text": [ "CA II" ], "offsets": [ [ 831, 836 ] ], "normalized": [] }, { "id": "11430635_T33", "type": "GENE-N", "text": [ "CA" ], "offsets": [ [ 886, 888 ] ], "normalized": [] }, { "id": "11430635_T34", "type": "GENE-Y", "text": [ "CA I" ], "offsets": [ [ 914, 918 ] ], "normalized": [] }, { "id": "11430635_T35", "type": "GENE-Y", "text": [ "CA II" ], "offsets": [ [ 923, 928 ] ], "normalized": [] }, { "id": "11430635_T36", "type": "GENE-N", "text": [ "CA" ], "offsets": [ [ 981, 983 ] ], "normalized": [] }, { "id": "11430635_T37", "type": "GENE-N", "text": [ "CA" ], "offsets": [ [ 1051, 1053 ] ], "normalized": [] }, { "id": "11430635_T38", "type": "GENE-Y", "text": [ "CA II" ], "offsets": [ [ 1105, 1110 ] ], "normalized": [] }, { "id": "11430635_T39", "type": "GENE-N", "text": [ "carbonic anhydrase" ], "offsets": [ [ 23, 41 ] ], "normalized": [] }, { "id": "11430635_T40", "type": "GENE-N", "text": [ "carbonic anhydrase" ], "offsets": [ [ 85, 103 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "17409426_title", "type": "title", "text": [ "Nonsteroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3epsilon." ], "offsets": [ [ 0, 106 ] ] }, { "id": "17409426_abstract", "type": "abstract", "text": [ "To determine the role of 14-3-3 in colorectal cancer apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs), we evaluated the effects of sulindac on 14-3-3epsilon protein expression in colorectal cancer cells. Sulindac sulfide inhibited 14-3-3epsilon proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner. Sulindac sulfone at 600 mumol/L inhibited 14-3-3epsilon protein expression in HT-29. Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac. Sulindac suppressed 14-3-3epsilon promoter activity. As 14-3-3epsilon promoter activation is mediated by peroxisome proliferator-activated receptor delta (PPARdelta), we determined the correlation between 14-3-3epsilon inhibition and PPARdelta suppression by NSAIDs. Sulindac sulfide inhibited PPARdelta protein expression and PPARdelta transcriptional activity. Overexpression of PPARdelta by adenoviral transfer rescued 14-3-3epsilon proteins from elimination by sulindac or indomethacin. NSAID-induced 14-3-3epsilon suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPARdelta transduction. Stable expression of 14-3-3epsilon in HT-29 significantly protected cells from apoptosis. Our findings shed light on a novel mechanism by which NSAIDs induce colorectal cancer apoptosis via the PPARdelta/14-3-3epsilon transcriptional pathway. These results suggest that 14-3-3epsilon is a target for the prevention and therapy of colorectal cancer." ], "offsets": [ [ 107, 1678 ] ] } ]

[ { "id": "17409426_T1", "type": "CHEMICAL", "text": [ "sulindac" ], "offsets": [ [ 1112, 1120 ] ], "normalized": [] }, { "id": "17409426_T2", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 1124, 1136 ] ], "normalized": [] }, { "id": "17409426_T3", "type": "CHEMICAL", "text": [ "sulindac" ], "offsets": [ [ 256, 264 ] ], "normalized": [] }, { "id": "17409426_T4", "type": "CHEMICAL", "text": [ "Sulindac sulfide" ], "offsets": [ [ 329, 345 ] ], "normalized": [] }, { "id": "17409426_T5", "type": "CHEMICAL", "text": [ "Sulindac sulfone" ], "offsets": [ [ 451, 467 ] ], "normalized": [] }, { "id": "17409426_T6", "type": "CHEMICAL", "text": [ "Indomethacin" ], "offsets": [ [ 536, 548 ] ], "normalized": [] }, { "id": "17409426_T7", "type": "CHEMICAL", "text": [ "SC-236" ], "offsets": [ [ 553, 559 ] ], "normalized": [] }, { "id": "17409426_T8", "type": "CHEMICAL", "text": [ "sulindac" ], "offsets": [ [ 637, 645 ] ], "normalized": [] }, { "id": "17409426_T9", "type": "CHEMICAL", "text": [ "Sulindac" ], "offsets": [ [ 647, 655 ] ], "normalized": [] }, { "id": "17409426_T10", "type": "CHEMICAL", "text": [ "Sulindac sulfide" ], "offsets": [ [ 914, 930 ] ], "normalized": [] }, { "id": "17409426_T11", "type": "GENE-Y", "text": [ "14-3-3epsilon" ], "offsets": [ [ 1152, 1165 ] ], "normalized": [] }, { "id": "17409426_T12", "type": "GENE-Y", "text": [ "cytosolic Bad" ], "offsets": [ [ 1206, 1219 ] ], "normalized": [] }, { "id": "17409426_T13", "type": "GENE-Y", "text": [ "mitochondrial Bad" ], "offsets": [ [ 1238, 1255 ] ], "normalized": [] }, { "id": "17409426_T14", "type": "GENE-Y", "text": [ "PPARdelta" ], "offsets": [ [ 1306, 1315 ] ], "normalized": [] }, { "id": "17409426_T15", "type": "GENE-Y", "text": [ "14-3-3epsilon" ], "offsets": [ [ 1351, 1364 ] ], "normalized": [] }, { "id": "17409426_T16", "type": "GENE-Y", "text": [ "PPARdelta" ], "offsets": [ [ 1524, 1533 ] ], "normalized": [] }, { "id": "17409426_T17", "type": "GENE-Y", "text": [ "14-3-3epsilon" ], "offsets": [ [ 1534, 1547 ] ], "normalized": [] }, { "id": "17409426_T18", "type": "GENE-Y", "text": [ "14-3-3epsilon" ], "offsets": [ [ 1600, 1613 ] ], "normalized": [] }, { "id": "17409426_T19", "type": "GENE-Y", "text": [ "14-3-3epsilon protein" ], "offsets": [ [ 268, 289 ] ], "normalized": [] }, { "id": "17409426_T20", "type": "GENE-Y", "text": [ "14-3-3epsilon proteins" ], "offsets": [ [ 356, 378 ] ], "normalized": [] }, { "id": "17409426_T21", "type": "GENE-N", "text": [ "14-3-3" ], "offsets": [ [ 132, 138 ] ], "normalized": [] }, { "id": "17409426_T22", "type": "GENE-Y", "text": [ "cyclooxygenase-2" ], "offsets": [ [ 573, 589 ] ], "normalized": [] }, { "id": "17409426_T23", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 591, 596 ] ], "normalized": [] }, { "id": "17409426_T24", "type": "GENE-N", "text": [ "14-3-3epsilon promoter" ], "offsets": [ [ 703, 725 ] ], "normalized": [] }, { "id": "17409426_T25", "type": "GENE-Y", "text": [ "peroxisome proliferator-activated receptor delta" ], "offsets": [ [ 752, 800 ] ], "normalized": [] }, { "id": "17409426_T26", "type": "GENE-Y", "text": [ "PPARdelta" ], "offsets": [ [ 802, 811 ] ], "normalized": [] }, { "id": "17409426_T27", "type": "GENE-Y", "text": [ "14-3-3epsilon" ], "offsets": [ [ 852, 865 ] ], "normalized": [] }, { "id": "17409426_T28", "type": "GENE-Y", "text": [ "PPARdelta" ], "offsets": [ [ 881, 890 ] ], "normalized": [] }, { "id": "17409426_T29", "type": "GENE-Y", "text": [ "PPARdelta" ], "offsets": [ [ 941, 950 ] ], "normalized": [] }, { "id": "17409426_T30", "type": "GENE-Y", "text": [ "PPARdelta" ], "offsets": [ [ 974, 983 ] ], "normalized": [] }, { "id": "17409426_T31", "type": "GENE-Y", "text": [ "PPARdelta" ], "offsets": [ [ 1028, 1037 ] ], "normalized": [] }, { "id": "17409426_T32", "type": "GENE-Y", "text": [ "14-3-3epsilon" ], "offsets": [ [ 1069, 1082 ] ], "normalized": [] }, { "id": "17409426_T33", "type": "GENE-Y", "text": [ "14-3-3epsilon" ], "offsets": [ [ 92, 105 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "3058238_title", "type": "title", "text": [ "Tamoxifen and fluoxymesterone versus tamoxifen and danazol in metastatic breast cancer--a randomized study." ], "offsets": [ [ 0, 107 ] ] }, { "id": "3058238_abstract", "type": "abstract", "text": [ "A prospective randomized trial of tamoxifen and fluoxymesterone versus tamoxifen and danazol in metastatic breast cancer was conducted from December 1980 to September 1985. Patients were eligible regardless of site of disease, estrogen receptor status, or age. Sixty-two of sixty-three randomized patients were evaluable for response. Overall response for tamoxifen and fluoxymesterone was 11% with 61% stabilization of disease, versus 12% response rate for tamoxifen and danazol with 59% stabilization. Toxicities with tamoxifen and fluoxymesterone were greater with an increase in masculinization. We conclude that the response rates to the combinations of tamoxifen and fluoxymesterone or tamoxifen and danazol reported are equivalent in this study but that the increased toxicity with tamoxifen and fluoxymesterone would make tamoxifen and danazol the treatment of choice if a combination were to be used." ], "offsets": [ [ 108, 1017 ] ] } ]

[ { "id": "3058238_T1", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 335, 343 ] ], "normalized": [] }, { "id": "3058238_T2", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 142, 151 ] ], "normalized": [] }, { "id": "3058238_T3", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 464, 473 ] ], "normalized": [] }, { "id": "3058238_T4", "type": "CHEMICAL", "text": [ "fluoxymesterone" ], "offsets": [ [ 478, 493 ] ], "normalized": [] }, { "id": "3058238_T5", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 566, 575 ] ], "normalized": [] }, { "id": "3058238_T6", "type": "CHEMICAL", "text": [ "danazol" ], "offsets": [ [ 580, 587 ] ], "normalized": [] }, { "id": "3058238_T7", "type": "CHEMICAL", "text": [ "fluoxymesterone" ], "offsets": [ [ 156, 171 ] ], "normalized": [] }, { "id": "3058238_T8", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 628, 637 ] ], "normalized": [] }, { "id": "3058238_T9", "type": "CHEMICAL", "text": [ "fluoxymesterone" ], "offsets": [ [ 642, 657 ] ], "normalized": [] }, { "id": "3058238_T10", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 767, 776 ] ], "normalized": [] }, { "id": "3058238_T11", "type": "CHEMICAL", "text": [ "fluoxymesterone" ], "offsets": [ [ 781, 796 ] ], "normalized": [] }, { "id": "3058238_T12", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 800, 809 ] ], "normalized": [] }, { "id": "3058238_T13", "type": "CHEMICAL", "text": [ "danazol" ], "offsets": [ [ 814, 821 ] ], "normalized": [] }, { "id": "3058238_T14", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 179, 188 ] ], "normalized": [] }, { "id": "3058238_T15", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 897, 906 ] ], "normalized": [] }, { "id": "3058238_T16", "type": "CHEMICAL", "text": [ "fluoxymesterone" ], "offsets": [ [ 911, 926 ] ], "normalized": [] }, { "id": "3058238_T17", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 938, 947 ] ], "normalized": [] }, { "id": "3058238_T18", "type": "CHEMICAL", "text": [ "danazol" ], "offsets": [ [ 952, 959 ] ], "normalized": [] }, { "id": "3058238_T19", "type": "CHEMICAL", "text": [ "danazol" ], "offsets": [ [ 193, 200 ] ], "normalized": [] }, { "id": "3058238_T20", "type": "CHEMICAL", "text": [ "Tamoxifen" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "3058238_T21", "type": "CHEMICAL", "text": [ "fluoxymesterone" ], "offsets": [ [ 14, 29 ] ], "normalized": [] }, { "id": "3058238_T22", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 37, 46 ] ], "normalized": [] }, { "id": "3058238_T23", "type": "CHEMICAL", "text": [ "danazol" ], "offsets": [ [ 51, 58 ] ], "normalized": [] }, { "id": "3058238_T24", "type": "GENE-Y", "text": [ "estrogen receptor" ], "offsets": [ [ 335, 352 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "10935465_title", "type": "title", "text": [ "The apoptosome: heart and soul of the cell death machine." ], "offsets": [ [ 0, 57 ] ] }, { "id": "10935465_abstract", "type": "abstract", "text": [ "Apoptosis is a fundamental biologic process by which metazoan cells orchestrate their own self-demise. Genetic analyses of the nematode C elegans identified three core components of the suicide apparatus which include CED-3, CED-4, and CED-9. An analogous set of core constituents exists in mammalian cells and includes caspase-9, Apaf-1, and bcl-2/xL, respectively. CED-3 and CED-4, along with their mammalian counterparts, function to kill cells, whereas CED-9 and its mammalian equivalents protect cells from death. These central components biochemically intermingle in a ternary complex recently dubbed the \"apoptosome.\" The C elegans protein EGL-1 and its mammalian counterparts, pro-apoptotic members of the bcl-2 family, induce cell death by disrupting apoptosome interactions. Thus, EGL-1 may represent a primordial signal integrator for the apoptosome. Various biochemical processes including oligomerization, adenosine triphosphate ATP/dATP binding, and cytochrome c interaction play a role in regulating the ternary death complex. Recent studies suggest that cell death receptors, such as CD95, may amplify their suicide signal by activating the apoptosome. These mutual associations by core components of the suicide apparatus provide a molecular framework in which diverse death signals likely interface. Understanding the apoptosome and its cellular connections will facilitate the design of novel therapeutic strategies for cancer and other disease states in which apoptosis plays a pivotal role." ], "offsets": [ [ 58, 1569 ] ] } ]

[ { "id": "10935465_T1", "type": "CHEMICAL", "text": [ "adenosine triphosphate" ], "offsets": [ [ 977, 999 ] ], "normalized": [] }, { "id": "10935465_T2", "type": "CHEMICAL", "text": [ "ATP" ], "offsets": [ [ 1000, 1003 ] ], "normalized": [] }, { "id": "10935465_T3", "type": "GENE-N", "text": [ "death receptors" ], "offsets": [ [ 1133, 1148 ] ], "normalized": [] }, { "id": "10935465_T4", "type": "GENE-Y", "text": [ "CD95" ], "offsets": [ [ 1158, 1162 ] ], "normalized": [] }, { "id": "10935465_T5", "type": "GENE-Y", "text": [ "CED-3" ], "offsets": [ [ 276, 281 ] ], "normalized": [] }, { "id": "10935465_T6", "type": "GENE-Y", "text": [ "CED-4" ], "offsets": [ [ 283, 288 ] ], "normalized": [] }, { "id": "10935465_T7", "type": "GENE-Y", "text": [ "CED-9" ], "offsets": [ [ 294, 299 ] ], "normalized": [] }, { "id": "10935465_T8", "type": "GENE-Y", "text": [ "caspase-9" ], "offsets": [ [ 378, 387 ] ], "normalized": [] }, { "id": "10935465_T9", "type": "GENE-Y", "text": [ "Apaf-1" ], "offsets": [ [ 389, 395 ] ], "normalized": [] }, { "id": "10935465_T10", "type": "GENE-N", "text": [ "bcl-2/xL" ], "offsets": [ [ 401, 409 ] ], "normalized": [] }, { "id": "10935465_T11", "type": "GENE-Y", "text": [ "CED-3" ], "offsets": [ [ 425, 430 ] ], "normalized": [] }, { "id": "10935465_T12", "type": "GENE-Y", "text": [ "CED-4" ], "offsets": [ [ 435, 440 ] ], "normalized": [] }, { "id": "10935465_T13", "type": "GENE-Y", "text": [ "CED-9" ], "offsets": [ [ 515, 520 ] ], "normalized": [] }, { "id": "10935465_T14", "type": "GENE-Y", "text": [ "EGL-1" ], "offsets": [ [ 705, 710 ] ], "normalized": [] }, { "id": "10935465_T15", "type": "GENE-N", "text": [ "bcl-2" ], "offsets": [ [ 772, 777 ] ], "normalized": [] }, { "id": "10935465_T16", "type": "GENE-Y", "text": [ "EGL-1" ], "offsets": [ [ 849, 854 ] ], "normalized": [] }, { "id": "10935465_T17", "type": "GENE-Y", "text": [ "cytochrome c" ], "offsets": [ [ 1022, 1034 ] ], "normalized": [] } ]

[]

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[ { "id": "23623751_title", "type": "title", "text": [ "Adolescence methylphenidate treatment in a rodent model of attention deficit/hyperactivity disorder: Dopamine transporter function and cellular distribution in adulthood." ], "offsets": [ [ 0, 170 ] ] }, { "id": "23623751_abstract", "type": "abstract", "text": [ "Attention deficit/hyperactivity disorder (ADHD) is attributed to dysfunction of the prefrontal cortex. Methylphenidate, an inhibitor of dopamine and norepinephrine transporters (DAT and NET, respectively), is a standard treatment for ADHD. The Spontaneously Hypertensive Rat (SHR) is a well-established animal model of ADHD. Our previous results showed that methylphenidate treatment in adolescent SHR enhanced cocaine self-administration during adulthood, and alterations in DAT function in prefrontal cortex play a role in this response. Importantly, prefrontal cortex subregions, orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC), have been shown to have distinct roles in ADHD and cocaine self-administration. In the current study, SHR, Wistar-Kyoto (WKY) and Wistar (WIS) rats received a therapeutically relevant dose of methylphenidate (1.5mg/kg, p.o.) or vehicle during adolescence and then OFC and mPFC DAT function and cellular expression were assessed during adulthood. In both OFC and mPFC, no strain differences in Vmax or Km for dopamine uptake into synaptosomes were found between vehicle-treated SHR, WKY and WIS. Methylphenidate increased DAT Vmax in SHR mPFC and decreased DAT Vmax in WKY OFC. Also, methylphenidate decreased DAT Km in WIS OFC. Further, methylphenidate did not alter DAT cellular localization, indicating that methylphenidate treatment during adolescence regulated DAT function in SHR mPFC in a trafficking-independent manner. Thus, the increase in mPFC DAT function was an SHR-specific long term consequence of methylphenidate treatment during adolescence, which may be responsible for the treatment-induced alterations in behavior including the observed increases in cocaine self-administration." ], "offsets": [ [ 171, 1915 ] ] } ]

[ { "id": "23623751_T1", "type": "CHEMICAL", "text": [ "Methylphenidate" ], "offsets": [ [ 274, 289 ] ], "normalized": [] }, { "id": "23623751_T2", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 1226, 1234 ] ], "normalized": [] }, { "id": "23623751_T3", "type": "CHEMICAL", "text": [ "Methylphenidate" ], "offsets": [ [ 1313, 1328 ] ], "normalized": [] }, { "id": "23623751_T4", "type": "CHEMICAL", "text": [ "methylphenidate" ], "offsets": [ [ 1401, 1416 ] ], "normalized": [] }, { "id": "23623751_T5", "type": "CHEMICAL", "text": [ "methylphenidate" ], "offsets": [ [ 1455, 1470 ] ], "normalized": [] }, { "id": "23623751_T6", "type": "CHEMICAL", "text": [ "methylphenidate" ], "offsets": [ [ 1528, 1543 ] ], "normalized": [] }, { "id": "23623751_T7", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 307, 315 ] ], "normalized": [] }, { "id": "23623751_T8", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 320, 334 ] ], "normalized": [] }, { "id": "23623751_T9", "type": "CHEMICAL", "text": [ "methylphenidate" ], "offsets": [ [ 1730, 1745 ] ], "normalized": [] }, { "id": "23623751_T10", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 1887, 1894 ] ], "normalized": [] }, { "id": "23623751_T11", "type": "CHEMICAL", "text": [ "methylphenidate" ], "offsets": [ [ 529, 544 ] ], "normalized": [] }, { "id": "23623751_T12", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 582, 589 ] ], "normalized": [] }, { "id": "23623751_T13", "type": "CHEMICAL", "text": [ "cocaine" ], "offsets": [ [ 869, 876 ] ], "normalized": [] }, { "id": "23623751_T14", "type": "CHEMICAL", "text": [ "methylphenidate" ], "offsets": [ [ 1010, 1025 ] ], "normalized": [] }, { "id": "23623751_T15", "type": "CHEMICAL", "text": [ "Dopamine" ], "offsets": [ [ 101, 109 ] ], "normalized": [] }, { "id": "23623751_T16", "type": "CHEMICAL", "text": [ "methylphenidate" ], "offsets": [ [ 12, 27 ] ], "normalized": [] }, { "id": "23623751_T17", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 1339, 1342 ] ], "normalized": [] }, { "id": "23623751_T18", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 1374, 1377 ] ], "normalized": [] }, { "id": "23623751_T19", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 1427, 1430 ] ], "normalized": [] }, { "id": "23623751_T20", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 1485, 1488 ] ], "normalized": [] }, { "id": "23623751_T21", "type": "GENE-N", "text": [ "dopamine and norepinephrine transporters" ], "offsets": [ [ 307, 347 ] ], "normalized": [] }, { "id": "23623751_T22", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 1583, 1586 ] ], "normalized": [] }, { "id": "23623751_T23", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 1672, 1675 ] ], "normalized": [] }, { "id": "23623751_T24", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 349, 352 ] ], "normalized": [] }, { "id": "23623751_T25", "type": "GENE-Y", "text": [ "NET" ], "offsets": [ [ 357, 360 ] ], "normalized": [] }, { "id": "23623751_T26", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 647, 650 ] ], "normalized": [] }, { "id": "23623751_T27", "type": "GENE-Y", "text": [ "DAT" ], "offsets": [ [ 1095, 1098 ] ], "normalized": [] }, { "id": "23623751_T28", "type": "GENE-Y", "text": [ "Dopamine transporter" ], "offsets": [ [ 101, 121 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23623751_0", "type": "INHIBITOR", "arg1_id": "23623751_T1", "arg2_id": "23623751_T24", "normalized": [] }, { "id": "23623751_1", "type": "INHIBITOR", "arg1_id": "23623751_T1", "arg2_id": "23623751_T25", "normalized": [] }, { "id": "23623751_2", "type": "ACTIVATOR", "arg1_id": "23623751_T3", "arg2_id": "23623751_T17", "normalized": [] }, { "id": "23623751_3", "type": "INHIBITOR", "arg1_id": "23623751_T3", "arg2_id": "23623751_T18", "normalized": [] }, { "id": "23623751_4", "type": "INHIBITOR", "arg1_id": "23623751_T4", "arg2_id": "23623751_T19", "normalized": [] } ]

[ { "id": "23434227_title", "type": "title", "text": [ "Synthesis and cytotoxicity evaluation of oleanolic acid derivatives." ], "offsets": [ [ 0, 68 ] ] }, { "id": "23434227_abstract", "type": "abstract", "text": [ "Twelve derivatives of oleanolic acid (1) have been synthesized and evaluated for their inhibitory activities against the growth of prostate PC3, breast MCF-7, lung A549, and gastric BGC-823 cancer cells by MTT assays. Within these series of derivatives, compound 17 exhibited the most potent cytotoxicity against PC3 cell line (IC50=0.39 μM) and compound 28 displayed the best activity against A549 cell line (IC50=0.22 μM). SAR analysis indicates that H-donor substitution at C-3 position of oleanolic acid may be advantageous for improvement of cytotoxicity against PC3, A549 and MCF-7 cell lines." ], "offsets": [ [ 69, 668 ] ] } ]

[ { "id": "23434227_T1", "type": "CHEMICAL", "text": [ "MTT" ], "offsets": [ [ 275, 278 ] ], "normalized": [] }, { "id": "23434227_T2", "type": "CHEMICAL", "text": [ "oleanolic acid" ], "offsets": [ [ 91, 105 ] ], "normalized": [] }, { "id": "23434227_T3", "type": "CHEMICAL", "text": [ "H" ], "offsets": [ [ 522, 523 ] ], "normalized": [] }, { "id": "23434227_T4", "type": "CHEMICAL", "text": [ "oleanolic acid" ], "offsets": [ [ 562, 576 ] ], "normalized": [] }, { "id": "23434227_T5", "type": "CHEMICAL", "text": [ "oleanolic acid" ], "offsets": [ [ 41, 55 ] ], "normalized": [] } ]

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[ { "id": "16249524_title", "type": "title", "text": [ "Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity." ], "offsets": [ [ 0, 75 ] ] }, { "id": "16249524_abstract", "type": "abstract", "text": [ "Obesity continues to be a burgeoning health problem worldwide. Before their removal from the market, fenfluramine and the more active enantiomer dexfenfluramine were considered to be among the most effective of weight loss agents. Much of the weight loss produced by fenfluramine was attributed to the direct activation of serotonin 5-HT(2C) receptors in the central nervous system via the desmethyl-metabolite of fenfluramine, norfenfluramine. Norfenfluramine, however, is non-selective, activating additional serotonin receptors, such as 5-HT(2A) and 5-HT(2B), which likely mediated the heart valve hypertrophy seen in many patients. Development of highly selective 5-HT(2C) agonists may recapitulate the clinical anti-obesity properties observed with fenfluramine while avoiding the significant cardiovascular and pulmonary side effects." ], "offsets": [ [ 76, 916 ] ] } ]

[ { "id": "16249524_T1", "type": "CHEMICAL", "text": [ "fenfluramine" ], "offsets": [ [ 177, 189 ] ], "normalized": [] }, { "id": "16249524_T2", "type": "CHEMICAL", "text": [ "dexfenfluramine" ], "offsets": [ [ 221, 236 ] ], "normalized": [] }, { "id": "16249524_T3", "type": "CHEMICAL", "text": [ "fenfluramine" ], "offsets": [ [ 343, 355 ] ], "normalized": [] }, { "id": "16249524_T4", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 399, 408 ] ], "normalized": [] }, { "id": "16249524_T5", "type": "CHEMICAL", "text": [ "fenfluramine" ], "offsets": [ [ 490, 502 ] ], "normalized": [] }, { "id": "16249524_T6", "type": "CHEMICAL", "text": [ "norfenfluramin" ], "offsets": [ [ 504, 518 ] ], "normalized": [] }, { "id": "16249524_T7", "type": "CHEMICAL", "text": [ "Norfenfluramine" ], "offsets": [ [ 521, 536 ] ], "normalized": [] }, { "id": "16249524_T8", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 587, 596 ] ], "normalized": [] }, { "id": "16249524_T9", "type": "CHEMICAL", "text": [ "fenfluramine" ], "offsets": [ [ 830, 842 ] ], "normalized": [] }, { "id": "16249524_T10", "type": "CHEMICAL", "text": [ "Serotonin" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "16249524_T11", "type": "GENE-Y", "text": [ "serotonin 5-HT(2C) receptors" ], "offsets": [ [ 399, 427 ] ], "normalized": [] }, { "id": "16249524_T12", "type": "GENE-N", "text": [ "serotonin receptors" ], "offsets": [ [ 587, 606 ] ], "normalized": [] }, { "id": "16249524_T13", "type": "GENE-Y", "text": [ "5-HT(2A)" ], "offsets": [ [ 616, 624 ] ], "normalized": [] }, { "id": "16249524_T14", "type": "GENE-Y", "text": [ "5-HT(2B)" ], "offsets": [ [ 629, 637 ] ], "normalized": [] }, { "id": "16249524_T15", "type": "GENE-Y", "text": [ "5-HT(2C)" ], "offsets": [ [ 744, 752 ] ], "normalized": [] }, { "id": "16249524_T16", "type": "GENE-Y", "text": [ "Serotonin 5-ht2c receptor" ], "offsets": [ [ 0, 25 ] ], "normalized": [] } ]

[]

[]

[ { "id": "16249524_0", "type": "ACTIVATOR", "arg1_id": "16249524_T3", "arg2_id": "16249524_T11", "normalized": [] }, { "id": "16249524_1", "type": "ACTIVATOR", "arg1_id": "16249524_T5", "arg2_id": "16249524_T11", "normalized": [] }, { "id": "16249524_2", "type": "ACTIVATOR", "arg1_id": "16249524_T6", "arg2_id": "16249524_T11", "normalized": [] }, { "id": "16249524_3", "type": "ACTIVATOR", "arg1_id": "16249524_T7", "arg2_id": "16249524_T12", "normalized": [] }, { "id": "16249524_4", "type": "ACTIVATOR", "arg1_id": "16249524_T7", "arg2_id": "16249524_T13", "normalized": [] }, { "id": "16249524_5", "type": "ACTIVATOR", "arg1_id": "16249524_T7", "arg2_id": "16249524_T14", "normalized": [] } ]

[ { "id": "10670413_title", "type": "title", "text": [ "The prostaglandin E series modulates high-voltage-activated calcium channels probably through the EP3 receptor in rat paratracheal ganglia." ], "offsets": [ [ 0, 139 ] ] }, { "id": "10670413_abstract", "type": "abstract", "text": [ "The modulation of high-voltage-activated (HVA) Ca2+ channels by the prostaglandin E series (PGE1 and PGE2) was studied in the paratracheal ganglion cells. Prostaglandin E1, E2, STA2 (a stable analogue of thromboxane A2), 17-phenyl-trinor-PGE2 (an EP1-selective agonist) and sulprostone (an EP3-selective agonist) inhibited the HVA Ca2+ current (HVA ICa) dose-dependently, and the rank order of potency to inhibit HVA Ca2+ channels was sulprostone>PGE2, PGE1>STA2>>17-phenyl-trinor-PGE2. SC-51089 (10(-5) M), a selective EP1-receptor antagonist, showed no effect on the PGE1- or PGE2-induced inhibition of the HVA ICa, thereby indicating that PGE1- and PGE2-induced inhibition of the HVA Ca2+ channels is possibly mediated by the EP3 receptor. The PGE1-sensitive component of the current was markedly reduced in the presence of omega-conotoxin-GVIA (3x10(-6) M), but not with nifedipine (3x10(-6) M). PGE1 and PGE2 also inhibited the remaining ICa in a saturating concentration of nifedipine, omega-conotoxin-GVIA and omega-conotoxin-MVIIC, suggesting that R-type Ca2+ channels are involved. The inhibitory effect of PGE1 or sulprostone was prevented by pretreatment with pertussis toxin [islet activating protein (IAP)] or phorbol-12-myristate-13-acetate (PMA), and the protein kinase C (PKC) inhibitor chelerythrine blocked the action of PMA. It was concluded that PGE1 selectively reduces both N- and R-type Ca2+ currents by activating a G-protein probably through the EP3 receptor in paratracheal ganglion cells." ], "offsets": [ [ 140, 1655 ] ] } ]

[ { "id": "10670413_T1", "type": "CHEMICAL", "text": [ "PGE2" ], "offsets": [ [ 241, 245 ] ], "normalized": [] }, { "id": "10670413_T2", "type": "CHEMICAL", "text": [ "Ca2+" ], "offsets": [ [ 1203, 1207 ] ], "normalized": [] }, { "id": "10670413_T3", "type": "CHEMICAL", "text": [ "PGE1" ], "offsets": [ [ 1256, 1260 ] ], "normalized": [] }, { "id": "10670413_T4", "type": "CHEMICAL", "text": [ "sulprostone" ], "offsets": [ [ 1264, 1275 ] ], "normalized": [] }, { "id": "10670413_T5", "type": "CHEMICAL", "text": [ "phorbol-12-myristate-13-acetate" ], "offsets": [ [ 1363, 1394 ] ], "normalized": [] }, { "id": "10670413_T6", "type": "CHEMICAL", "text": [ "PMA" ], "offsets": [ [ 1396, 1399 ] ], "normalized": [] }, { "id": "10670413_T7", "type": "CHEMICAL", "text": [ "chelerythrine" ], "offsets": [ [ 1443, 1456 ] ], "normalized": [] }, { "id": "10670413_T8", "type": "CHEMICAL", "text": [ "PMA" ], "offsets": [ [ 1479, 1482 ] ], "normalized": [] }, { "id": "10670413_T9", "type": "CHEMICAL", "text": [ "PGE1" ], "offsets": [ [ 1506, 1510 ] ], "normalized": [] }, { "id": "10670413_T10", "type": "CHEMICAL", "text": [ "Ca2+" ], "offsets": [ [ 1550, 1554 ] ], "normalized": [] }, { "id": "10670413_T11", "type": "CHEMICAL", "text": [ "Prostaglandin E1, E2," ], "offsets": [ [ 295, 316 ] ], "normalized": [] }, { "id": "10670413_T12", "type": "CHEMICAL", "text": [ "STA2" ], "offsets": [ [ 317, 321 ] ], "normalized": [] }, { "id": "10670413_T13", "type": "CHEMICAL", "text": [ "thromboxane A2" ], "offsets": [ [ 344, 358 ] ], "normalized": [] }, { "id": "10670413_T14", "type": "CHEMICAL", "text": [ "17-phenyl-trinor-PGE2" ], "offsets": [ [ 361, 382 ] ], "normalized": [] }, { "id": "10670413_T15", "type": "CHEMICAL", "text": [ "sulprostone" ], "offsets": [ [ 414, 425 ] ], "normalized": [] }, { "id": "10670413_T16", "type": "CHEMICAL", "text": [ "Ca2+" ], "offsets": [ [ 471, 475 ] ], "normalized": [] }, { "id": "10670413_T17", "type": "CHEMICAL", "text": [ "Ca2+" ], "offsets": [ [ 557, 561 ] ], "normalized": [] }, { "id": "10670413_T18", "type": "CHEMICAL", "text": [ "sulprostone" ], "offsets": [ [ 575, 586 ] ], "normalized": [] }, { "id": "10670413_T19", "type": "CHEMICAL", "text": [ "PGE2" ], "offsets": [ [ 587, 591 ] ], "normalized": [] }, { "id": "10670413_T20", "type": "CHEMICAL", "text": [ "PGE1" ], "offsets": [ [ 593, 597 ] ], "normalized": [] }, { "id": "10670413_T21", "type": "CHEMICAL", "text": [ "STA2" ], "offsets": [ [ 598, 602 ] ], "normalized": [] }, { "id": "10670413_T22", "type": "CHEMICAL", "text": [ "17-phenyl-trinor-PGE2" ], "offsets": [ [ 604, 625 ] ], "normalized": [] }, { "id": "10670413_T23", "type": "CHEMICAL", "text": [ "Ca2+" ], "offsets": [ [ 187, 191 ] ], "normalized": [] }, { "id": "10670413_T24", "type": "CHEMICAL", "text": [ "SC-51089" ], "offsets": [ [ 627, 635 ] ], "normalized": [] }, { "id": "10670413_T25", "type": "CHEMICAL", "text": [ "PGE1" ], "offsets": [ [ 709, 713 ] ], "normalized": [] }, { "id": "10670413_T26", "type": "CHEMICAL", "text": [ "PGE2" ], "offsets": [ [ 718, 722 ] ], "normalized": [] }, { "id": "10670413_T27", "type": "CHEMICAL", "text": [ "PGE1" ], "offsets": [ [ 782, 786 ] ], "normalized": [] }, { "id": "10670413_T28", "type": "CHEMICAL", "text": [ "PGE2" ], "offsets": [ [ 792, 796 ] ], "normalized": [] }, { "id": "10670413_T29", "type": "CHEMICAL", "text": [ "Ca2+" ], "offsets": [ [ 827, 831 ] ], "normalized": [] }, { "id": "10670413_T30", "type": "CHEMICAL", "text": [ "prostaglandin E" ], "offsets": [ [ 208, 223 ] ], "normalized": [] }, { "id": "10670413_T31", "type": "CHEMICAL", "text": [ "PGE1" ], "offsets": [ [ 887, 891 ] ], "normalized": [] }, { "id": "10670413_T32", "type": "CHEMICAL", "text": [ "nifedipine" ], "offsets": [ [ 1015, 1025 ] ], "normalized": [] }, { "id": "10670413_T33", "type": "CHEMICAL", "text": [ "PGE1" ], "offsets": [ [ 1040, 1044 ] ], "normalized": [] }, { "id": "10670413_T34", "type": "CHEMICAL", "text": [ "PGE2" ], "offsets": [ [ 1049, 1053 ] ], "normalized": [] }, { "id": "10670413_T35", "type": "CHEMICAL", "text": [ "PGE1" ], "offsets": [ [ 232, 236 ] ], "normalized": [] }, { "id": "10670413_T36", "type": "CHEMICAL", "text": [ "nifedipine" ], "offsets": [ [ 1120, 1130 ] ], "normalized": [] }, { "id": "10670413_T37", "type": "CHEMICAL", "text": [ "prostaglandin E" ], "offsets": [ [ 4, 19 ] ], "normalized": [] }, { "id": "10670413_T38", "type": "CHEMICAL", "text": [ "calcium" ], "offsets": [ [ 60, 67 ] ], "normalized": [] }, { "id": "10670413_T39", "type": "GENE-N", "text": [ "R-type Ca2+ channels" ], "offsets": [ [ 1196, 1216 ] ], "normalized": [] }, { "id": "10670413_T40", "type": "GENE-N", "text": [ "pertussis toxin" ], "offsets": [ [ 1311, 1326 ] ], "normalized": [] }, { "id": "10670413_T41", "type": "GENE-N", "text": [ "islet activating protein" ], "offsets": [ [ 1328, 1352 ] ], "normalized": [] }, { "id": "10670413_T42", "type": "GENE-N", "text": [ "IAP" ], "offsets": [ [ 1354, 1357 ] ], "normalized": [] }, { "id": "10670413_T43", "type": "GENE-N", "text": [ "protein kinase C" ], "offsets": [ [ 1410, 1426 ] ], "normalized": [] }, { "id": "10670413_T44", "type": "GENE-N", "text": [ "PKC" ], "offsets": [ [ 1428, 1431 ] ], "normalized": [] }, { "id": "10670413_T45", "type": "GENE-N", "text": [ "G-protein" ], "offsets": [ [ 1580, 1589 ] ], "normalized": [] }, { "id": "10670413_T46", "type": "GENE-Y", "text": [ "EP3 receptor" ], "offsets": [ [ 1611, 1623 ] ], "normalized": [] }, { "id": "10670413_T47", "type": "GENE-N", "text": [ "high-voltage-activated (HVA) Ca2+ channels" ], "offsets": [ [ 158, 200 ] ], "normalized": [] }, { "id": "10670413_T48", "type": "GENE-Y", "text": [ "EP1" ], "offsets": [ [ 387, 390 ] ], "normalized": [] }, { "id": "10670413_T49", "type": "GENE-Y", "text": [ "EP3" ], "offsets": [ [ 430, 433 ] ], "normalized": [] }, { "id": "10670413_T50", "type": "GENE-N", "text": [ "HVA Ca2+ channels" ], "offsets": [ [ 553, 570 ] ], "normalized": [] }, { "id": "10670413_T51", "type": "GENE-Y", "text": [ "EP1-receptor" ], "offsets": [ [ 660, 672 ] ], "normalized": [] }, { "id": "10670413_T52", "type": "GENE-N", "text": [ "HVA Ca2+ channels" ], "offsets": [ [ 823, 840 ] ], "normalized": [] }, { "id": "10670413_T53", "type": "GENE-Y", "text": [ "EP3 receptor" ], "offsets": [ [ 869, 881 ] ], "normalized": [] }, { "id": "10670413_T54", "type": "GENE-N", "text": [ "high-voltage-activated calcium channels" ], "offsets": [ [ 37, 76 ] ], "normalized": [] }, { "id": "10670413_T55", "type": "GENE-Y", "text": [ "EP3 receptor" ], "offsets": [ [ 98, 110 ] ], "normalized": [] } ]

[]

[]

[ { "id": "10670413_0", "type": "AGONIST", "arg1_id": "10670413_T14", "arg2_id": "10670413_T48", "normalized": [] }, { "id": "10670413_1", "type": "AGONIST", "arg1_id": "10670413_T15", "arg2_id": "10670413_T49", "normalized": [] }, { "id": "10670413_2", "type": "ANTAGONIST", "arg1_id": "10670413_T24", "arg2_id": "10670413_T51", "normalized": [] }, { "id": "10670413_3", "type": "INHIBITOR", "arg1_id": "10670413_T7", "arg2_id": "10670413_T43", "normalized": [] }, { "id": "10670413_4", "type": "INHIBITOR", "arg1_id": "10670413_T7", "arg2_id": "10670413_T44", "normalized": [] }, { "id": "10670413_5", "type": "ACTIVATOR", "arg1_id": "10670413_T9", "arg2_id": "10670413_T45", "normalized": [] }, { "id": "10670413_6", "type": "INHIBITOR", "arg1_id": "10670413_T18", "arg2_id": "10670413_T50", "normalized": [] }, { "id": "10670413_7", "type": "INHIBITOR", "arg1_id": "10670413_T19", "arg2_id": "10670413_T50", "normalized": [] }, { "id": "10670413_8", "type": "INHIBITOR", "arg1_id": "10670413_T20", "arg2_id": "10670413_T50", "normalized": [] }, { "id": "10670413_9", "type": "INHIBITOR", "arg1_id": "10670413_T21", "arg2_id": "10670413_T50", "normalized": [] }, { "id": "10670413_10", "type": "INHIBITOR", "arg1_id": "10670413_T22", "arg2_id": "10670413_T50", "normalized": [] }, { "id": "10670413_11", "type": "INHIBITOR", "arg1_id": "10670413_T27", "arg2_id": "10670413_T52", "normalized": [] }, { "id": "10670413_12", "type": "INHIBITOR", "arg1_id": "10670413_T28", "arg2_id": "10670413_T52", "normalized": [] } ]

[ { "id": "9406449_title", "type": "title", "text": [ "Species differences between chickens and rats in chemical properties of adipose tissue lipoprotein lipase." ], "offsets": [ [ 0, 106 ] ] }, { "id": "9406449_abstract", "type": "abstract", "text": [ "Chemical characterization of chicken and rat lipoprotein lipase (LPL) was carried out following purification of LPL. Molecular weight and isoelectric point of both purified enzymes were determined to be 60 KDa and pH 4, while optimum temperature and pH to yield the maximal activity were about 37 degrees C and pH 8.5. Metallic ions, NaCl and protamine sulfate reduced, and heparin increased, both LPL activities. Michaelis constants for LPLs determined with triolein emulsion as the substrate were 0.98 and 1.57, and those of Vmax were 379.2 and 181.3, in chickens and rats, respectively. Triton WR-1339 caused mixed-type inhibition in rat, but inhibited chicken LPL noncompetitively. In LPLs of chickens and rats, values of Ki were 66.7 and 36.4 with triolein emulsion as the substrate, and 832.4 and 66.0 with respective VLDL as the substrate. These results show species difference between chickens and rats in the affinity to lipoproteins of LPL and inhibition of LPL by Triton WR-1339." ], "offsets": [ [ 107, 1097 ] ] } ]

[ { "id": "9406449_T1", "type": "CHEMICAL", "text": [ "NaCl" ], "offsets": [ [ 441, 445 ] ], "normalized": [] }, { "id": "9406449_T2", "type": "CHEMICAL", "text": [ "sulfate" ], "offsets": [ [ 460, 467 ] ], "normalized": [] }, { "id": "9406449_T3", "type": "CHEMICAL", "text": [ "triolein" ], "offsets": [ [ 566, 574 ] ], "normalized": [] }, { "id": "9406449_T4", "type": "CHEMICAL", "text": [ "triolein" ], "offsets": [ [ 860, 868 ] ], "normalized": [] }, { "id": "9406449_T5", "type": "GENE-N", "text": [ "LPL" ], "offsets": [ [ 219, 222 ] ], "normalized": [] }, { "id": "9406449_T6", "type": "GENE-N", "text": [ "chicken and rat lipoprotein lipase" ], "offsets": [ [ 136, 170 ] ], "normalized": [] }, { "id": "9406449_T7", "type": "GENE-N", "text": [ "LPL" ], "offsets": [ [ 505, 508 ] ], "normalized": [] }, { "id": "9406449_T8", "type": "GENE-N", "text": [ "LPLs" ], "offsets": [ [ 545, 549 ] ], "normalized": [] }, { "id": "9406449_T9", "type": "GENE-Y", "text": [ "chicken LPL" ], "offsets": [ [ 763, 774 ] ], "normalized": [] }, { "id": "9406449_T10", "type": "GENE-N", "text": [ "LPL" ], "offsets": [ [ 172, 175 ] ], "normalized": [] }, { "id": "9406449_T11", "type": "GENE-N", "text": [ "LPLs" ], "offsets": [ [ 796, 800 ] ], "normalized": [] }, { "id": "9406449_T12", "type": "GENE-N", "text": [ "VLDL" ], "offsets": [ [ 931, 935 ] ], "normalized": [] }, { "id": "9406449_T13", "type": "GENE-N", "text": [ "lipoproteins" ], "offsets": [ [ 1037, 1049 ] ], "normalized": [] }, { "id": "9406449_T14", "type": "GENE-N", "text": [ "LPL" ], "offsets": [ [ 1053, 1056 ] ], "normalized": [] }, { "id": "9406449_T15", "type": "GENE-N", "text": [ "LPL" ], "offsets": [ [ 1075, 1078 ] ], "normalized": [] }, { "id": "9406449_T16", "type": "GENE-N", "text": [ "lipoprotein lipase" ], "offsets": [ [ 87, 105 ] ], "normalized": [] } ]

[]

[]

[ { "id": "9406449_0", "type": "INHIBITOR", "arg1_id": "9406449_T1", "arg2_id": "9406449_T7", "normalized": [] }, { "id": "9406449_1", "type": "INHIBITOR", "arg1_id": "9406449_T2", "arg2_id": "9406449_T7", "normalized": [] }, { "id": "9406449_2", "type": "SUBSTRATE", "arg1_id": "9406449_T4", "arg2_id": "9406449_T11", "normalized": [] }, { "id": "9406449_3", "type": "SUBSTRATE", "arg1_id": "9406449_T3", "arg2_id": "9406449_T8", "normalized": [] } ]

[ { "id": "9311592_title", "type": "title", "text": [ "Strong decrease in biotin content may correlate with metabolic alterations in colorectal adenocarcinoma." ], "offsets": [ [ 0, 104 ] ] }, { "id": "9311592_abstract", "type": "abstract", "text": [ "Short-chain fatty acids are an important source of energy for colonocytes. One of these is propionate, which is metabolized through carboxylation by propionyl-CoA carboxylase (PCC), an enzyme encoded by 2 genes, PCCA and PCCB. The co-factor of this reaction is biotin, a product of intestinal bacterial metabolism, as is propionate. Despite detailed knowledge about the metabolic effects and physiology of biotin, the relative amounts of this vitamin in normal colonic mucosae and in tumour tissue remains quite unknown. The biotin content in normal and cancerous cells from the distal digestive tract was examined on 10 pairs of tissue specimens of colorectal cancer and adjacent normal mucosae using reflectance in situ hybridization (RISH). Having observed a high biotin content in colon mucosae and a low content in colorectal-cancer cells, we then studied the transcription levels of PCCA and PCCB genes in 9 colorectal cancers and the corresponding mucosae. In all cases, the levels of mRNA were lower in colorectal cancers than in normal mucosae, the decrease being always more marked for PCCB than for PCCA. In normal mucosae and in adenocarcinoma cancer cells, PCCA and PCCB transcription levels were strongly related to the amount of biotin detected, but not to the number of chromosomes 13 (which carries PCCA) or 3 (which carries PCCB)." ], "offsets": [ [ 105, 1453 ] ] } ]

[ { "id": "9311592_T1", "type": "CHEMICAL", "text": [ "fatty acids" ], "offsets": [ [ 117, 128 ] ], "normalized": [] }, { "id": "9311592_T2", "type": "CHEMICAL", "text": [ "biotin" ], "offsets": [ [ 1349, 1355 ] ], "normalized": [] }, { "id": "9311592_T3", "type": "CHEMICAL", "text": [ "propionyl-CoA" ], "offsets": [ [ 254, 267 ] ], "normalized": [] }, { "id": "9311592_T4", "type": "CHEMICAL", "text": [ "biotin" ], "offsets": [ [ 366, 372 ] ], "normalized": [] }, { "id": "9311592_T5", "type": "CHEMICAL", "text": [ "propionate" ], "offsets": [ [ 426, 436 ] ], "normalized": [] }, { "id": "9311592_T6", "type": "CHEMICAL", "text": [ "biotin" ], "offsets": [ [ 511, 517 ] ], "normalized": [] }, { "id": "9311592_T7", "type": "CHEMICAL", "text": [ "biotin" ], "offsets": [ [ 630, 636 ] ], "normalized": [] }, { "id": "9311592_T8", "type": "CHEMICAL", "text": [ "biotin" ], "offsets": [ [ 872, 878 ] ], "normalized": [] }, { "id": "9311592_T9", "type": "CHEMICAL", "text": [ "propionate" ], "offsets": [ [ 196, 206 ] ], "normalized": [] }, { "id": "9311592_T10", "type": "CHEMICAL", "text": [ "biotin" ], "offsets": [ [ 19, 25 ] ], "normalized": [] }, { "id": "9311592_T11", "type": "GENE-Y", "text": [ "PCCB" ], "offsets": [ [ 1201, 1205 ] ], "normalized": [] }, { "id": "9311592_T12", "type": "GENE-Y", "text": [ "PCCA" ], "offsets": [ [ 1215, 1219 ] ], "normalized": [] }, { "id": "9311592_T13", "type": "GENE-Y", "text": [ "PCCA" ], "offsets": [ [ 1275, 1279 ] ], "normalized": [] }, { "id": "9311592_T14", "type": "GENE-Y", "text": [ "PCCB" ], "offsets": [ [ 1284, 1288 ] ], "normalized": [] }, { "id": "9311592_T15", "type": "GENE-Y", "text": [ "PCCA" ], "offsets": [ [ 1421, 1425 ] ], "normalized": [] }, { "id": "9311592_T16", "type": "GENE-Y", "text": [ "PCCB" ], "offsets": [ [ 1447, 1451 ] ], "normalized": [] }, { "id": "9311592_T17", "type": "GENE-N", "text": [ "propionyl-CoA carboxylase" ], "offsets": [ [ 254, 279 ] ], "normalized": [] }, { "id": "9311592_T18", "type": "GENE-N", "text": [ "PCC" ], "offsets": [ [ 281, 284 ] ], "normalized": [] }, { "id": "9311592_T19", "type": "GENE-Y", "text": [ "PCCA" ], "offsets": [ [ 317, 321 ] ], "normalized": [] }, { "id": "9311592_T20", "type": "GENE-Y", "text": [ "PCCB" ], "offsets": [ [ 326, 330 ] ], "normalized": [] }, { "id": "9311592_T21", "type": "GENE-Y", "text": [ "PCCA" ], "offsets": [ [ 994, 998 ] ], "normalized": [] }, { "id": "9311592_T22", "type": "GENE-Y", "text": [ "PCCB" ], "offsets": [ [ 1003, 1007 ] ], "normalized": [] } ]

[]

[]

[ { "id": "9311592_0", "type": "SUBSTRATE", "arg1_id": "9311592_T9", "arg2_id": "9311592_T17", "normalized": [] }, { "id": "9311592_1", "type": "SUBSTRATE", "arg1_id": "9311592_T9", "arg2_id": "9311592_T18", "normalized": [] }, { "id": "9311592_2", "type": "SUBSTRATE", "arg1_id": "9311592_T9", "arg2_id": "9311592_T19", "normalized": [] }, { "id": "9311592_3", "type": "SUBSTRATE", "arg1_id": "9311592_T9", "arg2_id": "9311592_T20", "normalized": [] } ]

[ { "id": "11447307_title", "type": "title", "text": [ "Hemodynamic effects of bosentan in patients with chronic heart failure." ], "offsets": [ [ 0, 71 ] ] }, { "id": "11447307_abstract", "type": "abstract", "text": [ "A role of the potent and long-acting vasoconstrictor peptide endothelin-1 and the pathophysiology of chronic human heart failure has been postulated based upon indirect evidence such as elevated plasma endothelin-1 levels and their with the degree of hemodynamic impairment. The advent of specific of endothelin-1 receptor antagonists has provided the opportunity not only to directly evaluate its pathophysiological role but also to assess its potential role as a new approach to heart failure therapy. This brief review summarizes the evidence linking endothelin-1 to the pathophysiology of chronic heart failure and the clinical results obtained in patients during acute, intravenous and more prolonged, oral administration with bosentan, a mixed ET(A)/ET(B)-receptor antagonist. Bosentan acutely and during short-term oral therapy markedly improved hemodynamics in patients in addition to standard heart failure therapy, including an ACE-inhibitor. These effects were associated with a reduced responsiveness of the renin-angiotensin system to diuretic therapy and reduced basal plasma aldosterone levels. Although the hemodynamic and neurohumoral profile of short-term bosentan therapy looks promising for the treatment of patients with chronic heart failure appropriate trials will have to be performed to document clinical benefit during long-term therapy. Finally, the question remains open whether mixed endothelin-1 receptor antagonists like bosentan will have similar effects as compared to antagonists which block the ET(A) receptor only." ], "offsets": [ [ 72, 1622 ] ] } ]

[ { "id": "11447307_T1", "type": "CHEMICAL", "text": [ "angiotensin" ], "offsets": [ [ 1098, 1109 ] ], "normalized": [] }, { "id": "11447307_T2", "type": "CHEMICAL", "text": [ "aldosterone" ], "offsets": [ [ 1162, 1173 ] ], "normalized": [] }, { "id": "11447307_T3", "type": "CHEMICAL", "text": [ "bosentan" ], "offsets": [ [ 1246, 1254 ] ], "normalized": [] }, { "id": "11447307_T4", "type": "CHEMICAL", "text": [ "bosentan" ], "offsets": [ [ 1524, 1532 ] ], "normalized": [] }, { "id": "11447307_T5", "type": "CHEMICAL", "text": [ "bosentan" ], "offsets": [ [ 804, 812 ] ], "normalized": [] }, { "id": "11447307_T6", "type": "CHEMICAL", "text": [ "Bosentan" ], "offsets": [ [ 855, 863 ] ], "normalized": [] }, { "id": "11447307_T7", "type": "CHEMICAL", "text": [ "bosentan" ], "offsets": [ [ 23, 31 ] ], "normalized": [] }, { "id": "11447307_T8", "type": "GENE-Y", "text": [ "renin" ], "offsets": [ [ 1092, 1097 ] ], "normalized": [] }, { "id": "11447307_T9", "type": "GENE-Y", "text": [ "angiotensin" ], "offsets": [ [ 1098, 1109 ] ], "normalized": [] }, { "id": "11447307_T10", "type": "GENE-Y", "text": [ "endothelin-1 receptor" ], "offsets": [ [ 1485, 1506 ] ], "normalized": [] }, { "id": "11447307_T11", "type": "GENE-Y", "text": [ "ET(A) receptor" ], "offsets": [ [ 1602, 1616 ] ], "normalized": [] }, { "id": "11447307_T12", "type": "GENE-Y", "text": [ "endothelin-1" ], "offsets": [ [ 274, 286 ] ], "normalized": [] }, { "id": "11447307_T13", "type": "GENE-Y", "text": [ "endothelin-1 receptor" ], "offsets": [ [ 373, 394 ] ], "normalized": [] }, { "id": "11447307_T14", "type": "GENE-Y", "text": [ "endothelin-1" ], "offsets": [ [ 626, 638 ] ], "normalized": [] }, { "id": "11447307_T15", "type": "GENE-Y", "text": [ "endothelin-1" ], "offsets": [ [ 133, 145 ] ], "normalized": [] }, { "id": "11447307_T16", "type": "GENE-Y", "text": [ "ET(A)" ], "offsets": [ [ 822, 827 ] ], "normalized": [] }, { "id": "11447307_T17", "type": "GENE-Y", "text": [ "ET(B)-receptor" ], "offsets": [ [ 828, 842 ] ], "normalized": [] }, { "id": "11447307_T18", "type": "GENE-Y", "text": [ "ACE" ], "offsets": [ [ 1010, 1013 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11447307_0", "type": "ANTAGONIST", "arg1_id": "11447307_T5", "arg2_id": "11447307_T16", "normalized": [] }, { "id": "11447307_1", "type": "ANTAGONIST", "arg1_id": "11447307_T5", "arg2_id": "11447307_T17", "normalized": [] }, { "id": "11447307_2", "type": "ANTAGONIST", "arg1_id": "11447307_T4", "arg2_id": "11447307_T10", "normalized": [] } ]

[ { "id": "23586470_title", "type": "title", "text": [ "Quantitative Determination of Lateral Concentration and Depth Profile of Histidine-Tagged Recombinant Proteins Probed by Grazing Incidence X-ray Fluorescence." ], "offsets": [ [ 0, 158 ] ] }, { "id": "23586470_abstract", "type": "abstract", "text": [ "We have demonstrated that the complementary combination of grazing incidence X-ray fluorescence (GIXF) with specular X-ray reflectivity (XRR) can be used to quantitatively determine the density profiles of Ni(2)(+) ions complexed with chelator headgroups as well as S atoms in recombinant proteins anchored to lipid monolayers at the air/water interface. First, we prepared phospholipid monolayers incorporating chelator lipid anchors at different molar fractions at the air/water interface. The fine-structures perpendicular to the global plane of monolayers were characterized by XRR in the presence of Ni(2)(+) ions, yielding the thickness, roughness, and electron density of the stratified lipid monolayers. X-ray fluorescence intensities from Ni Kα core levels recorded at the incidence angles below and above the critical angle of total reflection allow for the determination of the position and lateral density of Ni(2)(+) ions associated with chelator headgroups with a high spatial accuracy (±5 Å). The coupling of histidine-tagged Xenopus cadherin 11 (Xcad-11) can also be identified by changes in the fines-structures using XRR. Although fluorescence intensities from S Kα level were much weaker than Ni Kα signals, we could detect the location of S atoms in recombinant Xcad-11 proteins." ], "offsets": [ [ 159, 1458 ] ] } ]

[ { "id": "23586470_T1", "type": "CHEMICAL", "text": [ "histidine" ], "offsets": [ [ 1183, 1192 ] ], "normalized": [] }, { "id": "23586470_T2", "type": "CHEMICAL", "text": [ "S" ], "offsets": [ [ 1338, 1339 ] ], "normalized": [] }, { "id": "23586470_T3", "type": "CHEMICAL", "text": [ "Ni" ], "offsets": [ [ 1371, 1373 ] ], "normalized": [] }, { "id": "23586470_T4", "type": "CHEMICAL", "text": [ "S" ], "offsets": [ [ 1418, 1419 ] ], "normalized": [] }, { "id": "23586470_T5", "type": "CHEMICAL", "text": [ "Ni(2)(+)" ], "offsets": [ [ 365, 373 ] ], "normalized": [] }, { "id": "23586470_T6", "type": "CHEMICAL", "text": [ "S" ], "offsets": [ [ 425, 426 ] ], "normalized": [] }, { "id": "23586470_T7", "type": "CHEMICAL", "text": [ "Ni(2)(+)" ], "offsets": [ [ 764, 772 ] ], "normalized": [] }, { "id": "23586470_T8", "type": "CHEMICAL", "text": [ "Ni" ], "offsets": [ [ 907, 909 ] ], "normalized": [] }, { "id": "23586470_T9", "type": "CHEMICAL", "text": [ "Ni(2)(+)" ], "offsets": [ [ 1080, 1088 ] ], "normalized": [] }, { "id": "23586470_T10", "type": "CHEMICAL", "text": [ "Histidine" ], "offsets": [ [ 73, 82 ] ], "normalized": [] }, { "id": "23586470_T11", "type": "GENE-Y", "text": [ "Xenopus cadherin 11" ], "offsets": [ [ 1200, 1219 ] ], "normalized": [] }, { "id": "23586470_T12", "type": "GENE-Y", "text": [ "Xcad-11" ], "offsets": [ [ 1221, 1228 ] ], "normalized": [] }, { "id": "23586470_T13", "type": "GENE-Y", "text": [ "Xcad-11" ], "offsets": [ [ 1441, 1448 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23586470_0", "type": "PART-OF", "arg1_id": "23586470_T4", "arg2_id": "23586470_T13", "normalized": [] }, { "id": "23586470_1", "type": "DIRECT-REGULATOR", "arg1_id": "23586470_T3", "arg2_id": "23586470_T13", "normalized": [] }, { "id": "23586470_2", "type": "PART-OF", "arg1_id": "23586470_T2", "arg2_id": "23586470_T13", "normalized": [] } ]

[ { "id": "23425274_title", "type": "title", "text": [ "Gel electrophoretic methods for the analysis of biosimilar pharmaceuticals using the example of recombinant erythropoietin." ], "offsets": [ [ 0, 123 ] ] }, { "id": "23425274_abstract", "type": "abstract", "text": [ "Due to their versatility and cost-effectiveness, gel electrophoretic methods provide an important set of tools for the analysis of therapeutic proteins. As an increasing number of biosimilar pharmaceuticals are entering the market, techniques are required that allow reliable demonstration of comparability of these products with the reference products. Isoelectric focusing, SDS-PAGE, native PAGE and 2D electrophoresis (2D-PAGE) have been frequently applied for this purpose. Supplementary techniques are fluorophore-assisted carbohydrate electrophoresis and sarcosyl-PAGE. Of additional importance is the comparison of recombinant with endogenously synthesized glycoproteins. Reagent array analysis combined with SDS-PAGE and western blotting proved especially useful for this purpose. As an example for the application of these methods, the analysis of recombinant originator erythropoietins and some of their biosimilar counterparts is described." ], "offsets": [ [ 124, 1075 ] ] } ]

[ { "id": "23425274_T1", "type": "CHEMICAL", "text": [ "SDS" ], "offsets": [ [ 500, 503 ] ], "normalized": [] }, { "id": "23425274_T2", "type": "CHEMICAL", "text": [ "carbohydrate" ], "offsets": [ [ 652, 664 ] ], "normalized": [] }, { "id": "23425274_T3", "type": "CHEMICAL", "text": [ "sarcosyl" ], "offsets": [ [ 685, 693 ] ], "normalized": [] }, { "id": "23425274_T4", "type": "CHEMICAL", "text": [ "SDS" ], "offsets": [ [ 840, 843 ] ], "normalized": [] }, { "id": "23425274_T5", "type": "GENE-Y", "text": [ "erythropoietins" ], "offsets": [ [ 1004, 1019 ] ], "normalized": [] }, { "id": "23425274_T6", "type": "GENE-Y", "text": [ "erythropoietin" ], "offsets": [ [ 108, 122 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "22966070_title", "type": "title", "text": [ "Tub has a key role in insulin and leptin signaling and action in vivo in hypothalamic nuclei." ], "offsets": [ [ 0, 93 ] ] }, { "id": "22966070_abstract", "type": "abstract", "text": [ "Mutation of tub gene in mice induces obesity, suggesting that tub could be an important regulator of energy balance. In the current study, we investigated whether insulin, leptin, and obesity can modulate Tub in vivo in hypothalamic nuclei, and we investigated possible consequences on energy balance, neuropeptide expression, and hepatic glucose metabolism. Food intake, metabolic characteristics, signaling proteins, and neuropeptide expression were measured in response to fasting and refeeding, intracerebroventricular insulin and leptin, and Tub antisense oligonucleotide (ASO). Tub tyrosine phosphorylation (Tub-p-tyr) is modulated by nutritional status. Tub is a substrate of insulin receptor tyrosine kinase (IRTK) and leptin receptor (LEPR)-Janus kinase 2 (JAK2) in hypothalamic nuclei. After leptin or insulin stimulation, Tub translocates to the nucleus. Inhibition of Tub expression in hypothalamus by ASO increased food intake, fasting blood glucose, and hepatic glucose output, decreased O(2) consumption, and blunted the effect of insulin or leptin on proopiomelanocortin, thyroid-releasing hormone, melanin-concentrating hormone, and orexin expression. In hypothalamus of mice administered a high-fat diet, there is a reduction in leptin and insulin-induced Tub-p-tyr and nuclear translocation, which is reversed by reducing protein tyrosine phosphatase 1B expression. These results indicate that Tub has a key role in the control of insulin and leptin effects on food intake, and the modulation of Tub may contribute to insulin and leptin resistance in DIO mice." ], "offsets": [ [ 94, 1673 ] ] } ]

[ { "id": "22966070_T1", "type": "CHEMICAL", "text": [ "O(2)" ], "offsets": [ [ 1096, 1100 ] ], "normalized": [] }, { "id": "22966070_T2", "type": "CHEMICAL", "text": [ "tyr" ], "offsets": [ [ 1374, 1377 ] ], "normalized": [] }, { "id": "22966070_T3", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 1443, 1451 ] ], "normalized": [] }, { "id": "22966070_T4", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 433, 440 ] ], "normalized": [] }, { "id": "22966070_T5", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 682, 690 ] ], "normalized": [] }, { "id": "22966070_T6", "type": "CHEMICAL", "text": [ "tyr" ], "offsets": [ [ 714, 717 ] ], "normalized": [] }, { "id": "22966070_T7", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 794, 802 ] ], "normalized": [] }, { "id": "22966070_T8", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 1049, 1056 ] ], "normalized": [] }, { "id": "22966070_T9", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 1070, 1077 ] ], "normalized": [] }, { "id": "22966070_T10", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 1140, 1147 ] ], "normalized": [] }, { "id": "22966070_T11", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 1151, 1157 ] ], "normalized": [] }, { "id": "22966070_T12", "type": "GENE-Y", "text": [ "proopiomelanocortin" ], "offsets": [ [ 1161, 1180 ] ], "normalized": [] }, { "id": "22966070_T13", "type": "GENE-Y", "text": [ "thyroid-releasing hormone" ], "offsets": [ [ 1182, 1207 ] ], "normalized": [] }, { "id": "22966070_T14", "type": "GENE-Y", "text": [ "melanin-concentrating hormone" ], "offsets": [ [ 1209, 1238 ] ], "normalized": [] }, { "id": "22966070_T15", "type": "GENE-Y", "text": [ "orexin" ], "offsets": [ [ 1244, 1250 ] ], "normalized": [] }, { "id": "22966070_T16", "type": "GENE-Y", "text": [ "tub" ], "offsets": [ [ 106, 109 ] ], "normalized": [] }, { "id": "22966070_T17", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 1341, 1347 ] ], "normalized": [] }, { "id": "22966070_T18", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 1352, 1359 ] ], "normalized": [] }, { "id": "22966070_T19", "type": "GENE-Y", "text": [ "Tub" ], "offsets": [ [ 1368, 1371 ] ], "normalized": [] }, { "id": "22966070_T20", "type": "GENE-Y", "text": [ "protein tyrosine phosphatase 1B" ], "offsets": [ [ 1435, 1466 ] ], "normalized": [] }, { "id": "22966070_T21", "type": "GENE-Y", "text": [ "Tub" ], "offsets": [ [ 1507, 1510 ] ], "normalized": [] }, { "id": "22966070_T22", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 1544, 1551 ] ], "normalized": [] }, { "id": "22966070_T23", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 1556, 1562 ] ], "normalized": [] }, { "id": "22966070_T24", "type": "GENE-Y", "text": [ "Tub" ], "offsets": [ [ 1609, 1612 ] ], "normalized": [] }, { "id": "22966070_T25", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 1631, 1638 ] ], "normalized": [] }, { "id": "22966070_T26", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 1643, 1649 ] ], "normalized": [] }, { "id": "22966070_T27", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 257, 264 ] ], "normalized": [] }, { "id": "22966070_T28", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 266, 272 ] ], "normalized": [] }, { "id": "22966070_T29", "type": "GENE-Y", "text": [ "Tub" ], "offsets": [ [ 299, 302 ] ], "normalized": [] }, { "id": "22966070_T30", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 617, 624 ] ], "normalized": [] }, { "id": "22966070_T31", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 629, 635 ] ], "normalized": [] }, { "id": "22966070_T32", "type": "GENE-Y", "text": [ "Tub" ], "offsets": [ [ 641, 644 ] ], "normalized": [] }, { "id": "22966070_T33", "type": "GENE-Y", "text": [ "Tub" ], "offsets": [ [ 678, 681 ] ], "normalized": [] }, { "id": "22966070_T34", "type": "GENE-Y", "text": [ "tub" ], "offsets": [ [ 156, 159 ] ], "normalized": [] }, { "id": "22966070_T35", "type": "GENE-Y", "text": [ "Tub" ], "offsets": [ [ 755, 758 ] ], "normalized": [] }, { "id": "22966070_T36", "type": "GENE-Y", "text": [ "insulin receptor tyrosine kinase" ], "offsets": [ [ 777, 809 ] ], "normalized": [] }, { "id": "22966070_T37", "type": "GENE-Y", "text": [ "IRTK" ], "offsets": [ [ 811, 815 ] ], "normalized": [] }, { "id": "22966070_T38", "type": "GENE-Y", "text": [ "leptin receptor" ], "offsets": [ [ 821, 836 ] ], "normalized": [] }, { "id": "22966070_T39", "type": "GENE-Y", "text": [ "LEPR" ], "offsets": [ [ 838, 842 ] ], "normalized": [] }, { "id": "22966070_T40", "type": "GENE-Y", "text": [ "Janus kinase 2" ], "offsets": [ [ 844, 858 ] ], "normalized": [] }, { "id": "22966070_T41", "type": "GENE-Y", "text": [ "JAK2" ], "offsets": [ [ 860, 864 ] ], "normalized": [] }, { "id": "22966070_T42", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 896, 902 ] ], "normalized": [] }, { "id": "22966070_T43", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 906, 913 ] ], "normalized": [] }, { "id": "22966070_T44", "type": "GENE-Y", "text": [ "Tub" ], "offsets": [ [ 927, 930 ] ], "normalized": [] }, { "id": "22966070_T45", "type": "GENE-Y", "text": [ "Tub" ], "offsets": [ [ 974, 977 ] ], "normalized": [] }, { "id": "22966070_T46", "type": "GENE-Y", "text": [ "Tub" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "22966070_T47", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 22, 29 ] ], "normalized": [] }, { "id": "22966070_T48", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 34, 40 ] ], "normalized": [] } ]

[]

[]

[ { "id": "22966070_0", "type": "PART-OF", "arg1_id": "22966070_T5", "arg2_id": "22966070_T33", "normalized": [] }, { "id": "22966070_1", "type": "PART-OF", "arg1_id": "22966070_T6", "arg2_id": "22966070_T33", "normalized": [] }, { "id": "22966070_2", "type": "PART-OF", "arg1_id": "22966070_T2", "arg2_id": "22966070_T19", "normalized": [] } ]

[ { "id": "23201927_title", "type": "title", "text": [ "Cardioprotective effect of salvianolic acid B against arsenic trioxide-induced injury in cardiac H9c2 cells via the PI3K/Akt signal pathway." ], "offsets": [ [ 0, 140 ] ] }, { "id": "23201927_abstract", "type": "abstract", "text": [ "The clinical use of arsenic trioxide (ATO), a potent anti-neoplastic agent, is often limited because of its severe cardiotoxicity. Salviae miltiorrhiza is widely used for the treatment of cardiovascular diseases. One of the most abundant ingredients of S. miltiorrhiza is salvianolic acid B (Sal B). The present study was designed to evaluate whether Sal B protects against ATO-induced cardiac cell injury in vitro. With MTT cell viability assay, LDH release, ROS generation, caspase-3 activity assay and Hoechst 33342/PI staining, we found that Sal B pretreatment provided significantly protection against ATO-induced cell death. The effect was correlated with the activation of the PI3K/Akt signal pathway. Conversely, blocking Akt activation with the PI3K inhibitor LY294002 effectively suppressed the protective effect of Sal B against ATO-induced cell apoptosis. In addition, the PI3K inhibitor partially blocked the effects of Sal B on the upregulation of Bcl-2 and Bcl-xl protein expression, and downregulation of Bax protein expression. Collectively, the results showed that Sal B decreased the apoptosis and necrosis of H9c2 cardiomyocytes caused by ATO treatment, and PI3K played a crucial role in enhancing cell survival during this process. These observations indicate that Sal B has the potential to exert cardioprotective effects against ATO toxicity." ], "offsets": [ [ 141, 1506 ] ] } ]

[ { "id": "23201927_T1", "type": "CHEMICAL", "text": [ "Sal B" ], "offsets": [ [ 1224, 1229 ] ], "normalized": [] }, { "id": "23201927_T2", "type": "CHEMICAL", "text": [ "ATO" ], "offsets": [ [ 1300, 1303 ] ], "normalized": [] }, { "id": "23201927_T3", "type": "CHEMICAL", "text": [ "Sal B" ], "offsets": [ [ 1427, 1432 ] ], "normalized": [] }, { "id": "23201927_T4", "type": "CHEMICAL", "text": [ "ATO" ], "offsets": [ [ 1493, 1496 ] ], "normalized": [] }, { "id": "23201927_T5", "type": "CHEMICAL", "text": [ "arsenic trioxide" ], "offsets": [ [ 161, 177 ] ], "normalized": [] }, { "id": "23201927_T6", "type": "CHEMICAL", "text": [ "salvianolic acid B" ], "offsets": [ [ 413, 431 ] ], "normalized": [] }, { "id": "23201927_T7", "type": "CHEMICAL", "text": [ "Sal B" ], "offsets": [ [ 433, 438 ] ], "normalized": [] }, { "id": "23201927_T8", "type": "CHEMICAL", "text": [ "Sal B" ], "offsets": [ [ 492, 497 ] ], "normalized": [] }, { "id": "23201927_T9", "type": "CHEMICAL", "text": [ "ATO" ], "offsets": [ [ 515, 518 ] ], "normalized": [] }, { "id": "23201927_T10", "type": "CHEMICAL", "text": [ "ATO" ], "offsets": [ [ 179, 182 ] ], "normalized": [] }, { "id": "23201927_T11", "type": "CHEMICAL", "text": [ "MTT" ], "offsets": [ [ 562, 565 ] ], "normalized": [] }, { "id": "23201927_T12", "type": "CHEMICAL", "text": [ "Hoechst 33342" ], "offsets": [ [ 646, 659 ] ], "normalized": [] }, { "id": "23201927_T13", "type": "CHEMICAL", "text": [ "Sal B" ], "offsets": [ [ 687, 692 ] ], "normalized": [] }, { "id": "23201927_T14", "type": "CHEMICAL", "text": [ "ATO" ], "offsets": [ [ 748, 751 ] ], "normalized": [] }, { "id": "23201927_T15", "type": "CHEMICAL", "text": [ "LY294002" ], "offsets": [ [ 910, 918 ] ], "normalized": [] }, { "id": "23201927_T16", "type": "CHEMICAL", "text": [ "Sal B" ], "offsets": [ [ 967, 972 ] ], "normalized": [] }, { "id": "23201927_T17", "type": "CHEMICAL", "text": [ "ATO" ], "offsets": [ [ 981, 984 ] ], "normalized": [] }, { "id": "23201927_T18", "type": "CHEMICAL", "text": [ "Sal B" ], "offsets": [ [ 1074, 1079 ] ], "normalized": [] }, { "id": "23201927_T19", "type": "CHEMICAL", "text": [ "salvianolic acid B" ], "offsets": [ [ 27, 45 ] ], "normalized": [] }, { "id": "23201927_T20", "type": "CHEMICAL", "text": [ "arsenic trioxide" ], "offsets": [ [ 54, 70 ] ], "normalized": [] }, { "id": "23201927_T21", "type": "GENE-Y", "text": [ "Bax" ], "offsets": [ [ 1162, 1165 ] ], "normalized": [] }, { "id": "23201927_T22", "type": "GENE-N", "text": [ "PI3K" ], "offsets": [ [ 1319, 1323 ] ], "normalized": [] }, { "id": "23201927_T23", "type": "GENE-N", "text": [ "LDH" ], "offsets": [ [ 588, 591 ] ], "normalized": [] }, { "id": "23201927_T24", "type": "GENE-Y", "text": [ "caspase-3" ], "offsets": [ [ 617, 626 ] ], "normalized": [] }, { "id": "23201927_T25", "type": "GENE-N", "text": [ "PI3K" ], "offsets": [ [ 825, 829 ] ], "normalized": [] }, { "id": "23201927_T26", "type": "GENE-N", "text": [ "Akt" ], "offsets": [ [ 830, 833 ] ], "normalized": [] }, { "id": "23201927_T27", "type": "GENE-N", "text": [ "Akt" ], "offsets": [ [ 871, 874 ] ], "normalized": [] }, { "id": "23201927_T28", "type": "GENE-N", "text": [ "PI3K" ], "offsets": [ [ 895, 899 ] ], "normalized": [] }, { "id": "23201927_T29", "type": "GENE-N", "text": [ "PI3K" ], "offsets": [ [ 1026, 1030 ] ], "normalized": [] }, { "id": "23201927_T30", "type": "GENE-Y", "text": [ "Bcl-2" ], "offsets": [ [ 1103, 1108 ] ], "normalized": [] }, { "id": "23201927_T31", "type": "GENE-Y", "text": [ "Bcl-xl" ], "offsets": [ [ 1113, 1119 ] ], "normalized": [] }, { "id": "23201927_T32", "type": "GENE-N", "text": [ "PI3K" ], "offsets": [ [ 116, 120 ] ], "normalized": [] }, { "id": "23201927_T33", "type": "GENE-N", "text": [ "Akt" ], "offsets": [ [ 121, 124 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23201927_0", "type": "INHIBITOR", "arg1_id": "23201927_T15", "arg2_id": "23201927_T28", "normalized": [] }, { "id": "23201927_1", "type": "INHIBITOR", "arg1_id": "23201927_T15", "arg2_id": "23201927_T27", "normalized": [] }, { "id": "23201927_2", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23201927_T18", "arg2_id": "23201927_T30", "normalized": [] }, { "id": "23201927_3", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23201927_T18", "arg2_id": "23201927_T31", "normalized": [] }, { "id": "23201927_4", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23201927_T18", "arg2_id": "23201927_T21", "normalized": [] } ]

[ { "id": "15942707_title", "type": "title", "text": [ "Carvedilol prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in pressure-overloaded rat heart." ], "offsets": [ [ 0, 166 ] ] }, { "id": "15942707_abstract", "type": "abstract", "text": [ "The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of HIF-1alpha in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of carvedilol on both myocardial HIF-1alpha expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. Carvedilol at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with carvedilol. The increased wall thickness and heart weight was reversed to normal by carvedilol. Western blot showed that HIF-1alpha, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with valsartan, doxazosin, or N-acetylcysteine did not significantly affect HIF-1alpha and VEGF proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of HIF-1alpha, VEGF and BNP increased and mRNA of NGF-beta decreased in the banding group. Treatment with carvedilol reversed both protein and mRNA of HIF-1alpha, VEGF, BNP, and NGF-beta to the baseline values. Increased immunohistochemical labeling of HIF-1alpha, VEGF, and BNP in the ventricular myocardium was observed in the banding group and carvedilol again normalized the labeling. In conclusion, HIF-1alpha, VEGF, and BNP mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with carvedilol is associated with a reversal of abnormal regulation of HIF-1alpha, VEGF, BNP, and NGF-beta in the hypertrophic myocardium." ], "offsets": [ [ 167, 2424 ] ] } ]

[ { "id": "15942707_T1", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 1170, 1180 ] ], "normalized": [] }, { "id": "15942707_T2", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 1254, 1264 ] ], "normalized": [] }, { "id": "15942707_T3", "type": "CHEMICAL", "text": [ "valsartan" ], "offsets": [ [ 1500, 1509 ] ], "normalized": [] }, { "id": "15942707_T4", "type": "CHEMICAL", "text": [ "doxazosin" ], "offsets": [ [ 1511, 1520 ] ], "normalized": [] }, { "id": "15942707_T5", "type": "CHEMICAL", "text": [ "N-acetylcysteine" ], "offsets": [ [ 1525, 1541 ] ], "normalized": [] }, { "id": "15942707_T6", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 1793, 1803 ] ], "normalized": [] }, { "id": "15942707_T7", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 2034, 2044 ] ], "normalized": [] }, { "id": "15942707_T8", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 2290, 2300 ] ], "normalized": [] }, { "id": "15942707_T9", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 519, 529 ] ], "normalized": [] }, { "id": "15942707_T10", "type": "CHEMICAL", "text": [ "Carvedilol" ], "offsets": [ [ 709, 719 ] ], "normalized": [] }, { "id": "15942707_T11", "type": "CHEMICAL", "text": [ "Carvedilol" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "15942707_T12", "type": "GENE-Y", "text": [ "HIF-1alpha" ], "offsets": [ [ 1291, 1301 ] ], "normalized": [] }, { "id": "15942707_T13", "type": "GENE-Y", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1303, 1337 ] ], "normalized": [] }, { "id": "15942707_T14", "type": "GENE-Y", "text": [ "VEGF" ], "offsets": [ [ 1339, 1343 ] ], "normalized": [] }, { "id": "15942707_T15", "type": "GENE-Y", "text": [ "brain natriuretic peptide" ], "offsets": [ [ 1349, 1374 ] ], "normalized": [] }, { "id": "15942707_T16", "type": "GENE-Y", "text": [ "BNP" ], "offsets": [ [ 1376, 1379 ] ], "normalized": [] }, { "id": "15942707_T17", "type": "GENE-Y", "text": [ "HIF-1alpha" ], "offsets": [ [ 288, 298 ] ], "normalized": [] }, { "id": "15942707_T18", "type": "GENE-Y", "text": [ "nerve growth factor-beta" ], "offsets": [ [ 1412, 1436 ] ], "normalized": [] }, { "id": "15942707_T19", "type": "GENE-Y", "text": [ "NGF-beta" ], "offsets": [ [ 1438, 1446 ] ], "normalized": [] }, { "id": "15942707_T20", "type": "GENE-Y", "text": [ "HIF-1alpha" ], "offsets": [ [ 1571, 1581 ] ], "normalized": [] }, { "id": "15942707_T21", "type": "GENE-Y", "text": [ "VEGF" ], "offsets": [ [ 1586, 1590 ] ], "normalized": [] }, { "id": "15942707_T22", "type": "GENE-Y", "text": [ "HIF-1alpha" ], "offsets": [ [ 1690, 1700 ] ], "normalized": [] }, { "id": "15942707_T23", "type": "GENE-Y", "text": [ "VEGF" ], "offsets": [ [ 1702, 1706 ] ], "normalized": [] }, { "id": "15942707_T24", "type": "GENE-Y", "text": [ "BNP" ], "offsets": [ [ 1711, 1714 ] ], "normalized": [] }, { "id": "15942707_T25", "type": "GENE-Y", "text": [ "NGF-beta" ], "offsets": [ [ 1737, 1745 ] ], "normalized": [] }, { "id": "15942707_T26", "type": "GENE-Y", "text": [ "HIF-1alpha" ], "offsets": [ [ 1838, 1848 ] ], "normalized": [] }, { "id": "15942707_T27", "type": "GENE-Y", "text": [ "VEGF" ], "offsets": [ [ 1850, 1854 ] ], "normalized": [] }, { "id": "15942707_T28", "type": "GENE-Y", "text": [ "BNP" ], "offsets": [ [ 1856, 1859 ] ], "normalized": [] }, { "id": "15942707_T29", "type": "GENE-Y", "text": [ "NGF-beta" ], "offsets": [ [ 1865, 1873 ] ], "normalized": [] }, { "id": "15942707_T30", "type": "GENE-Y", "text": [ "HIF-1alpha" ], "offsets": [ [ 1940, 1950 ] ], "normalized": [] }, { "id": "15942707_T31", "type": "GENE-Y", "text": [ "VEGF" ], "offsets": [ [ 1952, 1956 ] ], "normalized": [] }, { "id": "15942707_T32", "type": "GENE-Y", "text": [ "BNP" ], "offsets": [ [ 1962, 1965 ] ], "normalized": [] }, { "id": "15942707_T33", "type": "GENE-Y", "text": [ "HIF-1alpha" ], "offsets": [ [ 2091, 2101 ] ], "normalized": [] }, { "id": "15942707_T34", "type": "GENE-Y", "text": [ "VEGF" ], "offsets": [ [ 2103, 2107 ] ], "normalized": [] }, { "id": "15942707_T35", "type": "GENE-Y", "text": [ "BNP" ], "offsets": [ [ 2113, 2116 ] ], "normalized": [] }, { "id": "15942707_T36", "type": "GENE-Y", "text": [ "NGF-beta" ], "offsets": [ [ 2170, 2178 ] ], "normalized": [] }, { "id": "15942707_T37", "type": "GENE-Y", "text": [ "HIF-1alpha" ], "offsets": [ [ 379, 389 ] ], "normalized": [] }, { "id": "15942707_T38", "type": "GENE-Y", "text": [ "HIF-1alpha" ], "offsets": [ [ 2357, 2367 ] ], "normalized": [] }, { "id": "15942707_T39", "type": "GENE-Y", "text": [ "VEGF" ], "offsets": [ [ 2369, 2373 ] ], "normalized": [] }, { "id": "15942707_T40", "type": "GENE-Y", "text": [ "BNP" ], "offsets": [ [ 2375, 2378 ] ], "normalized": [] }, { "id": "15942707_T41", "type": "GENE-Y", "text": [ "NGF-beta" ], "offsets": [ [ 2384, 2392 ] ], "normalized": [] }, { "id": "15942707_T42", "type": "GENE-Y", "text": [ "HIF-1alpha" ], "offsets": [ [ 549, 559 ] ], "normalized": [] }, { "id": "15942707_T43", "type": "GENE-Y", "text": [ "Hypoxia-inducible factor-1alpha" ], "offsets": [ [ 255, 286 ] ], "normalized": [] }, { "id": "15942707_T44", "type": "GENE-Y", "text": [ "hypoxia-inducible factor-1alpha" ], "offsets": [ [ 62, 93 ] ], "normalized": [] }, { "id": "15942707_T45", "type": "GENE-Y", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 98, 132 ] ], "normalized": [] } ]

[]

[]

[ { "id": "15942707_0", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "15942707_T11", "arg2_id": "15942707_T44", "normalized": [] }, { "id": "15942707_1", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "15942707_T11", "arg2_id": "15942707_T45", "normalized": [] }, { "id": "15942707_2", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "15942707_T6", "arg2_id": "15942707_T26", "normalized": [] }, { "id": "15942707_3", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "15942707_T6", "arg2_id": "15942707_T27", "normalized": [] }, { "id": "15942707_4", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "15942707_T6", "arg2_id": "15942707_T28", "normalized": [] }, { "id": "15942707_5", "type": "INDIRECT-UPREGULATOR", "arg1_id": "15942707_T6", "arg2_id": "15942707_T29", "normalized": [] }, { "id": "15942707_6", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "15942707_T7", "arg2_id": "15942707_T30", "normalized": [] }, { "id": "15942707_7", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "15942707_T7", "arg2_id": "15942707_T31", "normalized": [] }, { "id": "15942707_8", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "15942707_T7", "arg2_id": "15942707_T32", "normalized": [] }, { "id": "15942707_9", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "15942707_T8", "arg2_id": "15942707_T38", "normalized": [] }, { "id": "15942707_10", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "15942707_T8", "arg2_id": "15942707_T39", "normalized": [] }, { "id": "15942707_11", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "15942707_T8", "arg2_id": "15942707_T40", "normalized": [] } ]

[ { "id": "22064666_title", "type": "title", "text": [ "Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction." ], "offsets": [ [ 0, 132 ] ] }, { "id": "22064666_abstract", "type": "abstract", "text": [ "Erectile dysfunction (ED) is usually treated with sildenafil. Although genetic polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may impair endogenous NO formation, there is little information about how eNOS polymorphisms and haplotypes affect the responses to sildenafil. We studied 118 patients; 63 patients had ED secondary to radical prostatectomy (PED) and 55 had organic, clinical ED. eNOS genotypes for three eNOS polymorphisms (T(-786)C, rs2070744; a variable number of tandem repeats (VNTR) in intron 4; and Glu298Asp, rs1799983) were determined, and eNOS haplotypes were estimated using PHASE 2.1. The clinical responses to sildenafil were evaluated and the patients were classified as good responders (GR) or poor responders (PR) when their changes in five-item version of International Index for Erectile Function questionnaire were above or below the median value. The TC/CC genotypes and the C allele for the T(-786)C polymorphism were more common in GR, compared with PR patients with PED. However, the 4b4a/4a4a genotypes and the 4a allele for the VNTR polymorphism in intron 4 were more common in GR, compared with PR patients with clinical ED. The C-4a-Glu haplotype was more common in GR than in PR patients with PED. Conversely, the T-4b-Asp haplotype was less common in GR than in PR patients with PED. No other significant differences were found. Our findings show evidence that eNOS polymorphisms affect the responses of PED and clinical ED patients to sildenafil." ], "offsets": [ [ 133, 1637 ] ] } ]

[ { "id": "22064666_T1", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 245, 257 ] ], "normalized": [] }, { "id": "22064666_T2", "type": "CHEMICAL", "text": [ "sildenafil" ], "offsets": [ [ 1626, 1636 ] ], "normalized": [] }, { "id": "22064666_T3", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 301, 303 ] ], "normalized": [] }, { "id": "22064666_T4", "type": "CHEMICAL", "text": [ "sildenafil" ], "offsets": [ [ 411, 421 ] ], "normalized": [] }, { "id": "22064666_T5", "type": "CHEMICAL", "text": [ "sildenafil" ], "offsets": [ [ 183, 193 ] ], "normalized": [] }, { "id": "22064666_T6", "type": "CHEMICAL", "text": [ "sildenafil" ], "offsets": [ [ 784, 794 ] ], "normalized": [] }, { "id": "22064666_T7", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 12, 24 ] ], "normalized": [] }, { "id": "22064666_T8", "type": "CHEMICAL", "text": [ "sildenafil" ], "offsets": [ [ 83, 93 ] ], "normalized": [] }, { "id": "22064666_T9", "type": "GENE-Y", "text": [ "endothelial nitric oxide synthase" ], "offsets": [ [ 233, 266 ] ], "normalized": [] }, { "id": "22064666_T10", "type": "GENE-Y", "text": [ "eNOS" ], "offsets": [ [ 268, 272 ] ], "normalized": [] }, { "id": "22064666_T11", "type": "GENE-Y", "text": [ "eNOS" ], "offsets": [ [ 1551, 1555 ] ], "normalized": [] }, { "id": "22064666_T12", "type": "GENE-Y", "text": [ "eNOS" ], "offsets": [ [ 353, 357 ] ], "normalized": [] }, { "id": "22064666_T13", "type": "GENE-Y", "text": [ "eNOS" ], "offsets": [ [ 541, 545 ] ], "normalized": [] }, { "id": "22064666_T14", "type": "GENE-Y", "text": [ "eNOS" ], "offsets": [ [ 566, 570 ] ], "normalized": [] }, { "id": "22064666_T15", "type": "GENE-Y", "text": [ "eNOS" ], "offsets": [ [ 710, 714 ] ], "normalized": [] }, { "id": "22064666_T16", "type": "GENE-Y", "text": [ "Endothelial nitric oxide synthase" ], "offsets": [ [ 0, 33 ] ], "normalized": [] } ]

[]

[]

[ { "id": "22064666_0", "type": "PRODUCT-OF", "arg1_id": "22064666_T3", "arg2_id": "22064666_T9", "normalized": [] }, { "id": "22064666_1", "type": "PRODUCT-OF", "arg1_id": "22064666_T3", "arg2_id": "22064666_T10", "normalized": [] } ]

[ { "id": "7511163_title", "type": "title", "text": [ "5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone and its corresponding N-cyclopropylmethyl analog, N-cyclopropylmethylnor-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)- 7,8-dihydromorphinone: mu-selective irreversible opioid antagonists." ], "offsets": [ [ 0, 256 ] ] }, { "id": "7511163_abstract", "type": "abstract", "text": [ "5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone (MET-CAMO) and its corresponding N-cyclopropylmethyl analog, N-cyclopropylmethylnor-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)- 7,8-dihydromorphinone (N-CPM-MET-CAMO) were tested in opioid receptor binding assays and in the mouse tail-flick test in order to characterize the affinity, selectivity and antinociceptive properties of these two compounds. Incubating bovine striatal membranes with either MET-CAMO or N-CPM-MET-CAMO produced a wash-resistant, concentration- and time-dependent inhibition of the binding of the mu-selective ligand, [3H]-[D-Ala2,MePhe4,Gly(ol)5]enkephalin, but with no change in delta or kappa binding. Preincubating membranes with N-CPM-MET-CAMO decreased the maximum binding value for [3H]-[D-Ala2,MePhe4,Gly(ol)5]enkephalin binding without changing the Kd value. In the mouse tail-flick assay, MET-CAMO and N-CPM-MET-CAMO did not produce any antinociception up to a dose of 100 nmol after i.c.v. administration. However, pretreatment of mice with either compound produced a time- and dose-dependent antagonism of morphine-induced antinociception. Analgesia mediated by delta or kappa opioids was not altered by either MET-CAMO or N-CPM-MET-CAMO at a dose of up to 100 nmol. The mu antagonistic effect of 1 nmol of MET-CAMO and N-CPM-MET-CAMO appeared at 8 hr and lasted up to 72 hr, with a maximal effect at 16 to 24 hr after i.c.v. administration. Pretreatment of mice with 1 nmol of MET-CAMO or N-CPM-MET-CAMO, given by i.c.v. administration at -24 hr, produced a rightward and downward shift of dose-response line of i.c.v. morphine.(ABSTRACT TRUNCATED AT 250 WORDS)" ], "offsets": [ [ 257, 1927 ] ] } ]

[ { "id": "7511163_T1", "type": "CHEMICAL", "text": [ "5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone" ], "offsets": [ [ 257, 324 ] ], "normalized": [] }, { "id": "7511163_T2", "type": "CHEMICAL", "text": [ "N-cyclopropylmethyl" ], "offsets": [ [ 358, 377 ] ], "normalized": [] }, { "id": "7511163_T3", "type": "CHEMICAL", "text": [ "morphine" ], "offsets": [ [ 1371, 1379 ] ], "normalized": [] }, { "id": "7511163_T4", "type": "CHEMICAL", "text": [ "MET-CAMO" ], "offsets": [ [ 1476, 1484 ] ], "normalized": [] }, { "id": "7511163_T5", "type": "CHEMICAL", "text": [ "N-CPM-MET-CAMO" ], "offsets": [ [ 1488, 1502 ] ], "normalized": [] }, { "id": "7511163_T6", "type": "CHEMICAL", "text": [ "N-cyclopropylmethylnor-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)- 7,8-dihydromorphinone" ], "offsets": [ [ 386, 477 ] ], "normalized": [] }, { "id": "7511163_T7", "type": "CHEMICAL", "text": [ "MET-CAMO" ], "offsets": [ [ 1572, 1580 ] ], "normalized": [] }, { "id": "7511163_T8", "type": "CHEMICAL", "text": [ "N-CPM-MET-CAMO" ], "offsets": [ [ 1585, 1599 ] ], "normalized": [] }, { "id": "7511163_T9", "type": "CHEMICAL", "text": [ "MET-CAMO" ], "offsets": [ [ 1743, 1751 ] ], "normalized": [] }, { "id": "7511163_T10", "type": "CHEMICAL", "text": [ "N-CPM-MET-CAMO" ], "offsets": [ [ 1755, 1769 ] ], "normalized": [] }, { "id": "7511163_T11", "type": "CHEMICAL", "text": [ "N-CPM-MET-CAMO" ], "offsets": [ [ 479, 493 ] ], "normalized": [] }, { "id": "7511163_T12", "type": "CHEMICAL", "text": [ "MET-CAMO" ], "offsets": [ [ 729, 737 ] ], "normalized": [] }, { "id": "7511163_T13", "type": "CHEMICAL", "text": [ "N-CPM-MET-CAMO" ], "offsets": [ [ 741, 755 ] ], "normalized": [] }, { "id": "7511163_T14", "type": "CHEMICAL", "text": [ "[3H]-[D-Ala2,MePhe4,Gly(ol)5]enkephalin" ], "offsets": [ [ 871, 910 ] ], "normalized": [] }, { "id": "7511163_T15", "type": "CHEMICAL", "text": [ "MET-CAMO" ], "offsets": [ [ 326, 334 ] ], "normalized": [] }, { "id": "7511163_T16", "type": "CHEMICAL", "text": [ "N-CPM-MET-CAMO" ], "offsets": [ [ 987, 1001 ] ], "normalized": [] }, { "id": "7511163_T17", "type": "CHEMICAL", "text": [ "[3H]-[D-Ala2,MePhe4,Gly(ol)5]enkephalin" ], "offsets": [ [ 1042, 1081 ] ], "normalized": [] }, { "id": "7511163_T18", "type": "CHEMICAL", "text": [ "MET-CAMO" ], "offsets": [ [ 1152, 1160 ] ], "normalized": [] }, { "id": "7511163_T19", "type": "CHEMICAL", "text": [ "N-CPM-MET-CAMO" ], "offsets": [ [ 1165, 1179 ] ], "normalized": [] }, { "id": "7511163_T20", "type": "CHEMICAL", "text": [ "5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone" ], "offsets": [ [ 0, 67 ] ], "normalized": [] }, { "id": "7511163_T21", "type": "CHEMICAL", "text": [ "N-cyclopropylmethylnor-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)- 7,8-dihydromorphinone" ], "offsets": [ [ 118, 209 ] ], "normalized": [] }, { "id": "7511163_T22", "type": "CHEMICAL", "text": [ "N-cyclopropylmethyl" ], "offsets": [ [ 90, 109 ] ], "normalized": [] }, { "id": "7511163_T23", "type": "GENE-N", "text": [ "opioid receptor" ], "offsets": [ [ 510, 525 ] ], "normalized": [] } ]

[]

[]

[ { "id": "7511163_0", "type": "DIRECT-REGULATOR", "arg1_id": "7511163_T1", "arg2_id": "7511163_T23", "normalized": [] }, { "id": "7511163_1", "type": "DIRECT-REGULATOR", "arg1_id": "7511163_T15", "arg2_id": "7511163_T23", "normalized": [] }, { "id": "7511163_2", "type": "DIRECT-REGULATOR", "arg1_id": "7511163_T2", "arg2_id": "7511163_T23", "normalized": [] }, { "id": "7511163_3", "type": "DIRECT-REGULATOR", "arg1_id": "7511163_T6", "arg2_id": "7511163_T23", "normalized": [] }, { "id": "7511163_4", "type": "DIRECT-REGULATOR", "arg1_id": "7511163_T11", "arg2_id": "7511163_T23", "normalized": [] } ]

[ { "id": "23171045_title", "type": "title", "text": [ "New 2-(aryloxy)-3-phenylpropanoic acids as peroxisome proliferator-activated receptor α/γ dual agonists able to upregulate mitochondrial carnitine shuttle system gene expression." ], "offsets": [ [ 0, 178 ] ] }, { "id": "23171045_abstract", "type": "abstract", "text": [ "The preparation of a series of 2-(aryloxy)-3-phenylpropanoic acids, resulting from the introduction of different substituents into the biphenyl system of the previously reported peroxisome proliferator-activated receptor α/γ (PPARα/γ) dual agonist 1, allowed the identification of new ligands with higher potency on PPARα and fine-tuned moderate PPARγ activity. For the most promising stereoisomer (S)-16, X-ray and calorimetric studies in PPARγ revealed, at high ligand concentration, the presence of two molecules simultaneously bound to the receptor. On the basis of these results and docking experiments in both receptor subtypes, a molecular explanation was provided for its different behavior as a full and partial agonist of PPARα and PPARγ, respectively. The effects of (S)-16 on mitochondrial acylcarnitine carrier and carnitine-palmitoyl-transferase 1 gene expression, two key components of the carnitine shuttle system, were also investigated, allowing the hypothesis of a more beneficial pharmacological profile of this compound compared to the less potent PPARα agonist fibrates currently used in therapy." ], "offsets": [ [ 179, 1297 ] ] } ]

[ { "id": "23171045_T1", "type": "CHEMICAL", "text": [ "biphenyl" ], "offsets": [ [ 314, 322 ] ], "normalized": [] }, { "id": "23171045_T2", "type": "CHEMICAL", "text": [ "2-(aryloxy)-3-phenylpropanoic acids" ], "offsets": [ [ 210, 245 ] ], "normalized": [] }, { "id": "23171045_T3", "type": "CHEMICAL", "text": [ "acylcarnitine" ], "offsets": [ [ 981, 994 ] ], "normalized": [] }, { "id": "23171045_T4", "type": "CHEMICAL", "text": [ "carnitine" ], "offsets": [ [ 1007, 1016 ] ], "normalized": [] }, { "id": "23171045_T5", "type": "CHEMICAL", "text": [ "palmitoyl" ], "offsets": [ [ 1017, 1026 ] ], "normalized": [] }, { "id": "23171045_T6", "type": "CHEMICAL", "text": [ "carnitine" ], "offsets": [ [ 1084, 1093 ] ], "normalized": [] }, { "id": "23171045_T7", "type": "CHEMICAL", "text": [ "carnitine" ], "offsets": [ [ 137, 146 ] ], "normalized": [] }, { "id": "23171045_T8", "type": "CHEMICAL", "text": [ "2-(aryloxy)-3-phenylpropanoic acids" ], "offsets": [ [ 4, 39 ] ], "normalized": [] }, { "id": "23171045_T9", "type": "GENE-Y", "text": [ "PPARα" ], "offsets": [ [ 1248, 1253 ] ], "normalized": [] }, { "id": "23171045_T10", "type": "GENE-N", "text": [ "peroxisome proliferator-activated receptor α/γ" ], "offsets": [ [ 357, 403 ] ], "normalized": [] }, { "id": "23171045_T11", "type": "GENE-N", "text": [ "PPARα/γ" ], "offsets": [ [ 405, 412 ] ], "normalized": [] }, { "id": "23171045_T12", "type": "GENE-Y", "text": [ "PPARα" ], "offsets": [ [ 495, 500 ] ], "normalized": [] }, { "id": "23171045_T13", "type": "GENE-Y", "text": [ "PPARγ" ], "offsets": [ [ 525, 530 ] ], "normalized": [] }, { "id": "23171045_T14", "type": "GENE-Y", "text": [ "PPARγ" ], "offsets": [ [ 619, 624 ] ], "normalized": [] }, { "id": "23171045_T15", "type": "GENE-Y", "text": [ "PPARα" ], "offsets": [ [ 911, 916 ] ], "normalized": [] }, { "id": "23171045_T16", "type": "GENE-Y", "text": [ "PPARγ" ], "offsets": [ [ 921, 926 ] ], "normalized": [] }, { "id": "23171045_T17", "type": "GENE-Y", "text": [ "mitochondrial acylcarnitine carrier" ], "offsets": [ [ 967, 1002 ] ], "normalized": [] }, { "id": "23171045_T18", "type": "GENE-Y", "text": [ "carnitine-palmitoyl-transferase 1" ], "offsets": [ [ 1007, 1040 ] ], "normalized": [] }, { "id": "23171045_T19", "type": "GENE-N", "text": [ "peroxisome proliferator-activated receptor α/γ" ], "offsets": [ [ 43, 89 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23171045_0", "type": "SUBSTRATE", "arg1_id": "23171045_T6", "arg2_id": "23171045_T17", "normalized": [] }, { "id": "23171045_1", "type": "SUBSTRATE", "arg1_id": "23171045_T6", "arg2_id": "23171045_T18", "normalized": [] }, { "id": "23171045_2", "type": "DIRECT-REGULATOR", "arg1_id": "23171045_T2", "arg2_id": "23171045_T12", "normalized": [] } ]

[ { "id": "12671891_title", "type": "title", "text": [ "Methionine adenosyltransferase II beta subunit gene expression provides a proliferative advantage in human hepatoma." ], "offsets": [ [ 0, 116 ] ] }, { "id": "12671891_abstract", "type": "abstract", "text": [ "BACKGROUND & AIMS: Of the 2 genes (MAT1A, MAT2A) encoding methionine adenosyltransferase, the enzyme that synthesizes S-adenosylmethionine, MAT1A, is expressed in liver, whereas MAT2A is expressed in extrahepatic tissues. In liver, MAT2A expression associates with growth, dedifferentiation, and cancer. Here, we identified the beta subunit as a regulator of proliferation in human hepatoma cell lines. The beta subunit has been cloned and shown to lower the K(m) of methionine adenosyltransferase II alpha2 (the MAT2A product) for methionine and to render the enzyme more susceptible to S-adenosylmethionine inhibition. METHODS: Methionine adenosyltransferase II alpha2 and beta subunit expression was analyzed in human and rat liver and hepatoma cell lines and their interaction studied in HuH7 cells. beta Subunit expression was up- and down-regulated in human hepatoma cell lines and the effect on DNA synthesis determined. RESULTS: We found that beta subunit is expressed in rat extrahepatic tissues but not in normal liver. In human liver, beta subunit expression associates with cirrhosis and hepatoma. beta Subunit is expressed in most (HepG2, PLC, and Hep3B) but not all (HuH7) hepatoma cell lines. Transfection of beta subunit reduced S-adenosylmethionine content and stimulated DNA synthesis in HuH7 cells, whereas down-regulation of beta subunit expression diminished DNA synthesis in HepG2. The interaction between methionine adenosyltransferase II alpha2 and beta subunit was demonstrated in HuH7 cells. CONCLUSIONS: Our findings indicate that beta subunit associates with cirrhosis and cancer providing a proliferative advantage in hepatoma cells through its interaction with methionine adenosyltransferase II alpha2 and down-regulation of S-adenosylmethionine levels." ], "offsets": [ [ 117, 1900 ] ] } ]

[ { "id": "12671891_T1", "type": "CHEMICAL", "text": [ "S-adenosylmethionine" ], "offsets": [ [ 235, 255 ] ], "normalized": [] }, { "id": "12671891_T2", "type": "CHEMICAL", "text": [ "S-adenosylmethionine" ], "offsets": [ [ 1362, 1382 ] ], "normalized": [] }, { "id": "12671891_T3", "type": "CHEMICAL", "text": [ "methionine" ], "offsets": [ [ 1545, 1555 ] ], "normalized": [] }, { "id": "12671891_T4", "type": "CHEMICAL", "text": [ "methionine" ], "offsets": [ [ 1808, 1818 ] ], "normalized": [] }, { "id": "12671891_T5", "type": "CHEMICAL", "text": [ "S-adenosylmethionine" ], "offsets": [ [ 1872, 1892 ] ], "normalized": [] }, { "id": "12671891_T6", "type": "CHEMICAL", "text": [ "methionine" ], "offsets": [ [ 584, 594 ] ], "normalized": [] }, { "id": "12671891_T7", "type": "CHEMICAL", "text": [ "methionine" ], "offsets": [ [ 649, 659 ] ], "normalized": [] }, { "id": "12671891_T8", "type": "CHEMICAL", "text": [ "methionine" ], "offsets": [ [ 175, 185 ] ], "normalized": [] }, { "id": "12671891_T9", "type": "CHEMICAL", "text": [ "S-adenosylmethionine" ], "offsets": [ [ 705, 725 ] ], "normalized": [] }, { "id": "12671891_T10", "type": "CHEMICAL", "text": [ "Methionine" ], "offsets": [ [ 747, 757 ] ], "normalized": [] }, { "id": "12671891_T11", "type": "CHEMICAL", "text": [ "Methionine" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "12671891_T12", "type": "GENE-Y", "text": [ "MAT1A" ], "offsets": [ [ 257, 262 ] ], "normalized": [] }, { "id": "12671891_T13", "type": "GENE-N", "text": [ "methionine adenosyltransferase II alpha2 and beta" ], "offsets": [ [ 1545, 1594 ] ], "normalized": [] }, { "id": "12671891_T14", "type": "GENE-Y", "text": [ "methionine adenosyltransferase II alpha2" ], "offsets": [ [ 1808, 1848 ] ], "normalized": [] }, { "id": "12671891_T15", "type": "GENE-Y", "text": [ "MAT2A" ], "offsets": [ [ 295, 300 ] ], "normalized": [] }, { "id": "12671891_T16", "type": "GENE-Y", "text": [ "MAT2A" ], "offsets": [ [ 349, 354 ] ], "normalized": [] }, { "id": "12671891_T17", "type": "GENE-Y", "text": [ "MAT1A" ], "offsets": [ [ 152, 157 ] ], "normalized": [] }, { "id": "12671891_T18", "type": "GENE-Y", "text": [ "MAT2A" ], "offsets": [ [ 159, 164 ] ], "normalized": [] }, { "id": "12671891_T19", "type": "GENE-Y", "text": [ "methionine adenosyltransferase II alpha2" ], "offsets": [ [ 584, 624 ] ], "normalized": [] }, { "id": "12671891_T20", "type": "GENE-Y", "text": [ "MAT2A" ], "offsets": [ [ 630, 635 ] ], "normalized": [] }, { "id": "12671891_T21", "type": "GENE-N", "text": [ "methionine adenosyltransferase" ], "offsets": [ [ 175, 205 ] ], "normalized": [] }, { "id": "12671891_T22", "type": "GENE-N", "text": [ "Methionine adenosyltransferase II alpha2 and beta" ], "offsets": [ [ 747, 796 ] ], "normalized": [] }, { "id": "12671891_T23", "type": "GENE-Y", "text": [ "Methionine adenosyltransferase II beta" ], "offsets": [ [ 0, 38 ] ], "normalized": [] } ]

[]

[]

[ { "id": "12671891_0", "type": "PRODUCT-OF", "arg1_id": "12671891_T1", "arg2_id": "12671891_T21", "normalized": [] }, { "id": "12671891_1", "type": "PRODUCT-OF", "arg1_id": "12671891_T1", "arg2_id": "12671891_T17", "normalized": [] }, { "id": "12671891_2", "type": "PRODUCT-OF", "arg1_id": "12671891_T1", "arg2_id": "12671891_T18", "normalized": [] }, { "id": "12671891_3", "type": "SUBSTRATE", "arg1_id": "12671891_T7", "arg2_id": "12671891_T19", "normalized": [] }, { "id": "12671891_4", "type": "SUBSTRATE", "arg1_id": "12671891_T7", "arg2_id": "12671891_T20", "normalized": [] }, { "id": "12671891_5", "type": "INHIBITOR", "arg1_id": "12671891_T9", "arg2_id": "12671891_T19", "normalized": [] }, { "id": "12671891_6", "type": "INHIBITOR", "arg1_id": "12671891_T9", "arg2_id": "12671891_T20", "normalized": [] } ]

[ { "id": "23292249_title", "type": "title", "text": [ "The physico-chemical \"anatomy\" of the tautomerization through the DPT of the biologically important pairs of hypoxanthine with DNA bases: QM and QTAIM perspectives." ], "offsets": [ [ 0, 164 ] ] }, { "id": "23292249_abstract", "type": "abstract", "text": [ "The biologically important tautomerization of the Hyp·Cyt, Hyp*·Thy and Hyp·Hyp base pairs to the Hyp*·Cyt*, Hyp·Thy* and Hyp*·Hyp* base pairs, respectively, by the double proton transfer (DPT) was comprehensively studied in vacuo and in the continuum with a low dielectric constant (ε = 4) corresponding to hydrophobic interfaces of protein-nucleic acid interactions by combining theoretical investigations at the B3LYP/6-311++G(d,p) level of QM theory with QTAIM topological analysis. Based on the sweeps of the energetic, electron-topological, geometric and polar parameters, which describe the course of the tautomerization along the intrinsic reaction coordinate (IRC), it was proved that the tautomerization through the DPT is concerted and asynchronous process for the Hyp·Cyt and Hyp*·Thy base pairs, while concerted and synchronous for the Hyp·Hyp homodimer. The continuum with ε = 4 does not affect qualitatively the course of the tautomerization reaction for all studied complexes. The nine key points along the IRC of the Hyp·Cyt↔Hyp*·Cyt* and Hyp*·Thy↔Hyp·Thy* tautomerizations and the six key points of the Hyp·Hyp↔Hyp*·Hyp* tautomerization have been identified and fully characterized. These key points could be considered as electron-topological \"fingerprints\" of concerted asynchronous (for Hyp·Cyt and Hyp*·Thy) or synchronous (for Hyp·Hyp) tautomerization process via the DPT. It was found, that in the Hyp*·Cyt*, Hyp·Thy*, Hyp·Hyp and Hyp*·Hyp* base pairs all H-bonds are significantly cooperative and mutually reinforce each other, while the C2H…O2 H-bond in the Hyp·Cyt base pair and the O6H…O4 H-bond in the Hyp*·Thy base pair behave anti-cooperatively, i.e., they become weakened, while two others become strengthened." ], "offsets": [ [ 165, 1907 ] ] } ]

[ { "id": "23292249_T1", "type": "CHEMICAL", "text": [ "Cyt" ], "offsets": [ [ 268, 271 ] ], "normalized": [] }, { "id": "23292249_T2", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1199, 1202 ] ], "normalized": [] }, { "id": "23292249_T3", "type": "CHEMICAL", "text": [ "Cyt" ], "offsets": [ [ 1203, 1206 ] ], "normalized": [] }, { "id": "23292249_T4", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1207, 1210 ] ], "normalized": [] }, { "id": "23292249_T5", "type": "CHEMICAL", "text": [ "Cyt" ], "offsets": [ [ 1212, 1215 ] ], "normalized": [] }, { "id": "23292249_T6", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1221, 1224 ] ], "normalized": [] }, { "id": "23292249_T7", "type": "CHEMICAL", "text": [ "Thy" ], "offsets": [ [ 1226, 1229 ] ], "normalized": [] }, { "id": "23292249_T8", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1230, 1233 ] ], "normalized": [] }, { "id": "23292249_T9", "type": "CHEMICAL", "text": [ "Thy" ], "offsets": [ [ 1234, 1237 ] ], "normalized": [] }, { "id": "23292249_T10", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 274, 277 ] ], "normalized": [] }, { "id": "23292249_T11", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1286, 1289 ] ], "normalized": [] }, { "id": "23292249_T12", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1290, 1293 ] ], "normalized": [] }, { "id": "23292249_T13", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1294, 1297 ] ], "normalized": [] }, { "id": "23292249_T14", "type": "CHEMICAL", "text": [ "Thy" ], "offsets": [ [ 278, 281 ] ], "normalized": [] }, { "id": "23292249_T15", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1299, 1302 ] ], "normalized": [] }, { "id": "23292249_T16", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 287, 290 ] ], "normalized": [] }, { "id": "23292249_T17", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 292, 295 ] ], "normalized": [] }, { "id": "23292249_T18", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1473, 1476 ] ], "normalized": [] }, { "id": "23292249_T19", "type": "CHEMICAL", "text": [ "Cyt" ], "offsets": [ [ 1477, 1480 ] ], "normalized": [] }, { "id": "23292249_T20", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1485, 1488 ] ], "normalized": [] }, { "id": "23292249_T21", "type": "CHEMICAL", "text": [ "Thy" ], "offsets": [ [ 1490, 1493 ] ], "normalized": [] }, { "id": "23292249_T22", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1515, 1518 ] ], "normalized": [] }, { "id": "23292249_T23", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1519, 1522 ] ], "normalized": [] }, { "id": "23292249_T24", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1587, 1590 ] ], "normalized": [] }, { "id": "23292249_T25", "type": "CHEMICAL", "text": [ "Cyt" ], "offsets": [ [ 1592, 1595 ] ], "normalized": [] }, { "id": "23292249_T26", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1598, 1601 ] ], "normalized": [] }, { "id": "23292249_T27", "type": "CHEMICAL", "text": [ "Thy" ], "offsets": [ [ 1602, 1605 ] ], "normalized": [] }, { "id": "23292249_T28", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1608, 1611 ] ], "normalized": [] }, { "id": "23292249_T29", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1612, 1615 ] ], "normalized": [] }, { "id": "23292249_T30", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1620, 1623 ] ], "normalized": [] }, { "id": "23292249_T31", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1625, 1628 ] ], "normalized": [] }, { "id": "23292249_T32", "type": "CHEMICAL", "text": [ "H" ], "offsets": [ [ 1645, 1646 ] ], "normalized": [] }, { "id": "23292249_T33", "type": "CHEMICAL", "text": [ "C2H" ], "offsets": [ [ 1728, 1731 ] ], "normalized": [] }, { "id": "23292249_T34", "type": "CHEMICAL", "text": [ "O2 H" ], "offsets": [ [ 1732, 1736 ] ], "normalized": [] }, { "id": "23292249_T35", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1749, 1752 ] ], "normalized": [] }, { "id": "23292249_T36", "type": "CHEMICAL", "text": [ "Cyt" ], "offsets": [ [ 1753, 1756 ] ], "normalized": [] }, { "id": "23292249_T37", "type": "CHEMICAL", "text": [ "O6" ], "offsets": [ [ 1775, 1777 ] ], "normalized": [] }, { "id": "23292249_T38", "type": "CHEMICAL", "text": [ "H" ], "offsets": [ [ 1777, 1778 ] ], "normalized": [] }, { "id": "23292249_T39", "type": "CHEMICAL", "text": [ "O4" ], "offsets": [ [ 1779, 1781 ] ], "normalized": [] }, { "id": "23292249_T40", "type": "CHEMICAL", "text": [ "H" ], "offsets": [ [ 1782, 1783 ] ], "normalized": [] }, { "id": "23292249_T41", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1796, 1799 ] ], "normalized": [] }, { "id": "23292249_T42", "type": "CHEMICAL", "text": [ "Thy" ], "offsets": [ [ 1801, 1804 ] ], "normalized": [] }, { "id": "23292249_T43", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 215, 218 ] ], "normalized": [] }, { "id": "23292249_T44", "type": "CHEMICAL", "text": [ "Cyt" ], "offsets": [ [ 219, 222 ] ], "normalized": [] }, { "id": "23292249_T45", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 224, 227 ] ], "normalized": [] }, { "id": "23292249_T46", "type": "CHEMICAL", "text": [ "Thy" ], "offsets": [ [ 229, 232 ] ], "normalized": [] }, { "id": "23292249_T47", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 237, 240 ] ], "normalized": [] }, { "id": "23292249_T48", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 241, 244 ] ], "normalized": [] }, { "id": "23292249_T49", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 941, 944 ] ], "normalized": [] }, { "id": "23292249_T50", "type": "CHEMICAL", "text": [ "Cyt" ], "offsets": [ [ 945, 948 ] ], "normalized": [] }, { "id": "23292249_T51", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 953, 956 ] ], "normalized": [] }, { "id": "23292249_T52", "type": "CHEMICAL", "text": [ "Thy" ], "offsets": [ [ 958, 961 ] ], "normalized": [] }, { "id": "23292249_T53", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1014, 1017 ] ], "normalized": [] }, { "id": "23292249_T54", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 1018, 1021 ] ], "normalized": [] }, { "id": "23292249_T55", "type": "CHEMICAL", "text": [ "Hyp" ], "offsets": [ [ 263, 266 ] ], "normalized": [] }, { "id": "23292249_T56", "type": "CHEMICAL", "text": [ "hypoxanthine" ], "offsets": [ [ 109, 121 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "9231746_title", "type": "title", "text": [ "Mechanisms of inhibition of calmodulin-stimulated cyclic nucleotide phosphodiesterase by dihydropyridine calcium antagonists." ], "offsets": [ [ 0, 125 ] ] }, { "id": "9231746_abstract", "type": "abstract", "text": [ "Calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) is one of the key enzymes involved in the complex interaction between the cyclic nucleotide and Ca2+ second-messenger systems. CaMPDE exists as tissue-specific isozymes, and initially these isozymes were designated according to their respective subunit molecular mass. A variety of pharmacological agents have been used to inhibit CaMPDE, and this inhibition occurs mostly via Ca2+-dependent association with the proteins. We have examined the effect of dihydropyridine Ca2+-channel blockers felodipine and nicardipine on CaMPDE. The results suggest that the 63-kDa (PDE 1B1) and 60-kDa (PDE 1A2) CaMPDE isozymes are inhibited by felodipine and nicardipine by partial competitive inhibition and that these two Ca2+ antagonists appear to counteract each other. This study further demonstrates the existence of a specific site, distinct from the active site on CaMPDE, that exhibits high-affinity binding of these drugs. Felodipine and nicardipine have similar affinities for 60-kDa CaMPDE isozymes but bring about different levels of enzyme inhibition, suggesting the possibility of designing specific drugs that can protect the enzyme from inhibition by dihydropyridine Ca2+-channel blockers." ], "offsets": [ [ 126, 1384 ] ] } ]

[ { "id": "9231746_T1", "type": "CHEMICAL", "text": [ "nicardipine" ], "offsets": [ [ 1126, 1137 ] ], "normalized": [] }, { "id": "9231746_T2", "type": "CHEMICAL", "text": [ "dihydropyridine" ], "offsets": [ [ 1346, 1361 ] ], "normalized": [] }, { "id": "9231746_T3", "type": "CHEMICAL", "text": [ "Ca2+" ], "offsets": [ [ 1362, 1366 ] ], "normalized": [] }, { "id": "9231746_T4", "type": "CHEMICAL", "text": [ "nucleotide" ], "offsets": [ [ 273, 283 ] ], "normalized": [] }, { "id": "9231746_T5", "type": "CHEMICAL", "text": [ "Ca2+" ], "offsets": [ [ 288, 292 ] ], "normalized": [] }, { "id": "9231746_T6", "type": "CHEMICAL", "text": [ "nucleotide" ], "offsets": [ [ 154, 164 ] ], "normalized": [] }, { "id": "9231746_T7", "type": "CHEMICAL", "text": [ "Ca2+" ], "offsets": [ [ 569, 573 ] ], "normalized": [] }, { "id": "9231746_T8", "type": "CHEMICAL", "text": [ "dihydropyridine" ], "offsets": [ [ 646, 661 ] ], "normalized": [] }, { "id": "9231746_T9", "type": "CHEMICAL", "text": [ "Ca2+" ], "offsets": [ [ 662, 666 ] ], "normalized": [] }, { "id": "9231746_T10", "type": "CHEMICAL", "text": [ "felodipine" ], "offsets": [ [ 684, 694 ] ], "normalized": [] }, { "id": "9231746_T11", "type": "CHEMICAL", "text": [ "nicardipine" ], "offsets": [ [ 699, 710 ] ], "normalized": [] }, { "id": "9231746_T12", "type": "CHEMICAL", "text": [ "felodipine" ], "offsets": [ [ 822, 832 ] ], "normalized": [] }, { "id": "9231746_T13", "type": "CHEMICAL", "text": [ "nicardipine" ], "offsets": [ [ 837, 848 ] ], "normalized": [] }, { "id": "9231746_T14", "type": "CHEMICAL", "text": [ "Ca2+" ], "offsets": [ [ 902, 906 ] ], "normalized": [] }, { "id": "9231746_T15", "type": "CHEMICAL", "text": [ "Felodipine" ], "offsets": [ [ 1111, 1121 ] ], "normalized": [] }, { "id": "9231746_T16", "type": "CHEMICAL", "text": [ "nucleotide" ], "offsets": [ [ 57, 67 ] ], "normalized": [] }, { "id": "9231746_T17", "type": "GENE-N", "text": [ "Calmodulin-dependent cyclic nucleotide phosphodiesterase" ], "offsets": [ [ 126, 182 ] ], "normalized": [] }, { "id": "9231746_T18", "type": "GENE-N", "text": [ "CaMPDE" ], "offsets": [ [ 1173, 1179 ] ], "normalized": [] }, { "id": "9231746_T19", "type": "GENE-N", "text": [ "Ca2+-channel" ], "offsets": [ [ 1362, 1374 ] ], "normalized": [] }, { "id": "9231746_T20", "type": "GENE-N", "text": [ "CaMPDE" ], "offsets": [ [ 319, 325 ] ], "normalized": [] }, { "id": "9231746_T21", "type": "GENE-N", "text": [ "CaMPDE" ], "offsets": [ [ 523, 529 ] ], "normalized": [] }, { "id": "9231746_T22", "type": "GENE-N", "text": [ "Ca2+-channel" ], "offsets": [ [ 662, 674 ] ], "normalized": [] }, { "id": "9231746_T23", "type": "GENE-N", "text": [ "CaMPDE" ], "offsets": [ [ 184, 190 ] ], "normalized": [] }, { "id": "9231746_T24", "type": "GENE-N", "text": [ "CaMPDE" ], "offsets": [ [ 714, 720 ] ], "normalized": [] }, { "id": "9231746_T25", "type": "GENE-Y", "text": [ "PDE 1B1" ], "offsets": [ [ 759, 766 ] ], "normalized": [] }, { "id": "9231746_T26", "type": "GENE-Y", "text": [ "PDE 1A2" ], "offsets": [ [ 780, 787 ] ], "normalized": [] }, { "id": "9231746_T27", "type": "GENE-N", "text": [ "CaMPDE" ], "offsets": [ [ 789, 795 ] ], "normalized": [] }, { "id": "9231746_T28", "type": "GENE-N", "text": [ "CaMPDE" ], "offsets": [ [ 1051, 1057 ] ], "normalized": [] }, { "id": "9231746_T29", "type": "GENE-N", "text": [ "calmodulin-stimulated cyclic nucleotide phosphodiesterase" ], "offsets": [ [ 28, 85 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23032515_title", "type": "title", "text": [ "8-Hydroxycalamenene isolated from the rhizomes of Reynoutria elliptica exerts neuroprotective effects both in vitro and in vivo." ], "offsets": [ [ 0, 128 ] ] }, { "id": "23032515_abstract", "type": "abstract", "text": [ "Retinal ganglion cells (RGCs) death caused by oxidative stress is a common risk factor for glaucoma. In the present study, 8-hydroxycalamenene was isolated from the hexane fraction of Reynoutria elliptica. We showed that 8-hydroxycalamenene attenuated the cell death of transformed RGC-5 cells. This compound also produced a dose-dependent decrease in the expression of apoptotic proteins (cleaved PARP and caspase-3) induced by l-buthionine-(S,R)-sulfoximine (BSO) plus glutamate and stimulated glutathione and glutathione S-transferase activity. Moreover, the addition of 8-hydroxycalamenene to cell cultures restored the reduced mitochondrial membrane potential resulting from glutamate/BSO treatment. The presence of N-methyl-d-aspartate in the retina of rats affected the thickness of the inner plexiform layer (IPL) and increased the number of TUNEL-positive RGCs. However, 8-hydroxycalamenene protected against thinning of the IPL and reduced TUNEL-positive cells in the ganglion cell layer. Thus, 8-hydroxycalamenene isolated from R. elliptica exerts neuroprotective effects both in vitro and in vivo." ], "offsets": [ [ 129, 1238 ] ] } ]

[ { "id": "23032515_T1", "type": "CHEMICAL", "text": [ "8-hydroxycalamenene" ], "offsets": [ [ 1134, 1153 ] ], "normalized": [] }, { "id": "23032515_T2", "type": "CHEMICAL", "text": [ "8-hydroxycalamenene" ], "offsets": [ [ 252, 271 ] ], "normalized": [] }, { "id": "23032515_T3", "type": "CHEMICAL", "text": [ "hexane" ], "offsets": [ [ 294, 300 ] ], "normalized": [] }, { "id": "23032515_T4", "type": "CHEMICAL", "text": [ "8-hydroxycalamenene" ], "offsets": [ [ 350, 369 ] ], "normalized": [] }, { "id": "23032515_T5", "type": "CHEMICAL", "text": [ "l-buthionine-(S,R)-sulfoximine" ], "offsets": [ [ 558, 588 ] ], "normalized": [] }, { "id": "23032515_T6", "type": "CHEMICAL", "text": [ "BSO" ], "offsets": [ [ 590, 593 ] ], "normalized": [] }, { "id": "23032515_T7", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 600, 609 ] ], "normalized": [] }, { "id": "23032515_T8", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 625, 636 ] ], "normalized": [] }, { "id": "23032515_T9", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 641, 652 ] ], "normalized": [] }, { "id": "23032515_T10", "type": "CHEMICAL", "text": [ "S" ], "offsets": [ [ 653, 654 ] ], "normalized": [] }, { "id": "23032515_T11", "type": "CHEMICAL", "text": [ "8-hydroxycalamenene" ], "offsets": [ [ 703, 722 ] ], "normalized": [] }, { "id": "23032515_T12", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 809, 818 ] ], "normalized": [] }, { "id": "23032515_T13", "type": "CHEMICAL", "text": [ "BSO" ], "offsets": [ [ 819, 822 ] ], "normalized": [] }, { "id": "23032515_T14", "type": "CHEMICAL", "text": [ "N-methyl-d-aspartate" ], "offsets": [ [ 850, 870 ] ], "normalized": [] }, { "id": "23032515_T15", "type": "CHEMICAL", "text": [ "8-hydroxycalamenene" ], "offsets": [ [ 1009, 1028 ] ], "normalized": [] }, { "id": "23032515_T16", "type": "CHEMICAL", "text": [ "8-Hydroxycalamenene" ], "offsets": [ [ 0, 19 ] ], "normalized": [] }, { "id": "23032515_T17", "type": "GENE-N", "text": [ "cleaved PARP" ], "offsets": [ [ 519, 531 ] ], "normalized": [] }, { "id": "23032515_T18", "type": "GENE-Y", "text": [ "caspase-3" ], "offsets": [ [ 536, 545 ] ], "normalized": [] }, { "id": "23032515_T19", "type": "GENE-N", "text": [ "glutathione S-transferase" ], "offsets": [ [ 641, 666 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23032515_0", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23032515_T5", "arg2_id": "23032515_T17", "normalized": [] }, { "id": "23032515_1", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23032515_T5", "arg2_id": "23032515_T18", "normalized": [] }, { "id": "23032515_2", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23032515_T6", "arg2_id": "23032515_T17", "normalized": [] }, { "id": "23032515_3", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23032515_T6", "arg2_id": "23032515_T18", "normalized": [] }, { "id": "23032515_4", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23032515_T7", "arg2_id": "23032515_T17", "normalized": [] }, { "id": "23032515_5", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23032515_T7", "arg2_id": "23032515_T18", "normalized": [] } ]

[ { "id": "10070614_title", "type": "title", "text": [ "The human NADH: ubiquinone oxidoreductase NDUFS5 (15 kDa) subunit: cDNA cloning, chromosomal localization, tissue distribution and the absence of mutations in isolated complex I-deficient patients." ], "offsets": [ [ 0, 197 ] ] }, { "id": "10070614_abstract", "type": "abstract", "text": [ "We have cloned the cDNA of the NDUFS5 subunit (15 kDa) of the human mitochondrial respiratory chain complex NADH: ubiquinone oxidoreductase (complex I). The open reading frame consists of 321 base-pairs, coding for 106 amino acids, with a calculated molecular mass of 12.5 kDa. There is an 81.0% identity with the bovine equivalent on cDNA level and 74.5% identity on amino acid basis. PCR analysis of rodent-human somatic cell hybrids revealed that the human NDUFS5 gene maps to chromosome 1. The NDUFS5 mRNA is expressed ubiquitously in human tissues, with a relative higher expression in human heart, skeletal muscle, liver, kidney and fetal heart. A mutation detection study of twenty isolated enzymatic complex I-deficient patients revealed no mutations, nor polymorphisms." ], "offsets": [ [ 198, 976 ] ] } ]

[ { "id": "10070614_T1", "type": "CHEMICAL", "text": [ "NADH" ], "offsets": [ [ 306, 310 ] ], "normalized": [] }, { "id": "10070614_T2", "type": "CHEMICAL", "text": [ "ubiquinone" ], "offsets": [ [ 312, 322 ] ], "normalized": [] }, { "id": "10070614_T3", "type": "CHEMICAL", "text": [ "amino acids" ], "offsets": [ [ 417, 428 ] ], "normalized": [] }, { "id": "10070614_T4", "type": "CHEMICAL", "text": [ "amino acid" ], "offsets": [ [ 566, 576 ] ], "normalized": [] }, { "id": "10070614_T5", "type": "CHEMICAL", "text": [ "NADH" ], "offsets": [ [ 10, 14 ] ], "normalized": [] }, { "id": "10070614_T6", "type": "CHEMICAL", "text": [ "ubiquinone" ], "offsets": [ [ 16, 26 ] ], "normalized": [] }, { "id": "10070614_T7", "type": "GENE-Y", "text": [ "NDUFS5 subunit (15 kDa)" ], "offsets": [ [ 229, 252 ] ], "normalized": [] }, { "id": "10070614_T8", "type": "GENE-Y", "text": [ "human NDUFS5" ], "offsets": [ [ 652, 664 ] ], "normalized": [] }, { "id": "10070614_T9", "type": "GENE-Y", "text": [ "NDUFS5" ], "offsets": [ [ 696, 702 ] ], "normalized": [] }, { "id": "10070614_T10", "type": "GENE-N", "text": [ "human mitochondrial respiratory chain complex NADH: ubiquinone oxidoreductase (complex I)" ], "offsets": [ [ 260, 349 ] ], "normalized": [] }, { "id": "10070614_T11", "type": "GENE-N", "text": [ "complex I" ], "offsets": [ [ 906, 915 ] ], "normalized": [] }, { "id": "10070614_T12", "type": "GENE-N", "text": [ "complex I" ], "offsets": [ [ 168, 177 ] ], "normalized": [] }, { "id": "10070614_T13", "type": "GENE-Y", "text": [ "human NADH: ubiquinone oxidoreductase NDUFS5 (15 kDa) subunit" ], "offsets": [ [ 4, 65 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "10765977_title", "type": "title", "text": [ "Effect of L-arginine-nitric oxide system on the metabolism of essential fatty acids in chemical-induced diabetes mellitus." ], "offsets": [ [ 0, 122 ] ] }, { "id": "10765977_abstract", "type": "abstract", "text": [ "Several studies have shown that the activities of delta-6-desaturase and delta-5-desaturase are depressed in experimental diabetes and in humans with insulin- and non-insulin-dependent diabetes mellitus (type I and type II diabetes mellitus respectively). Furthermore, treatment with insulin is known to correct the defects in desaturases in rats and humans with diabetes, especially in type I. In a recent study, we demonstrated that L-arginine and nitric oxide can prevent alloxan-induced beta cell damage, and the severity of diabetes, and restore the antioxidant status to near normal levels. But, no information is available as to the relationship between L-arginine-nitric oxide system and the metabolism of essential fatty acids in diabetes mellitus. In the present study, it was noted that the plasma levels of saturated fatty acids: stearic and palmitic were increased where as unsaturated fatty acids such as oleic, linoleic, gamma-linolenic and eicosapentaenoic acids (OA, LA, GLA and EPA respectively) were decreased in alloxan-induced diabetic rats. In the liver phospholipid (PL) fraction, GLA, DGLA (dihomo-GLA) and alpha-linolenic acid (ALA) were decreased in the alloxan-treated group; in the muscle PL fraction, LA, GLA and DGLA were low, whereas an increase in the saturated fatty acid content was noted. L-arginine (the precursor of nitric oxide) and sodium nitroprusside (a nitric oxide donor) treatment of alloxan-induced diabetic rats enhanced the levels of LA, GLA and DGLA. Further, nitric oxide synthase inhibitor, L-NMMA, prevented this beneficial action of L-arginine-nitric oxide system on essential fatty acid metabolism. The abnormalities in the essential fatty acid metabolism observed also reverted to normalcy following control of diabetes with insulin. These results indicate that nitric oxide can enhance the activities of delta-6- and delta-5 desaturases, which are depressed in diabetes, and suggests that there is a close interaction between L-arginine-nitric oxide system and the metabolism of essential fatty acids." ], "offsets": [ [ 123, 2179 ] ] } ]

[ { "id": "10765977_T1", "type": "CHEMICAL", "text": [ "alloxan" ], "offsets": [ [ 1155, 1162 ] ], "normalized": [] }, { "id": "10765977_T2", "type": "CHEMICAL", "text": [ "GLA" ], "offsets": [ [ 1227, 1230 ] ], "normalized": [] }, { "id": "10765977_T3", "type": "CHEMICAL", "text": [ "dihomo-GLA" ], "offsets": [ [ 1238, 1248 ] ], "normalized": [] }, { "id": "10765977_T4", "type": "CHEMICAL", "text": [ "alpha-linolenic acid" ], "offsets": [ [ 1254, 1274 ] ], "normalized": [] }, { "id": "10765977_T5", "type": "CHEMICAL", "text": [ "ALA" ], "offsets": [ [ 1276, 1279 ] ], "normalized": [] }, { "id": "10765977_T6", "type": "CHEMICAL", "text": [ "alloxan" ], "offsets": [ [ 1303, 1310 ] ], "normalized": [] }, { "id": "10765977_T7", "type": "CHEMICAL", "text": [ "LA" ], "offsets": [ [ 1353, 1355 ] ], "normalized": [] }, { "id": "10765977_T8", "type": "CHEMICAL", "text": [ "GLA" ], "offsets": [ [ 1357, 1360 ] ], "normalized": [] }, { "id": "10765977_T9", "type": "CHEMICAL", "text": [ "saturated fatty acid" ], "offsets": [ [ 1407, 1427 ] ], "normalized": [] }, { "id": "10765977_T10", "type": "CHEMICAL", "text": [ "L-arginine" ], "offsets": [ [ 1447, 1457 ] ], "normalized": [] }, { "id": "10765977_T11", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 1476, 1488 ] ], "normalized": [] }, { "id": "10765977_T12", "type": "CHEMICAL", "text": [ "sodium nitroprusside" ], "offsets": [ [ 1494, 1514 ] ], "normalized": [] }, { "id": "10765977_T13", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 1518, 1530 ] ], "normalized": [] }, { "id": "10765977_T14", "type": "CHEMICAL", "text": [ "alloxan" ], "offsets": [ [ 1551, 1558 ] ], "normalized": [] }, { "id": "10765977_T15", "type": "CHEMICAL", "text": [ "LA" ], "offsets": [ [ 1604, 1606 ] ], "normalized": [] }, { "id": "10765977_T16", "type": "CHEMICAL", "text": [ "GLA" ], "offsets": [ [ 1608, 1611 ] ], "normalized": [] }, { "id": "10765977_T17", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 1631, 1643 ] ], "normalized": [] }, { "id": "10765977_T18", "type": "CHEMICAL", "text": [ "L-NMMA" ], "offsets": [ [ 1664, 1670 ] ], "normalized": [] }, { "id": "10765977_T19", "type": "CHEMICAL", "text": [ "L-arginine" ], "offsets": [ [ 1708, 1718 ] ], "normalized": [] }, { "id": "10765977_T20", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 1719, 1731 ] ], "normalized": [] }, { "id": "10765977_T21", "type": "CHEMICAL", "text": [ "essential fatty acid" ], "offsets": [ [ 1742, 1762 ] ], "normalized": [] }, { "id": "10765977_T22", "type": "CHEMICAL", "text": [ "essential fatty acid" ], "offsets": [ [ 1800, 1820 ] ], "normalized": [] }, { "id": "10765977_T23", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 1939, 1951 ] ], "normalized": [] }, { "id": "10765977_T24", "type": "CHEMICAL", "text": [ "L-arginine" ], "offsets": [ [ 2104, 2114 ] ], "normalized": [] }, { "id": "10765977_T25", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 2115, 2127 ] ], "normalized": [] }, { "id": "10765977_T26", "type": "CHEMICAL", "text": [ "essential fatty acids" ], "offsets": [ [ 2157, 2178 ] ], "normalized": [] }, { "id": "10765977_T27", "type": "CHEMICAL", "text": [ "L-arginine" ], "offsets": [ [ 558, 568 ] ], "normalized": [] }, { "id": "10765977_T28", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 573, 585 ] ], "normalized": [] }, { "id": "10765977_T29", "type": "CHEMICAL", "text": [ "alloxan" ], "offsets": [ [ 598, 605 ] ], "normalized": [] }, { "id": "10765977_T30", "type": "CHEMICAL", "text": [ "L-arginine" ], "offsets": [ [ 784, 794 ] ], "normalized": [] }, { "id": "10765977_T31", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 795, 807 ] ], "normalized": [] }, { "id": "10765977_T32", "type": "CHEMICAL", "text": [ "essential fatty acids" ], "offsets": [ [ 837, 858 ] ], "normalized": [] }, { "id": "10765977_T33", "type": "CHEMICAL", "text": [ "saturated fatty acids" ], "offsets": [ [ 942, 963 ] ], "normalized": [] }, { "id": "10765977_T34", "type": "CHEMICAL", "text": [ "unsaturated fatty acids" ], "offsets": [ [ 1010, 1033 ] ], "normalized": [] }, { "id": "10765977_T35", "type": "CHEMICAL", "text": [ "oleic, linoleic, gamma-linolenic and eicosapentaenoic acids" ], "offsets": [ [ 1042, 1101 ] ], "normalized": [] }, { "id": "10765977_T36", "type": "CHEMICAL", "text": [ "OA" ], "offsets": [ [ 1103, 1105 ] ], "normalized": [] }, { "id": "10765977_T37", "type": "CHEMICAL", "text": [ "LA" ], "offsets": [ [ 1107, 1109 ] ], "normalized": [] }, { "id": "10765977_T38", "type": "CHEMICAL", "text": [ "GLA" ], "offsets": [ [ 1111, 1114 ] ], "normalized": [] }, { "id": "10765977_T39", "type": "CHEMICAL", "text": [ "EPA" ], "offsets": [ [ 1119, 1122 ] ], "normalized": [] }, { "id": "10765977_T40", "type": "CHEMICAL", "text": [ "L-arginine" ], "offsets": [ [ 10, 20 ] ], "normalized": [] }, { "id": "10765977_T41", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 21, 33 ] ], "normalized": [] }, { "id": "10765977_T42", "type": "CHEMICAL", "text": [ "essential fatty acids" ], "offsets": [ [ 62, 83 ] ], "normalized": [] }, { "id": "10765977_T43", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 273, 280 ] ], "normalized": [] }, { "id": "10765977_T44", "type": "GENE-N", "text": [ "nitric oxide synthase" ], "offsets": [ [ 1631, 1652 ] ], "normalized": [] }, { "id": "10765977_T45", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 290, 297 ] ], "normalized": [] }, { "id": "10765977_T46", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 1902, 1909 ] ], "normalized": [] }, { "id": "10765977_T47", "type": "GENE-N", "text": [ "delta-6- and delta-5 desaturases" ], "offsets": [ [ 1982, 2014 ] ], "normalized": [] }, { "id": "10765977_T48", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 407, 414 ] ], "normalized": [] }, { "id": "10765977_T49", "type": "GENE-N", "text": [ "desaturases" ], "offsets": [ [ 450, 461 ] ], "normalized": [] }, { "id": "10765977_T50", "type": "GENE-Y", "text": [ "delta-6-desaturase" ], "offsets": [ [ 173, 191 ] ], "normalized": [] }, { "id": "10765977_T51", "type": "GENE-Y", "text": [ "delta-5-desaturase" ], "offsets": [ [ 196, 214 ] ], "normalized": [] } ]

[]

[]

[ { "id": "10765977_0", "type": "INHIBITOR", "arg1_id": "10765977_T18", "arg2_id": "10765977_T44", "normalized": [] } ]

[ { "id": "23153456_title", "type": "title", "text": [ "IFNα converts IL-22 into a cytokine efficiently activating STAT1 and its downstream targets." ], "offsets": [ [ 0, 92 ] ] }, { "id": "23153456_abstract", "type": "abstract", "text": [ "Besides their antiviral activity, type I Interferons (IFN) display context-specific immunomodulation. In contrast to long-known IFNα/β, Interleukin (IL)-22 is an anti-bacterial, largely tissue protective cytokine that recently gained attention. Herein, cellular IFNα/IL-22 interactions are investigated. We report that pre-conditioning of epithelial cells with IFNα initiated dramatic changes in IL-22 signaling normally dominated by signal transducer and activator of transcription (STAT)-3. Specifically, by using human DLD1 colon epithelial/carcinoma cells we demonstrate that, upon IFNα, IL-22 converts into a cytokine robustly activating STAT1 and its downstream pro-inflammatory targets CXCL9, CXCL10, and inducible nitric oxide synthase (iNOS). Accordingly, only after IFNα pre-incubation was IL-22-induced STAT1 binding to the CXCL10 promoter detectable. Using the viral mimic polyinosinic:polycytidylic acid and the IFNα/β antagonist B18R we furthermore demonstrate the capability of endogenous IFN to promote IL-22-induced STAT1 activation and expression of CXCL10. IL-22-induced STAT1 activation subsequent to IFNα priming became likewise apparent in human Caco2 colon epithelial/carcinoma cells, HepG2 hepatoma cells, and primary keratinocytes. Current observations may relate to characteristics of IFNα/β in clinical therapy and expose margins of tissue protection by IL-22 application." ], "offsets": [ [ 93, 1492 ] ] } ]

[ { "id": "23153456_T1", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 815, 827 ] ], "normalized": [] }, { "id": "23153456_T2", "type": "CHEMICAL", "text": [ "polyinosinic:polycytidylic acid" ], "offsets": [ [ 978, 1009 ] ], "normalized": [] }, { "id": "23153456_T3", "type": "GENE-N", "text": [ "IFN" ], "offsets": [ [ 1097, 1100 ] ], "normalized": [] }, { "id": "23153456_T4", "type": "GENE-Y", "text": [ "IL-22" ], "offsets": [ [ 1112, 1117 ] ], "normalized": [] }, { "id": "23153456_T5", "type": "GENE-Y", "text": [ "STAT1" ], "offsets": [ [ 1126, 1131 ] ], "normalized": [] }, { "id": "23153456_T6", "type": "GENE-Y", "text": [ "CXCL10" ], "offsets": [ [ 1161, 1167 ] ], "normalized": [] }, { "id": "23153456_T7", "type": "GENE-Y", "text": [ "IL-22" ], "offsets": [ [ 1169, 1174 ] ], "normalized": [] }, { "id": "23153456_T8", "type": "GENE-Y", "text": [ "STAT1" ], "offsets": [ [ 1183, 1188 ] ], "normalized": [] }, { "id": "23153456_T9", "type": "GENE-N", "text": [ "IFNα" ], "offsets": [ [ 1214, 1218 ] ], "normalized": [] }, { "id": "23153456_T10", "type": "GENE-N", "text": [ "IFNα/β" ], "offsets": [ [ 221, 227 ] ], "normalized": [] }, { "id": "23153456_T11", "type": "GENE-N", "text": [ "IFNα/β" ], "offsets": [ [ 1404, 1410 ] ], "normalized": [] }, { "id": "23153456_T12", "type": "GENE-Y", "text": [ "Interleukin (IL)-22" ], "offsets": [ [ 229, 248 ] ], "normalized": [] }, { "id": "23153456_T13", "type": "GENE-Y", "text": [ "IL-22" ], "offsets": [ [ 1474, 1479 ] ], "normalized": [] }, { "id": "23153456_T14", "type": "GENE-N", "text": [ "cytokine" ], "offsets": [ [ 297, 305 ] ], "normalized": [] }, { "id": "23153456_T15", "type": "GENE-N", "text": [ "IFNα" ], "offsets": [ [ 355, 359 ] ], "normalized": [] }, { "id": "23153456_T16", "type": "GENE-Y", "text": [ "IL-22" ], "offsets": [ [ 360, 365 ] ], "normalized": [] }, { "id": "23153456_T17", "type": "GENE-N", "text": [ "type I Interferons" ], "offsets": [ [ 127, 145 ] ], "normalized": [] }, { "id": "23153456_T18", "type": "GENE-N", "text": [ "IFNα" ], "offsets": [ [ 454, 458 ] ], "normalized": [] }, { "id": "23153456_T19", "type": "GENE-Y", "text": [ "IL-22" ], "offsets": [ [ 489, 494 ] ], "normalized": [] }, { "id": "23153456_T20", "type": "GENE-Y", "text": [ "signal transducer and activator of transcription (STAT)-3" ], "offsets": [ [ 527, 584 ] ], "normalized": [] }, { "id": "23153456_T21", "type": "GENE-N", "text": [ "IFN" ], "offsets": [ [ 147, 150 ] ], "normalized": [] }, { "id": "23153456_T22", "type": "GENE-N", "text": [ "IFNα" ], "offsets": [ [ 679, 683 ] ], "normalized": [] }, { "id": "23153456_T23", "type": "GENE-Y", "text": [ "IL-22" ], "offsets": [ [ 685, 690 ] ], "normalized": [] }, { "id": "23153456_T24", "type": "GENE-N", "text": [ "cytokine" ], "offsets": [ [ 707, 715 ] ], "normalized": [] }, { "id": "23153456_T25", "type": "GENE-Y", "text": [ "STAT1" ], "offsets": [ [ 736, 741 ] ], "normalized": [] }, { "id": "23153456_T26", "type": "GENE-Y", "text": [ "CXCL9" ], "offsets": [ [ 786, 791 ] ], "normalized": [] }, { "id": "23153456_T27", "type": "GENE-Y", "text": [ "CXCL10" ], "offsets": [ [ 793, 799 ] ], "normalized": [] }, { "id": "23153456_T28", "type": "GENE-Y", "text": [ "inducible nitric oxide synthase" ], "offsets": [ [ 805, 836 ] ], "normalized": [] }, { "id": "23153456_T29", "type": "GENE-Y", "text": [ "iNOS" ], "offsets": [ [ 838, 842 ] ], "normalized": [] }, { "id": "23153456_T30", "type": "GENE-N", "text": [ "IFNα" ], "offsets": [ [ 869, 873 ] ], "normalized": [] }, { "id": "23153456_T31", "type": "GENE-Y", "text": [ "IL-22" ], "offsets": [ [ 893, 898 ] ], "normalized": [] }, { "id": "23153456_T32", "type": "GENE-Y", "text": [ "STAT1" ], "offsets": [ [ 907, 912 ] ], "normalized": [] }, { "id": "23153456_T33", "type": "GENE-N", "text": [ "CXCL10 promoter" ], "offsets": [ [ 928, 943 ] ], "normalized": [] }, { "id": "23153456_T34", "type": "GENE-N", "text": [ "IFNα/β" ], "offsets": [ [ 1018, 1024 ] ], "normalized": [] }, { "id": "23153456_T35", "type": "GENE-N", "text": [ "IFNα" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "23153456_T36", "type": "GENE-Y", "text": [ "IL-22" ], "offsets": [ [ 14, 19 ] ], "normalized": [] }, { "id": "23153456_T37", "type": "GENE-N", "text": [ "cytokine" ], "offsets": [ [ 27, 35 ] ], "normalized": [] }, { "id": "23153456_T38", "type": "GENE-Y", "text": [ "STAT1" ], "offsets": [ [ 59, 64 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "8319997_title", "type": "title", "text": [ "Comparative effects of three different potent renin inhibitors in primates." ], "offsets": [ [ 0, 75 ] ] }, { "id": "8319997_abstract", "type": "abstract", "text": [ "The goal of the present study was to compare the effects of three potent reference renin inhibitors (remikiren, CGP 38560A, and enalkiren) in sodium-depleted normotensive squirrel monkeys. In these monkeys, arterial pressure was measured in the conscious state with a telemetry system. Oral and intravenous maximal effective doses of the three renin inhibitors were compared in parallel groups of monkeys. In additional experiments, remikiren was given on top of either CGP 38560A or enalkiren in the same animals. Finally, the three drugs were compared with the angiotensin converting enzyme inhibitor cilazapril. The effects of the three drugs on the plasma components of the renin-angiotensin system (plasma renin activity, immunoreactive renin, and immunoreactive angiotensin II concentrations) were also measured. Our results show that remikiren was as effective as cilazapril and markedly more effective than CGP 38560A or enalkiren in reducing arterial pressure in our monkey model. Interestingly, these differences in arterial pressure could not be explained by differences of in vitro potency or different biochemical changes of the plasma components of the renin-angiotensin system, because the inhibitors all reduced immunoreactive angiotensin II to similarly low levels. One possible explanation is that, in our model, remikiren in contrast to CGP 38560A and enalkiren is able to inhibit renin in a functionally important extraplasmatic compartment." ], "offsets": [ [ 76, 1537 ] ] } ]

[ { "id": "8319997_T1", "type": "CHEMICAL", "text": [ "remikiren" ], "offsets": [ [ 177, 186 ] ], "normalized": [] }, { "id": "8319997_T2", "type": "CHEMICAL", "text": [ "CGP 38560A" ], "offsets": [ [ 188, 198 ] ], "normalized": [] }, { "id": "8319997_T3", "type": "CHEMICAL", "text": [ "enalkiren" ], "offsets": [ [ 204, 213 ] ], "normalized": [] }, { "id": "8319997_T4", "type": "CHEMICAL", "text": [ "remikiren" ], "offsets": [ [ 1407, 1416 ] ], "normalized": [] }, { "id": "8319997_T5", "type": "CHEMICAL", "text": [ "CGP 38560A" ], "offsets": [ [ 1432, 1442 ] ], "normalized": [] }, { "id": "8319997_T6", "type": "CHEMICAL", "text": [ "enalkiren" ], "offsets": [ [ 1447, 1456 ] ], "normalized": [] }, { "id": "8319997_T7", "type": "CHEMICAL", "text": [ "sodium" ], "offsets": [ [ 218, 224 ] ], "normalized": [] }, { "id": "8319997_T8", "type": "CHEMICAL", "text": [ "CGP 38560A" ], "offsets": [ [ 546, 556 ] ], "normalized": [] }, { "id": "8319997_T9", "type": "CHEMICAL", "text": [ "enalkiren" ], "offsets": [ [ 560, 569 ] ], "normalized": [] }, { "id": "8319997_T10", "type": "CHEMICAL", "text": [ "cilazapril" ], "offsets": [ [ 679, 689 ] ], "normalized": [] }, { "id": "8319997_T11", "type": "CHEMICAL", "text": [ "remikiren" ], "offsets": [ [ 917, 926 ] ], "normalized": [] }, { "id": "8319997_T12", "type": "CHEMICAL", "text": [ "cilazapril" ], "offsets": [ [ 947, 957 ] ], "normalized": [] }, { "id": "8319997_T13", "type": "CHEMICAL", "text": [ "CGP 38560A" ], "offsets": [ [ 991, 1001 ] ], "normalized": [] }, { "id": "8319997_T14", "type": "CHEMICAL", "text": [ "enalkiren" ], "offsets": [ [ 1005, 1014 ] ], "normalized": [] }, { "id": "8319997_T15", "type": "GENE-Y", "text": [ "renin" ], "offsets": [ [ 1243, 1248 ] ], "normalized": [] }, { "id": "8319997_T16", "type": "GENE-Y", "text": [ "angiotensin" ], "offsets": [ [ 1249, 1260 ] ], "normalized": [] }, { "id": "8319997_T17", "type": "GENE-Y", "text": [ "angiotensin II" ], "offsets": [ [ 1319, 1333 ] ], "normalized": [] }, { "id": "8319997_T18", "type": "GENE-Y", "text": [ "renin" ], "offsets": [ [ 1476, 1481 ] ], "normalized": [] }, { "id": "8319997_T19", "type": "GENE-Y", "text": [ "renin" ], "offsets": [ [ 420, 425 ] ], "normalized": [] }, { "id": "8319997_T20", "type": "GENE-Y", "text": [ "angiotensin converting enzyme" ], "offsets": [ [ 639, 668 ] ], "normalized": [] }, { "id": "8319997_T21", "type": "GENE-Y", "text": [ "renin" ], "offsets": [ [ 754, 759 ] ], "normalized": [] }, { "id": "8319997_T22", "type": "GENE-Y", "text": [ "angiotensin" ], "offsets": [ [ 760, 771 ] ], "normalized": [] }, { "id": "8319997_T23", "type": "GENE-Y", "text": [ "renin" ], "offsets": [ [ 787, 792 ] ], "normalized": [] }, { "id": "8319997_T24", "type": "GENE-Y", "text": [ "renin" ], "offsets": [ [ 818, 823 ] ], "normalized": [] }, { "id": "8319997_T25", "type": "GENE-Y", "text": [ "angiotensin II" ], "offsets": [ [ 844, 858 ] ], "normalized": [] }, { "id": "8319997_T26", "type": "GENE-Y", "text": [ "renin" ], "offsets": [ [ 159, 164 ] ], "normalized": [] }, { "id": "8319997_T27", "type": "GENE-N", "text": [ "renin" ], "offsets": [ [ 46, 51 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23317165_title", "type": "title", "text": [ "Recent Developments of p38α MAP Kinase Inhibitors as Antiinflammatory Agents Based on the Imidazole Scaffolds." ], "offsets": [ [ 0, 110 ] ] }, { "id": "23317165_abstract", "type": "abstract", "text": [ "Rheumatoid arthritis (RA) and other chronic inflammatory diseases are always the major therapeutic challenges. Recent research efforts provided new insights into the molecular basis of these diseases and new opportunities for developing improved anti-inflammatory drugs. The p38 mitogen-activated protein (MAP) kinase plays a central role in the regulation of the biosynthesis and release of several proinflammatory cytokines including tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β). Hence, inhibition of the p38 MAP kinase is regarded as a promising therapeutic strategy for controlling inflammatory diseases. A diverse range of p38α MAP kinase inhibitors have been developed as potential anti-inflammatory agents, and some of them have entered the phase II clinical trials. The imidazole derivatives are known as competitive inhibitors at the ATP binding site of the p38α MAP kinase. Modifications on the imidazole scaffold have led to a large amount of potent p38α MAP kinase inhibitors. This review will summarize the developments of small molecule p38α MAP kinase inhibitors based on the imidazole core scaffolds in recent 10 years. Variations at the N1, C2, C4 and C5 positions of imidazole were introduced, and the structure-activity relationships of these imidazole inhibitors were also discussed." ], "offsets": [ [ 111, 1436 ] ] } ]

[ { "id": "23317165_T1", "type": "CHEMICAL", "text": [ "imidazole" ], "offsets": [ [ 1224, 1233 ] ], "normalized": [] }, { "id": "23317165_T2", "type": "CHEMICAL", "text": [ "imidazole" ], "offsets": [ [ 1318, 1327 ] ], "normalized": [] }, { "id": "23317165_T3", "type": "CHEMICAL", "text": [ "imidazole" ], "offsets": [ [ 1395, 1404 ] ], "normalized": [] }, { "id": "23317165_T4", "type": "CHEMICAL", "text": [ "imidazole" ], "offsets": [ [ 911, 920 ] ], "normalized": [] }, { "id": "23317165_T5", "type": "CHEMICAL", "text": [ "ATP" ], "offsets": [ [ 976, 979 ] ], "normalized": [] }, { "id": "23317165_T6", "type": "CHEMICAL", "text": [ "imidazole" ], "offsets": [ [ 1038, 1047 ] ], "normalized": [] }, { "id": "23317165_T7", "type": "CHEMICAL", "text": [ "Imidazole" ], "offsets": [ [ 90, 99 ] ], "normalized": [] }, { "id": "23317165_T8", "type": "GENE-Y", "text": [ "p38α" ], "offsets": [ [ 1184, 1188 ] ], "normalized": [] }, { "id": "23317165_T9", "type": "GENE-N", "text": [ "MAP kinase" ], "offsets": [ [ 1189, 1199 ] ], "normalized": [] }, { "id": "23317165_T10", "type": "GENE-N", "text": [ "p38" ], "offsets": [ [ 386, 389 ] ], "normalized": [] }, { "id": "23317165_T11", "type": "GENE-N", "text": [ "mitogen-activated protein (MAP) kinase" ], "offsets": [ [ 390, 428 ] ], "normalized": [] }, { "id": "23317165_T12", "type": "GENE-N", "text": [ "cytokines" ], "offsets": [ [ 527, 536 ] ], "normalized": [] }, { "id": "23317165_T13", "type": "GENE-Y", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 547, 574 ] ], "normalized": [] }, { "id": "23317165_T14", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 576, 581 ] ], "normalized": [] }, { "id": "23317165_T15", "type": "GENE-Y", "text": [ "interleukin-1 beta" ], "offsets": [ [ 587, 605 ] ], "normalized": [] }, { "id": "23317165_T16", "type": "GENE-Y", "text": [ "IL-1β" ], "offsets": [ [ 607, 612 ] ], "normalized": [] }, { "id": "23317165_T17", "type": "GENE-N", "text": [ "p38" ], "offsets": [ [ 640, 643 ] ], "normalized": [] }, { "id": "23317165_T18", "type": "GENE-N", "text": [ "MAP kinase" ], "offsets": [ [ 644, 654 ] ], "normalized": [] }, { "id": "23317165_T19", "type": "GENE-Y", "text": [ "p38α" ], "offsets": [ [ 761, 765 ] ], "normalized": [] }, { "id": "23317165_T20", "type": "GENE-N", "text": [ "MAP kinase" ], "offsets": [ [ 766, 776 ] ], "normalized": [] }, { "id": "23317165_T21", "type": "GENE-Y", "text": [ "p38α" ], "offsets": [ [ 1000, 1004 ] ], "normalized": [] }, { "id": "23317165_T22", "type": "GENE-N", "text": [ "MAP kinase" ], "offsets": [ [ 1005, 1015 ] ], "normalized": [] }, { "id": "23317165_T23", "type": "GENE-Y", "text": [ "p38α" ], "offsets": [ [ 1094, 1098 ] ], "normalized": [] }, { "id": "23317165_T24", "type": "GENE-N", "text": [ "MAP kinase" ], "offsets": [ [ 1099, 1109 ] ], "normalized": [] }, { "id": "23317165_T25", "type": "GENE-Y", "text": [ "p38α" ], "offsets": [ [ 23, 27 ] ], "normalized": [] }, { "id": "23317165_T26", "type": "GENE-N", "text": [ "MAP Kinase" ], "offsets": [ [ 28, 38 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23317165_0", "type": "INHIBITOR", "arg1_id": "23317165_T4", "arg2_id": "23317165_T21", "normalized": [] }, { "id": "23317165_1", "type": "INHIBITOR", "arg1_id": "23317165_T4", "arg2_id": "23317165_T22", "normalized": [] }, { "id": "23317165_2", "type": "DIRECT-REGULATOR", "arg1_id": "23317165_T5", "arg2_id": "23317165_T21", "normalized": [] }, { "id": "23317165_3", "type": "DIRECT-REGULATOR", "arg1_id": "23317165_T5", "arg2_id": "23317165_T22", "normalized": [] }, { "id": "23317165_4", "type": "INHIBITOR", "arg1_id": "23317165_T6", "arg2_id": "23317165_T23", "normalized": [] }, { "id": "23317165_5", "type": "INHIBITOR", "arg1_id": "23317165_T6", "arg2_id": "23317165_T24", "normalized": [] }, { "id": "23317165_6", "type": "INHIBITOR", "arg1_id": "23317165_T1", "arg2_id": "23317165_T8", "normalized": [] }, { "id": "23317165_7", "type": "INHIBITOR", "arg1_id": "23317165_T1", "arg2_id": "23317165_T9", "normalized": [] } ]

[ { "id": "23487486_title", "type": "title", "text": [ "Effects of progesterone and medroxyprogesterone on actin remodeling and neuronal spine formation." ], "offsets": [ [ 0, 97 ] ] }, { "id": "23487486_abstract", "type": "abstract", "text": [ "Sex steroids are important regulators of neuronal cell morphology, and this is critical for gender differences in brain function and dysfunction. Neuronal morphology is controlled by multiprotein complexes including moesin (a member of the ezrin/radixin/moesin family), focal adhesion kinase (FAK), or the Wiskott-Aldrich syndrome protein-family verprolin homologous (WAVE1) protein, controlling dynamic remodeling of the cytoskeleton and cell membrane. We investigated the actions of natural progesterone (P) and of the synthetic progestin medroxyprogesterone acetate (MPA) on actin remodeling, focal adhesion complex formation, and actin branching in rat cortical neurons. Treatment with P and, to a lesser extent, MPA, increases the number and density of dendritic spines. P increases the phosphorylation of moesin, FAK, and WAVE1, and their redistribution toward cell membrane sites where spines are formed. Signaling to moesin is achieved by PR via a Gα/Gβ-dependent signaling to the small GTPase Ras homolog gene family, member A and its related kinase, Rho-associated kinase-2. In parallel, WAVE1 recruitment is triggered by a Gαi/Gβ-dependent signaling of PR to c-Src, FAK, and Rac1 GTPase. Rac1 recruits cyclin-dependent kinase-5, which phosphorylates WAVE1. Silencing of moesin, FAK, or WAVE1 abrogates the increase in dendritic spines induced by progesterone. In all applications, MPA is found to act similar to P, albeit with a lower efficacy. In conclusion, our findings indicate that the control of actin polymerization and branching and focal adhesion complex formation via moesin, FAK, and WAVE1 is a key function of progesterone receptor in neurons, which may be relevant for the regulation of dendritic spine turnover and neuronal plasticity." ], "offsets": [ [ 98, 1858 ] ] } ]

[ { "id": "23487486_T1", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 1455, 1467 ] ], "normalized": [] }, { "id": "23487486_T2", "type": "CHEMICAL", "text": [ "MPA" ], "offsets": [ [ 1490, 1493 ] ], "normalized": [] }, { "id": "23487486_T3", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 1731, 1743 ] ], "normalized": [] }, { "id": "23487486_T4", "type": "CHEMICAL", "text": [ "steroids" ], "offsets": [ [ 102, 110 ] ], "normalized": [] }, { "id": "23487486_T5", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 591, 603 ] ], "normalized": [] }, { "id": "23487486_T6", "type": "CHEMICAL", "text": [ "progestin" ], "offsets": [ [ 629, 638 ] ], "normalized": [] }, { "id": "23487486_T7", "type": "CHEMICAL", "text": [ "medroxyprogesterone acetate" ], "offsets": [ [ 639, 666 ] ], "normalized": [] }, { "id": "23487486_T8", "type": "CHEMICAL", "text": [ "MPA" ], "offsets": [ [ 668, 671 ] ], "normalized": [] }, { "id": "23487486_T9", "type": "CHEMICAL", "text": [ "MPA" ], "offsets": [ [ 815, 818 ] ], "normalized": [] }, { "id": "23487486_T10", "type": "CHEMICAL", "text": [ "progesterone" ], "offsets": [ [ 11, 23 ] ], "normalized": [] }, { "id": "23487486_T11", "type": "CHEMICAL", "text": [ "medroxyprogesterone" ], "offsets": [ [ 28, 47 ] ], "normalized": [] }, { "id": "23487486_T12", "type": "GENE-N", "text": [ "kinase" ], "offsets": [ [ 1150, 1156 ] ], "normalized": [] }, { "id": "23487486_T13", "type": "GENE-Y", "text": [ "Rho-associated kinase-2" ], "offsets": [ [ 1158, 1181 ] ], "normalized": [] }, { "id": "23487486_T14", "type": "GENE-Y", "text": [ "WAVE1" ], "offsets": [ [ 1196, 1201 ] ], "normalized": [] }, { "id": "23487486_T15", "type": "GENE-N", "text": [ "Gαi" ], "offsets": [ [ 1232, 1235 ] ], "normalized": [] }, { "id": "23487486_T16", "type": "GENE-N", "text": [ "Gβ" ], "offsets": [ [ 1236, 1238 ] ], "normalized": [] }, { "id": "23487486_T17", "type": "GENE-Y", "text": [ "PR" ], "offsets": [ [ 1262, 1264 ] ], "normalized": [] }, { "id": "23487486_T18", "type": "GENE-Y", "text": [ "c-Src" ], "offsets": [ [ 1268, 1273 ] ], "normalized": [] }, { "id": "23487486_T19", "type": "GENE-Y", "text": [ "FAK" ], "offsets": [ [ 1275, 1278 ] ], "normalized": [] }, { "id": "23487486_T20", "type": "GENE-Y", "text": [ "Rac1" ], "offsets": [ [ 1284, 1288 ] ], "normalized": [] }, { "id": "23487486_T21", "type": "GENE-N", "text": [ "GTPase" ], "offsets": [ [ 1289, 1295 ] ], "normalized": [] }, { "id": "23487486_T22", "type": "GENE-Y", "text": [ "Rac1" ], "offsets": [ [ 1297, 1301 ] ], "normalized": [] }, { "id": "23487486_T23", "type": "GENE-Y", "text": [ "cyclin-dependent kinase-5" ], "offsets": [ [ 1311, 1336 ] ], "normalized": [] }, { "id": "23487486_T24", "type": "GENE-Y", "text": [ "WAVE1" ], "offsets": [ [ 1359, 1364 ] ], "normalized": [] }, { "id": "23487486_T25", "type": "GENE-Y", "text": [ "moesin" ], "offsets": [ [ 1379, 1385 ] ], "normalized": [] }, { "id": "23487486_T26", "type": "GENE-Y", "text": [ "FAK" ], "offsets": [ [ 1387, 1390 ] ], "normalized": [] }, { "id": "23487486_T27", "type": "GENE-Y", "text": [ "WAVE1" ], "offsets": [ [ 1395, 1400 ] ], "normalized": [] }, { "id": "23487486_T28", "type": "GENE-N", "text": [ "actin" ], "offsets": [ [ 1611, 1616 ] ], "normalized": [] }, { "id": "23487486_T29", "type": "GENE-Y", "text": [ "moesin" ], "offsets": [ [ 1687, 1693 ] ], "normalized": [] }, { "id": "23487486_T30", "type": "GENE-Y", "text": [ "FAK" ], "offsets": [ [ 1695, 1698 ] ], "normalized": [] }, { "id": "23487486_T31", "type": "GENE-Y", "text": [ "WAVE1" ], "offsets": [ [ 1704, 1709 ] ], "normalized": [] }, { "id": "23487486_T32", "type": "GENE-Y", "text": [ "progesterone receptor" ], "offsets": [ [ 1731, 1752 ] ], "normalized": [] }, { "id": "23487486_T33", "type": "GENE-Y", "text": [ "moesin" ], "offsets": [ [ 314, 320 ] ], "normalized": [] }, { "id": "23487486_T34", "type": "GENE-Y", "text": [ "ezrin" ], "offsets": [ [ 338, 343 ] ], "normalized": [] }, { "id": "23487486_T35", "type": "GENE-Y", "text": [ "radixin" ], "offsets": [ [ 344, 351 ] ], "normalized": [] }, { "id": "23487486_T36", "type": "GENE-Y", "text": [ "moesin" ], "offsets": [ [ 352, 358 ] ], "normalized": [] }, { "id": "23487486_T37", "type": "GENE-Y", "text": [ "focal adhesion kinase" ], "offsets": [ [ 368, 389 ] ], "normalized": [] }, { "id": "23487486_T38", "type": "GENE-Y", "text": [ "FAK" ], "offsets": [ [ 391, 394 ] ], "normalized": [] }, { "id": "23487486_T39", "type": "GENE-Y", "text": [ "Wiskott-Aldrich syndrome protein-family verprolin homologous (WAVE1) protein" ], "offsets": [ [ 404, 480 ] ], "normalized": [] }, { "id": "23487486_T40", "type": "GENE-N", "text": [ "actin" ], "offsets": [ [ 676, 681 ] ], "normalized": [] }, { "id": "23487486_T41", "type": "GENE-N", "text": [ "focal adhesion complex" ], "offsets": [ [ 694, 716 ] ], "normalized": [] }, { "id": "23487486_T42", "type": "GENE-N", "text": [ "actin" ], "offsets": [ [ 732, 737 ] ], "normalized": [] }, { "id": "23487486_T43", "type": "GENE-Y", "text": [ "moesin" ], "offsets": [ [ 909, 915 ] ], "normalized": [] }, { "id": "23487486_T44", "type": "GENE-Y", "text": [ "FAK" ], "offsets": [ [ 917, 920 ] ], "normalized": [] }, { "id": "23487486_T45", "type": "GENE-Y", "text": [ "WAVE1" ], "offsets": [ [ 926, 931 ] ], "normalized": [] }, { "id": "23487486_T46", "type": "GENE-Y", "text": [ "moesin" ], "offsets": [ [ 1023, 1029 ] ], "normalized": [] }, { "id": "23487486_T47", "type": "GENE-Y", "text": [ "PR" ], "offsets": [ [ 1045, 1047 ] ], "normalized": [] }, { "id": "23487486_T48", "type": "GENE-N", "text": [ "Gα" ], "offsets": [ [ 1054, 1056 ] ], "normalized": [] }, { "id": "23487486_T49", "type": "GENE-N", "text": [ "Gβ" ], "offsets": [ [ 1057, 1059 ] ], "normalized": [] }, { "id": "23487486_T50", "type": "GENE-Y", "text": [ "small GTPase Ras" ], "offsets": [ [ 1087, 1103 ] ], "normalized": [] } ]

[]

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[ { "id": "23360295_title", "type": "title", "text": [ "Effects of polymer end-group chemistry and order of deposition on controlled protein delivery from layer-by-layer assembly." ], "offsets": [ [ 0, 123 ] ] }, { "id": "23360295_abstract", "type": "abstract", "text": [ "Layer-by-layer (LBL) assembly is an attractive platform for controlled release of biologics given its mild fabrication process and versatility in coating substrates of any shape. Proteins can be incorporated into LBL coatings by sequentially depositing oppositely charged polyelectrolytes, which self-assemble into nanoscale films on medical devices or tissue engineering scaffolds. However, previously reported LBL platforms often require the use of a few hundred layers to avoid burst release, which hinders their broad translation due to the lengthy fabrication process, cost, and batch-to-batch variability. Here we report a biodegradable LBL platform composed of only 10 layers with tunable protein release kinetics, which is an order of magnitude less than previously reported LBL platforms. We performed a combinatorial study to examine the effects of polymer chemistry and order of deposition of poly(β-amino) esters on protein release kinetics under 81 LBL assembly conditions. Using the optimal \"polyelectrolyte couples\" for constructing the LBL film, basic fibroblast growth factor (bFGF) was released gradually over 14 days with retained biological activity to stimulate cell proliferation. The method reported herein is applicable for coating various substrates including metals, polymers, and ceramics and may be used for a broad range of biomedical and tissue engineering applications." ], "offsets": [ [ 124, 1524 ] ] } ]

[ { "id": "23360295_T1", "type": "CHEMICAL", "text": [ "poly(β-amino) esters" ], "offsets": [ [ 1028, 1048 ] ], "normalized": [] }, { "id": "23360295_T2", "type": "GENE-Y", "text": [ "basic fibroblast growth factor" ], "offsets": [ [ 1186, 1216 ] ], "normalized": [] }, { "id": "23360295_T3", "type": "GENE-Y", "text": [ "bFGF" ], "offsets": [ [ 1218, 1222 ] ], "normalized": [] } ]

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[ { "id": "17653133_title", "type": "title", "text": [ "Determination of dimethylarginine dimethylaminohydrolase activity in the kidney." ], "offsets": [ [ 0, 80 ] ] }, { "id": "17653133_abstract", "type": "abstract", "text": [ "Dimethylarginine dimethylaminohydrolase (DDAH) metabolizes asymmetric dimethylarginine to generate L-citrulline and is present in large quantities in the kidney. We present a new study that optimizes the Prescott-Jones colorimetric assay to measure DDAH-dependent L-citrulline generation in kidney homogenates. We found that the removal of urea with urease is necessary since urea also produces a positive reaction. Deproteinization with sulfosalicylic acid was found to be optimal and that protease inhibitors were not necessary. All assays were conducted in phosphate buffer, since other common additives can create false positive and false negative reactions. Arginase or nitric oxide synthase isoenzymes were not found to influence L-citrulline production. Our optimized L-citrulline production assay to measure DDAH activity correlated closely with the direct measure of the rate of asymmetric dimethylarginine consumption. Using this assay, we found that both superoxide and nitric oxide inhibit renal cortical DDAH activity in vitro." ], "offsets": [ [ 81, 1121 ] ] } ]

[ { "id": "17653133_T1", "type": "CHEMICAL", "text": [ "Dimethylarginine" ], "offsets": [ [ 81, 97 ] ], "normalized": [] }, { "id": "17653133_T2", "type": "CHEMICAL", "text": [ "L-citrulline" ], "offsets": [ [ 345, 357 ] ], "normalized": [] }, { "id": "17653133_T3", "type": "CHEMICAL", "text": [ "urea" ], "offsets": [ [ 421, 425 ] ], "normalized": [] }, { "id": "17653133_T4", "type": "CHEMICAL", "text": [ "urea" ], "offsets": [ [ 457, 461 ] ], "normalized": [] }, { "id": "17653133_T5", "type": "CHEMICAL", "text": [ "sulfosalicylic acid" ], "offsets": [ [ 519, 538 ] ], "normalized": [] }, { "id": "17653133_T6", "type": "CHEMICAL", "text": [ "phosphate" ], "offsets": [ [ 641, 650 ] ], "normalized": [] }, { "id": "17653133_T7", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 756, 768 ] ], "normalized": [] }, { "id": "17653133_T8", "type": "CHEMICAL", "text": [ "dimethylarginine" ], "offsets": [ [ 151, 167 ] ], "normalized": [] }, { "id": "17653133_T9", "type": "CHEMICAL", "text": [ "L-citrulline" ], "offsets": [ [ 817, 829 ] ], "normalized": [] }, { "id": "17653133_T10", "type": "CHEMICAL", "text": [ "L-citrulline" ], "offsets": [ [ 856, 868 ] ], "normalized": [] }, { "id": "17653133_T11", "type": "CHEMICAL", "text": [ "dimethylarginine" ], "offsets": [ [ 980, 996 ] ], "normalized": [] }, { "id": "17653133_T12", "type": "CHEMICAL", "text": [ "superoxide" ], "offsets": [ [ 1047, 1057 ] ], "normalized": [] }, { "id": "17653133_T13", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 1062, 1074 ] ], "normalized": [] }, { "id": "17653133_T14", "type": "CHEMICAL", "text": [ "L-citrulline" ], "offsets": [ [ 180, 192 ] ], "normalized": [] }, { "id": "17653133_T15", "type": "CHEMICAL", "text": [ "dimethylarginine" ], "offsets": [ [ 17, 33 ] ], "normalized": [] }, { "id": "17653133_T16", "type": "GENE-Y", "text": [ "Dimethylarginine dimethylaminohydrolase" ], "offsets": [ [ 81, 120 ] ], "normalized": [] }, { "id": "17653133_T17", "type": "GENE-Y", "text": [ "DDAH" ], "offsets": [ [ 1098, 1102 ] ], "normalized": [] }, { "id": "17653133_T18", "type": "GENE-Y", "text": [ "DDAH" ], "offsets": [ [ 330, 334 ] ], "normalized": [] }, { "id": "17653133_T19", "type": "GENE-N", "text": [ "urease" ], "offsets": [ [ 431, 437 ] ], "normalized": [] }, { "id": "17653133_T20", "type": "GENE-Y", "text": [ "DDAH" ], "offsets": [ [ 122, 126 ] ], "normalized": [] }, { "id": "17653133_T21", "type": "GENE-N", "text": [ "protease" ], "offsets": [ [ 572, 580 ] ], "normalized": [] }, { "id": "17653133_T22", "type": "GENE-N", "text": [ "Arginase" ], "offsets": [ [ 744, 752 ] ], "normalized": [] }, { "id": "17653133_T23", "type": "GENE-N", "text": [ "nitric oxide synthase" ], "offsets": [ [ 756, 777 ] ], "normalized": [] }, { "id": "17653133_T24", "type": "GENE-Y", "text": [ "DDAH" ], "offsets": [ [ 897, 901 ] ], "normalized": [] }, { "id": "17653133_T25", "type": "GENE-Y", "text": [ "dimethylarginine dimethylaminohydrolase" ], "offsets": [ [ 17, 56 ] ], "normalized": [] } ]

[]

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[ { "id": "17653133_0", "type": "SUBSTRATE", "arg1_id": "17653133_T8", "arg2_id": "17653133_T16", "normalized": [] }, { "id": "17653133_1", "type": "SUBSTRATE", "arg1_id": "17653133_T8", "arg2_id": "17653133_T20", "normalized": [] }, { "id": "17653133_2", "type": "PRODUCT-OF", "arg1_id": "17653133_T14", "arg2_id": "17653133_T16", "normalized": [] }, { "id": "17653133_3", "type": "PRODUCT-OF", "arg1_id": "17653133_T14", "arg2_id": "17653133_T20", "normalized": [] }, { "id": "17653133_4", "type": "PRODUCT-OF", "arg1_id": "17653133_T2", "arg2_id": "17653133_T18", "normalized": [] }, { "id": "17653133_5", "type": "PRODUCT-OF", "arg1_id": "17653133_T10", "arg2_id": "17653133_T24", "normalized": [] }, { "id": "17653133_6", "type": "INHIBITOR", "arg1_id": "17653133_T12", "arg2_id": "17653133_T17", "normalized": [] }, { "id": "17653133_7", "type": "INHIBITOR", "arg1_id": "17653133_T13", "arg2_id": "17653133_T17", "normalized": [] }, { "id": "17653133_8", "type": "SUBSTRATE", "arg1_id": "17653133_T3", "arg2_id": "17653133_T19", "normalized": [] }, { "id": "17653133_9", "type": "SUBSTRATE", "arg1_id": "17653133_T11", "arg2_id": "17653133_T24", "normalized": [] } ]

[ { "id": "23259865_title", "type": "title", "text": [ "Synthesis and biological evaluation of indenoisoquinolines that inhibit both tyrosyl-DNA phosphodiesterase I (Tdp1) and topoisomerase I (Top1)." ], "offsets": [ [ 0, 143 ] ] }, { "id": "23259865_abstract", "type": "abstract", "text": [ "Tyrosyl-DNA phosphodiesterase I (Tdp1) plays a key role in the repair of damaged DNA resulting from the topoisomerase I (Top1) inhibitor camptothecin and a variety of other DNA-damaging anticancer agents. This report documents the design, synthesis, and evaluation of new indenoisoquinolines that are dual inhibitors of both Tdp1 and Top1. Enzyme inhibitory data and cytotoxicity data from human cancer cell cultures were used to establish structure-activity relationships. The potencies of the indenoisoquinolines against Tdp1 ranged from 5 μM to 111 μM, which places the more active compounds among the most potent known inhibitors of this target. The cytotoxicity mean graph midpoints ranged from 0.02 to 2.34 μM. Dual Tdp1-Top1 inhibitors are of interest because the Top1 and Tdp1 inhibitory activities could theoretically work synergistically to create more effective anticancer agents." ], "offsets": [ [ 144, 1035 ] ] } ]

[ { "id": "23259865_T1", "type": "CHEMICAL", "text": [ "camptothecin" ], "offsets": [ [ 281, 293 ] ], "normalized": [] }, { "id": "23259865_T2", "type": "CHEMICAL", "text": [ "indenoisoquinolines" ], "offsets": [ [ 416, 435 ] ], "normalized": [] }, { "id": "23259865_T3", "type": "CHEMICAL", "text": [ "indenoisoquinolines" ], "offsets": [ [ 639, 658 ] ], "normalized": [] }, { "id": "23259865_T4", "type": "CHEMICAL", "text": [ "indenoisoquinolines" ], "offsets": [ [ 39, 58 ] ], "normalized": [] }, { "id": "23259865_T5", "type": "GENE-Y", "text": [ "Tyrosyl-DNA phosphodiesterase I" ], "offsets": [ [ 144, 175 ] ], "normalized": [] }, { "id": "23259865_T6", "type": "GENE-Y", "text": [ "topoisomerase I" ], "offsets": [ [ 248, 263 ] ], "normalized": [] }, { "id": "23259865_T7", "type": "GENE-Y", "text": [ "Top1" ], "offsets": [ [ 265, 269 ] ], "normalized": [] }, { "id": "23259865_T8", "type": "GENE-Y", "text": [ "Tdp1" ], "offsets": [ [ 469, 473 ] ], "normalized": [] }, { "id": "23259865_T9", "type": "GENE-Y", "text": [ "Tdp1" ], "offsets": [ [ 177, 181 ] ], "normalized": [] }, { "id": "23259865_T10", "type": "GENE-Y", "text": [ "Top1" ], "offsets": [ [ 478, 482 ] ], "normalized": [] }, { "id": "23259865_T11", "type": "GENE-Y", "text": [ "Tdp1" ], "offsets": [ [ 667, 671 ] ], "normalized": [] }, { "id": "23259865_T12", "type": "GENE-Y", "text": [ "Tdp1" ], "offsets": [ [ 866, 870 ] ], "normalized": [] }, { "id": "23259865_T13", "type": "GENE-Y", "text": [ "Top1" ], "offsets": [ [ 871, 875 ] ], "normalized": [] }, { "id": "23259865_T14", "type": "GENE-Y", "text": [ "Top1" ], "offsets": [ [ 915, 919 ] ], "normalized": [] }, { "id": "23259865_T15", "type": "GENE-Y", "text": [ "Tdp1" ], "offsets": [ [ 924, 928 ] ], "normalized": [] }, { "id": "23259865_T16", "type": "GENE-Y", "text": [ "Tdp1" ], "offsets": [ [ 110, 114 ] ], "normalized": [] }, { "id": "23259865_T17", "type": "GENE-Y", "text": [ "topoisomerase I" ], "offsets": [ [ 120, 135 ] ], "normalized": [] }, { "id": "23259865_T18", "type": "GENE-Y", "text": [ "Top1" ], "offsets": [ [ 137, 141 ] ], "normalized": [] }, { "id": "23259865_T19", "type": "GENE-Y", "text": [ "tyrosyl-DNA phosphodiesterase I" ], "offsets": [ [ 77, 108 ] ], "normalized": [] } ]

[]

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[ { "id": "23259865_0", "type": "INHIBITOR", "arg1_id": "23259865_T4", "arg2_id": "23259865_T19", "normalized": [] }, { "id": "23259865_1", "type": "INHIBITOR", "arg1_id": "23259865_T4", "arg2_id": "23259865_T16", "normalized": [] }, { "id": "23259865_2", "type": "INHIBITOR", "arg1_id": "23259865_T4", "arg2_id": "23259865_T17", "normalized": [] }, { "id": "23259865_3", "type": "INHIBITOR", "arg1_id": "23259865_T4", "arg2_id": "23259865_T18", "normalized": [] }, { "id": "23259865_4", "type": "INHIBITOR", "arg1_id": "23259865_T1", "arg2_id": "23259865_T6", "normalized": [] }, { "id": "23259865_5", "type": "INHIBITOR", "arg1_id": "23259865_T1", "arg2_id": "23259865_T7", "normalized": [] }, { "id": "23259865_6", "type": "INHIBITOR", "arg1_id": "23259865_T2", "arg2_id": "23259865_T8", "normalized": [] }, { "id": "23259865_7", "type": "INHIBITOR", "arg1_id": "23259865_T2", "arg2_id": "23259865_T10", "normalized": [] }, { "id": "23259865_8", "type": "INHIBITOR", "arg1_id": "23259865_T3", "arg2_id": "23259865_T11", "normalized": [] } ]

[ { "id": "23613080_title", "type": "title", "text": [ "Hierarchical NiO microflake films with high coloration efficiency, cyclic stability and low power consumption for applications in a complementary electrochromic device." ], "offsets": [ [ 0, 168 ] ] }, { "id": "23613080_abstract", "type": "abstract", "text": [ "We 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": [ [ 169, 1337 ] ] } ]

[ { "id": "23613080_T1", "type": "CHEMICAL", "text": [ "FTO" ], "offsets": [ [ 289, 292 ] ], "normalized": [] }, { "id": "23613080_T2", "type": "CHEMICAL", "text": [ "NiO" ], "offsets": [ [ 222, 225 ] ], "normalized": [] }, { "id": "23613080_T3", "type": "CHEMICAL", "text": [ "NiO" ], "offsets": [ [ 721, 724 ] ], "normalized": [] }, { "id": "23613080_T4", "type": "CHEMICAL", "text": [ "WO3" ], "offsets": [ [ 761, 764 ] ], "normalized": [] }, { "id": "23613080_T5", "type": "CHEMICAL", "text": [ "NiO" ], "offsets": [ [ 13, 16 ] ], "normalized": [] } ]

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[]

[ { "id": "15286093_title", "type": "title", "text": [ "Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain histamine H1-receptor occupancy using 11C-doxepin positron emission tomography." ], "offsets": [ [ 0, 200 ] ] }, { "id": "15286093_abstract", "type": "abstract", "text": [ "Histamine H1-receptor (H1R) antagonists, or antihistamines, often induce sedative side effects when used for the treatment of allergic disorders. This study compared the sedative profiles of the second-generation antihistamines, fexofenadine and cetirizine, using 3 different criteria: subjective sleepiness evaluated by the Stanford Sleepiness Scale, objective psychomotor tests (simple and choice reaction time tests and visual discrimination tests at 4 different exposure durations), and measurement of histamine H1-receptor occupancy (H1RO) in the brain. Subjective sleepiness and psychomotor performance were measured in 20 healthy Japanese volunteers at baseline and 90 min after administration of fexofenadine 120 mg or cetirizine 20 mg in a double-blind, placebo-controlled crossover study. Hydroxyzine 30 mg was included as a positive control. H1RO was measured using positron emission tomography (PET) with (11)C-doxepin in 12 of the 20 subjects, and a further 11 volunteers were recruited to act as controls. In psychomotor tests, fexofenadine was not significantly different from placebo and significantly less impairing than cetirizine on some tasks, as well as significantly less impairing than hydroxyzine on all tasks. For subjective sleepiness, fexofenadine was not significantly different from placebo, whereas cetirizine showed a trend toward increased sleepiness compared with fexofenadine and placebo. H1RO was negligible with fexofenadine (-0.1%) but moderately high with cetirizine (26.0%). In conclusion, fexofenadine 120 mg is distinguishable from cetirizine 20 mg, as assessed by H1RO and psychomotor testing." ], "offsets": [ [ 201, 1836 ] ] } ]

[ { "id": "15286093_T1", "type": "CHEMICAL", "text": [ "Histamine" ], "offsets": [ [ 201, 210 ] ], "normalized": [] }, { "id": "15286093_T2", "type": "CHEMICAL", "text": [ "fexofenadine" ], "offsets": [ [ 1243, 1255 ] ], "normalized": [] }, { "id": "15286093_T3", "type": "CHEMICAL", "text": [ "cetirizine" ], "offsets": [ [ 1339, 1349 ] ], "normalized": [] }, { "id": "15286093_T4", "type": "CHEMICAL", "text": [ "hydroxyzine" ], "offsets": [ [ 1410, 1421 ] ], "normalized": [] }, { "id": "15286093_T5", "type": "CHEMICAL", "text": [ "fexofenadine" ], "offsets": [ [ 1463, 1475 ] ], "normalized": [] }, { "id": "15286093_T6", "type": "CHEMICAL", "text": [ "cetirizine" ], "offsets": [ [ 1530, 1540 ] ], "normalized": [] }, { "id": "15286093_T7", "type": "CHEMICAL", "text": [ "fexofenadine" ], "offsets": [ [ 1598, 1610 ] ], "normalized": [] }, { "id": "15286093_T8", "type": "CHEMICAL", "text": [ "fexofenadine" ], "offsets": [ [ 1649, 1661 ] ], "normalized": [] }, { "id": "15286093_T9", "type": "CHEMICAL", "text": [ "cetirizine" ], "offsets": [ [ 1695, 1705 ] ], "normalized": [] }, { "id": "15286093_T10", "type": "CHEMICAL", "text": [ "fexofenadine" ], "offsets": [ [ 1730, 1742 ] ], "normalized": [] }, { "id": "15286093_T11", "type": "CHEMICAL", "text": [ "cetirizine" ], "offsets": [ [ 1774, 1784 ] ], "normalized": [] }, { "id": "15286093_T12", "type": "CHEMICAL", "text": [ "antihistamines" ], "offsets": [ [ 414, 428 ] ], "normalized": [] }, { "id": "15286093_T13", "type": "CHEMICAL", "text": [ "fexofenadine" ], "offsets": [ [ 430, 442 ] ], "normalized": [] }, { "id": "15286093_T14", "type": "CHEMICAL", "text": [ "cetirizine" ], "offsets": [ [ 447, 457 ] ], "normalized": [] }, { "id": "15286093_T15", "type": "CHEMICAL", "text": [ "antihistamines" ], "offsets": [ [ 245, 259 ] ], "normalized": [] }, { "id": "15286093_T16", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 707, 716 ] ], "normalized": [] }, { "id": "15286093_T17", "type": "CHEMICAL", "text": [ "fexofenadine" ], "offsets": [ [ 905, 917 ] ], "normalized": [] }, { "id": "15286093_T18", "type": "CHEMICAL", "text": [ "cetirizine" ], "offsets": [ [ 928, 938 ] ], "normalized": [] }, { "id": "15286093_T19", "type": "CHEMICAL", "text": [ "Hydroxyzine" ], "offsets": [ [ 1000, 1011 ] ], "normalized": [] }, { "id": "15286093_T20", "type": "CHEMICAL", "text": [ "(11)C-doxepin" ], "offsets": [ [ 1118, 1131 ] ], "normalized": [] }, { "id": "15286093_T21", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 121, 130 ] ], "normalized": [] }, { "id": "15286093_T22", "type": "CHEMICAL", "text": [ "11C-doxepin" ], "offsets": [ [ 159, 170 ] ], "normalized": [] }, { "id": "15286093_T23", "type": "CHEMICAL", "text": [ "fexofenadine" ], "offsets": [ [ 19, 31 ] ], "normalized": [] }, { "id": "15286093_T24", "type": "CHEMICAL", "text": [ "cetirizine" ], "offsets": [ [ 36, 46 ] ], "normalized": [] }, { "id": "15286093_T25", "type": "GENE-Y", "text": [ "Histamine H1-receptor" ], "offsets": [ [ 201, 222 ] ], "normalized": [] }, { "id": "15286093_T26", "type": "GENE-Y", "text": [ "H1R" ], "offsets": [ [ 224, 227 ] ], "normalized": [] }, { "id": "15286093_T27", "type": "GENE-Y", "text": [ "histamine H1-receptor" ], "offsets": [ [ 707, 728 ] ], "normalized": [] }, { "id": "15286093_T28", "type": "GENE-Y", "text": [ "histamine H1-receptor" ], "offsets": [ [ 121, 142 ] ], "normalized": [] } ]

[]

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[ { "id": "15286093_0", "type": "DIRECT-REGULATOR", "arg1_id": "15286093_T22", "arg2_id": "15286093_T28", "normalized": [] }, { "id": "15286093_1", "type": "ANTAGONIST", "arg1_id": "15286093_T15", "arg2_id": "15286093_T25", "normalized": [] }, { "id": "15286093_2", "type": "ANTAGONIST", "arg1_id": "15286093_T15", "arg2_id": "15286093_T26", "normalized": [] } ]

[ { "id": "15489888_title", "type": "title", "text": [ "Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-kappaB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation." ], "offsets": [ [ 0, 199 ] ] }, { "id": "15489888_abstract", "type": "abstract", "text": [ "Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin have been shown to suppress transcription factor NF-kappaB, which controls the expression of genes such as cyclooxygenase (COX)-2 and cyclin D1, leading to inhibition of proliferation of tumor cells. There is no systematic study as to how these drugs differ in their ability to suppress NF-kappaB activation and NF-kappaB-regulated gene expression or cell proliferation. In the present study, we investigated the effect of almost a dozen different commonly used NSAIDs on tumor necrosis factor (TNF)-induced NF-kappaB activation and NF-kappaB-regulated gene products, and on cell proliferation. Dexamethasone, an anti-inflammatory steroid, was included for comparison with NSAIDs. As indicated by DNA binding, none of the drugs alone activated NF-kappaB. All compounds inhibited TNF-induced NF-kappaB activation, but with highly variable efficacy. The 50% inhibitory concentration required was 5.67, 3.49, 3.03, 1.25, 0.94, 0.60, 0.38, 0.084, 0.043, 0.027, 0.024, and 0.010 mM for aspirin, ibuprofen, sulindac, phenylbutazone, naproxen, indomethacin, diclofenac, resveratrol, curcumin, dexamethasone, celecoxib, and tamoxifen, respectively. All drugs inhibited IkappaBalpha kinase and suppressed IkappaBalpha degradation and NF-kappaB-regulated reporter gene expression. They also suppressed NF-kappaB-regulated COX-2 and cyclin D1 protein expression in a dose-dependent manner. All compounds inhibited the proliferation of tumor cells, with 50% inhibitory concentrations of 6.09, 1.12, 0.65, 0.49, 1.01, 0.19, 0.36, 0.012, 0.016, 0.047, 0.013, and 0.008 mM for aspirin, ibuprofen, sulindac, phenylbutazone, naproxen, indomethacin, diclofenac, resveratrol, curcumin, dexamethasone, celecoxib, and tamoxifen, respectively. Overall these results indicate that aspirin and ibuprofen are least potent, while resveratrol, curcumin, celecoxib, and tamoxifen are the most potent anti-inflammatory and antiproliferative agents of those we studied." ], "offsets": [ [ 200, 2201 ] ] } ]

[ { "id": "15489888_T1", "type": "CHEMICAL", "text": [ "aspirin" ], "offsets": [ [ 1243, 1250 ] ], "normalized": [] }, { "id": "15489888_T2", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 1252, 1261 ] ], "normalized": [] }, { "id": "15489888_T3", "type": "CHEMICAL", "text": [ "sulindac" ], "offsets": [ [ 1263, 1271 ] ], "normalized": [] }, { "id": "15489888_T4", "type": "CHEMICAL", "text": [ "phenylbutazone" ], "offsets": [ [ 1273, 1287 ] ], "normalized": [] }, { "id": "15489888_T5", "type": "CHEMICAL", "text": [ "naproxen" ], "offsets": [ [ 1289, 1297 ] ], "normalized": [] }, { "id": "15489888_T6", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 1299, 1311 ] ], "normalized": [] }, { "id": "15489888_T7", "type": "CHEMICAL", "text": [ "diclofenac" ], "offsets": [ [ 1313, 1323 ] ], "normalized": [] }, { "id": "15489888_T8", "type": "CHEMICAL", "text": [ "resveratrol" ], "offsets": [ [ 1325, 1336 ] ], "normalized": [] }, { "id": "15489888_T9", "type": "CHEMICAL", "text": [ "curcumin" ], "offsets": [ [ 1338, 1346 ] ], "normalized": [] }, { "id": "15489888_T10", "type": "CHEMICAL", "text": [ "dexamethasone" ], "offsets": [ [ 1348, 1361 ] ], "normalized": [] }, { "id": "15489888_T11", "type": "CHEMICAL", "text": [ "celecoxib" ], "offsets": [ [ 1363, 1372 ] ], "normalized": [] }, { "id": "15489888_T12", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1378, 1387 ] ], "normalized": [] }, { "id": "15489888_T13", "type": "CHEMICAL", "text": [ "aspirin" ], "offsets": [ [ 1824, 1831 ] ], "normalized": [] }, { "id": "15489888_T14", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 1833, 1842 ] ], "normalized": [] }, { "id": "15489888_T15", "type": "CHEMICAL", "text": [ "sulindac" ], "offsets": [ [ 1844, 1852 ] ], "normalized": [] }, { "id": "15489888_T16", "type": "CHEMICAL", "text": [ "phenylbutazone" ], "offsets": [ [ 1854, 1868 ] ], "normalized": [] }, { "id": "15489888_T17", "type": "CHEMICAL", "text": [ "naproxen" ], "offsets": [ [ 1870, 1878 ] ], "normalized": [] }, { "id": "15489888_T18", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 1880, 1892 ] ], "normalized": [] }, { "id": "15489888_T19", "type": "CHEMICAL", "text": [ "diclofenac" ], "offsets": [ [ 1894, 1904 ] ], "normalized": [] }, { "id": "15489888_T20", "type": "CHEMICAL", "text": [ "resveratrol" ], "offsets": [ [ 1906, 1917 ] ], "normalized": [] }, { "id": "15489888_T21", "type": "CHEMICAL", "text": [ "curcumin" ], "offsets": [ [ 1919, 1927 ] ], "normalized": [] }, { "id": "15489888_T22", "type": "CHEMICAL", "text": [ "dexamethasone" ], "offsets": [ [ 1929, 1942 ] ], "normalized": [] }, { "id": "15489888_T23", "type": "CHEMICAL", "text": [ "celecoxib" ], "offsets": [ [ 1944, 1953 ] ], "normalized": [] }, { "id": "15489888_T24", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 1959, 1968 ] ], "normalized": [] }, { "id": "15489888_T25", "type": "CHEMICAL", "text": [ "aspirin" ], "offsets": [ [ 2020, 2027 ] ], "normalized": [] }, { "id": "15489888_T26", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 2032, 2041 ] ], "normalized": [] }, { "id": "15489888_T27", "type": "CHEMICAL", "text": [ "resveratrol" ], "offsets": [ [ 2066, 2077 ] ], "normalized": [] }, { "id": "15489888_T28", "type": "CHEMICAL", "text": [ "curcumin" ], "offsets": [ [ 2079, 2087 ] ], "normalized": [] }, { "id": "15489888_T29", "type": "CHEMICAL", "text": [ "celecoxib" ], "offsets": [ [ 2089, 2098 ] ], "normalized": [] }, { "id": "15489888_T30", "type": "CHEMICAL", "text": [ "tamoxifen" ], "offsets": [ [ 2104, 2113 ] ], "normalized": [] }, { "id": "15489888_T31", "type": "CHEMICAL", "text": [ "Dexamethasone" ], "offsets": [ [ 857, 870 ] ], "normalized": [] }, { "id": "15489888_T32", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 893, 900 ] ], "normalized": [] }, { "id": "15489888_T33", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 311, 320 ] ], "normalized": [] }, { "id": "15489888_T34", "type": "GENE-Y", "text": [ "IkappaBalpha" ], "offsets": [ [ 1423, 1435 ] ], "normalized": [] }, { "id": "15489888_T35", "type": "GENE-N", "text": [ "kinase" ], "offsets": [ [ 1436, 1442 ] ], "normalized": [] }, { "id": "15489888_T36", "type": "GENE-Y", "text": [ "IkappaBalpha" ], "offsets": [ [ 1458, 1470 ] ], "normalized": [] }, { "id": "15489888_T37", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 1487, 1496 ] ], "normalized": [] }, { "id": "15489888_T38", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 1554, 1563 ] ], "normalized": [] }, { "id": "15489888_T39", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1574, 1579 ] ], "normalized": [] }, { "id": "15489888_T40", "type": "GENE-Y", "text": [ "cyclin D1" ], "offsets": [ [ 1584, 1593 ] ], "normalized": [] }, { "id": "15489888_T41", "type": "GENE-Y", "text": [ "cyclooxygenase (COX)-2" ], "offsets": [ [ 369, 391 ] ], "normalized": [] }, { "id": "15489888_T42", "type": "GENE-Y", "text": [ "cyclin D1" ], "offsets": [ [ 396, 405 ] ], "normalized": [] }, { "id": "15489888_T43", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 549, 558 ] ], "normalized": [] }, { "id": "15489888_T44", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 574, 583 ] ], "normalized": [] }, { "id": "15489888_T45", "type": "GENE-N", "text": [ "tumor necrosis factor" ], "offsets": [ [ 734, 755 ] ], "normalized": [] }, { "id": "15489888_T46", "type": "GENE-N", "text": [ "TNF" ], "offsets": [ [ 757, 760 ] ], "normalized": [] }, { "id": "15489888_T47", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 770, 779 ] ], "normalized": [] }, { "id": "15489888_T48", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 795, 804 ] ], "normalized": [] }, { "id": "15489888_T49", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 1006, 1015 ] ], "normalized": [] }, { "id": "15489888_T50", "type": "GENE-N", "text": [ "TNF" ], "offsets": [ [ 1041, 1044 ] ], "normalized": [] }, { "id": "15489888_T51", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 1053, 1062 ] ], "normalized": [] }, { "id": "15489888_T52", "type": "GENE-Y", "text": [ "cyclooxygenase-2" ], "offsets": [ [ 124, 140 ] ], "normalized": [] }, { "id": "15489888_T53", "type": "GENE-Y", "text": [ "cyclin D1" ], "offsets": [ [ 145, 154 ] ], "normalized": [] }, { "id": "15489888_T54", "type": "GENE-N", "text": [ "NF-kappaB" ], "offsets": [ [ 74, 83 ] ], "normalized": [] } ]

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[ { "id": "23635319_title", "type": "title", "text": [ "Piezotronic Effect in Solution-Grown p-Type ZnO Nanowires and Films." ], "offsets": [ [ 0, 68 ] ] }, { "id": "23635319_abstract", "type": "abstract", "text": [ "Investigating the piezotronic effect in p-type piezoelectric semiconductor is critical for developing a complete piezotronic theory and designing/fabricating novel piezotronic applications with more complex functionality. Using a low temperature solution method, we were able to produce ultralong (up to 60 μm in length) Sb doped p-type ZnO nanowires on both rigid and flexible substrates. For the p-type nanowire field effect transistor, the on/off ratio, threshold voltage, mobility, and carrier concentration of 0.2% Sb-doped sample are found to be 10(5), 2.1 V, 0.82 cm(2)·V(-1)·s(-1), and 2.6 × 10(17) cm(-3), respectively, and the corresponding values for 1% Sb doped samples are 10(4), 2.0 V, 1.24 cm(2)·V(-1)·s(-1), and 3.8 × 10(17) cm(-3). We further investigated the universality of piezotronic effect in the as-synthesized Sb-doped p-type ZnO NWs and reported for the first time strain-gated piezotronic transistors as well as piezopotential-driven mechanical energy harvesting based on solution-grown p-type ZnO NWs. The results presented here broaden the scope of piezotronics and extend the framework for its potential applications in electronics, optoelectronics, smart MEMS/NEMS, and human-machine interfacing." ], "offsets": [ [ 69, 1295 ] ] } ]

[ { "id": "23635319_T1", "type": "CHEMICAL", "text": [ "ZnO" ], "offsets": [ [ 1089, 1092 ] ], "normalized": [] }, { "id": "23635319_T2", "type": "CHEMICAL", "text": [ "Sb" ], "offsets": [ [ 390, 392 ] ], "normalized": [] }, { "id": "23635319_T3", "type": "CHEMICAL", "text": [ "ZnO" ], "offsets": [ [ 406, 409 ] ], "normalized": [] }, { "id": "23635319_T4", "type": "CHEMICAL", "text": [ "Sb" ], "offsets": [ [ 589, 591 ] ], "normalized": [] }, { "id": "23635319_T5", "type": "CHEMICAL", "text": [ "Sb" ], "offsets": [ [ 734, 736 ] ], "normalized": [] }, { "id": "23635319_T6", "type": "CHEMICAL", "text": [ "Sb" ], "offsets": [ [ 903, 905 ] ], "normalized": [] }, { "id": "23635319_T7", "type": "CHEMICAL", "text": [ "ZnO" ], "offsets": [ [ 919, 922 ] ], "normalized": [] }, { "id": "23635319_T8", "type": "CHEMICAL", "text": [ "ZnO" ], "offsets": [ [ 44, 47 ] ], "normalized": [] } ]

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[ { "id": "23081912_title", "type": "title", "text": [ "Fungicide prochloraz and environmental pollutant dioxin induce the ABCG2 transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway." ], "offsets": [ [ 0, 170 ] ] }, { "id": "23081912_abstract", "type": "abstract", "text": [ "The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide prochloraz display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed \"dioxin response elements\" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter ABCG2 (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by AhR agonists including TCDD and prochloraz, we have systematically investigated the effect of both contaminants on functional ABCG2 transport activity in primary bovine mammary epithelial cells. TCDD or prochloraz doubled ABCG2-mediated Hoechst H33342 secretion. This effect was almost completely reversed by specific ABCG2 inhibitor Ko143. In further mechanistic studies, we showed that this induction was due to binding of activated AhR to DRE sequences in the ABCG2 5'-UTR. Receptor binding was significantly reduced by specific AhR antagonist salicyl amide. Induction of AhR by TCDD and prochloraz resulted in a time- and dose-dependent increase of ABCG2 gene expression and transporter protein levels. As ABCG2 represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent AhR agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary ABCG2 as a novel target gene of pesticide prochloraz and dioxin, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products." ], "offsets": [ [ 171, 1871 ] ] } ]

[ { "id": "23081912_T1", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 277, 281 ] ], "normalized": [] }, { "id": "23081912_T2", "type": "CHEMICAL", "text": [ "salicyl amide" ], "offsets": [ [ 1281, 1294 ] ], "normalized": [] }, { "id": "23081912_T3", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 1316, 1320 ] ], "normalized": [] }, { "id": "23081912_T4", "type": "CHEMICAL", "text": [ "prochloraz" ], "offsets": [ [ 1325, 1335 ] ], "normalized": [] }, { "id": "23081912_T5", "type": "CHEMICAL", "text": [ "imidazole" ], "offsets": [ [ 298, 307 ] ], "normalized": [] }, { "id": "23081912_T6", "type": "CHEMICAL", "text": [ "prochloraz" ], "offsets": [ [ 318, 328 ] ], "normalized": [] }, { "id": "23081912_T7", "type": "CHEMICAL", "text": [ "prochloraz" ], "offsets": [ [ 1730, 1740 ] ], "normalized": [] }, { "id": "23081912_T8", "type": "CHEMICAL", "text": [ "dioxin" ], "offsets": [ [ 1745, 1751 ] ], "normalized": [] }, { "id": "23081912_T9", "type": "CHEMICAL", "text": [ "aryl hydrocarbon" ], "offsets": [ [ 459, 475 ] ], "normalized": [] }, { "id": "23081912_T10", "type": "CHEMICAL", "text": [ "dioxin" ], "offsets": [ [ 513, 519 ] ], "normalized": [] }, { "id": "23081912_T11", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 757, 761 ] ], "normalized": [] }, { "id": "23081912_T12", "type": "CHEMICAL", "text": [ "prochloraz" ], "offsets": [ [ 766, 776 ] ], "normalized": [] }, { "id": "23081912_T13", "type": "CHEMICAL", "text": [ "2,3,7,8-tetrachlorodibenzo-p-dioxin" ], "offsets": [ [ 240, 275 ] ], "normalized": [] }, { "id": "23081912_T14", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 929, 933 ] ], "normalized": [] }, { "id": "23081912_T15", "type": "CHEMICAL", "text": [ "prochloraz" ], "offsets": [ [ 937, 947 ] ], "normalized": [] }, { "id": "23081912_T16", "type": "CHEMICAL", "text": [ "Hoechst H33342" ], "offsets": [ [ 971, 985 ] ], "normalized": [] }, { "id": "23081912_T17", "type": "CHEMICAL", "text": [ "Ko143" ], "offsets": [ [ 1068, 1073 ] ], "normalized": [] }, { "id": "23081912_T18", "type": "CHEMICAL", "text": [ "prochloraz" ], "offsets": [ [ 10, 20 ] ], "normalized": [] }, { "id": "23081912_T19", "type": "CHEMICAL", "text": [ "arylhydrocarbon" ], "offsets": [ [ 127, 142 ] ], "normalized": [] }, { "id": "23081912_T20", "type": "CHEMICAL", "text": [ "dioxin" ], "offsets": [ [ 49, 55 ] ], "normalized": [] }, { "id": "23081912_T21", "type": "GENE-N", "text": [ "DRE" ], "offsets": [ [ 1176, 1179 ] ], "normalized": [] }, { "id": "23081912_T22", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 1197, 1202 ] ], "normalized": [] }, { "id": "23081912_T23", "type": "GENE-Y", "text": [ "AhR" ], "offsets": [ [ 1266, 1269 ] ], "normalized": [] }, { "id": "23081912_T24", "type": "GENE-Y", "text": [ "AhR" ], "offsets": [ [ 1309, 1312 ] ], "normalized": [] }, { "id": "23081912_T26", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 1444, 1449 ] ], "normalized": [] }, { "id": "23081912_T27", "type": "GENE-Y", "text": [ "AhR" ], "offsets": [ [ 1556, 1559 ] ], "normalized": [] }, { "id": "23081912_T28", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 1688, 1693 ] ], "normalized": [] }, { "id": "23081912_T29", "type": "GENE-Y", "text": [ "aryl hydrocarbon receptor" ], "offsets": [ [ 459, 484 ] ], "normalized": [] }, { "id": "23081912_T30", "type": "GENE-Y", "text": [ "AhR" ], "offsets": [ [ 486, 489 ] ], "normalized": [] }, { "id": "23081912_T31", "type": "GENE-N", "text": [ "dioxin response elements" ], "offsets": [ [ 513, 537 ] ], "normalized": [] }, { "id": "23081912_T32", "type": "GENE-N", "text": [ "DREs" ], "offsets": [ [ 540, 544 ] ], "normalized": [] }, { "id": "23081912_T33", "type": "GENE-N", "text": [ "efflux transporter" ], "offsets": [ [ 588, 606 ] ], "normalized": [] }, { "id": "23081912_T34", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 607, 612 ] ], "normalized": [] }, { "id": "23081912_T35", "type": "GENE-Y", "text": [ "EU570105" ], "offsets": [ [ 628, 636 ] ], "normalized": [] }, { "id": "23081912_T36", "type": "GENE-Y", "text": [ "AhR" ], "offsets": [ [ 734, 737 ] ], "normalized": [] }, { "id": "23081912_T37", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 860, 865 ] ], "normalized": [] }, { "id": "23081912_T38", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 956, 961 ] ], "normalized": [] }, { "id": "23081912_T39", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 1052, 1057 ] ], "normalized": [] }, { "id": "23081912_T40", "type": "GENE-Y", "text": [ "AhR" ], "offsets": [ [ 1169, 1172 ] ], "normalized": [] }, { "id": "23081912_T41", "type": "GENE-Y", "text": [ "arylhydrocarbon receptor" ], "offsets": [ [ 127, 151 ] ], "normalized": [] }, { "id": "23081912_T42", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 67, 72 ] ], "normalized": [] }, { "id": "23081912_T25", "type": "GENE-Y", "text": [ "ABCG2" ], "offsets": [ [ 1387, 1392 ] ], "normalized": [] } ]

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[ { "id": "23081912_0", "type": "AGONIST", "arg1_id": "23081912_T11", "arg2_id": "23081912_T36", "normalized": [] }, { "id": "23081912_1", "type": "AGONIST", "arg1_id": "23081912_T12", "arg2_id": "23081912_T36", "normalized": [] }, { "id": "23081912_2", "type": "INHIBITOR", "arg1_id": "23081912_T17", "arg2_id": "23081912_T39", "normalized": [] }, { "id": "23081912_3", "type": "SUBSTRATE", "arg1_id": "23081912_T16", "arg2_id": "23081912_T38", "normalized": [] }, { "id": "23081912_4", "type": "ANTAGONIST", "arg1_id": "23081912_T2", "arg2_id": "23081912_T23", "normalized": [] }, { "id": "23081912_5", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23081912_T3", "arg2_id": "23081912_T25", "normalized": [] }, { "id": "23081912_6", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23081912_T4", "arg2_id": "23081912_T25", "normalized": [] } ]

[ { "id": "23509039_title", "type": "title", "text": [ "2-aminothiazoles with improved pharmacotherapeutic properties for treatment of prion disease." ], "offsets": [ [ 0, 93 ] ] }, { "id": "23509039_abstract", "type": "abstract", "text": [ "Recently, we described the aminothiazole lead (4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine (1), which exhibits many desirable properties, including excellent stability in liver microsomes, oral bioavailability of ∼40 %, and high exposure in the brains of mice. Despite its good pharmacokinetic properties, compound 1 exhibited only modest potency in mouse neuroblastoma cells overexpressing the disease-causing prion protein PrP(Sc) . Accordingly, we sought to identify analogues of 1 with improved antiprion potency in ScN2a-cl3 cells while retaining similar or superior properties. Herein we report the discovery of improved lead compounds such as (6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl)thiazol-2-yl]amine and cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl)amide, which exhibit brain exposure/EC50 ratios at least tenfold greater than that of compound 1." ], "offsets": [ [ 94, 979 ] ] } ]

[ { "id": "23509039_T1", "type": "CHEMICAL", "text": [ "aminothiazole" ], "offsets": [ [ 121, 134 ] ], "normalized": [] }, { "id": "23509039_T2", "type": "CHEMICAL", "text": [ "(4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine" ], "offsets": [ [ 140, 198 ] ], "normalized": [] }, { "id": "23509039_T3", "type": "CHEMICAL", "text": [ "(6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl)thiazol-2-yl]amine" ], "offsets": [ [ 758, 825 ] ], "normalized": [] }, { "id": "23509039_T4", "type": "CHEMICAL", "text": [ "cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl)amide" ], "offsets": [ [ 830, 887 ] ], "normalized": [] }, { "id": "23509039_T5", "type": "CHEMICAL", "text": [ "2-aminothiazoles" ], "offsets": [ [ 0, 16 ] ], "normalized": [] }, { "id": "23509039_T6", "type": "GENE-Y", "text": [ "prion protein PrP(Sc)" ], "offsets": [ [ 519, 540 ] ], "normalized": [] } ]

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[ { "id": "12588370_title", "type": "title", "text": [ "Selective cyclooxygenase-2 inhibition does not affect the healing of cutaneous full-thickness incisional wounds in SKH-1 mice." ], "offsets": [ [ 0, 126 ] ] }, { "id": "12588370_abstract", "type": "abstract", "text": [ "BACKGROUND: The inducible cyclooxygenase-2 (COX-2) enzyme is upregulated in inflammatory diseases, as well as in epithelial cancers, and has an established role in angiogenesis and tissue repair. OBJECTIVE: Because of these physiological effects and the widespread use of the selective COX-2 inhibitor, celecoxib, we wanted to determine if inhibition of COX-2 would affect incisional skin wound healing. METHODS: Using a cutaneous full-thickness, sutured, incisional wound model in hairless SKH-1 mice, we evaluated the role of COX-2 in the wound healing process by comparing the effects of a nonselective COX inhibitor, diclofenac, with a selective COX-2 inhibitor, SC-791. Healing was monitored for up to 28 days postincision histologically and for recovery of wound strength. RESULTS: COX-2 expression was observed over the first week of healing, peaking at day 3 and was not affected by treatment with the selective COX-2 or nonselective COX inhibitors. Infiltrating macrophages, as well as keratinocytes and dermal fibroblasts at the wound site, expressed COX-2. Neither selective COX-2, nor nonselective COX inhibition had a significant effect on the macroscopic or microscopic morphology of the wounds, whereas dexamethasone treatment resulted in epidermal and granulation tissue atrophy. In addition, neither selective COX-2, nor nonselective COX inhibition altered keratinocyte proliferation and differentiation, dermal angiogenesis or the recovery of wound tensile strength, whereas dexamethasone reduced the tensile strength of the wounds by 30-38% throughout the healing period. CONCLUSIONS: These data indicate that selective COX-2 inhibition does not affect the healing of surgical skin wounds." ], "offsets": [ [ 127, 1835 ] ] } ]

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[]

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[ { "id": "12588370_0", "type": "INHIBITOR", "arg1_id": "12588370_T3", "arg2_id": "12588370_T12", "normalized": [] }, { "id": "12588370_1", "type": "INHIBITOR", "arg1_id": "12588370_T4", "arg2_id": "12588370_T16", "normalized": [] } ]

[ { "id": "22983867_title", "type": "title", "text": [ "Swim training of monosodium L-glutamate-obese mice improves the impaired insulin receptor tyrosine phosphorylation in pancreatic islets." ], "offsets": [ [ 0, 136 ] ] }, { "id": "22983867_abstract", "type": "abstract", "text": [ "The goal of the present study was to investigate changes on glucose homoeostasis and of the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) signalling in pancreatic islets from MSG-obese mice submitted to or not submitted to swim training. Swim training of 90-day-old MSG mice was used to evaluate whether signalling pathways of the IR and IRS-1 in islets are involved with the insulin resistance and glucose intolerance observed in this obese animal model. The results showed that IR tyrosine phosphorylation (pIR) was reduced by 42 % in MSG-obese mice (MSG, 6.7 ± 0.2 arbitrary units (a.u.); control, 11.5 ± 0.4 a.u.); on the other hand, exercise training increased pIR by 76 % in MSG mice without affecting control mice (MSG, 11.8 ± 0.3; control, 12.8 ± 0.2 a.u.). Although the treatment with MSG increased IRS-1 tyrosine phosphorylation (pIRS-1) by 96 % (MSG, 17.02 ± 0.6; control, 8.7 ± 0.2 a.u.), exercise training also increased it in both groups (control, 13.6 ± 0.1; MSG, 22.2 ± 1.1 a.u.). Current research shows that the practice of swim training increases the tyrosine phosphorylation of IRS-1 which can modulate the effect caused by obesity in insulin receptors." ], "offsets": [ [ 137, 1326 ] ] } ]

[ { "id": "22983867_T1", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 1223, 1231 ] ], "normalized": [] }, { "id": "22983867_T2", "type": "CHEMICAL", "text": [ "MSG" ], "offsets": [ [ 329, 332 ] ], "normalized": [] }, { "id": "22983867_T3", "type": "CHEMICAL", "text": [ "MSG" ], "offsets": [ [ 420, 423 ] ], "normalized": [] }, { "id": "22983867_T4", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 553, 560 ] ], "normalized": [] }, { "id": "22983867_T5", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 637, 645 ] ], "normalized": [] }, { "id": "22983867_T6", "type": "CHEMICAL", "text": [ "MSG" ], "offsets": [ [ 691, 694 ] ], "normalized": [] }, { "id": "22983867_T7", "type": "CHEMICAL", "text": [ "MSG" ], "offsets": [ [ 707, 710 ] ], "normalized": [] }, { "id": "22983867_T8", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 197, 204 ] ], "normalized": [] }, { "id": "22983867_T9", "type": "CHEMICAL", "text": [ "MSG" ], "offsets": [ [ 835, 838 ] ], "normalized": [] }, { "id": "22983867_T10", "type": "CHEMICAL", "text": [ "MSG" ], "offsets": [ [ 876, 879 ] ], "normalized": [] }, { "id": "22983867_T11", "type": "CHEMICAL", "text": [ "MSG" ], "offsets": [ [ 948, 951 ] ], "normalized": [] }, { "id": "22983867_T12", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 968, 976 ] ], "normalized": [] }, { "id": "22983867_T13", "type": "CHEMICAL", "text": [ "MSG" ], "offsets": [ [ 1011, 1014 ] ], "normalized": [] }, { "id": "22983867_T14", "type": "CHEMICAL", "text": [ "MSG" ], "offsets": [ [ 1128, 1131 ] ], "normalized": [] }, { "id": "22983867_T15", "type": "CHEMICAL", "text": [ "monosodium L-glutamate" ], "offsets": [ [ 17, 39 ] ], "normalized": [] }, { "id": "22983867_T16", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 90, 98 ] ], "normalized": [] }, { "id": "22983867_T17", "type": "GENE-Y", "text": [ "IR" ], "offsets": [ [ 247, 249 ] ], "normalized": [] }, { "id": "22983867_T18", "type": "GENE-Y", "text": [ "IRS-1" ], "offsets": [ [ 1251, 1256 ] ], "normalized": [] }, { "id": "22983867_T19", "type": "GENE-Y", "text": [ "insulin receptors" ], "offsets": [ [ 1308, 1325 ] ], "normalized": [] }, { "id": "22983867_T20", "type": "GENE-Y", "text": [ "insulin receptor substrate-1" ], "offsets": [ [ 255, 283 ] ], "normalized": [] }, { "id": "22983867_T21", "type": "GENE-Y", "text": [ "IRS-1" ], "offsets": [ [ 285, 290 ] ], "normalized": [] }, { "id": "22983867_T22", "type": "GENE-Y", "text": [ "IR" ], "offsets": [ [ 485, 487 ] ], "normalized": [] }, { "id": "22983867_T23", "type": "GENE-Y", "text": [ "IRS-1" ], "offsets": [ [ 492, 497 ] ], "normalized": [] }, { "id": "22983867_T24", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 530, 537 ] ], "normalized": [] }, { "id": "22983867_T25", "type": "GENE-Y", "text": [ "IR" ], "offsets": [ [ 634, 636 ] ], "normalized": [] }, { "id": "22983867_T26", "type": "GENE-Y", "text": [ "pIR" ], "offsets": [ [ 663, 666 ] ], "normalized": [] }, { "id": "22983867_T27", "type": "GENE-Y", "text": [ "pIR" ], "offsets": [ [ 820, 823 ] ], "normalized": [] }, { "id": "22983867_T28", "type": "GENE-Y", "text": [ "IRS-1" ], "offsets": [ [ 962, 967 ] ], "normalized": [] }, { "id": "22983867_T29", "type": "GENE-Y", "text": [ "pIRS-1" ], "offsets": [ [ 994, 1000 ] ], "normalized": [] }, { "id": "22983867_T30", "type": "GENE-Y", "text": [ "insulin receptor" ], "offsets": [ [ 229, 245 ] ], "normalized": [] }, { "id": "22983867_T31", "type": "GENE-Y", "text": [ "insulin receptor" ], "offsets": [ [ 73, 89 ] ], "normalized": [] } ]

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[ { "id": "1647395_title", "type": "title", "text": [ "Evidence that estramustine binds MAP-1A to inhibit type IV collagenase secretion." ], "offsets": [ [ 0, 81 ] ] }, { "id": "1647395_abstract", "type": "abstract", "text": [ "Estramustine is a novel anti-microtubule drug shown to bind MAP-1 and MAP-2 (microtubule-associated proteins) in vitro. In this paper we have shown that estramustine specifically binds MAP-1A in Du 145a cells, resulting in disruption of MAP-1A microtubules and inhibition of type IV collagenase secretion. Immunofluorescence studies revealed that at 30 microM levels estramustine blocked type IV collagenase secretion by partial disruption of the MAP-1A microtubule networks. Immunoprecipitation studies with polyclonal antibodies provided quantitative evidence that 30-60 microM estramustine blocked secretion of a 105 x 10(3) Mr type IV collagenase. Pulse-labeling experiments confirmed that the effect was not a result of inhibition of either protein synthesis or altered rates of type IV collagenase turnover. Finally, drug uptake studies with [3H]estramustine, scintillation counting and fluorography demonstrated that the principal target of the drug was MAP-1A. For the first time we have shown that the drug blocks secretion by binding MAP-1A and causing incomplete disruption of the microtubule networks." ], "offsets": [ [ 82, 1195 ] ] } ]

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[]

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[ { "id": "23221868_title", "type": "title", "text": [ "Rufinamide attenuates mechanical allodynia in a model of neuropathic pain in the mouse and stabilizes voltage-gated sodium channel inactivated state." ], "offsets": [ [ 0, 149 ] ] }, { "id": "23221868_abstract", "type": "abstract", "text": [ "BACKGROUND: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. METHODS: We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. RESULTS: In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 +/- 0.03 g (mean +/- SD) to 1.99 +/- 0.26 g for rufinamide and 0.25 +/- 0.22 g to 1.92 +/- 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. CONCLUSIONS: At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain." ], "offsets": [ [ 150, 1951 ] ] } ]

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