Datasets:

bigbio

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drugprot

like 5

[ { "id": "6701456_title", "type": "title", "text": [ "Demonstration of histamine receptors on human platelets by flow cytometry." ], "offsets": [ [ 0, 74 ] ] }, { "id": "6701456_abstract", "type": "abstract", "text": [ "Fluoresceinated human albumin conjugated with histamine (FHA-HIS) has been used for the demonstration of histamine receptors on human platelets. Such receptors were demonstrated on 40-63% of peripheral blood platelets in 4 healthy donors. The binding of FHA-HIS was inhibited on 35-79% of the platelets by the histamine H1 receptor antagonists diphenhydramine and clemastine. The histamine H2 receptor antagonist cimetidine blocked the FHA-HIS binding on 14-37% of the platelets. It is concluded that histamine H1 as well as H2 receptors occur on human platelets but the receptors are not equally distributed in the platelet population." ], "offsets": [ [ 75, 711 ] ] } ]

[ { "id": "6701456_T1", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 180, 189 ] ], "normalized": [] }, { "id": "6701456_T2", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 385, 394 ] ], "normalized": [] }, { "id": "6701456_T3", "type": "CHEMICAL", "text": [ "diphenhydramine" ], "offsets": [ [ 419, 434 ] ], "normalized": [] }, { "id": "6701456_T4", "type": "CHEMICAL", "text": [ "clemastine" ], "offsets": [ [ 439, 449 ] ], "normalized": [] }, { "id": "6701456_T5", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 455, 464 ] ], "normalized": [] }, { "id": "6701456_T6", "type": "CHEMICAL", "text": [ "cimetidine" ], "offsets": [ [ 488, 498 ] ], "normalized": [] }, { "id": "6701456_T7", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 121, 130 ] ], "normalized": [] }, { "id": "6701456_T8", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 576, 585 ] ], "normalized": [] }, { "id": "6701456_T9", "type": "CHEMICAL", "text": [ "histamine" ], "offsets": [ [ 17, 26 ] ], "normalized": [] }, { "id": "6701456_T10", "type": "GENE-Y", "text": [ "Fluoresceinated human albumin" ], "offsets": [ [ 75, 104 ] ], "normalized": [] }, { "id": "6701456_T11", "type": "GENE-N", "text": [ "histamine receptors" ], "offsets": [ [ 180, 199 ] ], "normalized": [] }, { "id": "6701456_T12", "type": "GENE-Y", "text": [ "FHA" ], "offsets": [ [ 329, 332 ] ], "normalized": [] }, { "id": "6701456_T13", "type": "GENE-Y", "text": [ "histamine H1 receptor" ], "offsets": [ [ 385, 406 ] ], "normalized": [] }, { "id": "6701456_T14", "type": "GENE-Y", "text": [ "histamine H2 receptor" ], "offsets": [ [ 455, 476 ] ], "normalized": [] }, { "id": "6701456_T15", "type": "GENE-Y", "text": [ "FHA" ], "offsets": [ [ 511, 514 ] ], "normalized": [] }, { "id": "6701456_T16", "type": "GENE-Y", "text": [ "histamine H1" ], "offsets": [ [ 576, 588 ] ], "normalized": [] }, { "id": "6701456_T17", "type": "GENE-Y", "text": [ "H2 receptors" ], "offsets": [ [ 600, 612 ] ], "normalized": [] }, { "id": "6701456_T18", "type": "GENE-Y", "text": [ "FHA" ], "offsets": [ [ 132, 135 ] ], "normalized": [] }, { "id": "6701456_T19", "type": "GENE-N", "text": [ "histamine receptors" ], "offsets": [ [ 17, 36 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "15892618_title", "type": "title", "text": [ "Molecularly targeted therapy for gastrointestinal cancer." ], "offsets": [ [ 0, 57 ] ] }, { "id": "15892618_abstract", "type": "abstract", "text": [ "Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase (HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora kinase inhibitors, hedgehog inhibitors, and TGF-beta signalling inhibitors." ], "offsets": [ [ 58, 2442 ] ] } ]

[ { "id": "15892618_T1", "type": "CHEMICAL", "text": [ "Imatinib mesilate" ], "offsets": [ [ 201, 218 ] ], "normalized": [] }, { "id": "15892618_T2", "type": "CHEMICAL", "text": [ "gemcitabine" ], "offsets": [ [ 1668, 1679 ] ], "normalized": [] }, { "id": "15892618_T3", "type": "CHEMICAL", "text": [ "STI-571" ], "offsets": [ [ 220, 227 ] ], "normalized": [] }, { "id": "15892618_T4", "type": "CHEMICAL", "text": [ "Gleevec" ], "offsets": [ [ 229, 236 ] ], "normalized": [] }, { "id": "15892618_T5", "type": "CHEMICAL", "text": [ "thalidomide" ], "offsets": [ [ 1799, 1810 ] ], "normalized": [] }, { "id": "15892618_T6", "type": "CHEMICAL", "text": [ "farnesyl" ], "offsets": [ [ 1812, 1820 ] ], "normalized": [] }, { "id": "15892618_T7", "type": "CHEMICAL", "text": [ "R115777" ], "offsets": [ [ 1843, 1850 ] ], "normalized": [] }, { "id": "15892618_T8", "type": "CHEMICAL", "text": [ "tipifarnib" ], "offsets": [ [ 1852, 1862 ] ], "normalized": [] }, { "id": "15892618_T9", "type": "CHEMICAL", "text": [ "Zarnestra" ], "offsets": [ [ 1864, 1873 ] ], "normalized": [] }, { "id": "15892618_T10", "type": "CHEMICAL", "text": [ "bortezomib" ], "offsets": [ [ 1938, 1948 ] ], "normalized": [] }, { "id": "15892618_T11", "type": "CHEMICAL", "text": [ "Velcade" ], "offsets": [ [ 1950, 1957 ] ], "normalized": [] }, { "id": "15892618_T12", "type": "CHEMICAL", "text": [ "rapamycin" ], "offsets": [ [ 1984, 1993 ] ], "normalized": [] }, { "id": "15892618_T13", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 84, 92 ] ], "normalized": [] }, { "id": "15892618_T14", "type": "CHEMICAL", "text": [ "Gefitinib" ], "offsets": [ [ 797, 806 ] ], "normalized": [] }, { "id": "15892618_T15", "type": "CHEMICAL", "text": [ "ZD1839" ], "offsets": [ [ 808, 814 ] ], "normalized": [] }, { "id": "15892618_T16", "type": "CHEMICAL", "text": [ "Iressa" ], "offsets": [ [ 816, 822 ] ], "normalized": [] }, { "id": "15892618_T17", "type": "CHEMICAL", "text": [ "erlotinib" ], "offsets": [ [ 893, 902 ] ], "normalized": [] }, { "id": "15892618_T18", "type": "CHEMICAL", "text": [ "OSI-774" ], "offsets": [ [ 904, 911 ] ], "normalized": [] }, { "id": "15892618_T19", "type": "CHEMICAL", "text": [ "Tarceva" ], "offsets": [ [ 913, 920 ] ], "normalized": [] }, { "id": "15892618_T20", "type": "CHEMICAL", "text": [ "erlotinib" ], "offsets": [ [ 1015, 1024 ] ], "normalized": [] }, { "id": "15892618_T21", "type": "GENE-N", "text": [ "Receptor and non-receptor tyrosine kinases" ], "offsets": [ [ 58, 100 ] ], "normalized": [] }, { "id": "15892618_T22", "type": "GENE-Y", "text": [ "EGFR" ], "offsets": [ [ 1153, 1157 ] ], "normalized": [] }, { "id": "15892618_T23", "type": "GENE-Y", "text": [ "Vascular endothelial growth factor" ], "offsets": [ [ 1291, 1325 ] ], "normalized": [] }, { "id": "15892618_T24", "type": "GENE-Y", "text": [ "VEGF" ], "offsets": [ [ 1327, 1331 ] ], "normalized": [] }, { "id": "15892618_T25", "type": "GENE-N", "text": [ "VEGFR" ], "offsets": [ [ 1351, 1356 ] ], "normalized": [] }, { "id": "15892618_T26", "type": "GENE-Y", "text": [ "VEGF" ], "offsets": [ [ 1462, 1466 ] ], "normalized": [] }, { "id": "15892618_T27", "type": "GENE-Y", "text": [ "VEGFR2" ], "offsets": [ [ 1764, 1770 ] ], "normalized": [] }, { "id": "15892618_T28", "type": "GENE-Y", "text": [ "farnesyl transferase" ], "offsets": [ [ 1812, 1832 ] ], "normalized": [] }, { "id": "15892618_T29", "type": "GENE-N", "text": [ "matrix metalloproteinase" ], "offsets": [ [ 1880, 1904 ] ], "normalized": [] }, { "id": "15892618_T30", "type": "GENE-N", "text": [ "proteasome" ], "offsets": [ [ 1917, 1927 ] ], "normalized": [] }, { "id": "15892618_T31", "type": "GENE-Y", "text": [ "mammalian target of rapamycin" ], "offsets": [ [ 1964, 1993 ] ], "normalized": [] }, { "id": "15892618_T32", "type": "GENE-Y", "text": [ "mTOR" ], "offsets": [ [ 1995, 1999 ] ], "normalized": [] }, { "id": "15892618_T33", "type": "GENE-Y", "text": [ "cyclooxygenase-2" ], "offsets": [ [ 2013, 2029 ] ], "normalized": [] }, { "id": "15892618_T34", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 2031, 2036 ] ], "normalized": [] }, { "id": "15892618_T35", "type": "GENE-N", "text": [ "platelet derived growth factor receptor" ], "offsets": [ [ 2050, 2089 ] ], "normalized": [] }, { "id": "15892618_T36", "type": "GENE-Y", "text": [ "bcr" ], "offsets": [ [ 260, 263 ] ], "normalized": [] }, { "id": "15892618_T37", "type": "GENE-N", "text": [ "PDGF-R" ], "offsets": [ [ 2091, 2097 ] ], "normalized": [] }, { "id": "15892618_T38", "type": "GENE-N", "text": [ "protein kinase C" ], "offsets": [ [ 2111, 2127 ] ], "normalized": [] }, { "id": "15892618_T39", "type": "GENE-Y", "text": [ "abl" ], "offsets": [ [ 264, 267 ] ], "normalized": [] }, { "id": "15892618_T40", "type": "GENE-N", "text": [ "PKC" ], "offsets": [ [ 2129, 2132 ] ], "normalized": [] }, { "id": "15892618_T41", "type": "GENE-N", "text": [ "mitogen-activated protein kinase kinase (MEK) 1/2" ], "offsets": [ [ 2146, 2195 ] ], "normalized": [] }, { "id": "15892618_T42", "type": "GENE-N", "text": [ "TK" ], "offsets": [ [ 268, 270 ] ], "normalized": [] }, { "id": "15892618_T43", "type": "GENE-Y", "text": [ "Rous sarcoma virus transforming oncogene" ], "offsets": [ [ 2208, 2248 ] ], "normalized": [] }, { "id": "15892618_T44", "type": "GENE-Y", "text": [ "SRC" ], "offsets": [ [ 2250, 2253 ] ], "normalized": [] }, { "id": "15892618_T45", "type": "GENE-N", "text": [ "kinase" ], "offsets": [ [ 2255, 2261 ] ], "normalized": [] }, { "id": "15892618_T46", "type": "GENE-N", "text": [ "histondeacetylase" ], "offsets": [ [ 2274, 2291 ] ], "normalized": [] }, { "id": "15892618_T47", "type": "GENE-N", "text": [ "HDAC" ], "offsets": [ [ 2293, 2297 ] ], "normalized": [] }, { "id": "15892618_T48", "type": "GENE-N", "text": [ "hypoxia-inducible factor" ], "offsets": [ [ 2317, 2341 ] ], "normalized": [] }, { "id": "15892618_T49", "type": "GENE-N", "text": [ "HIF" ], "offsets": [ [ 2343, 2346 ] ], "normalized": [] }, { "id": "15892618_T50", "type": "GENE-N", "text": [ "aurora kinase" ], "offsets": [ [ 2360, 2373 ] ], "normalized": [] }, { "id": "15892618_T51", "type": "GENE-N", "text": [ "hedgehog" ], "offsets": [ [ 2386, 2394 ] ], "normalized": [] }, { "id": "15892618_T52", "type": "GENE-N", "text": [ "TGF-beta" ], "offsets": [ [ 2411, 2419 ] ], "normalized": [] }, { "id": "15892618_T53", "type": "GENE-Y", "text": [ "c-kit" ], "offsets": [ [ 359, 364 ] ], "normalized": [] }, { "id": "15892618_T54", "type": "GENE-N", "text": [ "receptor TK" ], "offsets": [ [ 365, 376 ] ], "normalized": [] }, { "id": "15892618_T55", "type": "GENE-N", "text": [ "TKs" ], "offsets": [ [ 102, 105 ] ], "normalized": [] }, { "id": "15892618_T56", "type": "GENE-Y", "text": [ "c-kit" ], "offsets": [ [ 548, 553 ] ], "normalized": [] }, { "id": "15892618_T57", "type": "GENE-Y", "text": [ "epidermal growth factor receptor" ], "offsets": [ [ 568, 600 ] ], "normalized": [] }, { "id": "15892618_T58", "type": "GENE-Y", "text": [ "EGFR" ], "offsets": [ [ 602, 606 ] ], "normalized": [] }, { "id": "15892618_T59", "type": "GENE-Y", "text": [ "EGFR" ], "offsets": [ [ 732, 736 ] ], "normalized": [] }, { "id": "15892618_T60", "type": "GENE-N", "text": [ "TK" ], "offsets": [ [ 756, 758 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "17544870_title", "type": "title", "text": [ "Alteration of gastric functions and candidate genes associated with weight reduction in response to sibutramine." ], "offsets": [ [ 0, 112 ] ] }, { "id": "17544870_abstract", "type": "abstract", "text": [ "BACKGROUND & AIMS: It is unclear whether weight loss with the noradrenergic (norepinephrine) and serotonergic (5-hydroxytryptamine) reuptake inhibitor, sibutramine, is associated with altered stomach functions and whether genetics influence treatment response. METHODS: Forty-eight overweight and obese but otherwise healthy participants were randomized to placebo or sibutramine (15 mg/day for 12 weeks). At baseline and posttreatment we measured the following: gastric emptying for solids and liquids by scintigraphy, gastric volumes by single-photon emission computed tomography, maximum tolerated volume and 30-minute postnutrient challenge symptoms, and selected gastrointestinal hormones. All participants received structured behavior therapy for weight management. The influence of candidate gene polymorphisms involved in norepinephrine and 5-hydroxytryptamine or receptor function (phenylethanolamine N-methyltransferase, guanine nucleotide binding protein beta polypeptide 3, alpha2A adrenoreceptor, and solute carrier family 6 [neurotransmitter transporter, serotonin] member 4 [homo sapiens] [SLC6A4]) on weight loss and gastric functions was evaluated. RESULTS: The overall average weight loss posttreatment was 5.4 +/- 0.8 (SEM) kg with sibutramine and 0.9 +/- 0.9 kg with placebo (P < .001). The sibutramine group showed significant retardation in gastric emptying of solids (P = .03), reduced maximum tolerated volume (P = .03), and increased postprandial peptide YY compared with the placebo group. Obese females showed greater effects of sibutramine on weight loss and gastric emptying of solids and liquids. Gastric volumes and postchallenge symptoms were not significantly different in the 2 treatment groups. The LS/SS genotype of the promoter for SLC6A4 was associated with enhanced weight loss with sibutramine. CONCLUSIONS: Weight reduction with sibutramine is associated with altered gastric functions and increased peptide YY and is significantly associated with SLC6A4 genotype. The role of genetic variation in SLC6A4 on weight loss in response to sibutramine deserves further study." ], "offsets": [ [ 113, 2224 ] ] } ]

[ { "id": "17544870_T1", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 1182, 1191 ] ], "normalized": [] }, { "id": "17544870_T2", "type": "CHEMICAL", "text": [ "5-hydroxytryptamine" ], "offsets": [ [ 224, 243 ] ], "normalized": [] }, { "id": "17544870_T3", "type": "CHEMICAL", "text": [ "sibutramine" ], "offsets": [ [ 1364, 1375 ] ], "normalized": [] }, { "id": "17544870_T4", "type": "CHEMICAL", "text": [ "sibutramine" ], "offsets": [ [ 1424, 1435 ] ], "normalized": [] }, { "id": "17544870_T5", "type": "CHEMICAL", "text": [ "sibutramine" ], "offsets": [ [ 265, 276 ] ], "normalized": [] }, { "id": "17544870_T6", "type": "CHEMICAL", "text": [ "sibutramine" ], "offsets": [ [ 1669, 1680 ] ], "normalized": [] }, { "id": "17544870_T7", "type": "CHEMICAL", "text": [ "sibutramine" ], "offsets": [ [ 1935, 1946 ] ], "normalized": [] }, { "id": "17544870_T8", "type": "CHEMICAL", "text": [ "sibutramine" ], "offsets": [ [ 1983, 1994 ] ], "normalized": [] }, { "id": "17544870_T9", "type": "CHEMICAL", "text": [ "sibutramine" ], "offsets": [ [ 2189, 2200 ] ], "normalized": [] }, { "id": "17544870_T10", "type": "CHEMICAL", "text": [ "sibutramine" ], "offsets": [ [ 481, 492 ] ], "normalized": [] }, { "id": "17544870_T11", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 190, 204 ] ], "normalized": [] }, { "id": "17544870_T12", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 943, 957 ] ], "normalized": [] }, { "id": "17544870_T13", "type": "CHEMICAL", "text": [ "5-hydroxytryptamine" ], "offsets": [ [ 962, 981 ] ], "normalized": [] }, { "id": "17544870_T14", "type": "CHEMICAL", "text": [ "phenylethanolamine" ], "offsets": [ [ 1004, 1022 ] ], "normalized": [] }, { "id": "17544870_T15", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 1023, 1024 ] ], "normalized": [] }, { "id": "17544870_T16", "type": "CHEMICAL", "text": [ "guanine nucleotide" ], "offsets": [ [ 1044, 1062 ] ], "normalized": [] }, { "id": "17544870_T17", "type": "CHEMICAL", "text": [ "sibutramine" ], "offsets": [ [ 100, 111 ] ], "normalized": [] }, { "id": "17544870_T18", "type": "GENE-Y", "text": [ "solute carrier family 6 [neurotransmitter transporter, serotonin] member 4" ], "offsets": [ [ 1127, 1201 ] ], "normalized": [] }, { "id": "17544870_T19", "type": "GENE-Y", "text": [ "SLC6A4" ], "offsets": [ [ 1218, 1224 ] ], "normalized": [] }, { "id": "17544870_T20", "type": "GENE-Y", "text": [ "peptide YY" ], "offsets": [ [ 1585, 1595 ] ], "normalized": [] }, { "id": "17544870_T21", "type": "GENE-Y", "text": [ "SLC6A4" ], "offsets": [ [ 1882, 1888 ] ], "normalized": [] }, { "id": "17544870_T22", "type": "GENE-Y", "text": [ "peptide YY" ], "offsets": [ [ 2054, 2064 ] ], "normalized": [] }, { "id": "17544870_T23", "type": "GENE-Y", "text": [ "SLC6A4" ], "offsets": [ [ 2102, 2108 ] ], "normalized": [] }, { "id": "17544870_T24", "type": "GENE-Y", "text": [ "SLC6A4" ], "offsets": [ [ 2152, 2158 ] ], "normalized": [] }, { "id": "17544870_T25", "type": "GENE-Y", "text": [ "guanine nucleotide binding protein beta polypeptide 3" ], "offsets": [ [ 1044, 1097 ] ], "normalized": [] }, { "id": "17544870_T26", "type": "GENE-Y", "text": [ "alpha2A adrenoreceptor" ], "offsets": [ [ 1099, 1121 ] ], "normalized": [] } ]

[]

[]

[ { "id": "17544870_0", "type": "INDIRECT-UPREGULATOR", "arg1_id": "17544870_T4", "arg2_id": "17544870_T20", "normalized": [] }, { "id": "17544870_1", "type": "INDIRECT-UPREGULATOR", "arg1_id": "17544870_T8", "arg2_id": "17544870_T22", "normalized": [] } ]

[ { "id": "22815248_title", "type": "title", "text": [ "Protective Effects of a Purified Saponin Mixture from Astragalus corniculatus Bieb., in vivo Hepatotoxicity Models." ], "offsets": [ [ 0, 115 ] ] }, { "id": "22815248_abstract", "type": "abstract", "text": [ "In this study, the in vivo effects of a purified saponin mixture (PSM), obtained from Astragalus corniculatus Bieb., were investigated using two in vivo hepatotoxicity models based on liver damage caused by paracetamol (PC) and carbon tetrachloride (CCl4 ). The effects of PSM were compared with silymarin. Male Wistar rats were challenged orally with 20% CCl4 or PC (2 g/kg) four days after being pre-treated with PSM (100 mg/kg) or silymarin (200 mg/kg). A significant decrease of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase (LDH) activities and glutathione (GSH) levels and an increase of malondialdehyde (MDA) quantity was observed after CCl4 and PC administration alone. PSM pre-treatment decreased serum transaminases and LDH activities and MDA levels and increased the levels of cell protector GSH. Biotransformation phase I enzymes were also assessed in both models. In the CCl4 hepatotoxicity model, pre-treatment with PSM or silymarin resulted in significantly increased activities of ethylmorphine-N-demethylase and aniline 4-hydroxylase activity and cytochrome P450, compared to the CCl4 only group. Neither silymarin nor PSM influenced PC biotransformation. Our results suggest that PSM, obtained from A. corniculatus, Bieb. showed in vivo hepatoprotective and antioxidant activities against CCl4 and PC-induced liver damage comparable to that of silymarin. Copyright © 2012 John Wiley & Sons, Ltd." ], "offsets": [ [ 116, 1559 ] ] } ]

[ { "id": "22815248_T1", "type": "CHEMICAL", "text": [ "ethylmorphine" ], "offsets": [ [ 1143, 1156 ] ], "normalized": [] }, { "id": "22815248_T2", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 1157, 1158 ] ], "normalized": [] }, { "id": "22815248_T3", "type": "CHEMICAL", "text": [ "aniline" ], "offsets": [ [ 1175, 1182 ] ], "normalized": [] }, { "id": "22815248_T4", "type": "CHEMICAL", "text": [ "CCl4" ], "offsets": [ [ 1243, 1247 ] ], "normalized": [] }, { "id": "22815248_T5", "type": "CHEMICAL", "text": [ "silymarin" ], "offsets": [ [ 1268, 1277 ] ], "normalized": [] }, { "id": "22815248_T6", "type": "CHEMICAL", "text": [ "CCl4" ], "offsets": [ [ 1453, 1457 ] ], "normalized": [] }, { "id": "22815248_T7", "type": "CHEMICAL", "text": [ "silymarin" ], "offsets": [ [ 1508, 1517 ] ], "normalized": [] }, { "id": "22815248_T8", "type": "CHEMICAL", "text": [ "paracetamol" ], "offsets": [ [ 323, 334 ] ], "normalized": [] }, { "id": "22815248_T9", "type": "CHEMICAL", "text": [ "carbon tetrachloride" ], "offsets": [ [ 344, 364 ] ], "normalized": [] }, { "id": "22815248_T10", "type": "CHEMICAL", "text": [ "CCl4" ], "offsets": [ [ 366, 370 ] ], "normalized": [] }, { "id": "22815248_T11", "type": "CHEMICAL", "text": [ "silymarin" ], "offsets": [ [ 412, 421 ] ], "normalized": [] }, { "id": "22815248_T12", "type": "CHEMICAL", "text": [ "CCl4" ], "offsets": [ [ 472, 476 ] ], "normalized": [] }, { "id": "22815248_T13", "type": "CHEMICAL", "text": [ "silymarin" ], "offsets": [ [ 550, 559 ] ], "normalized": [] }, { "id": "22815248_T14", "type": "CHEMICAL", "text": [ "aspartate" ], "offsets": [ [ 599, 608 ] ], "normalized": [] }, { "id": "22815248_T15", "type": "CHEMICAL", "text": [ "saponin" ], "offsets": [ [ 165, 172 ] ], "normalized": [] }, { "id": "22815248_T16", "type": "CHEMICAL", "text": [ "alanine" ], "offsets": [ [ 627, 634 ] ], "normalized": [] }, { "id": "22815248_T17", "type": "CHEMICAL", "text": [ "lactate" ], "offsets": [ [ 653, 660 ] ], "normalized": [] }, { "id": "22815248_T18", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 696, 707 ] ], "normalized": [] }, { "id": "22815248_T19", "type": "CHEMICAL", "text": [ "GSH" ], "offsets": [ [ 709, 712 ] ], "normalized": [] }, { "id": "22815248_T20", "type": "CHEMICAL", "text": [ "malondialdehyde" ], "offsets": [ [ 740, 755 ] ], "normalized": [] }, { "id": "22815248_T21", "type": "CHEMICAL", "text": [ "MDA" ], "offsets": [ [ 757, 760 ] ], "normalized": [] }, { "id": "22815248_T22", "type": "CHEMICAL", "text": [ "CCl4" ], "offsets": [ [ 790, 794 ] ], "normalized": [] }, { "id": "22815248_T23", "type": "CHEMICAL", "text": [ "MDA" ], "offsets": [ [ 895, 898 ] ], "normalized": [] }, { "id": "22815248_T24", "type": "CHEMICAL", "text": [ "GSH" ], "offsets": [ [ 949, 952 ] ], "normalized": [] }, { "id": "22815248_T25", "type": "CHEMICAL", "text": [ "CCl4" ], "offsets": [ [ 1030, 1034 ] ], "normalized": [] }, { "id": "22815248_T26", "type": "CHEMICAL", "text": [ "silymarin" ], "offsets": [ [ 1083, 1092 ] ], "normalized": [] }, { "id": "22815248_T27", "type": "CHEMICAL", "text": [ "Saponin" ], "offsets": [ [ 33, 40 ] ], "normalized": [] }, { "id": "22815248_T28", "type": "GENE-N", "text": [ "ethylmorphine-N-demethylase" ], "offsets": [ [ 1143, 1170 ] ], "normalized": [] }, { "id": "22815248_T29", "type": "GENE-N", "text": [ "aniline 4-hydroxylase" ], "offsets": [ [ 1175, 1196 ] ], "normalized": [] }, { "id": "22815248_T30", "type": "GENE-N", "text": [ "cytochrome P450" ], "offsets": [ [ 1210, 1225 ] ], "normalized": [] }, { "id": "22815248_T31", "type": "GENE-Y", "text": [ "aspartate aminotransferase" ], "offsets": [ [ 599, 625 ] ], "normalized": [] }, { "id": "22815248_T32", "type": "GENE-N", "text": [ "alanine aminotransferase" ], "offsets": [ [ 627, 651 ] ], "normalized": [] }, { "id": "22815248_T33", "type": "GENE-N", "text": [ "lactate dehydrogenase" ], "offsets": [ [ 653, 674 ] ], "normalized": [] }, { "id": "22815248_T34", "type": "GENE-N", "text": [ "LDH" ], "offsets": [ [ 676, 679 ] ], "normalized": [] }, { "id": "22815248_T35", "type": "GENE-N", "text": [ "serum transaminases" ], "offsets": [ [ 852, 871 ] ], "normalized": [] }, { "id": "22815248_T36", "type": "GENE-N", "text": [ "LDH" ], "offsets": [ [ 876, 879 ] ], "normalized": [] } ]

[]

[]

[ { "id": "22815248_0", "type": "INHIBITOR", "arg1_id": "22815248_T22", "arg2_id": "22815248_T31", "normalized": [] }, { "id": "22815248_1", "type": "INHIBITOR", "arg1_id": "22815248_T22", "arg2_id": "22815248_T32", "normalized": [] }, { "id": "22815248_2", "type": "INHIBITOR", "arg1_id": "22815248_T22", "arg2_id": "22815248_T33", "normalized": [] }, { "id": "22815248_3", "type": "INHIBITOR", "arg1_id": "22815248_T22", "arg2_id": "22815248_T34", "normalized": [] }, { "id": "22815248_4", "type": "ACTIVATOR", "arg1_id": "22815248_T26", "arg2_id": "22815248_T28", "normalized": [] }, { "id": "22815248_5", "type": "ACTIVATOR", "arg1_id": "22815248_T26", "arg2_id": "22815248_T29", "normalized": [] }, { "id": "22815248_6", "type": "ACTIVATOR", "arg1_id": "22815248_T26", "arg2_id": "22815248_T30", "normalized": [] }, { "id": "22815248_7", "type": "ACTIVATOR", "arg1_id": "22815248_T4", "arg2_id": "22815248_T30", "normalized": [] }, { "id": "22815248_8", "type": "ACTIVATOR", "arg1_id": "22815248_T4", "arg2_id": "22815248_T29", "normalized": [] }, { "id": "22815248_9", "type": "ACTIVATOR", "arg1_id": "22815248_T4", "arg2_id": "22815248_T28", "normalized": [] } ]

[ { "id": "15060759_title", "type": "title", "text": [ "Binding of (-)-[3H]-CGP12177 at two sites in recombinant human beta 1-adrenoceptors and interaction with beta-blockers." ], "offsets": [ [ 0, 119 ] ] }, { "id": "15060759_abstract", "type": "abstract", "text": [ "To verify the hypothesis that the non-conventional partial agonist (-)-CGP12177 binds at two beta(1)-adrenoceptor sites, human beta(1)-adrenoceptors, expressed in CHO cells, were labelled with (-)-[(3)H]-CGP12177. We compared the binding affinity and antagonist potency of 12 clinically used beta-blockers against the cyclic AMP-enhancing effects of (-)-isoprenaline and (-)-CGP12177.(-)-[(3)H]-CGP12177 bound to a high affinity site (H; K(H)=0.47 nM) and low affinity site (L); K(L)=235 nM). (-)-[(3)H]-CGP12177 dissociated from the beta(1)-adrenoceptors with a fast component (k(off)=0.45 min(-1)), consistent with the L-site, and a slow component (k(off)=0.017-0.033 min(-1)), consistent with the H-site. (-)-Isoprenaline and (-)-CGP12177 caused 96-fold and 12-fold maximal increases in cyclic AMP levels with -logEC(50)M of 8.2 and 7.6. (-)-CGP12177 antagonised the effects of (-)-isoprenaline with a pK(B) of 9.9. The beta-blockers antagonised the effects of (-)-isoprenaline more than the effects of (-)-CGP12177 with potency ratios: (-)-atenolol 1,000, (+/-)-metropolol 676, (-)-pindolol 631, (-)-timolol 589, (+/-)-carvedilol 204, (+/-)-oxprenolol 138, (+/-)-sotalol 132, (-)-propranolol 120, (+/-)-bisoprolol 95, (+/-)-alprenolol 81, (+/-)-nadolol 68 and (-)-bupranolol 56. In intact cells the binding constants of beta-blockers, estimated from competition with 3-5 nM (-)-[(3)H]-CGP12177 (binding to the H-site), correlated with the corresponding affinities estimated from antagonism of the (-)-isoprenaline effects. We conclude that (-)-[(3)H]-CGP12177 binds at two sites in the recombinant beta(1)-adrenoceptor. (-)-CGP12177 is an antagonist of catecholamine effects through the H-site and a non-conventional partial agonist through the L-site. beta-blockers are more potent antagonists through the H-site than the L-site." ], "offsets": [ [ 120, 1954 ] ] } ]

[ { "id": "15060759_T1", "type": "CHEMICAL", "text": [ "(-)-CGP12177" ], "offsets": [ [ 1126, 1138 ] ], "normalized": [] }, { "id": "15060759_T2", "type": "CHEMICAL", "text": [ "(-)-atenolol" ], "offsets": [ [ 1160, 1172 ] ], "normalized": [] }, { "id": "15060759_T3", "type": "CHEMICAL", "text": [ "(+/-)-metropolol" ], "offsets": [ [ 1180, 1196 ] ], "normalized": [] }, { "id": "15060759_T4", "type": "CHEMICAL", "text": [ "(-)-pindolol" ], "offsets": [ [ 1202, 1214 ] ], "normalized": [] }, { "id": "15060759_T5", "type": "CHEMICAL", "text": [ "(-)-timolol" ], "offsets": [ [ 1220, 1231 ] ], "normalized": [] }, { "id": "15060759_T6", "type": "CHEMICAL", "text": [ "(+/-)-carvedilol" ], "offsets": [ [ 1237, 1253 ] ], "normalized": [] }, { "id": "15060759_T7", "type": "CHEMICAL", "text": [ "(+/-)-oxprenolol" ], "offsets": [ [ 1259, 1275 ] ], "normalized": [] }, { "id": "15060759_T8", "type": "CHEMICAL", "text": [ "(+/-)-sotalol" ], "offsets": [ [ 1281, 1294 ] ], "normalized": [] }, { "id": "15060759_T9", "type": "CHEMICAL", "text": [ "(-)-propranolol" ], "offsets": [ [ 1300, 1315 ] ], "normalized": [] }, { "id": "15060759_T10", "type": "CHEMICAL", "text": [ "(+/-)-bisoprolol" ], "offsets": [ [ 1321, 1337 ] ], "normalized": [] }, { "id": "15060759_T11", "type": "CHEMICAL", "text": [ "(+/-)-alprenolol" ], "offsets": [ [ 1342, 1358 ] ], "normalized": [] }, { "id": "15060759_T12", "type": "CHEMICAL", "text": [ "(+/-)-nadolol" ], "offsets": [ [ 1363, 1376 ] ], "normalized": [] }, { "id": "15060759_T13", "type": "CHEMICAL", "text": [ "(-)-bupranolol" ], "offsets": [ [ 1384, 1398 ] ], "normalized": [] }, { "id": "15060759_T14", "type": "CHEMICAL", "text": [ "(-)-[(3)H]-CGP12177" ], "offsets": [ [ 1498, 1517 ] ], "normalized": [] }, { "id": "15060759_T15", "type": "CHEMICAL", "text": [ "(-)-isoprenaline" ], "offsets": [ [ 1621, 1637 ] ], "normalized": [] }, { "id": "15060759_T16", "type": "CHEMICAL", "text": [ "(-)-[(3)H]-CGP12177" ], "offsets": [ [ 1664, 1683 ] ], "normalized": [] }, { "id": "15060759_T17", "type": "CHEMICAL", "text": [ "(-)-CGP12177" ], "offsets": [ [ 1744, 1756 ] ], "normalized": [] }, { "id": "15060759_T18", "type": "CHEMICAL", "text": [ "catecholamine" ], "offsets": [ [ 1777, 1790 ] ], "normalized": [] }, { "id": "15060759_T19", "type": "CHEMICAL", "text": [ "(-)-[(3)H]-CGP12177" ], "offsets": [ [ 313, 332 ] ], "normalized": [] }, { "id": "15060759_T20", "type": "CHEMICAL", "text": [ "cyclic AMP" ], "offsets": [ [ 438, 448 ] ], "normalized": [] }, { "id": "15060759_T21", "type": "CHEMICAL", "text": [ "(-)-isoprenaline" ], "offsets": [ [ 470, 486 ] ], "normalized": [] }, { "id": "15060759_T22", "type": "CHEMICAL", "text": [ "(-)-CGP12177" ], "offsets": [ [ 491, 503 ] ], "normalized": [] }, { "id": "15060759_T23", "type": "CHEMICAL", "text": [ "(-)-[(3)H]-CGP12177" ], "offsets": [ [ 504, 523 ] ], "normalized": [] }, { "id": "15060759_T24", "type": "CHEMICAL", "text": [ "(-)-[(3)H]-CGP12177" ], "offsets": [ [ 613, 632 ] ], "normalized": [] }, { "id": "15060759_T25", "type": "CHEMICAL", "text": [ "(-)-CGP12177" ], "offsets": [ [ 187, 199 ] ], "normalized": [] }, { "id": "15060759_T26", "type": "CHEMICAL", "text": [ "(-)-Isoprenaline" ], "offsets": [ [ 828, 844 ] ], "normalized": [] }, { "id": "15060759_T27", "type": "CHEMICAL", "text": [ "(-)-CGP12177" ], "offsets": [ [ 849, 861 ] ], "normalized": [] }, { "id": "15060759_T28", "type": "CHEMICAL", "text": [ "cyclic AMP" ], "offsets": [ [ 910, 920 ] ], "normalized": [] }, { "id": "15060759_T29", "type": "CHEMICAL", "text": [ "(-)-CGP12177" ], "offsets": [ [ 961, 973 ] ], "normalized": [] }, { "id": "15060759_T30", "type": "CHEMICAL", "text": [ "(-)-isoprenaline" ], "offsets": [ [ 1001, 1017 ] ], "normalized": [] }, { "id": "15060759_T31", "type": "CHEMICAL", "text": [ "(-)-isoprenaline" ], "offsets": [ [ 1084, 1100 ] ], "normalized": [] }, { "id": "15060759_T32", "type": "CHEMICAL", "text": [ "(-)-[3H]-CGP12177" ], "offsets": [ [ 11, 28 ] ], "normalized": [] }, { "id": "15060759_T33", "type": "GENE-Y", "text": [ "human beta(1)-adrenoceptors" ], "offsets": [ [ 241, 268 ] ], "normalized": [] }, { "id": "15060759_T34", "type": "GENE-Y", "text": [ "beta(1)-adrenoceptor" ], "offsets": [ [ 1722, 1742 ] ], "normalized": [] }, { "id": "15060759_T35", "type": "GENE-Y", "text": [ "beta(1)-adrenoceptors" ], "offsets": [ [ 654, 675 ] ], "normalized": [] }, { "id": "15060759_T36", "type": "GENE-Y", "text": [ "beta(1)-adrenoceptor" ], "offsets": [ [ 213, 233 ] ], "normalized": [] }, { "id": "15060759_T37", "type": "GENE-Y", "text": [ "human beta 1-adrenoceptors" ], "offsets": [ [ 57, 83 ] ], "normalized": [] } ]

[]

[]

[ { "id": "15060759_0", "type": "DIRECT-REGULATOR", "arg1_id": "15060759_T32", "arg2_id": "15060759_T37", "normalized": [] }, { "id": "15060759_1", "type": "DIRECT-REGULATOR", "arg1_id": "15060759_T25", "arg2_id": "15060759_T36", "normalized": [] }, { "id": "15060759_2", "type": "DIRECT-REGULATOR", "arg1_id": "15060759_T25", "arg2_id": "15060759_T33", "normalized": [] }, { "id": "15060759_3", "type": "DIRECT-REGULATOR", "arg1_id": "15060759_T19", "arg2_id": "15060759_T36", "normalized": [] }, { "id": "15060759_4", "type": "DIRECT-REGULATOR", "arg1_id": "15060759_T19", "arg2_id": "15060759_T33", "normalized": [] }, { "id": "15060759_5", "type": "AGONIST", "arg1_id": "15060759_T25", "arg2_id": "15060759_T36", "normalized": [] }, { "id": "15060759_6", "type": "AGONIST", "arg1_id": "15060759_T25", "arg2_id": "15060759_T33", "normalized": [] }, { "id": "15060759_7", "type": "DIRECT-REGULATOR", "arg1_id": "15060759_T24", "arg2_id": "15060759_T35", "normalized": [] }, { "id": "15060759_8", "type": "DIRECT-REGULATOR", "arg1_id": "15060759_T16", "arg2_id": "15060759_T34", "normalized": [] } ]

[ { "id": "16249494_title", "type": "title", "text": [ "The effects of prostaglandin analogues on IOP in prostanoid FP-receptor-deficient mice." ], "offsets": [ [ 0, 87 ] ] }, { "id": "16249494_abstract", "type": "abstract", "text": [ "PURPOSE: This study was designed to clarify the involvement of the prostanoid FP receptor in the intraocular pressure (IOP)-lowering effects of latanoprost, travoprost, bimatoprost, and unoprostone with the use of FP-receptor-deficient (FPKO) mice. METHODS: FPKO and wild-type (WT) mice were bred and acclimatized under a 12-hour light-dark cycle. IOP was measured under general anesthesia by a microneedle METHOD: To evaluate the effects of each drug, a single drop (3 muL) of each drug solution was topically applied in a masked manner to a randomly selected eye. IOP reduction was evaluated by the difference in IOP between the treated eye and the untreated contralateral eye in the same mouse. First, the diurnal variation and baseline IOP in WT and FPKO mice were measured. Then, to determine the window feasible for demonstrating the most marked ocular hypotensive effect, 0.005% latanoprost was applied to WT mice during the day or at night. The time when the ocular hypotensive effect was larger was selected for further studies to evaluate the effects of latanoprost (0.005%), travoprost (0.004%), bimatoprost (0.03%), and unoprostone (0.12%). In addition, bunazosin (0.1%) was also applied to demonstrate functional uveoscleral outflow in FPKO mice. All experiments were conducted under a masked study design. RESULTS: The baseline IOP (mean +/- SEM) in WT and FPKO mice was 15.0 +/- 0.2 and 15.0 +/- 0.3 mm Hg, respectively, during the day, and 18.9 +/- 0.4 and 19.2 +/- 0.4 mm Hg, respectively, at night. In WT mice, latanoprost significantly lowered IOP both during the day and at night, at 2 to 6 hours and 1 to 6 hours after application, respectively. Maximal IOP reduction was observed at 3 hours after drug instillation both during the day (10.9 +/- 1.8%) and at night (23.2 +/- 1.1%). At 3 hours after instillation, latanoprost (10.9 +/- 1.8% and 23.2 +/- 1.1%, daytime and nighttime, respectively), travoprost (15.9 +/- 1.4% and 26.1 +/- 1.2%) and bimatoprost (8.8 +/- 2.0 and 19.8 +/- 1.5%) significantly lowered IOP in WT mice both during the day and at night; isopropyl unoprostone significantly lowered IOP at night (13.7 +/- 1.9%) but not during the day (5.3 +/- 3.2%). In FPKO mice, latanoprost, travoprost, bimatoprost, and unoprostone showed no significant IOP-lowering effect. Bunazosin significantly lowered IOP in both WT (22.1 +/- 1.6%) and FPKO mice (22.2 +/- 2.1%). CONCLUSIONS: A single application of latanoprost, travoprost, bimatoprost, or unoprostone had no effect on IOP in FPKO mice with presumed functional uveoscleral outflow pathways. The prostanoid FP receptor plays a crucial role in the mechanism of early IOP lowering of all commercially available prostaglandin analogues." ], "offsets": [ [ 88, 2807 ] ] } ]

[ { "id": "16249494_T1", "type": "CHEMICAL", "text": [ "latanoprost" ], "offsets": [ [ 1152, 1163 ] ], "normalized": [] }, { "id": "16249494_T2", "type": "CHEMICAL", "text": [ "travoprost" ], "offsets": [ [ 1174, 1184 ] ], "normalized": [] }, { "id": "16249494_T3", "type": "CHEMICAL", "text": [ "bimatoprost" ], "offsets": [ [ 1195, 1206 ] ], "normalized": [] }, { "id": "16249494_T4", "type": "CHEMICAL", "text": [ "unoprostone" ], "offsets": [ [ 1220, 1231 ] ], "normalized": [] }, { "id": "16249494_T5", "type": "CHEMICAL", "text": [ "bunazosin" ], "offsets": [ [ 1254, 1263 ] ], "normalized": [] }, { "id": "16249494_T6", "type": "CHEMICAL", "text": [ "latanoprost" ], "offsets": [ [ 232, 243 ] ], "normalized": [] }, { "id": "16249494_T7", "type": "CHEMICAL", "text": [ "latanoprost" ], "offsets": [ [ 1617, 1628 ] ], "normalized": [] }, { "id": "16249494_T8", "type": "CHEMICAL", "text": [ "travoprost" ], "offsets": [ [ 245, 255 ] ], "normalized": [] }, { "id": "16249494_T9", "type": "CHEMICAL", "text": [ "bimatoprost" ], "offsets": [ [ 257, 268 ] ], "normalized": [] }, { "id": "16249494_T10", "type": "CHEMICAL", "text": [ "latanoprost" ], "offsets": [ [ 1922, 1933 ] ], "normalized": [] }, { "id": "16249494_T11", "type": "CHEMICAL", "text": [ "unoprostone" ], "offsets": [ [ 274, 285 ] ], "normalized": [] }, { "id": "16249494_T12", "type": "CHEMICAL", "text": [ "travoprost" ], "offsets": [ [ 2006, 2016 ] ], "normalized": [] }, { "id": "16249494_T13", "type": "CHEMICAL", "text": [ "bimatoprost" ], "offsets": [ [ 2055, 2066 ] ], "normalized": [] }, { "id": "16249494_T14", "type": "CHEMICAL", "text": [ "isopropyl unoprostone" ], "offsets": [ [ 2170, 2191 ] ], "normalized": [] }, { "id": "16249494_T15", "type": "CHEMICAL", "text": [ "latanoprost" ], "offsets": [ [ 2296, 2307 ] ], "normalized": [] }, { "id": "16249494_T16", "type": "CHEMICAL", "text": [ "travoprost" ], "offsets": [ [ 2309, 2319 ] ], "normalized": [] }, { "id": "16249494_T17", "type": "CHEMICAL", "text": [ "bimatoprost" ], "offsets": [ [ 2321, 2332 ] ], "normalized": [] }, { "id": "16249494_T18", "type": "CHEMICAL", "text": [ "unoprostone" ], "offsets": [ [ 2338, 2349 ] ], "normalized": [] }, { "id": "16249494_T19", "type": "CHEMICAL", "text": [ "Bunazosin" ], "offsets": [ [ 2393, 2402 ] ], "normalized": [] }, { "id": "16249494_T20", "type": "CHEMICAL", "text": [ "latanoprost" ], "offsets": [ [ 2524, 2535 ] ], "normalized": [] }, { "id": "16249494_T21", "type": "CHEMICAL", "text": [ "travoprost" ], "offsets": [ [ 2537, 2547 ] ], "normalized": [] }, { "id": "16249494_T22", "type": "CHEMICAL", "text": [ "bimatoprost" ], "offsets": [ [ 2549, 2560 ] ], "normalized": [] }, { "id": "16249494_T23", "type": "CHEMICAL", "text": [ "unoprostone" ], "offsets": [ [ 2565, 2576 ] ], "normalized": [] }, { "id": "16249494_T24", "type": "CHEMICAL", "text": [ "prostanoid" ], "offsets": [ [ 2670, 2680 ] ], "normalized": [] }, { "id": "16249494_T25", "type": "CHEMICAL", "text": [ "prostaglandin" ], "offsets": [ [ 2783, 2796 ] ], "normalized": [] }, { "id": "16249494_T26", "type": "CHEMICAL", "text": [ "prostanoid" ], "offsets": [ [ 155, 165 ] ], "normalized": [] }, { "id": "16249494_T27", "type": "CHEMICAL", "text": [ "latanoprost" ], "offsets": [ [ 974, 985 ] ], "normalized": [] }, { "id": "16249494_T28", "type": "CHEMICAL", "text": [ "prostaglandin" ], "offsets": [ [ 15, 28 ] ], "normalized": [] }, { "id": "16249494_T29", "type": "CHEMICAL", "text": [ "prostanoid" ], "offsets": [ [ 49, 59 ] ], "normalized": [] }, { "id": "16249494_T30", "type": "GENE-Y", "text": [ "FP" ], "offsets": [ [ 1337, 1339 ] ], "normalized": [] }, { "id": "16249494_T31", "type": "GENE-Y", "text": [ "FP" ], "offsets": [ [ 1459, 1461 ] ], "normalized": [] }, { "id": "16249494_T32", "type": "GENE-Y", "text": [ "FP-receptor" ], "offsets": [ [ 302, 313 ] ], "normalized": [] }, { "id": "16249494_T33", "type": "GENE-Y", "text": [ "FP" ], "offsets": [ [ 2285, 2287 ] ], "normalized": [] }, { "id": "16249494_T34", "type": "GENE-Y", "text": [ "FP" ], "offsets": [ [ 2460, 2462 ] ], "normalized": [] }, { "id": "16249494_T35", "type": "GENE-Y", "text": [ "FP" ], "offsets": [ [ 325, 327 ] ], "normalized": [] }, { "id": "16249494_T36", "type": "GENE-Y", "text": [ "FP" ], "offsets": [ [ 2601, 2603 ] ], "normalized": [] }, { "id": "16249494_T37", "type": "GENE-Y", "text": [ "FP" ], "offsets": [ [ 346, 348 ] ], "normalized": [] }, { "id": "16249494_T38", "type": "GENE-Y", "text": [ "prostanoid FP receptor" ], "offsets": [ [ 155, 177 ] ], "normalized": [] }, { "id": "16249494_T39", "type": "GENE-Y", "text": [ "FP" ], "offsets": [ [ 842, 844 ] ], "normalized": [] }, { "id": "16249494_T40", "type": "GENE-Y", "text": [ "FP-receptor" ], "offsets": [ [ 60, 71 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "10334992_title", "type": "title", "text": [ "Identification of a nuclear receptor for bile acids." ], "offsets": [ [ 0, 52 ] ] }, { "id": "10334992_abstract", "type": "abstract", "text": [ "Bile acids are essential for the solubilization and transport of dietary lipids and are the major products of cholesterol catabolism. Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor. When bound to bile acids, FXR repressed transcription of the gene encoding cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, and activated the gene encoding intestinal bile acid-binding protein, which is a candidate bile acid transporter. These results demonstrate a mechanism by which bile acids transcriptionally regulate their biosynthesis and enterohepatic transport." ], "offsets": [ [ 53, 732 ] ] } ]

[ { "id": "10334992_T1", "type": "CHEMICAL", "text": [ "Bile acids" ], "offsets": [ [ 53, 63 ] ], "normalized": [] }, { "id": "10334992_T2", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 163, 174 ] ], "normalized": [] }, { "id": "10334992_T3", "type": "CHEMICAL", "text": [ "bile acids" ], "offsets": [ [ 220, 230 ] ], "normalized": [] }, { "id": "10334992_T4", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 396, 407 ] ], "normalized": [] }, { "id": "10334992_T5", "type": "CHEMICAL", "text": [ "bile acid" ], "offsets": [ [ 465, 474 ] ], "normalized": [] }, { "id": "10334992_T6", "type": "CHEMICAL", "text": [ "bile acid" ], "offsets": [ [ 529, 538 ] ], "normalized": [] }, { "id": "10334992_T7", "type": "CHEMICAL", "text": [ "bile acid" ], "offsets": [ [ 577, 586 ] ], "normalized": [] }, { "id": "10334992_T8", "type": "CHEMICAL", "text": [ "bile acids" ], "offsets": [ [ 647, 657 ] ], "normalized": [] }, { "id": "10334992_T9", "type": "CHEMICAL", "text": [ "bile acids" ], "offsets": [ [ 41, 51 ] ], "normalized": [] }, { "id": "10334992_T10", "type": "GENE-Y", "text": [ "farnesoid X receptor" ], "offsets": [ [ 265, 285 ] ], "normalized": [] }, { "id": "10334992_T11", "type": "GENE-Y", "text": [ "FXR" ], "offsets": [ [ 287, 290 ] ], "normalized": [] }, { "id": "10334992_T12", "type": "GENE-N", "text": [ "orphan nuclear receptor" ], "offsets": [ [ 296, 319 ] ], "normalized": [] }, { "id": "10334992_T13", "type": "GENE-Y", "text": [ "FXR" ], "offsets": [ [ 347, 350 ] ], "normalized": [] }, { "id": "10334992_T14", "type": "GENE-Y", "text": [ "cholesterol 7alpha-hydroxylase" ], "offsets": [ [ 396, 426 ] ], "normalized": [] }, { "id": "10334992_T15", "type": "GENE-Y", "text": [ "intestinal bile acid-binding protein" ], "offsets": [ [ 518, 554 ] ], "normalized": [] }, { "id": "10334992_T16", "type": "GENE-N", "text": [ "bile acid transporter" ], "offsets": [ [ 577, 598 ] ], "normalized": [] }, { "id": "10334992_T17", "type": "GENE-N", "text": [ "nuclear receptor" ], "offsets": [ [ 20, 36 ] ], "normalized": [] } ]

[]

[]

[ { "id": "10334992_0", "type": "DIRECT-REGULATOR", "arg1_id": "10334992_T3", "arg2_id": "10334992_T10", "normalized": [] }, { "id": "10334992_1", "type": "DIRECT-REGULATOR", "arg1_id": "10334992_T3", "arg2_id": "10334992_T11", "normalized": [] }, { "id": "10334992_2", "type": "DIRECT-REGULATOR", "arg1_id": "10334992_T3", "arg2_id": "10334992_T12", "normalized": [] }, { "id": "10334992_3", "type": "PRODUCT-OF", "arg1_id": "10334992_T5", "arg2_id": "10334992_T14", "normalized": [] } ]

[ { "id": "1400062_title", "type": "title", "text": [ "Prolonged pulmonary hypertension caused by platelet-activating factor and leukotriene C4 in the rat lung." ], "offsets": [ [ 0, 105 ] ] }, { "id": "1400062_abstract", "type": "abstract", "text": [ "Platelet-activating factor (PAF) and leukotrienes (LTs) are potent pulmonary hypertensive and inflammatory mediators produced by the lung. Previously we showed that a rapid injection of PAF into the pulmonary artery of an isolated rat lung produced an extended elevation in mean pulmonary arterial pressure (PAP). The objective of the present study was to determine whether the extended pressor response induced by PAF was caused by prolonged activation of the 5-lipoxygenase pathway or slow clearance of LTs from the lung parenchyma. Rat lungs were perfused with a nonrecirculating physiological salt solution that contained indomethacin and albumin. Five minutes after a rapid injection of PAF into the pulmonary artery catheter, the following elevations (mean % above baseline) were observed: PAP (83%), LTB4 (3,260%), LTC4 (1,490%), LTD4 (970%), and LTE4 (1,500%). At 20 min these levels declined but were still significantly elevated above baseline. The 5-lipoxygenase inhibitor diethylcarbamazine (DEC), administered before the PAF injection, inhibited the elevations of PAP and all LTs. DEC administration that began 5 min after PAF reduced PAP and only LTC4 levels at 20 min in comparison to lungs with no DEC. The 5-lipoxygenase-activating protein inhibitor MK886, administered orally 2-6 h before perfusion, also inhibited the pressor response to PAF as well as LT production, as did DEC. We conclude that 1) the extended pulmonary hypertension induced by PAF was caused mainly by prolonged activation of 5-lipoxygenase with LTC4 production, 2) the relative overall lung clearance of LTB4, LTD4, and LTE4 was slower than that of LTC4, and 3) LTB4, LTD4, and LTE4 had no appreciable pressor effect." ], "offsets": [ [ 106, 1813 ] ] } ]

[ { "id": "1400062_T1", "type": "CHEMICAL", "text": [ "DEC" ], "offsets": [ [ 1110, 1113 ] ], "normalized": [] }, { "id": "1400062_T2", "type": "CHEMICAL", "text": [ "LTs" ], "offsets": [ [ 1195, 1198 ] ], "normalized": [] }, { "id": "1400062_T3", "type": "CHEMICAL", "text": [ "DEC" ], "offsets": [ [ 1200, 1203 ] ], "normalized": [] }, { "id": "1400062_T4", "type": "CHEMICAL", "text": [ "LTC4" ], "offsets": [ [ 1267, 1271 ] ], "normalized": [] }, { "id": "1400062_T5", "type": "CHEMICAL", "text": [ "DEC" ], "offsets": [ [ 1320, 1323 ] ], "normalized": [] }, { "id": "1400062_T6", "type": "CHEMICAL", "text": [ "MK886" ], "offsets": [ [ 1373, 1378 ] ], "normalized": [] }, { "id": "1400062_T7", "type": "CHEMICAL", "text": [ "LT" ], "offsets": [ [ 1478, 1480 ] ], "normalized": [] }, { "id": "1400062_T8", "type": "CHEMICAL", "text": [ "DEC" ], "offsets": [ [ 1500, 1503 ] ], "normalized": [] }, { "id": "1400062_T9", "type": "CHEMICAL", "text": [ "LTC4" ], "offsets": [ [ 1641, 1645 ] ], "normalized": [] }, { "id": "1400062_T10", "type": "CHEMICAL", "text": [ "LTB4" ], "offsets": [ [ 1700, 1704 ] ], "normalized": [] }, { "id": "1400062_T11", "type": "CHEMICAL", "text": [ "LTD4" ], "offsets": [ [ 1706, 1710 ] ], "normalized": [] }, { "id": "1400062_T12", "type": "CHEMICAL", "text": [ "LTE4" ], "offsets": [ [ 1716, 1720 ] ], "normalized": [] }, { "id": "1400062_T13", "type": "CHEMICAL", "text": [ "LTC4" ], "offsets": [ [ 1745, 1749 ] ], "normalized": [] }, { "id": "1400062_T14", "type": "CHEMICAL", "text": [ "LTB4" ], "offsets": [ [ 1758, 1762 ] ], "normalized": [] }, { "id": "1400062_T15", "type": "CHEMICAL", "text": [ "LTD4" ], "offsets": [ [ 1764, 1768 ] ], "normalized": [] }, { "id": "1400062_T16", "type": "CHEMICAL", "text": [ "LTE4" ], "offsets": [ [ 1774, 1778 ] ], "normalized": [] }, { "id": "1400062_T17", "type": "CHEMICAL", "text": [ "leukotrienes" ], "offsets": [ [ 143, 155 ] ], "normalized": [] }, { "id": "1400062_T18", "type": "CHEMICAL", "text": [ "LTs" ], "offsets": [ [ 611, 614 ] ], "normalized": [] }, { "id": "1400062_T19", "type": "CHEMICAL", "text": [ "LTs" ], "offsets": [ [ 157, 160 ] ], "normalized": [] }, { "id": "1400062_T20", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 732, 744 ] ], "normalized": [] }, { "id": "1400062_T21", "type": "CHEMICAL", "text": [ "LTB4" ], "offsets": [ [ 913, 917 ] ], "normalized": [] }, { "id": "1400062_T22", "type": "CHEMICAL", "text": [ "LTC4" ], "offsets": [ [ 928, 932 ] ], "normalized": [] }, { "id": "1400062_T23", "type": "CHEMICAL", "text": [ "LTD4" ], "offsets": [ [ 943, 947 ] ], "normalized": [] }, { "id": "1400062_T24", "type": "CHEMICAL", "text": [ "LTE4" ], "offsets": [ [ 960, 964 ] ], "normalized": [] }, { "id": "1400062_T25", "type": "CHEMICAL", "text": [ "diethylcarbamazine" ], "offsets": [ [ 1090, 1108 ] ], "normalized": [] }, { "id": "1400062_T26", "type": "CHEMICAL", "text": [ "leukotriene C4" ], "offsets": [ [ 74, 88 ] ], "normalized": [] }, { "id": "1400062_T27", "type": "GENE-Y", "text": [ "5-lipoxygenase-activating protein" ], "offsets": [ [ 1329, 1362 ] ], "normalized": [] }, { "id": "1400062_T28", "type": "GENE-Y", "text": [ "5-lipoxygenase" ], "offsets": [ [ 1621, 1635 ] ], "normalized": [] }, { "id": "1400062_T29", "type": "GENE-Y", "text": [ "5-lipoxygenase" ], "offsets": [ [ 567, 581 ] ], "normalized": [] }, { "id": "1400062_T30", "type": "GENE-Y", "text": [ "albumin" ], "offsets": [ [ 749, 756 ] ], "normalized": [] }, { "id": "1400062_T31", "type": "GENE-Y", "text": [ "5-lipoxygenase" ], "offsets": [ [ 1065, 1079 ] ], "normalized": [] } ]

[]

[]

[ { "id": "1400062_0", "type": "INHIBITOR", "arg1_id": "1400062_T25", "arg2_id": "1400062_T31", "normalized": [] }, { "id": "1400062_1", "type": "INHIBITOR", "arg1_id": "1400062_T1", "arg2_id": "1400062_T31", "normalized": [] }, { "id": "1400062_2", "type": "INHIBITOR", "arg1_id": "1400062_T6", "arg2_id": "1400062_T27", "normalized": [] }, { "id": "1400062_3", "type": "PRODUCT-OF", "arg1_id": "1400062_T9", "arg2_id": "1400062_T28", "normalized": [] }, { "id": "1400062_4", "type": "PRODUCT-OF", "arg1_id": "1400062_T2", "arg2_id": "1400062_T31", "normalized": [] } ]

[ { "id": "23276150_title", "type": "title", "text": [ "Display of amino groups on substrate surfaces by simple dip-coating of methacrylate-based polymers and its application to DNA immobilization." ], "offsets": [ [ 0, 141 ] ] }, { "id": "23276150_abstract", "type": "abstract", "text": [ "The implementation of a reactive functional group onto a material surface is of great importance. Reactive functional groups (e.g., an amino group and a hydroxyl group) are usually hydrophilic, which makes it difficult to display them on a dry polymer surface. We here propose a novel method for displaying amino groups on the surfaces of polymeric substrates through dip-coating of a methacrylate-based copolymer. We synthesized copolymers composed of methyl methacrylate and 2-aminoethyl methacrylate with different protecting groups or ion-complexes on their amino groups, then dip-coated the copolymers onto a poly(methyl methacrylate) (PMMA) substrate. Evaluation using a cleavable fluorescent compound, which was synthesized in the present study to quantify a small amount (pmol/cm(2)) of amino groups on a solid surface, revealed that the protection of amino groups affected their surface segregation in the copolymer coating. p-Toluenesulfonate ion-complex and tert-butoxycarbonyl (Boc) protection of amino groups were found to effectively display amino groups on the surface (more than 70 pmol/cm(2)). The density of amino groups displayed on a surface can be easily controlled by mixing the copolymer and PMMA before dip-coating. Dip-coating of the copolymer with Boc protection on various polymeric substrates also successfully displayed amino groups on their surfaces. Finally, we demonstrated that the amino groups displayed can be utilized for the immobilization of a DNA oligonucleotide on a substrate surface." ], "offsets": [ [ 142, 1667 ] ] } ]

[ { "id": "23276150_T1", "type": "CHEMICAL", "text": [ "amino" ], "offsets": [ [ 1151, 1156 ] ], "normalized": [] }, { "id": "23276150_T2", "type": "CHEMICAL", "text": [ "amino" ], "offsets": [ [ 1198, 1203 ] ], "normalized": [] }, { "id": "23276150_T3", "type": "CHEMICAL", "text": [ "amino" ], "offsets": [ [ 1268, 1273 ] ], "normalized": [] }, { "id": "23276150_T4", "type": "CHEMICAL", "text": [ "PMMA" ], "offsets": [ [ 1357, 1361 ] ], "normalized": [] }, { "id": "23276150_T5", "type": "CHEMICAL", "text": [ "Boc" ], "offsets": [ [ 1416, 1419 ] ], "normalized": [] }, { "id": "23276150_T6", "type": "CHEMICAL", "text": [ "amino" ], "offsets": [ [ 1491, 1496 ] ], "normalized": [] }, { "id": "23276150_T7", "type": "CHEMICAL", "text": [ "amino" ], "offsets": [ [ 277, 282 ] ], "normalized": [] }, { "id": "23276150_T8", "type": "CHEMICAL", "text": [ "amino" ], "offsets": [ [ 1557, 1562 ] ], "normalized": [] }, { "id": "23276150_T9", "type": "CHEMICAL", "text": [ "hydroxyl" ], "offsets": [ [ 295, 303 ] ], "normalized": [] }, { "id": "23276150_T10", "type": "CHEMICAL", "text": [ "amino" ], "offsets": [ [ 449, 454 ] ], "normalized": [] }, { "id": "23276150_T11", "type": "CHEMICAL", "text": [ "methacrylate" ], "offsets": [ [ 527, 539 ] ], "normalized": [] }, { "id": "23276150_T12", "type": "CHEMICAL", "text": [ "methyl methacrylate" ], "offsets": [ [ 595, 614 ] ], "normalized": [] }, { "id": "23276150_T13", "type": "CHEMICAL", "text": [ "2-aminoethyl methacrylate" ], "offsets": [ [ 619, 644 ] ], "normalized": [] }, { "id": "23276150_T14", "type": "CHEMICAL", "text": [ "amino" ], "offsets": [ [ 704, 709 ] ], "normalized": [] }, { "id": "23276150_T15", "type": "CHEMICAL", "text": [ "poly(methyl methacrylate)" ], "offsets": [ [ 756, 781 ] ], "normalized": [] }, { "id": "23276150_T16", "type": "CHEMICAL", "text": [ "PMMA" ], "offsets": [ [ 783, 787 ] ], "normalized": [] }, { "id": "23276150_T17", "type": "CHEMICAL", "text": [ "amino" ], "offsets": [ [ 937, 942 ] ], "normalized": [] }, { "id": "23276150_T18", "type": "CHEMICAL", "text": [ "amino" ], "offsets": [ [ 1002, 1007 ] ], "normalized": [] }, { "id": "23276150_T19", "type": "CHEMICAL", "text": [ "p-Toluenesulfonate" ], "offsets": [ [ 1076, 1094 ] ], "normalized": [] }, { "id": "23276150_T20", "type": "CHEMICAL", "text": [ "tert-butoxycarbonyl" ], "offsets": [ [ 1111, 1130 ] ], "normalized": [] }, { "id": "23276150_T21", "type": "CHEMICAL", "text": [ "Boc" ], "offsets": [ [ 1132, 1135 ] ], "normalized": [] }, { "id": "23276150_T22", "type": "CHEMICAL", "text": [ "amino" ], "offsets": [ [ 11, 16 ] ], "normalized": [] }, { "id": "23276150_T23", "type": "CHEMICAL", "text": [ "methacrylate" ], "offsets": [ [ 71, 83 ] ], "normalized": [] } ]

[]

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[]

[ { "id": "23257178_title", "type": "title", "text": [ "Steroid toxicity and detoxification in ascomycetous fungi." ], "offsets": [ [ 0, 58 ] ] }, { "id": "23257178_abstract", "type": "abstract", "text": [ "In the last couple of decades fungal infections have become a significant clinical problem. A major interest into fungal steroid action has been provoked since research has proven that steroid hormones are toxic to fungi and affect the host/fungus relationship. Steroid hormones were found to differ in their antifungal activity in ascomycetous fungi Hortaea werneckii, Saccharomyces cerevisiae and Aspergillus oryzae. Dehydroepiandrosterone was shown to be the strongest inhibitor of growth in all three varieties of fungi followed by androstenedione and testosterone. For their protection, fungi use several mechanisms to lower the toxic effects of steroids. The efficiency of biotransformation in detoxification depended on the microorganism and steroid substrate used. Biotransformation was a relatively slow process as it also depended on the growth phase of the fungus. In addition to biotransformation, steroid extrusion out of the cells contributed to the lowering of the active intracellular steroid concentration. Plasma membrane Pdr5 transporter was found to be the most effective, followed by Snq2 transporter and vacuolar transporters Ybt1 and Ycf1. Proteins Aus1 and Dan1 were not found to be involved in steroid import. The research of possible targets of steroid hormone action in fungi suggests that steroid hormones inhibit ergosterol biosynthesis in S. cerevisiae and H. werneckii. Results of this inhibition caused changes in the sterol content of the cellular membrane. The presence of steroid hormones most probably causes the degradation of the Tat2 permease and impairment of tryptophan import." ], "offsets": [ [ 59, 1677 ] ] } ]

[ { "id": "23257178_T1", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 1060, 1067 ] ], "normalized": [] }, { "id": "23257178_T2", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 180, 187 ] ], "normalized": [] }, { "id": "23257178_T3", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 1278, 1285 ] ], "normalized": [] }, { "id": "23257178_T4", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 1330, 1337 ] ], "normalized": [] }, { "id": "23257178_T5", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 1376, 1383 ] ], "normalized": [] }, { "id": "23257178_T6", "type": "CHEMICAL", "text": [ "ergosterol" ], "offsets": [ [ 1401, 1411 ] ], "normalized": [] }, { "id": "23257178_T7", "type": "CHEMICAL", "text": [ "sterol" ], "offsets": [ [ 1509, 1515 ] ], "normalized": [] }, { "id": "23257178_T8", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 1566, 1573 ] ], "normalized": [] }, { "id": "23257178_T9", "type": "CHEMICAL", "text": [ "tryptophan" ], "offsets": [ [ 1659, 1669 ] ], "normalized": [] }, { "id": "23257178_T10", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 244, 251 ] ], "normalized": [] }, { "id": "23257178_T11", "type": "CHEMICAL", "text": [ "Steroid" ], "offsets": [ [ 321, 328 ] ], "normalized": [] }, { "id": "23257178_T12", "type": "CHEMICAL", "text": [ "androstenedione" ], "offsets": [ [ 595, 610 ] ], "normalized": [] }, { "id": "23257178_T13", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 615, 627 ] ], "normalized": [] }, { "id": "23257178_T14", "type": "CHEMICAL", "text": [ "steroids" ], "offsets": [ [ 710, 718 ] ], "normalized": [] }, { "id": "23257178_T15", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 808, 815 ] ], "normalized": [] }, { "id": "23257178_T16", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 969, 976 ] ], "normalized": [] }, { "id": "23257178_T17", "type": "CHEMICAL", "text": [ "Steroid" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "23257178_T18", "type": "GENE-N", "text": [ "Pdr5" ], "offsets": [ [ 1099, 1103 ] ], "normalized": [] }, { "id": "23257178_T19", "type": "GENE-N", "text": [ "Snq2" ], "offsets": [ [ 1164, 1168 ] ], "normalized": [] }, { "id": "23257178_T20", "type": "GENE-N", "text": [ "Ybt1" ], "offsets": [ [ 1207, 1211 ] ], "normalized": [] }, { "id": "23257178_T21", "type": "GENE-N", "text": [ "Ycf1" ], "offsets": [ [ 1216, 1220 ] ], "normalized": [] }, { "id": "23257178_T22", "type": "GENE-N", "text": [ "Aus1" ], "offsets": [ [ 1231, 1235 ] ], "normalized": [] }, { "id": "23257178_T23", "type": "GENE-N", "text": [ "Dan1" ], "offsets": [ [ 1240, 1244 ] ], "normalized": [] }, { "id": "23257178_T24", "type": "GENE-N", "text": [ "Tat2" ], "offsets": [ [ 1627, 1631 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23257178_0", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23257178_T8", "arg2_id": "23257178_T24", "normalized": [] } ]

[ { "id": "23239534_title", "type": "title", "text": [ "Threshold collision-induced dissociation of hydrated magnesium: experimental and theoretical investigation of the binding energies for Mg(2+)(H2O)x complexes (x=2-10)." ], "offsets": [ [ 0, 167 ] ] }, { "id": "23239534_abstract", "type": "abstract", "text": [ "The sequential bond energies of Mg(2+)(H2O)x complexes, in which x=2-10, are measured by threshold collision-induced dissociation in a guided ion beam tandem mass spectrometer. From an electrospray ionization source that produces an initial distribution of Mg(2+)(H2O)x complexes in which x=7-10, complexes down to x=3 are formed by using an in-source fragmentation technique. Complexes smaller than Mg(2+)(H2O)3 cannot be formed in this source because charge separation into MgOH(+)(H2O) and H3O(+) is a lower-energy pathway than simple water loss from Mg(2+)(H2O)3. The kinetic energy dependent cross sections for dissociation of Mg(2+)(H2O)x complexes, in which x=3-10, are examined over a wide energy range to monitor all dissociation products and are modeled to obtain 0 and 298 K binding energies. Analysis of both primary and secondary water molecule losses from each sized complex provides thermochemistry for the sequential hydration energies of Mg(2+) for x=2-10 and the first experimental values for x=2-4. Additionally, the thermodynamic onsets leading to the charge-separation products from Mg(2+)(H2O)3 and Mg(2+)(H2O)4 are determined for the first time. Our experimental results for x=3-7 agree well with quantum chemical calculations performed here and previously calculated binding enthalpies, as well as previous measurements for x=6. The present values for x=7-10 are slightly lower than previous experimental results and theory, but within experimental uncertainties." ], "offsets": [ [ 168, 1655 ] ] } ]

[ { "id": "23239534_T1", "type": "CHEMICAL", "text": [ "Mg(2+)(H2O)3" ], "offsets": [ [ 1272, 1284 ] ], "normalized": [] }, { "id": "23239534_T2", "type": "CHEMICAL", "text": [ "Mg(2+)(H2O)4" ], "offsets": [ [ 1289, 1301 ] ], "normalized": [] }, { "id": "23239534_T3", "type": "CHEMICAL", "text": [ "Mg(2+)(H2O)x" ], "offsets": [ [ 425, 437 ] ], "normalized": [] }, { "id": "23239534_T4", "type": "CHEMICAL", "text": [ "Mg(2+)(H2O)x" ], "offsets": [ [ 200, 212 ] ], "normalized": [] }, { "id": "23239534_T5", "type": "CHEMICAL", "text": [ "Mg(2+)(H2O)3" ], "offsets": [ [ 568, 580 ] ], "normalized": [] }, { "id": "23239534_T6", "type": "CHEMICAL", "text": [ "MgOH(+)(H2O)" ], "offsets": [ [ 644, 656 ] ], "normalized": [] }, { "id": "23239534_T7", "type": "CHEMICAL", "text": [ "H3O(+)" ], "offsets": [ [ 661, 667 ] ], "normalized": [] }, { "id": "23239534_T8", "type": "CHEMICAL", "text": [ "Mg(2+)(H2O)3" ], "offsets": [ [ 722, 734 ] ], "normalized": [] }, { "id": "23239534_T9", "type": "CHEMICAL", "text": [ "Mg(2+)(H2O)x" ], "offsets": [ [ 800, 812 ] ], "normalized": [] }, { "id": "23239534_T10", "type": "CHEMICAL", "text": [ "Mg(2+)" ], "offsets": [ [ 1123, 1129 ] ], "normalized": [] }, { "id": "23239534_T11", "type": "CHEMICAL", "text": [ "Mg(2+)(H2O)x" ], "offsets": [ [ 135, 147 ] ], "normalized": [] }, { "id": "23239534_T12", "type": "CHEMICAL", "text": [ "hydrated magnesium" ], "offsets": [ [ 44, 62 ] ], "normalized": [] } ]

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[]

[ { "id": "23552265_title", "type": "title", "text": [ "UVA photoirradiation of benzo[a]pyrene metabolites: induction of cytotoxicity, reactive oxygen species, and lipid peroxidation." ], "offsets": [ [ 0, 127 ] ] }, { "id": "23552265_abstract", "type": "abstract", "text": [ "Benzo[a]pyrene (BaP) is a prototype for studying carcinogenesis of polycyclic aromatic hydrocarbons (PAHs). We have long been interested in studying the phototoxicity of PAHs. In this study, we determined that metabolism of BaP by human skin HaCaT keratinocytes resulted in six identified phase I metabolites, for example, BaP trans-7,8-dihydrodiol (BaP t-7,8-diol), BaP t-4,5-diol, BaP t-9,10-diol, 3-hydroxybenzo[a]pyrene (3-OH-BaP), BaP (7,10/8,9)tetrol, and BaP (7/8,9,10)tetrol. The photocytotoxicity of BaP, 3-OH-BaP, BaP t-7,8-diol, BaP trans-7,8-diol-anti-9,10-epoxide (BPDE), and BaP (7,10/8,9)tetrol in the HaCaT keratinocytes was examined. When irradiated with 1.0 J/cm(2) UVA light, these compounds when tested at doses of 0.1, 0.2, and 0.5 μM, all induced photocytotoxicity in a dose-dependent manner. When photoirradiation was conducted in the presence of a lipid (methyl linoleate), BaP metabolites, BPDE, and three related PAHs, pyrene, 7,8,9,10-tetrahydro-BaP trans-7,8-diol, and 7,8,9,10-tetrahydro-BaP trans-9,10-diol, all induced lipid peroxidation. The formation of lipid peroxides by BaP t-7,8-diol was inhibited by NaN3 and enhanced by deuterated methanol, which suggests that singlet oxygen may be involved in the generation of lipid peroxides. The formation of lipid hydroperoxides was partially inhibited by superoxide dismutase (SOD). Electron spin resonance spin trapping experiments indicated that both singlet oxygen and superoxide radical anion were generated from UVA photoirradiation of BPDE in a light dose responding manner." ], "offsets": [ [ 128, 1687 ] ] } ]

[ { "id": "23552265_T1", "type": "CHEMICAL", "text": [ "Benzo[a]pyrene" ], "offsets": [ [ 128, 142 ] ], "normalized": [] }, { "id": "23552265_T2", "type": "CHEMICAL", "text": [ "PAHs" ], "offsets": [ [ 229, 233 ] ], "normalized": [] }, { "id": "23552265_T3", "type": "CHEMICAL", "text": [ "BaP t-7,8-diol" ], "offsets": [ [ 1234, 1248 ] ], "normalized": [] }, { "id": "23552265_T4", "type": "CHEMICAL", "text": [ "NaN3" ], "offsets": [ [ 1266, 1270 ] ], "normalized": [] }, { "id": "23552265_T5", "type": "CHEMICAL", "text": [ "deuterated methanol" ], "offsets": [ [ 1287, 1306 ] ], "normalized": [] }, { "id": "23552265_T6", "type": "CHEMICAL", "text": [ "oxygen" ], "offsets": [ [ 1336, 1342 ] ], "normalized": [] }, { "id": "23552265_T7", "type": "CHEMICAL", "text": [ "hydroperoxides" ], "offsets": [ [ 1420, 1434 ] ], "normalized": [] }, { "id": "23552265_T8", "type": "CHEMICAL", "text": [ "superoxide" ], "offsets": [ [ 1462, 1472 ] ], "normalized": [] }, { "id": "23552265_T9", "type": "CHEMICAL", "text": [ "oxygen" ], "offsets": [ [ 1568, 1574 ] ], "normalized": [] }, { "id": "23552265_T10", "type": "CHEMICAL", "text": [ "superoxide" ], "offsets": [ [ 1579, 1589 ] ], "normalized": [] }, { "id": "23552265_T11", "type": "CHEMICAL", "text": [ "BPDE" ], "offsets": [ [ 1648, 1652 ] ], "normalized": [] }, { "id": "23552265_T12", "type": "CHEMICAL", "text": [ "BaP" ], "offsets": [ [ 144, 147 ] ], "normalized": [] }, { "id": "23552265_T13", "type": "CHEMICAL", "text": [ "PAHs" ], "offsets": [ [ 298, 302 ] ], "normalized": [] }, { "id": "23552265_T14", "type": "CHEMICAL", "text": [ "BaP" ], "offsets": [ [ 352, 355 ] ], "normalized": [] }, { "id": "23552265_T15", "type": "CHEMICAL", "text": [ "BaP trans-7,8-dihydrodiol" ], "offsets": [ [ 451, 476 ] ], "normalized": [] }, { "id": "23552265_T16", "type": "CHEMICAL", "text": [ "BaP t-7,8-diol" ], "offsets": [ [ 478, 492 ] ], "normalized": [] }, { "id": "23552265_T17", "type": "CHEMICAL", "text": [ "BaP t-4,5-diol" ], "offsets": [ [ 495, 509 ] ], "normalized": [] }, { "id": "23552265_T18", "type": "CHEMICAL", "text": [ "BaP t-9,10-diol" ], "offsets": [ [ 511, 526 ] ], "normalized": [] }, { "id": "23552265_T19", "type": "CHEMICAL", "text": [ "3-hydroxybenzo[a]pyrene" ], "offsets": [ [ 528, 551 ] ], "normalized": [] }, { "id": "23552265_T20", "type": "CHEMICAL", "text": [ "3-OH-BaP" ], "offsets": [ [ 553, 561 ] ], "normalized": [] }, { "id": "23552265_T21", "type": "CHEMICAL", "text": [ "BaP (7,10/8,9)tetrol" ], "offsets": [ [ 564, 584 ] ], "normalized": [] }, { "id": "23552265_T22", "type": "CHEMICAL", "text": [ "BaP (7/8,9,10)tetrol" ], "offsets": [ [ 590, 610 ] ], "normalized": [] }, { "id": "23552265_T23", "type": "CHEMICAL", "text": [ "BaP" ], "offsets": [ [ 637, 640 ] ], "normalized": [] }, { "id": "23552265_T24", "type": "CHEMICAL", "text": [ "3-OH-BaP" ], "offsets": [ [ 642, 650 ] ], "normalized": [] }, { "id": "23552265_T25", "type": "CHEMICAL", "text": [ "BaP t-7,8-diol" ], "offsets": [ [ 652, 666 ] ], "normalized": [] }, { "id": "23552265_T26", "type": "CHEMICAL", "text": [ "BaP trans-7,8-diol-anti-9,10-epoxide" ], "offsets": [ [ 668, 704 ] ], "normalized": [] }, { "id": "23552265_T27", "type": "CHEMICAL", "text": [ "BPDE" ], "offsets": [ [ 706, 710 ] ], "normalized": [] }, { "id": "23552265_T28", "type": "CHEMICAL", "text": [ "BaP (7,10/8,9)tetrol" ], "offsets": [ [ 717, 737 ] ], "normalized": [] }, { "id": "23552265_T29", "type": "CHEMICAL", "text": [ "polycyclic aromatic hydrocarbons" ], "offsets": [ [ 195, 227 ] ], "normalized": [] }, { "id": "23552265_T30", "type": "CHEMICAL", "text": [ "methyl linoleate" ], "offsets": [ [ 1007, 1023 ] ], "normalized": [] }, { "id": "23552265_T31", "type": "CHEMICAL", "text": [ "BaP" ], "offsets": [ [ 1026, 1029 ] ], "normalized": [] }, { "id": "23552265_T32", "type": "CHEMICAL", "text": [ "BPDE" ], "offsets": [ [ 1043, 1047 ] ], "normalized": [] }, { "id": "23552265_T33", "type": "CHEMICAL", "text": [ "PAHs" ], "offsets": [ [ 1067, 1071 ] ], "normalized": [] }, { "id": "23552265_T34", "type": "CHEMICAL", "text": [ "pyrene" ], "offsets": [ [ 1073, 1079 ] ], "normalized": [] }, { "id": "23552265_T35", "type": "CHEMICAL", "text": [ "7,8,9,10-tetrahydro-BaP trans-7,8-diol" ], "offsets": [ [ 1081, 1119 ] ], "normalized": [] }, { "id": "23552265_T36", "type": "CHEMICAL", "text": [ "7,8,9,10-tetrahydro-BaP trans-9,10-diol" ], "offsets": [ [ 1125, 1164 ] ], "normalized": [] }, { "id": "23552265_T37", "type": "CHEMICAL", "text": [ "benzo[a]pyrene" ], "offsets": [ [ 24, 38 ] ], "normalized": [] }, { "id": "23552265_T38", "type": "CHEMICAL", "text": [ "oxygen" ], "offsets": [ [ 88, 94 ] ], "normalized": [] }, { "id": "23552265_T39", "type": "GENE-N", "text": [ "superoxide dismutase" ], "offsets": [ [ 1462, 1482 ] ], "normalized": [] }, { "id": "23552265_T40", "type": "GENE-N", "text": [ "SOD" ], "offsets": [ [ 1484, 1487 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "20497523_title", "type": "title", "text": [ "Suppression of the inflammatory response in experimental arthritis is mediated via estrogen receptor alpha but not estrogen receptor beta." ], "offsets": [ [ 0, 138 ] ] }, { "id": "20497523_abstract", "type": "abstract", "text": [ "INTRODUCTION: The immune modulatory role of estrogens in inflammation is complex. Both pro- and anti-inflammatory effects of estrogens have been described. Estrogens bind both estrogen receptor (ER)alpha and beta. The contribution of ERalpha and ERbeta to ER-mediated immune modulation was studied in delayed type hypersensitivity (DTH) and in experimental arthritis METHODS: ER-mediated suppression of rat adjuvant arthritis (AA) was studied using ethinyl-estradiol (EE) and a selective ERbeta agonist (ERB-79). Arthritis was followed for 2 weeks. Next, effects of ER agonists (ethinyl-estradiol, an ERalpha selective agonist (ERA-63) and a selective ERbeta agonist (ERB-79) on the development of a tetanus toxoid (TT)-specific delayed type hypersensitivity response in wild type (WT) and in ERalpha- or ERbeta-deficient mice were investigated. Finally, EE and ERA-63 were tested for their immune modulating potential in established collagen induced arthritis in DBA/1J mice. Arthritis was followed for three weeks. Joint pathology was examined by histology and radiology. Local synovial cytokine production was analyzed using Luminex technology. Sera were assessed for COMP as a biomarker of cartilage destruction. RESULTS: EE was found to suppress clinical signs and symptoms in rat AA. The selective ERbeta agonist ERB-79 had no effect on arthritis symptoms in this model. In the TT-specific DTH model, EE and the selective ERalpha agonist ERA-63 suppressed the TT-specific swelling response in WT and ERbetaKO mice but not in ERalphaKO mice. As seen in the AA model, the selective ERbeta agonist ERB-79 did not suppress inflammation. Treatment with EE or ERA-63 suppressed clinical signs in collagen induced arthritis (CIA) in WT mice. This was associated with reduced inflammatory infiltrates and decreased levels of proinflammatory cytokines in CIA joints. CONCLUSIONS: ERalpha, but not ERbeta, is key in ER-mediated suppression of experimental arthritis. It remains to be investigated how these findings translate to human autoimmune disease." ], "offsets": [ [ 139, 2189 ] ] } ]

[ { "id": "20497523_T1", "type": "CHEMICAL", "text": [ "EE" ], "offsets": [ [ 1365, 1367 ] ], "normalized": [] }, { "id": "20497523_T2", "type": "CHEMICAL", "text": [ "estrogens" ], "offsets": [ [ 264, 273 ] ], "normalized": [] }, { "id": "20497523_T3", "type": "CHEMICAL", "text": [ "ERB-79" ], "offsets": [ [ 1458, 1464 ] ], "normalized": [] }, { "id": "20497523_T4", "type": "CHEMICAL", "text": [ "EE" ], "offsets": [ [ 1546, 1548 ] ], "normalized": [] }, { "id": "20497523_T5", "type": "CHEMICAL", "text": [ "ERA-63" ], "offsets": [ [ 1583, 1589 ] ], "normalized": [] }, { "id": "20497523_T6", "type": "CHEMICAL", "text": [ "Estrogens" ], "offsets": [ [ 295, 304 ] ], "normalized": [] }, { "id": "20497523_T7", "type": "CHEMICAL", "text": [ "ERB-79" ], "offsets": [ [ 1740, 1746 ] ], "normalized": [] }, { "id": "20497523_T8", "type": "CHEMICAL", "text": [ "EE" ], "offsets": [ [ 1793, 1795 ] ], "normalized": [] }, { "id": "20497523_T9", "type": "CHEMICAL", "text": [ "ERA-63" ], "offsets": [ [ 1799, 1805 ] ], "normalized": [] }, { "id": "20497523_T10", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 315, 323 ] ], "normalized": [] }, { "id": "20497523_T11", "type": "CHEMICAL", "text": [ "estrogens" ], "offsets": [ [ 183, 192 ] ], "normalized": [] }, { "id": "20497523_T12", "type": "CHEMICAL", "text": [ "ethinyl-estradiol" ], "offsets": [ [ 588, 605 ] ], "normalized": [] }, { "id": "20497523_T13", "type": "CHEMICAL", "text": [ "EE" ], "offsets": [ [ 607, 609 ] ], "normalized": [] }, { "id": "20497523_T14", "type": "CHEMICAL", "text": [ "ERB-79" ], "offsets": [ [ 643, 649 ] ], "normalized": [] }, { "id": "20497523_T15", "type": "CHEMICAL", "text": [ "ethinyl-estradiol" ], "offsets": [ [ 718, 735 ] ], "normalized": [] }, { "id": "20497523_T16", "type": "CHEMICAL", "text": [ "ERA-63" ], "offsets": [ [ 767, 773 ] ], "normalized": [] }, { "id": "20497523_T17", "type": "CHEMICAL", "text": [ "ERB-79" ], "offsets": [ [ 807, 813 ] ], "normalized": [] }, { "id": "20497523_T18", "type": "CHEMICAL", "text": [ "EE" ], "offsets": [ [ 994, 996 ] ], "normalized": [] }, { "id": "20497523_T19", "type": "CHEMICAL", "text": [ "ERA-63" ], "offsets": [ [ 1001, 1007 ] ], "normalized": [] }, { "id": "20497523_T20", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 115, 123 ] ], "normalized": [] }, { "id": "20497523_T21", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 83, 91 ] ], "normalized": [] }, { "id": "20497523_T22", "type": "GENE-N", "text": [ "cytokine" ], "offsets": [ [ 1228, 1236 ] ], "normalized": [] }, { "id": "20497523_T23", "type": "GENE-Y", "text": [ "COMP" ], "offsets": [ [ 1310, 1314 ] ], "normalized": [] }, { "id": "20497523_T24", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 1443, 1449 ] ], "normalized": [] }, { "id": "20497523_T25", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 1567, 1574 ] ], "normalized": [] }, { "id": "20497523_T26", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 1645, 1651 ] ], "normalized": [] }, { "id": "20497523_T27", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 1670, 1677 ] ], "normalized": [] }, { "id": "20497523_T28", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 1725, 1731 ] ], "normalized": [] }, { "id": "20497523_T29", "type": "GENE-N", "text": [ "collagen" ], "offsets": [ [ 1835, 1843 ] ], "normalized": [] }, { "id": "20497523_T30", "type": "GENE-N", "text": [ "estrogen receptor (ER)alpha and beta" ], "offsets": [ [ 315, 351 ] ], "normalized": [] }, { "id": "20497523_T31", "type": "GENE-N", "text": [ "cytokines" ], "offsets": [ [ 1978, 1987 ] ], "normalized": [] }, { "id": "20497523_T32", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 2016, 2023 ] ], "normalized": [] }, { "id": "20497523_T33", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 2033, 2039 ] ], "normalized": [] }, { "id": "20497523_T34", "type": "GENE-Y", "text": [ "ER" ], "offsets": [ [ 2051, 2053 ] ], "normalized": [] }, { "id": "20497523_T35", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 373, 380 ] ], "normalized": [] }, { "id": "20497523_T36", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 385, 391 ] ], "normalized": [] }, { "id": "20497523_T37", "type": "GENE-Y", "text": [ "ER" ], "offsets": [ [ 395, 397 ] ], "normalized": [] }, { "id": "20497523_T38", "type": "GENE-Y", "text": [ "ER" ], "offsets": [ [ 515, 517 ] ], "normalized": [] }, { "id": "20497523_T39", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 627, 633 ] ], "normalized": [] }, { "id": "20497523_T40", "type": "GENE-Y", "text": [ "ER" ], "offsets": [ [ 705, 707 ] ], "normalized": [] }, { "id": "20497523_T41", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 740, 747 ] ], "normalized": [] }, { "id": "20497523_T42", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 791, 797 ] ], "normalized": [] }, { "id": "20497523_T43", "type": "GENE-Y", "text": [ "ERalpha" ], "offsets": [ [ 932, 939 ] ], "normalized": [] }, { "id": "20497523_T44", "type": "GENE-Y", "text": [ "ERbeta" ], "offsets": [ [ 944, 950 ] ], "normalized": [] }, { "id": "20497523_T45", "type": "GENE-N", "text": [ "collagen" ], "offsets": [ [ 1073, 1081 ] ], "normalized": [] }, { "id": "20497523_T46", "type": "GENE-Y", "text": [ "estrogen receptor beta" ], "offsets": [ [ 115, 137 ] ], "normalized": [] }, { "id": "20497523_T47", "type": "GENE-Y", "text": [ "estrogen receptor alpha" ], "offsets": [ [ 83, 106 ] ], "normalized": [] } ]

[]

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[ { "id": "20497523_0", "type": "AGONIST", "arg1_id": "20497523_T14", "arg2_id": "20497523_T39", "normalized": [] }, { "id": "20497523_1", "type": "AGONIST", "arg1_id": "20497523_T15", "arg2_id": "20497523_T40", "normalized": [] }, { "id": "20497523_2", "type": "AGONIST", "arg1_id": "20497523_T16", "arg2_id": "20497523_T41", "normalized": [] }, { "id": "20497523_3", "type": "AGONIST", "arg1_id": "20497523_T17", "arg2_id": "20497523_T42", "normalized": [] }, { "id": "20497523_4", "type": "AGONIST", "arg1_id": "20497523_T3", "arg2_id": "20497523_T24", "normalized": [] }, { "id": "20497523_5", "type": "AGONIST", "arg1_id": "20497523_T5", "arg2_id": "20497523_T25", "normalized": [] }, { "id": "20497523_6", "type": "AGONIST", "arg1_id": "20497523_T7", "arg2_id": "20497523_T28", "normalized": [] } ]

[ { "id": "17611273_title", "type": "title", "text": [ "Methylphenidate administration to juvenile rats alters brain areas involved in cognition, motivated behaviors, appetite, and stress." ], "offsets": [ [ 0, 132 ] ] }, { "id": "17611273_abstract", "type": "abstract", "text": [ "Thousands of children receive methylphenidate (MPH; Ritalin) for attention deficit/hyperactivity disorder (ADHD), yet the long-term neurochemical consequences of MPH treatment are unknown. To mimic clinical Ritalin treatment in children, male rats were injected with MPH (5 mg/kg) or vehicle twice daily from postnatal day 7 (PND7)-PND35. At the end of administration (PND35) or in adulthood (PND135), brain sections from littermate pairs were immunocytochemically labeled for neurotransmitters and cytological markers in 16 regions implicated in MPH effects and/or ADHD etiology. At PND35, the medial prefrontal cortex (mPFC) of rats given MPH showed 55% greater immunoreactivity (-ir) for the catecholamine marker tyrosine hydroxylase (TH), 60% more Nissl-stained cells, and 40% less norepinephrine transporter (NET)-ir density. In hippocampal dentate gyrus, MPH-receiving rats showed a 51% decrease in NET-ir density and a 61% expanded distribution of the new-cell marker PSA-NCAM (polysialylated form of neural cell adhesion molecule). In medial striatum, TH-ir decreased by 21%, and in hypothalamus neuropeptide Y-ir increased by 10% in MPH-exposed rats. At PND135, MPH-exposed rats exhibited decreased anxiety in the elevated plus-maze and a trend for decreased TH-ir in the mPFC. Neither PND35 nor PND135 rats showed major structural differences with MPH exposure. These findings suggest that developmental exposure to high therapeutic doses of MPH has short-term effects on select neurotransmitters in brain regions involved in motivated behaviors, cognition, appetite, and stress. Although the observed neuroanatomical changes largely resolve with time, chronic modulation of young brains with MPH may exert effects on brain neurochemistry that modify some behaviors even in adulthood." ], "offsets": [ [ 133, 1927 ] ] } ]

[ { "id": "17611273_T1", "type": "CHEMICAL", "text": [ "MPH" ], "offsets": [ [ 1275, 1278 ] ], "normalized": [] }, { "id": "17611273_T2", "type": "CHEMICAL", "text": [ "MPH" ], "offsets": [ [ 1491, 1494 ] ], "normalized": [] }, { "id": "17611273_T3", "type": "CHEMICAL", "text": [ "MPH" ], "offsets": [ [ 1585, 1588 ] ], "normalized": [] }, { "id": "17611273_T4", "type": "CHEMICAL", "text": [ "MPH" ], "offsets": [ [ 295, 298 ] ], "normalized": [] }, { "id": "17611273_T5", "type": "CHEMICAL", "text": [ "MPH" ], "offsets": [ [ 1836, 1839 ] ], "normalized": [] }, { "id": "17611273_T6", "type": "CHEMICAL", "text": [ "Ritalin" ], "offsets": [ [ 340, 347 ] ], "normalized": [] }, { "id": "17611273_T7", "type": "CHEMICAL", "text": [ "MPH" ], "offsets": [ [ 400, 403 ] ], "normalized": [] }, { "id": "17611273_T8", "type": "CHEMICAL", "text": [ "methylphenidate" ], "offsets": [ [ 163, 178 ] ], "normalized": [] }, { "id": "17611273_T9", "type": "CHEMICAL", "text": [ "MPH" ], "offsets": [ [ 180, 183 ] ], "normalized": [] }, { "id": "17611273_T10", "type": "CHEMICAL", "text": [ "Ritalin" ], "offsets": [ [ 185, 192 ] ], "normalized": [] }, { "id": "17611273_T11", "type": "CHEMICAL", "text": [ "MPH" ], "offsets": [ [ 680, 683 ] ], "normalized": [] }, { "id": "17611273_T12", "type": "CHEMICAL", "text": [ "MPH" ], "offsets": [ [ 774, 777 ] ], "normalized": [] }, { "id": "17611273_T13", "type": "CHEMICAL", "text": [ "catecholamine" ], "offsets": [ [ 828, 841 ] ], "normalized": [] }, { "id": "17611273_T14", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 849, 857 ] ], "normalized": [] }, { "id": "17611273_T15", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 919, 933 ] ], "normalized": [] }, { "id": "17611273_T16", "type": "CHEMICAL", "text": [ "MPH" ], "offsets": [ [ 994, 997 ] ], "normalized": [] }, { "id": "17611273_T17", "type": "CHEMICAL", "text": [ "Methylphenidate" ], "offsets": [ [ 0, 15 ] ], "normalized": [] }, { "id": "17611273_T18", "type": "GENE-Y", "text": [ "neural cell adhesion molecule" ], "offsets": [ [ 1141, 1170 ] ], "normalized": [] }, { "id": "17611273_T19", "type": "GENE-Y", "text": [ "TH" ], "offsets": [ [ 1193, 1195 ] ], "normalized": [] }, { "id": "17611273_T20", "type": "GENE-Y", "text": [ "neuropeptide Y" ], "offsets": [ [ 1237, 1251 ] ], "normalized": [] }, { "id": "17611273_T21", "type": "GENE-Y", "text": [ "TH" ], "offsets": [ [ 1401, 1403 ] ], "normalized": [] }, { "id": "17611273_T22", "type": "GENE-Y", "text": [ "tyrosine hydroxylase" ], "offsets": [ [ 849, 869 ] ], "normalized": [] }, { "id": "17611273_T23", "type": "GENE-Y", "text": [ "TH" ], "offsets": [ [ 871, 873 ] ], "normalized": [] }, { "id": "17611273_T24", "type": "GENE-Y", "text": [ "norepinephrine transporter" ], "offsets": [ [ 919, 945 ] ], "normalized": [] }, { "id": "17611273_T25", "type": "GENE-Y", "text": [ "NET" ], "offsets": [ [ 947, 950 ] ], "normalized": [] }, { "id": "17611273_T26", "type": "GENE-Y", "text": [ "NET" ], "offsets": [ [ 1038, 1041 ] ], "normalized": [] }, { "id": "17611273_T27", "type": "GENE-Y", "text": [ "NCAM" ], "offsets": [ [ 1112, 1116 ] ], "normalized": [] } ]

[]

[]

[ { "id": "17611273_0", "type": "INDIRECT-UPREGULATOR", "arg1_id": "17611273_T12", "arg2_id": "17611273_T23", "normalized": [] }, { "id": "17611273_1", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "17611273_T12", "arg2_id": "17611273_T24", "normalized": [] }, { "id": "17611273_2", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "17611273_T12", "arg2_id": "17611273_T25", "normalized": [] }, { "id": "17611273_3", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "17611273_T16", "arg2_id": "17611273_T26", "normalized": [] }, { "id": "17611273_4", "type": "INDIRECT-UPREGULATOR", "arg1_id": "17611273_T12", "arg2_id": "17611273_T22", "normalized": [] }, { "id": "17611273_5", "type": "INDIRECT-UPREGULATOR", "arg1_id": "17611273_T16", "arg2_id": "17611273_T27", "normalized": [] }, { "id": "17611273_6", "type": "INDIRECT-UPREGULATOR", "arg1_id": "17611273_T16", "arg2_id": "17611273_T18", "normalized": [] }, { "id": "17611273_7", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "17611273_T1", "arg2_id": "17611273_T19", "normalized": [] }, { "id": "17611273_8", "type": "INDIRECT-UPREGULATOR", "arg1_id": "17611273_T1", "arg2_id": "17611273_T20", "normalized": [] } ]

[ { "id": "16829128_title", "type": "title", "text": [ "More than cool: promiscuous relationships of menthol and other sensory compounds." ], "offsets": [ [ 0, 81 ] ] }, { "id": "16829128_abstract", "type": "abstract", "text": [ "Several temperature-activated transient receptor potential (thermoTRP) ion channels are the molecular receptors of natural compounds that evoke thermal and pain sensations. Menthol, popularly known for its cooling effect, activates TRPM8--a cold-activated thermoTRP ion channel. However, human physiological studies demonstrate a paradoxical role of menthol in modulation of warm sensation, and here, we show that menthol also activates heat-activated TRPV3. We further show that menthol inhibits TRPA1, potentially explaining the use of menthol as an analgesic. Similar to menthol, both camphor and cinnamaldehyde (initially reported to be specific activators of TRPV3 and TRPA1, respectively) also modulate other thermoTRPs. Therefore, we find that many \"sensory compounds\" presumed to be specific have a promiscuous relationship with thermoTRPs." ], "offsets": [ [ 82, 930 ] ] } ]

[ { "id": "16829128_T1", "type": "CHEMICAL", "text": [ "Menthol" ], "offsets": [ [ 255, 262 ] ], "normalized": [] }, { "id": "16829128_T2", "type": "CHEMICAL", "text": [ "menthol" ], "offsets": [ [ 432, 439 ] ], "normalized": [] }, { "id": "16829128_T3", "type": "CHEMICAL", "text": [ "menthol" ], "offsets": [ [ 496, 503 ] ], "normalized": [] }, { "id": "16829128_T4", "type": "CHEMICAL", "text": [ "menthol" ], "offsets": [ [ 562, 569 ] ], "normalized": [] }, { "id": "16829128_T5", "type": "CHEMICAL", "text": [ "menthol" ], "offsets": [ [ 620, 627 ] ], "normalized": [] }, { "id": "16829128_T6", "type": "CHEMICAL", "text": [ "menthol" ], "offsets": [ [ 656, 663 ] ], "normalized": [] }, { "id": "16829128_T7", "type": "CHEMICAL", "text": [ "camphor" ], "offsets": [ [ 670, 677 ] ], "normalized": [] }, { "id": "16829128_T8", "type": "CHEMICAL", "text": [ "cinnamaldehyde" ], "offsets": [ [ 682, 696 ] ], "normalized": [] }, { "id": "16829128_T9", "type": "CHEMICAL", "text": [ "menthol" ], "offsets": [ [ 45, 52 ] ], "normalized": [] }, { "id": "16829128_T10", "type": "GENE-Y", "text": [ "TRPM8" ], "offsets": [ [ 314, 319 ] ], "normalized": [] }, { "id": "16829128_T11", "type": "GENE-N", "text": [ "thermoTRP ion channel" ], "offsets": [ [ 338, 359 ] ], "normalized": [] }, { "id": "16829128_T12", "type": "GENE-Y", "text": [ "TRPV3" ], "offsets": [ [ 534, 539 ] ], "normalized": [] }, { "id": "16829128_T13", "type": "GENE-Y", "text": [ "TRPA1" ], "offsets": [ [ 579, 584 ] ], "normalized": [] }, { "id": "16829128_T14", "type": "GENE-Y", "text": [ "TRPV3" ], "offsets": [ [ 746, 751 ] ], "normalized": [] }, { "id": "16829128_T15", "type": "GENE-Y", "text": [ "TRPA1" ], "offsets": [ [ 756, 761 ] ], "normalized": [] }, { "id": "16829128_T16", "type": "GENE-N", "text": [ "thermoTRPs" ], "offsets": [ [ 797, 807 ] ], "normalized": [] }, { "id": "16829128_T17", "type": "GENE-N", "text": [ "thermoTRPs" ], "offsets": [ [ 919, 929 ] ], "normalized": [] }, { "id": "16829128_T18", "type": "GENE-N", "text": [ "temperature-activated transient receptor potential (thermoTRP) ion channels" ], "offsets": [ [ 90, 165 ] ], "normalized": [] } ]

[]

[]

[ { "id": "16829128_0", "type": "ACTIVATOR", "arg1_id": "16829128_T1", "arg2_id": "16829128_T10", "normalized": [] }, { "id": "16829128_1", "type": "ACTIVATOR", "arg1_id": "16829128_T1", "arg2_id": "16829128_T11", "normalized": [] }, { "id": "16829128_2", "type": "ACTIVATOR", "arg1_id": "16829128_T3", "arg2_id": "16829128_T12", "normalized": [] }, { "id": "16829128_3", "type": "INHIBITOR", "arg1_id": "16829128_T4", "arg2_id": "16829128_T13", "normalized": [] }, { "id": "16829128_4", "type": "ACTIVATOR", "arg1_id": "16829128_T6", "arg2_id": "16829128_T14", "normalized": [] }, { "id": "16829128_5", "type": "ACTIVATOR", "arg1_id": "16829128_T7", "arg2_id": "16829128_T14", "normalized": [] }, { "id": "16829128_6", "type": "ACTIVATOR", "arg1_id": "16829128_T8", "arg2_id": "16829128_T14", "normalized": [] }, { "id": "16829128_7", "type": "ACTIVATOR", "arg1_id": "16829128_T6", "arg2_id": "16829128_T15", "normalized": [] }, { "id": "16829128_8", "type": "ACTIVATOR", "arg1_id": "16829128_T7", "arg2_id": "16829128_T15", "normalized": [] }, { "id": "16829128_9", "type": "ACTIVATOR", "arg1_id": "16829128_T8", "arg2_id": "16829128_T15", "normalized": [] } ]

[ { "id": "19428322_title", "type": "title", "text": [ "AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C." ], "offsets": [ [ 0, 119 ] ] }, { "id": "19428322_abstract", "type": "abstract", "text": [ "We investigated the effect of compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), on proliferation and viability of human U251 and rat C6 glioma cell lines. Compound C caused G(2)/M cell cycle block, accompanied by apoptotic glioma cell death characterized by caspase activation, phosphatidylserine exposure and DNA fragmentation. The mechanisms underlying the pro-apoptotic action of compound C involved induction of oxidative stress and downregulation of antiapoptotic molecule Bcl-2, while no alteration of pro-apoptotic Bax was observed. Compound C diminished AMPK phosphorylation and enzymatic activity, resulting in reduced phosphorylation of its target acetyl CoA carboxylase. AMPK activators metformin and AICAR partly prevented the cell cycle block, oxidative stress and apoptosis induced by compound C. The small interfering RNA (siRNA) targeting of human AMPK mimicked compound C-induced G(2)/M cell cycle arrest, but failed to induce oxidative stress and apoptosis in U251 glioma cells. In conclusion, our data indicate that AMPK inhibition is required, but not sufficient for compound C-mediated apoptotic death of glioma cells." ], "offsets": [ [ 120, 1316 ] ] } ]

[ { "id": "19428322_T1", "type": "CHEMICAL", "text": [ "AMP" ], "offsets": [ [ 220, 223 ] ], "normalized": [] }, { "id": "19428322_T2", "type": "CHEMICAL", "text": [ "phosphatidylserine" ], "offsets": [ [ 455, 473 ] ], "normalized": [] }, { "id": "19428322_T3", "type": "CHEMICAL", "text": [ "acetyl CoA" ], "offsets": [ [ 835, 845 ] ], "normalized": [] }, { "id": "19428322_T4", "type": "CHEMICAL", "text": [ "metformin" ], "offsets": [ [ 875, 884 ] ], "normalized": [] }, { "id": "19428322_T5", "type": "CHEMICAL", "text": [ "AICAR" ], "offsets": [ [ 889, 894 ] ], "normalized": [] }, { "id": "19428322_T6", "type": "CHEMICAL", "text": [ "AMP" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "19428322_T7", "type": "GENE-N", "text": [ "AMP-activated protein kinase" ], "offsets": [ [ 220, 248 ] ], "normalized": [] }, { "id": "19428322_T8", "type": "GENE-N", "text": [ "AMPK" ], "offsets": [ [ 1212, 1216 ] ], "normalized": [] }, { "id": "19428322_T9", "type": "GENE-N", "text": [ "AMPK" ], "offsets": [ [ 250, 254 ] ], "normalized": [] }, { "id": "19428322_T10", "type": "GENE-N", "text": [ "caspase" ], "offsets": [ [ 435, 442 ] ], "normalized": [] }, { "id": "19428322_T11", "type": "GENE-N", "text": [ "Bcl-2" ], "offsets": [ [ 655, 660 ] ], "normalized": [] }, { "id": "19428322_T12", "type": "GENE-N", "text": [ "Bax" ], "offsets": [ [ 699, 702 ] ], "normalized": [] }, { "id": "19428322_T13", "type": "GENE-N", "text": [ "AMPK" ], "offsets": [ [ 739, 743 ] ], "normalized": [] }, { "id": "19428322_T14", "type": "GENE-N", "text": [ "acetyl CoA carboxylase" ], "offsets": [ [ 835, 857 ] ], "normalized": [] }, { "id": "19428322_T15", "type": "GENE-N", "text": [ "AMPK" ], "offsets": [ [ 859, 863 ] ], "normalized": [] }, { "id": "19428322_T16", "type": "GENE-Y", "text": [ "human AMPK" ], "offsets": [ [ 1035, 1045 ] ], "normalized": [] }, { "id": "19428322_T17", "type": "GENE-N", "text": [ "AMP-activated protein kinase" ], "offsets": [ [ 0, 28 ] ], "normalized": [] } ]

[]

[]

[ { "id": "19428322_0", "type": "ACTIVATOR", "arg1_id": "19428322_T4", "arg2_id": "19428322_T15", "normalized": [] }, { "id": "19428322_1", "type": "ACTIVATOR", "arg1_id": "19428322_T5", "arg2_id": "19428322_T15", "normalized": [] } ]

[ { "id": "23391631_title", "type": "title", "text": [ "The role of aryl hydrocarbon receptor signaling pathway in cardiotoxicity of acute lead intoxication in vivo and in vitro rat model." ], "offsets": [ [ 0, 132 ] ] }, { "id": "23391631_abstract", "type": "abstract", "text": [ "Lead (Pb(2+)) is a naturally occurring systemic toxicant heavy metal that affects several organs in the body including the kidneys, liver, and central nervous system. However, Pb(2+)-induced cardiotoxicity has never been investigated yet and the exact mechanism of Pb(2+) associated cardiotoxicity has not been studied. The current study was designed to investigate the potential effect of Pb(2+) to induce cardiotoxicity in vivo and in vitro rat model and to explore the molecular mechanisms and the role of aryl hydrocarbon receptor (AhR) and regulated gene, cytochrome P4501A1 (CYP1A1), in Pb(2+)-mediated cardiotoxicity. For these purposes, Wistar albino rats were treated with Pb(2+) (25, 50 and 100mg/kg, i.p.) for three days and the effects on physiological and histopathological parameters of cardiotoxicity were determined. At the in vitro level, rat cardiomyocyte H9c2 cell lines were incubated with increasing concentration of Pb(2+) (25, 50, and 100μM) and the expression of hypertrophic genes, α- and β-myosin heavy chain (α-MHC and β-MHC), brain Natriuretic Peptide (BNP), and CYP1A1 were determined at the mRNA and protein levels using real-time PCR and Western blot analysis, respectively. The results showed that Pb(2+) significantly induced cardiotoxicity and heart failure as evidenced by increase cardiac enzymes, lactate dehydrogenase and creatine kinase and changes in histopathology in vivo. In addition, Pb(2+) treatment induced β-MHC and BNP whereas inhibited α-MHC mRNA and protein levels in vivo in a dose-dependent manner. In contrast, at the in vitro level, Pb(2+) treatment induced both β-MHC and α-MHC mRNA levels in time- and dose-dependent manner. Importantly, these changes were accompanied with a proportional increase in the expression of CYP1A1 mRNA and protein expression levels, suggesting a role for the CYP1A1 in cardiotoxicity. The direct evidence for the involvement of CYP1A1 in the induction of cardiotoxicity by Pb(2+) was evidenced by the ability of AhR antagonist, resveratrol, to significantly inhibit the Pb(2+)-modulated effect on β-MHC and α-MHC mRNAs. It was concluded that acute lead exposure induced cardiotoxicity through AhR/CYP1A1-mediated mechanism." ], "offsets": [ [ 133, 2341 ] ] } ]

[ { "id": "23391631_T1", "type": "CHEMICAL", "text": [ "Pb(2+)" ], "offsets": [ [ 1363, 1369 ] ], "normalized": [] }, { "id": "23391631_T2", "type": "CHEMICAL", "text": [ "lactate" ], "offsets": [ [ 1467, 1474 ] ], "normalized": [] }, { "id": "23391631_T3", "type": "CHEMICAL", "text": [ "creatine" ], "offsets": [ [ 1493, 1501 ] ], "normalized": [] }, { "id": "23391631_T4", "type": "CHEMICAL", "text": [ "Pb(2+)" ], "offsets": [ [ 1561, 1567 ] ], "normalized": [] }, { "id": "23391631_T5", "type": "CHEMICAL", "text": [ "Pb(2+)" ], "offsets": [ [ 1720, 1726 ] ], "normalized": [] }, { "id": "23391631_T6", "type": "CHEMICAL", "text": [ "Pb(2+)" ], "offsets": [ [ 309, 315 ] ], "normalized": [] }, { "id": "23391631_T7", "type": "CHEMICAL", "text": [ "Pb(2+)" ], "offsets": [ [ 2091, 2097 ] ], "normalized": [] }, { "id": "23391631_T8", "type": "CHEMICAL", "text": [ "resveratrol" ], "offsets": [ [ 2146, 2157 ] ], "normalized": [] }, { "id": "23391631_T9", "type": "CHEMICAL", "text": [ "Pb(2+)" ], "offsets": [ [ 2188, 2194 ] ], "normalized": [] }, { "id": "23391631_T10", "type": "CHEMICAL", "text": [ "Pb(2+)" ], "offsets": [ [ 398, 404 ] ], "normalized": [] }, { "id": "23391631_T11", "type": "CHEMICAL", "text": [ "Pb(2+)" ], "offsets": [ [ 523, 529 ] ], "normalized": [] }, { "id": "23391631_T12", "type": "CHEMICAL", "text": [ "aryl hydrocarbon" ], "offsets": [ [ 642, 658 ] ], "normalized": [] }, { "id": "23391631_T13", "type": "CHEMICAL", "text": [ "Pb(2+)" ], "offsets": [ [ 726, 732 ] ], "normalized": [] }, { "id": "23391631_T14", "type": "CHEMICAL", "text": [ "Pb(2+)" ], "offsets": [ [ 139, 145 ] ], "normalized": [] }, { "id": "23391631_T15", "type": "CHEMICAL", "text": [ "Pb(2+)" ], "offsets": [ [ 815, 821 ] ], "normalized": [] }, { "id": "23391631_T16", "type": "CHEMICAL", "text": [ "Pb(2+)" ], "offsets": [ [ 1071, 1077 ] ], "normalized": [] }, { "id": "23391631_T17", "type": "CHEMICAL", "text": [ "aryl hydrocarbon" ], "offsets": [ [ 12, 28 ] ], "normalized": [] }, { "id": "23391631_T18", "type": "GENE-N", "text": [ "α- and β-myosin heavy chain" ], "offsets": [ [ 1140, 1167 ] ], "normalized": [] }, { "id": "23391631_T19", "type": "GENE-N", "text": [ "α-MHC" ], "offsets": [ [ 1169, 1174 ] ], "normalized": [] }, { "id": "23391631_T20", "type": "GENE-N", "text": [ "β-MHC" ], "offsets": [ [ 1179, 1184 ] ], "normalized": [] }, { "id": "23391631_T21", "type": "GENE-Y", "text": [ "brain Natriuretic Peptide" ], "offsets": [ [ 1187, 1212 ] ], "normalized": [] }, { "id": "23391631_T22", "type": "GENE-Y", "text": [ "BNP" ], "offsets": [ [ 1214, 1217 ] ], "normalized": [] }, { "id": "23391631_T23", "type": "GENE-Y", "text": [ "CYP1A1" ], "offsets": [ [ 1224, 1230 ] ], "normalized": [] }, { "id": "23391631_T24", "type": "GENE-N", "text": [ "lactate dehydrogenase" ], "offsets": [ [ 1467, 1488 ] ], "normalized": [] }, { "id": "23391631_T25", "type": "GENE-N", "text": [ "creatine kinase" ], "offsets": [ [ 1493, 1508 ] ], "normalized": [] }, { "id": "23391631_T26", "type": "GENE-N", "text": [ "β-MHC" ], "offsets": [ [ 1586, 1591 ] ], "normalized": [] }, { "id": "23391631_T27", "type": "GENE-Y", "text": [ "BNP" ], "offsets": [ [ 1596, 1599 ] ], "normalized": [] }, { "id": "23391631_T28", "type": "GENE-N", "text": [ "α-MHC" ], "offsets": [ [ 1618, 1623 ] ], "normalized": [] }, { "id": "23391631_T29", "type": "GENE-N", "text": [ "β-MHC" ], "offsets": [ [ 1750, 1755 ] ], "normalized": [] }, { "id": "23391631_T30", "type": "GENE-N", "text": [ "α-MHC" ], "offsets": [ [ 1760, 1765 ] ], "normalized": [] }, { "id": "23391631_T31", "type": "GENE-Y", "text": [ "CYP1A1" ], "offsets": [ [ 1908, 1914 ] ], "normalized": [] }, { "id": "23391631_T32", "type": "GENE-Y", "text": [ "CYP1A1" ], "offsets": [ [ 1977, 1983 ] ], "normalized": [] }, { "id": "23391631_T33", "type": "GENE-Y", "text": [ "CYP1A1" ], "offsets": [ [ 2046, 2052 ] ], "normalized": [] }, { "id": "23391631_T34", "type": "GENE-Y", "text": [ "AhR" ], "offsets": [ [ 2130, 2133 ] ], "normalized": [] }, { "id": "23391631_T35", "type": "GENE-N", "text": [ "β-MHC" ], "offsets": [ [ 2215, 2220 ] ], "normalized": [] }, { "id": "23391631_T36", "type": "GENE-N", "text": [ "α-MHC" ], "offsets": [ [ 2225, 2230 ] ], "normalized": [] }, { "id": "23391631_T37", "type": "GENE-Y", "text": [ "AhR" ], "offsets": [ [ 2311, 2314 ] ], "normalized": [] }, { "id": "23391631_T38", "type": "GENE-Y", "text": [ "CYP1A1" ], "offsets": [ [ 2315, 2321 ] ], "normalized": [] }, { "id": "23391631_T39", "type": "GENE-Y", "text": [ "aryl hydrocarbon receptor" ], "offsets": [ [ 642, 667 ] ], "normalized": [] }, { "id": "23391631_T40", "type": "GENE-Y", "text": [ "AhR" ], "offsets": [ [ 669, 672 ] ], "normalized": [] }, { "id": "23391631_T41", "type": "GENE-Y", "text": [ "cytochrome P4501A1" ], "offsets": [ [ 694, 712 ] ], "normalized": [] }, { "id": "23391631_T42", "type": "GENE-Y", "text": [ "CYP1A1" ], "offsets": [ [ 714, 720 ] ], "normalized": [] }, { "id": "23391631_T43", "type": "GENE-Y", "text": [ "aryl hydrocarbon receptor" ], "offsets": [ [ 12, 37 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23391631_0", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23391631_T1", "arg2_id": "23391631_T24", "normalized": [] }, { "id": "23391631_1", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23391631_T1", "arg2_id": "23391631_T25", "normalized": [] }, { "id": "23391631_2", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23391631_T4", "arg2_id": "23391631_T26", "normalized": [] }, { "id": "23391631_3", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23391631_T4", "arg2_id": "23391631_T27", "normalized": [] }, { "id": "23391631_4", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23391631_T4", "arg2_id": "23391631_T28", "normalized": [] }, { "id": "23391631_5", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23391631_T5", "arg2_id": "23391631_T29", "normalized": [] }, { "id": "23391631_6", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23391631_T5", "arg2_id": "23391631_T30", "normalized": [] }, { "id": "23391631_7", "type": "ANTAGONIST", "arg1_id": "23391631_T8", "arg2_id": "23391631_T34", "normalized": [] }, { "id": "23391631_8", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23391631_T9", "arg2_id": "23391631_T35", "normalized": [] }, { "id": "23391631_9", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23391631_T9", "arg2_id": "23391631_T36", "normalized": [] }, { "id": "23391631_10", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23391631_T8", "arg2_id": "23391631_T35", "normalized": [] }, { "id": "23391631_11", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23391631_T8", "arg2_id": "23391631_T36", "normalized": [] } ]

[ { "id": "23142547_title", "type": "title", "text": [ "A non-catalytic function of Rev1 in translesion DNA synthesis and mutagenesis is mediated by its stable interaction with Rad5." ], "offsets": [ [ 0, 126 ] ] }, { "id": "23142547_abstract", "type": "abstract", "text": [ "DNA damage tolerance consisting of template switching and translesion synthesis is a major cellular mechanism in response to unrepaired DNA lesions during replication. The Rev1 pathway constitutes the major mechanism of translesion synthesis and base damage-induced mutagenesis in model cell systems. Rev1 is a dCMP transferase, but additionally plays non-catalytic functions in translesion synthesis. Using the yeast model system, we attempted to gain further insights into the non-catalytic functions of Rev1. Rev1 stably interacts with Rad5 (a central component of the template switching pathway) via the C-terminal region of Rev1 and the N-terminal region of Rad5. Supporting functional significance of this interaction, both the Rev1 pathway and Rad5 are required for translesion synthesis and mutagenesis of 1,N(6)-ethenoadenine. Furthermore, disrupting the Rev1-Rad5 interaction by mutating Rev1 did not affect its dCMP transferase, but led to inactivation of the Rev1 non-catalytic function in translesion synthesis of UV-induced DNA damage. Deletion analysis revealed that the C-terminal 21-amino acid sequence of Rev1 is uniquely required for its interaction with Rad5 and is essential for its non-catalytic function. Deletion analysis additionally implicated a C-terminal region of Rev1 in its negative regulation. These results show that a non-catalytic function of Rev1 in translesion synthesis and mutagenesis is mediated by its interaction with Rad5." ], "offsets": [ [ 127, 1592 ] ] } ]

[ { "id": "23142547_T1", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 1213, 1214 ] ], "normalized": [] }, { "id": "23142547_T2", "type": "CHEMICAL", "text": [ "amino acid" ], "offsets": [ [ 1227, 1237 ] ], "normalized": [] }, { "id": "23142547_T3", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 1399, 1400 ] ], "normalized": [] }, { "id": "23142547_T4", "type": "CHEMICAL", "text": [ "dCMP" ], "offsets": [ [ 438, 442 ] ], "normalized": [] }, { "id": "23142547_T5", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 735, 736 ] ], "normalized": [] }, { "id": "23142547_T6", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 769, 770 ] ], "normalized": [] }, { "id": "23142547_T7", "type": "CHEMICAL", "text": [ "1,N(6)-ethenoadenine" ], "offsets": [ [ 941, 961 ] ], "normalized": [] }, { "id": "23142547_T8", "type": "CHEMICAL", "text": [ "dCMP" ], "offsets": [ [ 1049, 1053 ] ], "normalized": [] }, { "id": "23142547_T9", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 1250, 1254 ] ], "normalized": [] }, { "id": "23142547_T10", "type": "GENE-Y", "text": [ "Rad5" ], "offsets": [ [ 1301, 1305 ] ], "normalized": [] }, { "id": "23142547_T11", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 1420, 1424 ] ], "normalized": [] }, { "id": "23142547_T12", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 1505, 1509 ] ], "normalized": [] }, { "id": "23142547_T13", "type": "GENE-Y", "text": [ "Rad5" ], "offsets": [ [ 1587, 1591 ] ], "normalized": [] }, { "id": "23142547_T14", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 299, 303 ] ], "normalized": [] }, { "id": "23142547_T15", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 428, 432 ] ], "normalized": [] }, { "id": "23142547_T16", "type": "GENE-N", "text": [ "dCMP transferase" ], "offsets": [ [ 438, 454 ] ], "normalized": [] }, { "id": "23142547_T17", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 633, 637 ] ], "normalized": [] }, { "id": "23142547_T18", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 639, 643 ] ], "normalized": [] }, { "id": "23142547_T19", "type": "GENE-Y", "text": [ "Rad5" ], "offsets": [ [ 666, 670 ] ], "normalized": [] }, { "id": "23142547_T20", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 756, 760 ] ], "normalized": [] }, { "id": "23142547_T21", "type": "GENE-Y", "text": [ "Rad5" ], "offsets": [ [ 790, 794 ] ], "normalized": [] }, { "id": "23142547_T22", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 861, 865 ] ], "normalized": [] }, { "id": "23142547_T23", "type": "GENE-Y", "text": [ "Rad5" ], "offsets": [ [ 878, 882 ] ], "normalized": [] }, { "id": "23142547_T24", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 991, 995 ] ], "normalized": [] }, { "id": "23142547_T25", "type": "GENE-Y", "text": [ "Rad5" ], "offsets": [ [ 996, 1000 ] ], "normalized": [] }, { "id": "23142547_T26", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 1025, 1029 ] ], "normalized": [] }, { "id": "23142547_T27", "type": "GENE-N", "text": [ "dCMP transferase" ], "offsets": [ [ 1049, 1065 ] ], "normalized": [] }, { "id": "23142547_T28", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 1098, 1102 ] ], "normalized": [] }, { "id": "23142547_T29", "type": "GENE-Y", "text": [ "Rad5" ], "offsets": [ [ 121, 125 ] ], "normalized": [] }, { "id": "23142547_T30", "type": "GENE-Y", "text": [ "Rev1" ], "offsets": [ [ 28, 32 ] ], "normalized": [] } ]

[]

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[ { "id": "23142547_0", "type": "PART-OF", "arg1_id": "23142547_T5", "arg2_id": "23142547_T20", "normalized": [] }, { "id": "23142547_1", "type": "PART-OF", "arg1_id": "23142547_T6", "arg2_id": "23142547_T21", "normalized": [] }, { "id": "23142547_2", "type": "PART-OF", "arg1_id": "23142547_T2", "arg2_id": "23142547_T9", "normalized": [] }, { "id": "23142547_3", "type": "PART-OF", "arg1_id": "23142547_T1", "arg2_id": "23142547_T9", "normalized": [] }, { "id": "23142547_4", "type": "PART-OF", "arg1_id": "23142547_T3", "arg2_id": "23142547_T11", "normalized": [] } ]

[ { "id": "17704420_title", "type": "title", "text": [ "FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab." ], "offsets": [ [ 0, 186 ] ] }, { "id": "17704420_abstract", "type": "abstract", "text": [ "PURPOSE: Cetuximab, a chimeric immunoglobulin G 1 (IgG1) anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), has shown efficacy in 10% of patients with metastatic colorectal cancer (CRC). Recent studies demonstrate antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the modes of action for rituximab and trastuzumab. Fragment c (Fc) portion of IgG1 mAb has shown to induce ADCC. Fragment c gamma receptors (FcgammaR) play an important role in initiating ADCC. Studies have shown that two IgG FcgammaR polymorphisms (FCGR2A-H131R and FCGR3A-V158F) independently predict response to rituximab in patients with follicular lymphoma. We tested the hypothesis of whether these two polymorphisms are associated with clinical outcome in metastatic CRC patients treated with single-agent cetuximab. PATIENTS AND METHODS: Thirty-nine metastatic CRC patients were enrolled onto the ImClone0144 trial. Using an allele-specific polymerase chain reaction (PCR) -based method, gene polymorphisms of FCGA2A-H131R and FCGA3A-V158F were assessed from genomic DNA extracted from peripheral blood samples. RESULTS: FCGR2A-H131R and FCGR3A-V158F polymorphisms were independently associated with progression-free survival (PFS; P = .037 and .055, respectively; log-rank test). Combined analysis of these two polymorphisms showed that patients with the favorable genotypes (FCGR2A, any histidine allele, and FCGR3A, any phenylalanine allele) showed a median PFS of 3.7 months (95% CI, 2.4 to 4.4 months), whereas patients with any two unfavorable genotypes (FCGR2A arginine/arginine or valine/valine) had a PFS of 1.1 months (95% CI, 1.0 to 1.4 months; P = .004; log-rank test). CONCLUSION: Our preliminary data suggest that these two polymorphisms may be useful molecular markers to predict clinical outcome in metastatic CRC patients treated with cetuximab and that they may indicate a role of ADCC of cetuximab." ], "offsets": [ [ 187, 2110 ] ] } ]

[ { "id": "17704420_T1", "type": "CHEMICAL", "text": [ "histidine" ], "offsets": [ [ 1582, 1591 ] ], "normalized": [] }, { "id": "17704420_T2", "type": "CHEMICAL", "text": [ "phenylalanine" ], "offsets": [ [ 1616, 1629 ] ], "normalized": [] }, { "id": "17704420_T3", "type": "CHEMICAL", "text": [ "arginine" ], "offsets": [ [ 1761, 1769 ] ], "normalized": [] }, { "id": "17704420_T4", "type": "CHEMICAL", "text": [ "arginine" ], "offsets": [ [ 1770, 1778 ] ], "normalized": [] }, { "id": "17704420_T5", "type": "CHEMICAL", "text": [ "valine" ], "offsets": [ [ 1782, 1788 ] ], "normalized": [] }, { "id": "17704420_T6", "type": "CHEMICAL", "text": [ "valine" ], "offsets": [ [ 1789, 1795 ] ], "normalized": [] }, { "id": "17704420_T7", "type": "GENE-Y", "text": [ "FCGA2A" ], "offsets": [ [ 1203, 1209 ] ], "normalized": [] }, { "id": "17704420_T8", "type": "GENE-N", "text": [ "H131R" ], "offsets": [ [ 1210, 1215 ] ], "normalized": [] }, { "id": "17704420_T9", "type": "GENE-Y", "text": [ "FCGA3A" ], "offsets": [ [ 1220, 1226 ] ], "normalized": [] }, { "id": "17704420_T10", "type": "GENE-N", "text": [ "V158F" ], "offsets": [ [ 1227, 1232 ] ], "normalized": [] }, { "id": "17704420_T11", "type": "GENE-Y", "text": [ "FCGR2A" ], "offsets": [ [ 1314, 1320 ] ], "normalized": [] }, { "id": "17704420_T12", "type": "GENE-N", "text": [ "H131R" ], "offsets": [ [ 1321, 1326 ] ], "normalized": [] }, { "id": "17704420_T13", "type": "GENE-Y", "text": [ "FCGR3A" ], "offsets": [ [ 1331, 1337 ] ], "normalized": [] }, { "id": "17704420_T14", "type": "GENE-N", "text": [ "V158F" ], "offsets": [ [ 1338, 1343 ] ], "normalized": [] }, { "id": "17704420_T15", "type": "GENE-Y", "text": [ "FCGR2A" ], "offsets": [ [ 1570, 1576 ] ], "normalized": [] }, { "id": "17704420_T16", "type": "GENE-Y", "text": [ "FCGR3A" ], "offsets": [ [ 1604, 1610 ] ], "normalized": [] }, { "id": "17704420_T17", "type": "GENE-Y", "text": [ "FCGR2A" ], "offsets": [ [ 1754, 1760 ] ], "normalized": [] }, { "id": "17704420_T18", "type": "GENE-Y", "text": [ "immunoglobulin G 1" ], "offsets": [ [ 218, 236 ] ], "normalized": [] }, { "id": "17704420_T19", "type": "GENE-Y", "text": [ "IgG1" ], "offsets": [ [ 563, 567 ] ], "normalized": [] }, { "id": "17704420_T20", "type": "GENE-N", "text": [ "Fragment c gamma receptors" ], "offsets": [ [ 598, 624 ] ], "normalized": [] }, { "id": "17704420_T21", "type": "GENE-N", "text": [ "FcgammaR" ], "offsets": [ [ 626, 634 ] ], "normalized": [] }, { "id": "17704420_T22", "type": "GENE-Y", "text": [ "IgG1" ], "offsets": [ [ 238, 242 ] ], "normalized": [] }, { "id": "17704420_T23", "type": "GENE-N", "text": [ "IgG" ], "offsets": [ [ 707, 710 ] ], "normalized": [] }, { "id": "17704420_T24", "type": "GENE-N", "text": [ "FcgammaR" ], "offsets": [ [ 711, 719 ] ], "normalized": [] }, { "id": "17704420_T25", "type": "GENE-Y", "text": [ "FCGR2A" ], "offsets": [ [ 735, 741 ] ], "normalized": [] }, { "id": "17704420_T26", "type": "GENE-N", "text": [ "H131R" ], "offsets": [ [ 742, 747 ] ], "normalized": [] }, { "id": "17704420_T27", "type": "GENE-Y", "text": [ "FCGR3A" ], "offsets": [ [ 752, 758 ] ], "normalized": [] }, { "id": "17704420_T28", "type": "GENE-N", "text": [ "V158F" ], "offsets": [ [ 759, 764 ] ], "normalized": [] }, { "id": "17704420_T29", "type": "GENE-Y", "text": [ "epidermal growth factor receptor" ], "offsets": [ [ 249, 281 ] ], "normalized": [] }, { "id": "17704420_T30", "type": "GENE-Y", "text": [ "EGFR" ], "offsets": [ [ 283, 287 ] ], "normalized": [] }, { "id": "17704420_T31", "type": "GENE-Y", "text": [ "FCGR2A" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "17704420_T32", "type": "GENE-Y", "text": [ "FCGR3A" ], "offsets": [ [ 11, 17 ] ], "normalized": [] }, { "id": "17704420_T33", "type": "GENE-Y", "text": [ "epidermal growth factor receptor" ], "offsets": [ [ 68, 100 ] ], "normalized": [] } ]

[]

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[ { "id": "21926191_title", "type": "title", "text": [ "Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth." ], "offsets": [ [ 0, 125 ] ] }, { "id": "21926191_abstract", "type": "abstract", "text": [ "The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling." ], "offsets": [ [ 126, 1607 ] ] } ]

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[]

[]

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[ { "id": "2922761_title", "type": "title", "text": [ "Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K." ], "offsets": [ [ 0, 89 ] ] }, { "id": "2922761_abstract", "type": "abstract", "text": [ "The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on prothrombin times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated prothrombin times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in prothrombin times. In the high-dose ROAc group, there was a twofold increase in prothrombin times but only after prolonged dosing. In animals fed the NIH-07 diets, 13cisRA and ROAc induced multiple bone fractures at all dose levels. In contrast, 4HPR administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in prothrombin times occured as early as 1 week. The order of effect was 4HPR greater than ROAc greater than 13cisRA, with increases in prothrombin times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. 13cisRA and ROAc, but not 4HPR, caused a dose-dependent reduction in plasma osteocalcin, an effect that correlated with retinoid-induced bone effects. In contrast, serum alkaline phosphatase was elevated in animals dosed with 13cisRA or 4HPR but not in those dose with ROAc. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma osteocalcin is a better predictor of retinoid-induced bone effects than serum alkaline phosphatase." ], "offsets": [ [ 90, 2533 ] ] } ]

[ { "id": "2922761_T1", "type": "CHEMICAL", "text": [ "13cisRA" ], "offsets": [ [ 1199, 1206 ] ], "normalized": [] }, { "id": "2922761_T2", "type": "CHEMICAL", "text": [ "ROAc" ], "offsets": [ [ 1211, 1215 ] ], "normalized": [] }, { "id": "2922761_T3", "type": "CHEMICAL", "text": [ "4HPR" ], "offsets": [ [ 1281, 1285 ] ], "normalized": [] }, { "id": "2922761_T4", "type": "CHEMICAL", "text": [ "retinoid" ], "offsets": [ [ 1578, 1586 ] ], "normalized": [] }, { "id": "2922761_T5", "type": "CHEMICAL", "text": [ "4HPR" ], "offsets": [ [ 1714, 1718 ] ], "normalized": [] }, { "id": "2922761_T6", "type": "CHEMICAL", "text": [ "ROAc" ], "offsets": [ [ 1732, 1736 ] ], "normalized": [] }, { "id": "2922761_T7", "type": "CHEMICAL", "text": [ "13cisRA" ], "offsets": [ [ 1750, 1757 ] ], "normalized": [] }, { "id": "2922761_T8", "type": "CHEMICAL", "text": [ "retinoid" ], "offsets": [ [ 1866, 1874 ] ], "normalized": [] }, { "id": "2922761_T9", "type": "CHEMICAL", "text": [ "vitamin K" ], "offsets": [ [ 1961, 1970 ] ], "normalized": [] }, { "id": "2922761_T10", "type": "CHEMICAL", "text": [ "vitamin K" ], "offsets": [ [ 278, 287 ] ], "normalized": [] }, { "id": "2922761_T11", "type": "CHEMICAL", "text": [ "13cisRA" ], "offsets": [ [ 1991, 1998 ] ], "normalized": [] }, { "id": "2922761_T12", "type": "CHEMICAL", "text": [ "ROAc" ], "offsets": [ [ 2003, 2007 ] ], "normalized": [] }, { "id": "2922761_T13", "type": "CHEMICAL", "text": [ "4HPR" ], "offsets": [ [ 2017, 2021 ] ], "normalized": [] }, { "id": "2922761_T14", "type": "CHEMICAL", "text": [ "retinoid" ], "offsets": [ [ 2111, 2119 ] ], "normalized": [] }, { "id": "2922761_T15", "type": "CHEMICAL", "text": [ "13cisRA" ], "offsets": [ [ 2217, 2224 ] ], "normalized": [] }, { "id": "2922761_T16", "type": "CHEMICAL", "text": [ "4HPR" ], "offsets": [ [ 2228, 2232 ] ], "normalized": [] }, { "id": "2922761_T17", "type": "CHEMICAL", "text": [ "ROAc" ], "offsets": [ [ 2260, 2264 ] ], "normalized": [] }, { "id": "2922761_T18", "type": "CHEMICAL", "text": [ "ROAc" ], "offsets": [ [ 2400, 2404 ] ], "normalized": [] }, { "id": "2922761_T19", "type": "CHEMICAL", "text": [ "retinoid" ], "offsets": [ [ 2471, 2479 ] ], "normalized": [] }, { "id": "2922761_T20", "type": "CHEMICAL", "text": [ "13-cis-retinoic acid" ], "offsets": [ [ 332, 352 ] ], "normalized": [] }, { "id": "2922761_T21", "type": "CHEMICAL", "text": [ "13cisRA" ], "offsets": [ [ 354, 361 ] ], "normalized": [] }, { "id": "2922761_T22", "type": "CHEMICAL", "text": [ "retinyl acetate" ], "offsets": [ [ 364, 379 ] ], "normalized": [] }, { "id": "2922761_T23", "type": "CHEMICAL", "text": [ "ROAc" ], "offsets": [ [ 381, 385 ] ], "normalized": [] }, { "id": "2922761_T24", "type": "CHEMICAL", "text": [ "N-(4-hydroxyphenyl)retinamide" ], "offsets": [ [ 392, 421 ] ], "normalized": [] }, { "id": "2922761_T25", "type": "CHEMICAL", "text": [ "4HPR" ], "offsets": [ [ 423, 427 ] ], "normalized": [] }, { "id": "2922761_T26", "type": "CHEMICAL", "text": [ "vitamin K" ], "offsets": [ [ 508, 517 ] ], "normalized": [] }, { "id": "2922761_T27", "type": "CHEMICAL", "text": [ "menadione" ], "offsets": [ [ 576, 585 ] ], "normalized": [] }, { "id": "2922761_T28", "type": "CHEMICAL", "text": [ "vitamin K3" ], "offsets": [ [ 595, 605 ] ], "normalized": [] }, { "id": "2922761_T29", "type": "CHEMICAL", "text": [ "vitamin A" ], "offsets": [ [ 143, 152 ] ], "normalized": [] }, { "id": "2922761_T30", "type": "CHEMICAL", "text": [ "menadione" ], "offsets": [ [ 645, 654 ] ], "normalized": [] }, { "id": "2922761_T31", "type": "CHEMICAL", "text": [ "vitamin K" ], "offsets": [ [ 694, 703 ] ], "normalized": [] }, { "id": "2922761_T32", "type": "CHEMICAL", "text": [ "retinoids" ], "offsets": [ [ 709, 718 ] ], "normalized": [] }, { "id": "2922761_T33", "type": "CHEMICAL", "text": [ "menadione" ], "offsets": [ [ 797, 806 ] ], "normalized": [] }, { "id": "2922761_T34", "type": "CHEMICAL", "text": [ "4HPR" ], "offsets": [ [ 843, 847 ] ], "normalized": [] }, { "id": "2922761_T35", "type": "CHEMICAL", "text": [ "13cisRA" ], "offsets": [ [ 993, 1000 ] ], "normalized": [] }, { "id": "2922761_T36", "type": "CHEMICAL", "text": [ "ROAc" ], "offsets": [ [ 1071, 1075 ] ], "normalized": [] }, { "id": "2922761_T37", "type": "CHEMICAL", "text": [ "Retinoid" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "2922761_T38", "type": "CHEMICAL", "text": [ "vitamin K" ], "offsets": [ [ 79, 88 ] ], "normalized": [] }, { "id": "2922761_T39", "type": "GENE-Y", "text": [ "prothrombin" ], "offsets": [ [ 1115, 1126 ] ], "normalized": [] }, { "id": "2922761_T40", "type": "GENE-Y", "text": [ "prothrombin" ], "offsets": [ [ 1644, 1655 ] ], "normalized": [] }, { "id": "2922761_T41", "type": "GENE-Y", "text": [ "prothrombin" ], "offsets": [ [ 1777, 1788 ] ], "normalized": [] }, { "id": "2922761_T42", "type": "GENE-Y", "text": [ "osteocalcin" ], "offsets": [ [ 2067, 2078 ] ], "normalized": [] }, { "id": "2922761_T43", "type": "GENE-N", "text": [ "alkaline phosphatase" ], "offsets": [ [ 2161, 2181 ] ], "normalized": [] }, { "id": "2922761_T44", "type": "GENE-Y", "text": [ "osteocalcin" ], "offsets": [ [ 2434, 2445 ] ], "normalized": [] }, { "id": "2922761_T45", "type": "GENE-N", "text": [ "alkaline phosphatase" ], "offsets": [ [ 2512, 2532 ] ], "normalized": [] }, { "id": "2922761_T46", "type": "GENE-Y", "text": [ "prothrombin" ], "offsets": [ [ 736, 747 ] ], "normalized": [] }, { "id": "2922761_T47", "type": "GENE-Y", "text": [ "prothrombin" ], "offsets": [ [ 875, 886 ] ], "normalized": [] }, { "id": "2922761_T48", "type": "GENE-Y", "text": [ "prothrombin" ], "offsets": [ [ 1035, 1046 ] ], "normalized": [] } ]

[]

[]

[ { "id": "2922761_0", "type": "INDIRECT-UPREGULATOR", "arg1_id": "2922761_T34", "arg2_id": "2922761_T47", "normalized": [] }, { "id": "2922761_1", "type": "INDIRECT-UPREGULATOR", "arg1_id": "2922761_T36", "arg2_id": "2922761_T39", "normalized": [] }, { "id": "2922761_2", "type": "INDIRECT-UPREGULATOR", "arg1_id": "2922761_T5", "arg2_id": "2922761_T41", "normalized": [] }, { "id": "2922761_3", "type": "INDIRECT-UPREGULATOR", "arg1_id": "2922761_T6", "arg2_id": "2922761_T41", "normalized": [] }, { "id": "2922761_4", "type": "INDIRECT-UPREGULATOR", "arg1_id": "2922761_T7", "arg2_id": "2922761_T41", "normalized": [] }, { "id": "2922761_5", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "2922761_T11", "arg2_id": "2922761_T42", "normalized": [] }, { "id": "2922761_6", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "2922761_T12", "arg2_id": "2922761_T42", "normalized": [] }, { "id": "2922761_7", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "2922761_T13", "arg2_id": "2922761_T42", "normalized": [] }, { "id": "2922761_8", "type": "INDIRECT-UPREGULATOR", "arg1_id": "2922761_T15", "arg2_id": "2922761_T43", "normalized": [] }, { "id": "2922761_9", "type": "INDIRECT-UPREGULATOR", "arg1_id": "2922761_T16", "arg2_id": "2922761_T43", "normalized": [] } ]

[ { "id": "23087261_title", "type": "title", "text": [ "Lysine 48-linked polyubiquitination of organic anion transporter-1 is essential for its protein kinase C-regulated endocytosis." ], "offsets": [ [ 0, 127 ] ] }, { "id": "23087261_abstract", "type": "abstract", "text": [ "Organic anion transporter-1 (OAT1) mediates the body's disposition of a diverse array of environmental toxins and clinically important drugs. Therefore, understanding the regulation of this transporter has profound clinical significance. We had previously established that OAT1 undergoes constitutive internalization from and recycling back to the cell surface and that acute activation of protein kinase C (PKC) inhibits OAT1 activity by reducing OAT1 cell-surface expression through accelerating its internalization from cell surface to intracellular compartments. However, the underlying mechanisms are poorly understood. In the current study, we provide novel evidence that acute activation of PKC significantly enhances OAT1 ubiquitination both in vitro and ex vivo. We further show that ubiquitination of cell-surface OAT1 increases in cells transfected with dominant negative mutant of dynamin-2, a maneuver blocking OAT1 internalization, which suggests that OAT1 ubiquitination proceeds before OAT1 internalization. Mass spectroscopy has revealed that ubiquitination of OAT1 consists of polyubiquitin chains, primarily through lysine 48 linkage. Transfection of cells with the dominant negative mutant of ubiquitin Ub-K48R, which prevents the formation of Lys48-linked polyubiquitin chains, abolishes PKC-stimulated OAT1 ubiquitination and internalization. Together, our findings demonstrate for the first time that Lys48-linked polyubiquitination is essential for PKC-regulated OAT1 trafficking." ], "offsets": [ [ 128, 1632 ] ] } ]

[ { "id": "23087261_T1", "type": "CHEMICAL", "text": [ "lysine" ], "offsets": [ [ 1263, 1269 ] ], "normalized": [] }, { "id": "23087261_T2", "type": "CHEMICAL", "text": [ "Lys" ], "offsets": [ [ 1392, 1395 ] ], "normalized": [] }, { "id": "23087261_T3", "type": "CHEMICAL", "text": [ "Lys" ], "offsets": [ [ 1552, 1555 ] ], "normalized": [] }, { "id": "23087261_T4", "type": "CHEMICAL", "text": [ "Lysine" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "23087261_T5", "type": "GENE-Y", "text": [ "Organic anion transporter-1" ], "offsets": [ [ 128, 155 ] ], "normalized": [] }, { "id": "23087261_T6", "type": "GENE-Y", "text": [ "OAT1" ], "offsets": [ [ 1130, 1134 ] ], "normalized": [] }, { "id": "23087261_T7", "type": "GENE-Y", "text": [ "OAT1" ], "offsets": [ [ 1206, 1210 ] ], "normalized": [] }, { "id": "23087261_T8", "type": "GENE-N", "text": [ "PKC" ], "offsets": [ [ 1437, 1440 ] ], "normalized": [] }, { "id": "23087261_T9", "type": "GENE-Y", "text": [ "OAT1" ], "offsets": [ [ 1452, 1456 ] ], "normalized": [] }, { "id": "23087261_T10", "type": "GENE-N", "text": [ "PKC" ], "offsets": [ [ 1601, 1604 ] ], "normalized": [] }, { "id": "23087261_T11", "type": "GENE-Y", "text": [ "OAT1" ], "offsets": [ [ 1615, 1619 ] ], "normalized": [] }, { "id": "23087261_T12", "type": "GENE-Y", "text": [ "OAT1" ], "offsets": [ [ 401, 405 ] ], "normalized": [] }, { "id": "23087261_T13", "type": "GENE-Y", "text": [ "OAT1" ], "offsets": [ [ 157, 161 ] ], "normalized": [] }, { "id": "23087261_T14", "type": "GENE-N", "text": [ "protein kinase C" ], "offsets": [ [ 518, 534 ] ], "normalized": [] }, { "id": "23087261_T15", "type": "GENE-N", "text": [ "PKC" ], "offsets": [ [ 536, 539 ] ], "normalized": [] }, { "id": "23087261_T16", "type": "GENE-Y", "text": [ "OAT1" ], "offsets": [ [ 550, 554 ] ], "normalized": [] }, { "id": "23087261_T17", "type": "GENE-Y", "text": [ "OAT1" ], "offsets": [ [ 576, 580 ] ], "normalized": [] }, { "id": "23087261_T18", "type": "GENE-N", "text": [ "PKC" ], "offsets": [ [ 826, 829 ] ], "normalized": [] }, { "id": "23087261_T19", "type": "GENE-Y", "text": [ "OAT1" ], "offsets": [ [ 853, 857 ] ], "normalized": [] }, { "id": "23087261_T20", "type": "GENE-Y", "text": [ "OAT1" ], "offsets": [ [ 952, 956 ] ], "normalized": [] }, { "id": "23087261_T21", "type": "GENE-Y", "text": [ "dynamin-2" ], "offsets": [ [ 1021, 1030 ] ], "normalized": [] }, { "id": "23087261_T22", "type": "GENE-Y", "text": [ "OAT1" ], "offsets": [ [ 1052, 1056 ] ], "normalized": [] }, { "id": "23087261_T23", "type": "GENE-Y", "text": [ "OAT1" ], "offsets": [ [ 1094, 1098 ] ], "normalized": [] }, { "id": "23087261_T24", "type": "GENE-Y", "text": [ "organic anion transporter-1" ], "offsets": [ [ 39, 66 ] ], "normalized": [] }, { "id": "23087261_T25", "type": "GENE-N", "text": [ "protein kinase C" ], "offsets": [ [ 88, 104 ] ], "normalized": [] } ]

[]

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[]

[ { "id": "18408530_title", "type": "title", "text": [ "Clinical evidence for serotonin and norepinephrine reuptake inhibition of duloxetine." ], "offsets": [ [ 0, 85 ] ] }, { "id": "18408530_abstract", "type": "abstract", "text": [ "Most antidepressants in clinical use are believed to function by enhancing neurotransmission of serotonin [5-hydroxytryptamine (5-HT)] and/or norepinephrine (NE) via inhibition of neurotransmitter reuptake. Agents that affect reuptake of both 5-HT and NE (serotonin-norepinephrine reuptake inhibitors) have been postulated to offer greater efficacy for the treatment of major depressive disorder (MDD). These dual-acting agents also display a broader spectrum of action, including efficacy for MDD and associated painful physical symptoms, diabetic peripheral neuropathic pain, generalized anxiety disorder, and fibromyalgia syndrome. Substantial preclinical evidence shows that duloxetine, an approved drug for the treatment of MDD, generalized anxiety disorder, and the management of diabetic peripheral neuropathic pain, inhibits reuptake of both 5-HT and NE. This paper reviews clinical and neurochemical evidence of duloxetine's effects on 5-HT and NE reuptake inhibition. The clinical evidence supporting duloxetine's effects on NE reuptake inhibition includes indirect measures such as altered excretion of NE metabolites, cardiovascular effects, and treatment-emergent adverse event profiles similar to those for other drugs believed to act through the inhibition of NE reuptake. In summary, the data presented in this report provide clinical evidence of a mechanism for duloxetine involving both 5-HT and NE reuptake inhibition in humans and are consistent with preclinical evidence for 5-HT/NE reuptake inhibition." ], "offsets": [ [ 86, 1610 ] ] } ]

[ { "id": "18408530_T1", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 1121, 1123 ] ], "normalized": [] }, { "id": "18408530_T2", "type": "CHEMICAL", "text": [ "5-hydroxytryptamine" ], "offsets": [ [ 193, 212 ] ], "normalized": [] }, { "id": "18408530_T3", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 1200, 1202 ] ], "normalized": [] }, { "id": "18408530_T4", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 1361, 1363 ] ], "normalized": [] }, { "id": "18408530_T5", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 214, 218 ] ], "normalized": [] }, { "id": "18408530_T6", "type": "CHEMICAL", "text": [ "duloxetine" ], "offsets": [ [ 1465, 1475 ] ], "normalized": [] }, { "id": "18408530_T7", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 1491, 1495 ] ], "normalized": [] }, { "id": "18408530_T8", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 1500, 1502 ] ], "normalized": [] }, { "id": "18408530_T9", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 228, 242 ] ], "normalized": [] }, { "id": "18408530_T10", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 1582, 1586 ] ], "normalized": [] }, { "id": "18408530_T11", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 1587, 1589 ] ], "normalized": [] }, { "id": "18408530_T12", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 244, 246 ] ], "normalized": [] }, { "id": "18408530_T13", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 329, 333 ] ], "normalized": [] }, { "id": "18408530_T14", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 338, 340 ] ], "normalized": [] }, { "id": "18408530_T15", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 342, 351 ] ], "normalized": [] }, { "id": "18408530_T16", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 352, 366 ] ], "normalized": [] }, { "id": "18408530_T17", "type": "CHEMICAL", "text": [ "duloxetine" ], "offsets": [ [ 765, 775 ] ], "normalized": [] }, { "id": "18408530_T18", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 936, 940 ] ], "normalized": [] }, { "id": "18408530_T19", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 945, 947 ] ], "normalized": [] }, { "id": "18408530_T20", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 1031, 1035 ] ], "normalized": [] }, { "id": "18408530_T21", "type": "CHEMICAL", "text": [ "NE" ], "offsets": [ [ 1040, 1042 ] ], "normalized": [] }, { "id": "18408530_T22", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 182, 191 ] ], "normalized": [] }, { "id": "18408530_T23", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 22, 31 ] ], "normalized": [] }, { "id": "18408530_T24", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 36, 50 ] ], "normalized": [] }, { "id": "18408530_T25", "type": "CHEMICAL", "text": [ "duloxetine" ], "offsets": [ [ 74, 84 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "22585533_title", "type": "title", "text": [ "β-Eudesmol induces JNK-dependent apoptosis through the mitochondrial pathway in HL60 cells." ], "offsets": [ [ 0, 91 ] ] }, { "id": "22585533_abstract", "type": "abstract", "text": [ "β-eudesmol, a natural sesquiterpenol present in a variety of Chinese herbs, is known to inhibit the proliferation of human tumor cells. However, the molecular mechanisms of the effect of β-eudesmol on human tumor cells are unknown. In the present study, we report the cytotoxic effect of β-eudesmol on the human leukemia HL60 cells and its molecular mechanisms. The cytotoxic effect of β-eudesmol on HL60 cells was associated with apoptosis, which was characterized by the presence of DNA fragmentation. β-eudesmol-induced apoptosis was accompanied by cleavage of caspase-3, caspase-9, and poly (ADP-ribose) polymerase; downregulation of Bcl-2 expression; release of cytochrome c from mitochondria; and decrease in mitochondrial membrane potential (MMP). Activation of c-Jun N-terminal kinases (JNK) mitogen-activated protein kinases was observed in β-eudesmol-treated HL60 cells, and the inhibitor of JNK blocked the β-eudesmol-induced apoptosis, downregulation of Bcl-2, and the loss of MMP. These data suggest that β-eudesmol induces apoptosis in HL60 cells via the mitochondrial apoptotic pathway, which is controlled through JNK signaling. Copyright © 2012 John Wiley & Sons, Ltd." ], "offsets": [ [ 92, 1277 ] ] } ]

[ { "id": "22585533_T1", "type": "CHEMICAL", "text": [ "β-eudesmol" ], "offsets": [ [ 92, 102 ] ], "normalized": [] }, { "id": "22585533_T2", "type": "CHEMICAL", "text": [ "β-eudesmol" ], "offsets": [ [ 1110, 1120 ] ], "normalized": [] }, { "id": "22585533_T3", "type": "CHEMICAL", "text": [ "β-eudesmol" ], "offsets": [ [ 279, 289 ] ], "normalized": [] }, { "id": "22585533_T4", "type": "CHEMICAL", "text": [ "sesquiterpenol" ], "offsets": [ [ 114, 128 ] ], "normalized": [] }, { "id": "22585533_T5", "type": "CHEMICAL", "text": [ "β-eudesmol" ], "offsets": [ [ 380, 390 ] ], "normalized": [] }, { "id": "22585533_T6", "type": "CHEMICAL", "text": [ "β-eudesmol" ], "offsets": [ [ 478, 488 ] ], "normalized": [] }, { "id": "22585533_T7", "type": "CHEMICAL", "text": [ "β-eudesmol" ], "offsets": [ [ 596, 606 ] ], "normalized": [] }, { "id": "22585533_T8", "type": "CHEMICAL", "text": [ "poly (ADP-ribose)" ], "offsets": [ [ 682, 699 ] ], "normalized": [] }, { "id": "22585533_T9", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 867, 868 ] ], "normalized": [] }, { "id": "22585533_T10", "type": "CHEMICAL", "text": [ "β-eudesmol" ], "offsets": [ [ 942, 952 ] ], "normalized": [] }, { "id": "22585533_T11", "type": "CHEMICAL", "text": [ "β-eudesmol" ], "offsets": [ [ 1010, 1020 ] ], "normalized": [] }, { "id": "22585533_T12", "type": "CHEMICAL", "text": [ "β-Eudesmol" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "22585533_T13", "type": "GENE-N", "text": [ "JNK" ], "offsets": [ [ 1222, 1225 ] ], "normalized": [] }, { "id": "22585533_T14", "type": "GENE-Y", "text": [ "caspase-3" ], "offsets": [ [ 656, 665 ] ], "normalized": [] }, { "id": "22585533_T15", "type": "GENE-Y", "text": [ "caspase-9" ], "offsets": [ [ 667, 676 ] ], "normalized": [] }, { "id": "22585533_T16", "type": "GENE-N", "text": [ "poly (ADP-ribose) polymerase" ], "offsets": [ [ 682, 710 ] ], "normalized": [] }, { "id": "22585533_T17", "type": "GENE-Y", "text": [ "Bcl-2" ], "offsets": [ [ 730, 735 ] ], "normalized": [] }, { "id": "22585533_T18", "type": "GENE-Y", "text": [ "cytochrome c" ], "offsets": [ [ 759, 771 ] ], "normalized": [] }, { "id": "22585533_T19", "type": "GENE-N", "text": [ "c-Jun N-terminal kinases" ], "offsets": [ [ 861, 885 ] ], "normalized": [] }, { "id": "22585533_T20", "type": "GENE-N", "text": [ "JNK" ], "offsets": [ [ 887, 890 ] ], "normalized": [] }, { "id": "22585533_T21", "type": "GENE-N", "text": [ "mitogen-activated protein kinases" ], "offsets": [ [ 892, 925 ] ], "normalized": [] }, { "id": "22585533_T22", "type": "GENE-N", "text": [ "JNK" ], "offsets": [ [ 994, 997 ] ], "normalized": [] }, { "id": "22585533_T23", "type": "GENE-Y", "text": [ "Bcl-2" ], "offsets": [ [ 1058, 1063 ] ], "normalized": [] }, { "id": "22585533_T24", "type": "GENE-N", "text": [ "JNK" ], "offsets": [ [ 19, 22 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23613149_title", "type": "title", "text": [ "Dietary Flaxseed Oil Supplementation Mitigates the Effect of Lead on the Enzymes of Carbohydrate Metabolism, Brush Border Membrane, and Oxidative Stress in Rat Kidney Tissues." ], "offsets": [ [ 0, 175 ] ] }, { "id": "23613149_abstract", "type": "abstract", "text": [ "Lead is a heavy metal widely distributed in the environment. Lead is a ubiquitous environmental toxin that is capable of causing numerous acute and chronic illnesses. Human and animal exposure demonstrates that lead is nephrotoxic. However, attempts to reduce lead-induced nephrotoxicity were not found suitable for clinical use. Recently, flaxseed oil (FXO), a rich source of ω-3 fatty acids and lignans, has been shown to prevent/reduce the progression of certain types of cardiovascular and renal disorders. In view of this, the present study investigates the protective effect of FXO on lead acetate (PbAc)-induced renal damage. Rats were pre-fed normal diet and the diet rich in FXO for 14 days, and then, four doses of lead acetate (25 mg/kg body weight) were administered intraperitoneally while still on diet. Various serum parameters, enzymes of carbohydrate metabolism, brush border membrane (BBM), and oxidative stress were analyzed in rat kidney. PbAc nephrotoxicity was characterized by increased serum creatinine and blood urea nitrogen. PbAc increased the activities of lactate dehydrogenase and NADP-malic enzyme, whereas it decreased malate and glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1, 6-bisphosphatase, and BBM enzyme activities. PbAc caused oxidant/antioxidant imbalances as reflected by increased lipid peroxidation and decreased activities of superoxide dismutase, glutathione peroxidase, and catalase. In contrast, FXO alone enhanced the enzyme activities of carbohydrate metabolism, BBM, and antioxidant defense system. FXO feeding to PbAc-treated rats markedly enhanced resistance to PbAc-elicited deleterious effects. In conclusion, dietary FXO supplementation ameliorated PbAc-induced specific metabolic alterations and oxidative damage by empowering antioxidant defense mechanism and improving BBM integrity and energy metabolism." ], "offsets": [ [ 176, 2062 ] ] } ]

[ { "id": "23613149_T1", "type": "CHEMICAL", "text": [ "creatinine" ], "offsets": [ [ 1192, 1202 ] ], "normalized": [] }, { "id": "23613149_T2", "type": "CHEMICAL", "text": [ "urea" ], "offsets": [ [ 1213, 1217 ] ], "normalized": [] }, { "id": "23613149_T3", "type": "CHEMICAL", "text": [ "nitrogen" ], "offsets": [ [ 1218, 1226 ] ], "normalized": [] }, { "id": "23613149_T4", "type": "CHEMICAL", "text": [ "PbAc" ], "offsets": [ [ 1228, 1232 ] ], "normalized": [] }, { "id": "23613149_T5", "type": "CHEMICAL", "text": [ "lactate" ], "offsets": [ [ 1261, 1268 ] ], "normalized": [] }, { "id": "23613149_T6", "type": "CHEMICAL", "text": [ "NADP" ], "offsets": [ [ 1287, 1291 ] ], "normalized": [] }, { "id": "23613149_T7", "type": "CHEMICAL", "text": [ "malate" ], "offsets": [ [ 1327, 1333 ] ], "normalized": [] }, { "id": "23613149_T8", "type": "CHEMICAL", "text": [ "glucose-6-phosphate" ], "offsets": [ [ 1338, 1357 ] ], "normalized": [] }, { "id": "23613149_T9", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 1373, 1380 ] ], "normalized": [] }, { "id": "23613149_T10", "type": "CHEMICAL", "text": [ "fructose" ], "offsets": [ [ 1396, 1404 ] ], "normalized": [] }, { "id": "23613149_T11", "type": "CHEMICAL", "text": [ "PbAc" ], "offsets": [ [ 1453, 1457 ] ], "normalized": [] }, { "id": "23613149_T12", "type": "CHEMICAL", "text": [ "superoxide" ], "offsets": [ [ 1569, 1579 ] ], "normalized": [] }, { "id": "23613149_T13", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 1591, 1602 ] ], "normalized": [] }, { "id": "23613149_T14", "type": "CHEMICAL", "text": [ "carbohydrate" ], "offsets": [ [ 1686, 1698 ] ], "normalized": [] }, { "id": "23613149_T15", "type": "CHEMICAL", "text": [ "PbAc" ], "offsets": [ [ 1763, 1767 ] ], "normalized": [] }, { "id": "23613149_T16", "type": "CHEMICAL", "text": [ "PbAc" ], "offsets": [ [ 1813, 1817 ] ], "normalized": [] }, { "id": "23613149_T17", "type": "CHEMICAL", "text": [ "PbAc" ], "offsets": [ [ 1903, 1907 ] ], "normalized": [] }, { "id": "23613149_T18", "type": "CHEMICAL", "text": [ "ω-3 fatty acids" ], "offsets": [ [ 553, 568 ] ], "normalized": [] }, { "id": "23613149_T19", "type": "CHEMICAL", "text": [ "lignans" ], "offsets": [ [ 573, 580 ] ], "normalized": [] }, { "id": "23613149_T20", "type": "CHEMICAL", "text": [ "lead acetate" ], "offsets": [ [ 767, 779 ] ], "normalized": [] }, { "id": "23613149_T21", "type": "CHEMICAL", "text": [ "PbAc" ], "offsets": [ [ 781, 785 ] ], "normalized": [] }, { "id": "23613149_T22", "type": "CHEMICAL", "text": [ "lead acetate" ], "offsets": [ [ 901, 913 ] ], "normalized": [] }, { "id": "23613149_T23", "type": "CHEMICAL", "text": [ "carbohydrate" ], "offsets": [ [ 1031, 1043 ] ], "normalized": [] }, { "id": "23613149_T24", "type": "CHEMICAL", "text": [ "PbAc" ], "offsets": [ [ 1135, 1139 ] ], "normalized": [] }, { "id": "23613149_T25", "type": "CHEMICAL", "text": [ "Carbohydrate" ], "offsets": [ [ 84, 96 ] ], "normalized": [] }, { "id": "23613149_T26", "type": "GENE-N", "text": [ "lactate dehydrogenase" ], "offsets": [ [ 1261, 1282 ] ], "normalized": [] }, { "id": "23613149_T27", "type": "GENE-N", "text": [ "NADP-malic enzyme" ], "offsets": [ [ 1287, 1304 ] ], "normalized": [] }, { "id": "23613149_T28", "type": "GENE-N", "text": [ "malate and glucose-6-phosphate dehydrogenase" ], "offsets": [ [ 1327, 1371 ] ], "normalized": [] }, { "id": "23613149_T29", "type": "GENE-Y", "text": [ "glucose-6-phosphatase" ], "offsets": [ [ 1373, 1394 ] ], "normalized": [] }, { "id": "23613149_T30", "type": "GENE-N", "text": [ "fructose-1, 6-bisphosphatase" ], "offsets": [ [ 1396, 1424 ] ], "normalized": [] }, { "id": "23613149_T31", "type": "GENE-N", "text": [ "superoxide dismutase" ], "offsets": [ [ 1569, 1589 ] ], "normalized": [] }, { "id": "23613149_T32", "type": "GENE-N", "text": [ "glutathione peroxidase" ], "offsets": [ [ 1591, 1613 ] ], "normalized": [] }, { "id": "23613149_T33", "type": "GENE-Y", "text": [ "catalase" ], "offsets": [ [ 1619, 1627 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23454149_title", "type": "title", "text": [ "Inhibition of angiogenesis and invasion by DMBT is mediated by downregulation of VEGF and MMP-9 through Akt pathway in MDA-MB-231 breast cancer cells." ], "offsets": [ [ 0, 150 ] ] }, { "id": "23454149_abstract", "type": "abstract", "text": [ "Invasion, either directly or via metastasis formation, is the main cause of death in cancer patients, development of efficient anti-invasive agents is an important research challenge. In order to obtain more potent inhibitors, a series of brartemicin analogs were synthesized and evaluated for their inhibitory activity against invasion. Among the synthetic analogs tested, DMBT, 6,6'-bis (2,3-dimethoxybenzoyl)-a,a-d-trehalose, was found to be the most potent anti-invasive agent. But the effects of DMBT on breast cancer cells were not known. In this study, the effects of DMBT on invasion and metastasis in MDA-MB-231 cells were investigated. MTT assay showed that no obvious inhibitory or cytotoxic effect of DMBT was found. DMBT could inhibit invasion, migration and tube formation of HUVECs. Gelatin zymography showed that DMBT inhibited secretion and activity of MMP-9. Western blotting demonstrated that DMBT effectively suppressed the expression of VEGF, p-VEGFR-2, p-EGFR, and p-Akt. These results suggested that DMBT could inhibit invasion and angiogenesis by downregulation of VEGFand MMP-9, resulting from the inhibition of Akt pathway. DMBT might be a promising lead molecule for the anti-metastasis and serve as a therapeutic agent to inhibit breast cancer cell invasion and metastasis." ], "offsets": [ [ 151, 1452 ] ] } ]

[ { "id": "23454149_T1", "type": "CHEMICAL", "text": [ "DMBT" ], "offsets": [ [ 1174, 1178 ] ], "normalized": [] }, { "id": "23454149_T2", "type": "CHEMICAL", "text": [ "DMBT" ], "offsets": [ [ 1301, 1305 ] ], "normalized": [] }, { "id": "23454149_T3", "type": "CHEMICAL", "text": [ "brartemicin" ], "offsets": [ [ 390, 401 ] ], "normalized": [] }, { "id": "23454149_T4", "type": "CHEMICAL", "text": [ "DMBT" ], "offsets": [ [ 525, 529 ] ], "normalized": [] }, { "id": "23454149_T5", "type": "CHEMICAL", "text": [ "6,6'-bis (2,3-dimethoxybenzoyl)-a,a-d-trehalose" ], "offsets": [ [ 531, 578 ] ], "normalized": [] }, { "id": "23454149_T6", "type": "CHEMICAL", "text": [ "DMBT" ], "offsets": [ [ 652, 656 ] ], "normalized": [] }, { "id": "23454149_T7", "type": "CHEMICAL", "text": [ "DMBT" ], "offsets": [ [ 726, 730 ] ], "normalized": [] }, { "id": "23454149_T8", "type": "CHEMICAL", "text": [ "MTT" ], "offsets": [ [ 797, 800 ] ], "normalized": [] }, { "id": "23454149_T9", "type": "CHEMICAL", "text": [ "DMBT" ], "offsets": [ [ 864, 868 ] ], "normalized": [] }, { "id": "23454149_T10", "type": "CHEMICAL", "text": [ "DMBT" ], "offsets": [ [ 880, 884 ] ], "normalized": [] }, { "id": "23454149_T11", "type": "CHEMICAL", "text": [ "DMBT" ], "offsets": [ [ 980, 984 ] ], "normalized": [] }, { "id": "23454149_T12", "type": "CHEMICAL", "text": [ "DMBT" ], "offsets": [ [ 1063, 1067 ] ], "normalized": [] }, { "id": "23454149_T13", "type": "CHEMICAL", "text": [ "DMBT" ], "offsets": [ [ 43, 47 ] ], "normalized": [] }, { "id": "23454149_T14", "type": "GENE-N", "text": [ "VEGF" ], "offsets": [ [ 1240, 1244 ] ], "normalized": [] }, { "id": "23454149_T15", "type": "GENE-Y", "text": [ "MMP-9" ], "offsets": [ [ 1248, 1253 ] ], "normalized": [] }, { "id": "23454149_T16", "type": "GENE-N", "text": [ "Akt" ], "offsets": [ [ 1288, 1291 ] ], "normalized": [] }, { "id": "23454149_T17", "type": "GENE-Y", "text": [ "MMP-9" ], "offsets": [ [ 1021, 1026 ] ], "normalized": [] }, { "id": "23454149_T18", "type": "GENE-N", "text": [ "VEGF" ], "offsets": [ [ 1109, 1113 ] ], "normalized": [] }, { "id": "23454149_T19", "type": "GENE-Y", "text": [ "p-VEGFR-2" ], "offsets": [ [ 1115, 1124 ] ], "normalized": [] }, { "id": "23454149_T20", "type": "GENE-Y", "text": [ "p-EGFR" ], "offsets": [ [ 1126, 1132 ] ], "normalized": [] }, { "id": "23454149_T21", "type": "GENE-N", "text": [ "p-Akt" ], "offsets": [ [ 1138, 1143 ] ], "normalized": [] }, { "id": "23454149_T22", "type": "GENE-N", "text": [ "Akt" ], "offsets": [ [ 104, 107 ] ], "normalized": [] }, { "id": "23454149_T23", "type": "GENE-N", "text": [ "VEGF" ], "offsets": [ [ 81, 85 ] ], "normalized": [] }, { "id": "23454149_T24", "type": "GENE-Y", "text": [ "MMP-9" ], "offsets": [ [ 90, 95 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "11067741_title", "type": "title", "text": [ "Stable expression of varied levels of inducible nitric oxide synthase in primary cultures of endothelial cells." ], "offsets": [ [ 0, 111 ] ] }, { "id": "11067741_abstract", "type": "abstract", "text": [ "Nitric oxide (NO*), generated by nitric oxide synthase (NOS II) from immunostimulated cells during infection, plays an important role in host immune defense against microbial invasion. The impact of different rates of NO* production on host cell function has not been defined. Herein, we describe the development of a method to express varied levels of murine NOS II in bovine pulmonary artery endothelial cells. A retroviral vector (pMFGSNOS) encoding NOS II was used to transduce primary cultures of endothelial cells. Bovine endothelial cells were susceptible to this transduction and up to 18% of the cells expressed immunodetectable murine NOS II. The NOS II-transduced endothelial cells were cultured on the three-dimensional matrix, Gelfoam, for 8-10 days. Stable expression of NOS II was assessed by measuring nitrite accumulation in media every 2 days. By day 10, endothelial cells on Gelfoam were found to secrete NO* at a rate exceeding 1.0 microM/h/10(6) cells, concomitant with an enhanced level of NOS II activity. Argininosuccinate synthetase, a key enzyme in the metabolism of l-citrulline to l-arginine, increased as well, perhaps in response to dimunition of the intracellular arginine pool corresponding to the observed high output of NO*. In spite of the continuous flux of NO*, endothelial cell viability was not effected. This system provides the opportunity to assess the impact of different levels of sustained NO* production on endothelial cell physiology." ], "offsets": [ [ 112, 1593 ] ] } ]

[ { "id": "11067741_T1", "type": "CHEMICAL", "text": [ "Nitric oxide" ], "offsets": [ [ 112, 124 ] ], "normalized": [] }, { "id": "11067741_T2", "type": "CHEMICAL", "text": [ "Argininosuccinate" ], "offsets": [ [ 1141, 1158 ] ], "normalized": [] }, { "id": "11067741_T3", "type": "CHEMICAL", "text": [ "l-citrulline" ], "offsets": [ [ 1205, 1217 ] ], "normalized": [] }, { "id": "11067741_T4", "type": "CHEMICAL", "text": [ "l-arginine" ], "offsets": [ [ 1221, 1231 ] ], "normalized": [] }, { "id": "11067741_T5", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 1366, 1368 ] ], "normalized": [] }, { "id": "11067741_T6", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 1406, 1408 ] ], "normalized": [] }, { "id": "11067741_T7", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 126, 128 ] ], "normalized": [] }, { "id": "11067741_T8", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 1547, 1549 ] ], "normalized": [] }, { "id": "11067741_T9", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 330, 332 ] ], "normalized": [] }, { "id": "11067741_T10", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 145, 157 ] ], "normalized": [] }, { "id": "11067741_T11", "type": "CHEMICAL", "text": [ "nitrite" ], "offsets": [ [ 930, 937 ] ], "normalized": [] }, { "id": "11067741_T12", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 1036, 1038 ] ], "normalized": [] }, { "id": "11067741_T13", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 48, 60 ] ], "normalized": [] }, { "id": "11067741_T14", "type": "GENE-Y", "text": [ "NOS II" ], "offsets": [ [ 1124, 1130 ] ], "normalized": [] }, { "id": "11067741_T15", "type": "GENE-Y", "text": [ "Argininosuccinate synthetase" ], "offsets": [ [ 1141, 1169 ] ], "normalized": [] }, { "id": "11067741_T16", "type": "GENE-N", "text": [ "nitric oxide synthase" ], "offsets": [ [ 145, 166 ] ], "normalized": [] }, { "id": "11067741_T17", "type": "GENE-Y", "text": [ "murine NOS II" ], "offsets": [ [ 465, 478 ] ], "normalized": [] }, { "id": "11067741_T18", "type": "GENE-Y", "text": [ "NOS II" ], "offsets": [ [ 565, 571 ] ], "normalized": [] }, { "id": "11067741_T19", "type": "GENE-Y", "text": [ "NOS II" ], "offsets": [ [ 168, 174 ] ], "normalized": [] }, { "id": "11067741_T20", "type": "GENE-Y", "text": [ "murine NOS II" ], "offsets": [ [ 750, 763 ] ], "normalized": [] }, { "id": "11067741_T21", "type": "GENE-Y", "text": [ "NOS II" ], "offsets": [ [ 769, 775 ] ], "normalized": [] }, { "id": "11067741_T22", "type": "GENE-Y", "text": [ "NOS II" ], "offsets": [ [ 897, 903 ] ], "normalized": [] }, { "id": "11067741_T23", "type": "GENE-Y", "text": [ "inducible nitric oxide synthase" ], "offsets": [ [ 38, 69 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11067741_0", "type": "PRODUCT-OF", "arg1_id": "11067741_T1", "arg2_id": "11067741_T16", "normalized": [] }, { "id": "11067741_1", "type": "PRODUCT-OF", "arg1_id": "11067741_T7", "arg2_id": "11067741_T16", "normalized": [] }, { "id": "11067741_2", "type": "PRODUCT-OF", "arg1_id": "11067741_T1", "arg2_id": "11067741_T19", "normalized": [] }, { "id": "11067741_3", "type": "PRODUCT-OF", "arg1_id": "11067741_T7", "arg2_id": "11067741_T19", "normalized": [] }, { "id": "11067741_4", "type": "PRODUCT-OF", "arg1_id": "11067741_T12", "arg2_id": "11067741_T14", "normalized": [] }, { "id": "11067741_5", "type": "PRODUCT-OF", "arg1_id": "11067741_T11", "arg2_id": "11067741_T22", "normalized": [] }, { "id": "11067741_6", "type": "SUBSTRATE", "arg1_id": "11067741_T3", "arg2_id": "11067741_T15", "normalized": [] }, { "id": "11067741_7", "type": "PRODUCT-OF", "arg1_id": "11067741_T4", "arg2_id": "11067741_T15", "normalized": [] } ]

[ { "id": "23228182_title", "type": "title", "text": [ "Amino acid-based zwitterionic poly(serine methacrylate) as an antifouling material." ], "offsets": [ [ 0, 83 ] ] }, { "id": "23228182_abstract", "type": "abstract", "text": [ "A serine-based zwitterionic poly(serine methacrylate) (pSerMA) was developed in this work to be used as a potential antifouling material. A surface-initiated photoiniferter-mediated polymerization (SI-PIMP) method was used to graft polymer brushes on gold surfaces. The pSerMA-grafted samples with different polymer film thicknesses were readily prepared by varying the UV-irradiation time. With the optimal film thickness, the adsorptions from bovine serum albumin, human serum, and human plasma onto the pSerMA-grafted surfaces, as evaluated by a surface plasmon resonance (SPR) biosensor, were 1.8, 9.2, and 12.9 ng/cm(2), respectively, comparable to the traditional antifouling material such as poly(ethylene glycol). The pSerMA-grafted surfaces also strongly resisted adhesion from bovine aortic endothelial cells. This is the first work to develop an amino acid-based zwitterionic polymer as an antifouling material, demonstrating that pSerMA is a promising alternative to the traditional ethylene glycol-based antifouling materials." ], "offsets": [ [ 84, 1123 ] ] } ]

[ { "id": "23228182_T1", "type": "CHEMICAL", "text": [ "zwitterionic poly(serine methacrylate)" ], "offsets": [ [ 99, 137 ] ], "normalized": [] }, { "id": "23228182_T2", "type": "CHEMICAL", "text": [ "pSerMA" ], "offsets": [ [ 354, 360 ] ], "normalized": [] }, { "id": "23228182_T3", "type": "CHEMICAL", "text": [ "serine" ], "offsets": [ [ 86, 92 ] ], "normalized": [] }, { "id": "23228182_T4", "type": "CHEMICAL", "text": [ "pSerMA" ], "offsets": [ [ 590, 596 ] ], "normalized": [] }, { "id": "23228182_T5", "type": "CHEMICAL", "text": [ "pSerMA" ], "offsets": [ [ 139, 145 ] ], "normalized": [] }, { "id": "23228182_T6", "type": "CHEMICAL", "text": [ "poly(ethylene glycol)" ], "offsets": [ [ 783, 804 ] ], "normalized": [] }, { "id": "23228182_T7", "type": "CHEMICAL", "text": [ "pSerMA" ], "offsets": [ [ 810, 816 ] ], "normalized": [] }, { "id": "23228182_T8", "type": "CHEMICAL", "text": [ "amino acid" ], "offsets": [ [ 941, 951 ] ], "normalized": [] }, { "id": "23228182_T9", "type": "CHEMICAL", "text": [ "pSerMA" ], "offsets": [ [ 1026, 1032 ] ], "normalized": [] }, { "id": "23228182_T10", "type": "CHEMICAL", "text": [ "ethylene glycol" ], "offsets": [ [ 1079, 1094 ] ], "normalized": [] }, { "id": "23228182_T11", "type": "CHEMICAL", "text": [ "Amino acid" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "23228182_T12", "type": "CHEMICAL", "text": [ "zwitterionic poly(serine methacrylate)" ], "offsets": [ [ 17, 55 ] ], "normalized": [] }, { "id": "23228182_T13", "type": "GENE-Y", "text": [ "bovine serum albumin" ], "offsets": [ [ 529, 549 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "22722028_title", "type": "title", "text": [ "Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model." ], "offsets": [ [ 0, 141 ] ] }, { "id": "22722028_abstract", "type": "abstract", "text": [ "Anxiety disorders are characterized by persistent, excessive fear. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We previously reported that 129S1/SvImJ (S1) mice show no extinction learning following normal fear conditioning. We now demonstrate that weak fear conditioning does permit fear reduction during massed extinction training in S1 mice, but reveals specific deficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with d-cycloserine (N-methly-d-aspartate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training. We next examined the ability of different drugs and non-pharmacological manipulations to rescue the extreme fear extinction deficit in S1 following normal fear conditioning with the ultimate aim to produce low fear levels in extinction retrieval tests. Results showed that deep brain stimulation (DBS) by applying high frequency stimulation to the nucleus accumbens (ventral striatum) during extinction training, indeed significantly reduced fear during extinction retrieval compared to sham stimulation controls. Rescue of both impaired extinction acquisition and deficient extinction consolidation/retrieval was achieved with prior extinction training administration of valproic acid (a GABAergic enhancer and HDAC inhibitor) or AMN082 [metabotropic glutamate receptor 7 (mGlu7) agonist], while MS-275 or PEPA (AMPA receptor potentiator) failed to affect extinction acquisition in S1 mice. Collectively, these data identify potential beneficial effects of DBS and various drug treatments, including those with HDAC inhibiting or mGlu7 agonism properties, as adjuncts to overcome treatment resistance in exposure-based therapies. This article is part of a Special Issue entitled 'Cognitive Enhancers'." ], "offsets": [ [ 142, 2065 ] ] } ]

[ { "id": "22722028_T1", "type": "CHEMICAL", "text": [ "valproic acid" ], "offsets": [ [ 1535, 1548 ] ], "normalized": [] }, { "id": "22722028_T2", "type": "CHEMICAL", "text": [ "AMN082" ], "offsets": [ [ 1594, 1600 ] ], "normalized": [] }, { "id": "22722028_T3", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 1615, 1624 ] ], "normalized": [] }, { "id": "22722028_T4", "type": "CHEMICAL", "text": [ "MS-275" ], "offsets": [ [ 1660, 1666 ] ], "normalized": [] }, { "id": "22722028_T5", "type": "CHEMICAL", "text": [ "PEPA" ], "offsets": [ [ 1670, 1674 ] ], "normalized": [] }, { "id": "22722028_T6", "type": "CHEMICAL", "text": [ "AMPA" ], "offsets": [ [ 1676, 1680 ] ], "normalized": [] }, { "id": "22722028_T7", "type": "CHEMICAL", "text": [ "d-cycloserine" ], "offsets": [ [ 725, 738 ] ], "normalized": [] }, { "id": "22722028_T8", "type": "CHEMICAL", "text": [ "N-methly-d-aspartate" ], "offsets": [ [ 740, 760 ] ], "normalized": [] }, { "id": "22722028_T9", "type": "CHEMICAL", "text": [ "MS-275" ], "offsets": [ [ 781, 787 ] ], "normalized": [] }, { "id": "22722028_T10", "type": "GENE-N", "text": [ "HDAC" ], "offsets": [ [ 1575, 1579 ] ], "normalized": [] }, { "id": "22722028_T11", "type": "GENE-Y", "text": [ "metabotropic glutamate receptor 7" ], "offsets": [ [ 1602, 1635 ] ], "normalized": [] }, { "id": "22722028_T12", "type": "GENE-Y", "text": [ "mGlu7" ], "offsets": [ [ 1637, 1642 ] ], "normalized": [] }, { "id": "22722028_T13", "type": "GENE-N", "text": [ "AMPA receptor" ], "offsets": [ [ 1676, 1689 ] ], "normalized": [] }, { "id": "22722028_T14", "type": "GENE-N", "text": [ "HDAC" ], "offsets": [ [ 1875, 1879 ] ], "normalized": [] }, { "id": "22722028_T15", "type": "GENE-Y", "text": [ "mGlu7" ], "offsets": [ [ 1894, 1899 ] ], "normalized": [] }, { "id": "22722028_T16", "type": "GENE-N", "text": [ "histone deacetylase" ], "offsets": [ [ 789, 808 ] ], "normalized": [] }, { "id": "22722028_T17", "type": "GENE-N", "text": [ "HDAC" ], "offsets": [ [ 810, 814 ] ], "normalized": [] }, { "id": "22722028_T18", "type": "GENE-N", "text": [ "histone deacetylase" ], "offsets": [ [ 24, 43 ] ], "normalized": [] } ]

[]

[]

[ { "id": "22722028_0", "type": "INHIBITOR", "arg1_id": "22722028_T9", "arg2_id": "22722028_T16", "normalized": [] }, { "id": "22722028_1", "type": "INHIBITOR", "arg1_id": "22722028_T9", "arg2_id": "22722028_T17", "normalized": [] }, { "id": "22722028_2", "type": "INHIBITOR", "arg1_id": "22722028_T1", "arg2_id": "22722028_T10", "normalized": [] }, { "id": "22722028_3", "type": "AGONIST", "arg1_id": "22722028_T2", "arg2_id": "22722028_T11", "normalized": [] }, { "id": "22722028_4", "type": "AGONIST", "arg1_id": "22722028_T2", "arg2_id": "22722028_T12", "normalized": [] }, { "id": "22722028_5", "type": "ACTIVATOR", "arg1_id": "22722028_T4", "arg2_id": "22722028_T13", "normalized": [] }, { "id": "22722028_6", "type": "ACTIVATOR", "arg1_id": "22722028_T5", "arg2_id": "22722028_T13", "normalized": [] } ]

[ { "id": "23183374_title", "type": "title", "text": [ "A combined nuclear and nucleolar localization motif in activation-induced cytidine deaminase (AID) controls immunoglobulin class switching." ], "offsets": [ [ 0, 139 ] ] }, { "id": "23183374_abstract", "type": "abstract", "text": [ "Activation-induced cytidine deaminase (AID) is a DNA mutator enzyme essential for adaptive immunity. AID initiates somatic hypermutation and class switch recombination (CSR) by deaminating cytosine to uracil in specific immunoglobulin (Ig) gene regions. However, other loci, including cancer-related genes, are also targeted. Thus, tight regulation of AID is crucial to balance immunity versus disease such as cancer. AID is regulated by several mechanisms including nucleocytoplasmic shuttling. Here we have studied nuclear import kinetics and subnuclear trafficking of AID in live cells and characterized in detail its nuclear localization signal. Importantly, we find that the nuclear localization signal motif also directs AID to nucleoli where it colocalizes with its interaction partner, catenin-β-like 1 (CTNNBL1), and physically associates with nucleolin and nucleophosmin. Moreover, we demonstrate that release of AID from nucleoli is dependent on its C-terminal motif. Finally, we find that CSR efficiency correlates strongly with the arithmetic product of AID nuclear import rate and DNA deamination activity. Our findings suggest that directional nucleolar transit is important for the physiological function of AID and demonstrate that nuclear/nucleolar import and DNA cytosine deamination together define the biological activity of AID. This is the first study on subnuclear trafficking of AID and demonstrates a new level in its complex regulation. In addition, our results resolve the problem related to dissociation of deamination activity and CSR activity of AID mutants." ], "offsets": [ [ 140, 1729 ] ] } ]

[ { "id": "23183374_T1", "type": "CHEMICAL", "text": [ "cytosine" ], "offsets": [ [ 1422, 1430 ] ], "normalized": [] }, { "id": "23183374_T2", "type": "CHEMICAL", "text": [ "cytosine" ], "offsets": [ [ 329, 337 ] ], "normalized": [] }, { "id": "23183374_T3", "type": "CHEMICAL", "text": [ "cytidine" ], "offsets": [ [ 159, 167 ] ], "normalized": [] }, { "id": "23183374_T4", "type": "CHEMICAL", "text": [ "uracil" ], "offsets": [ [ 341, 347 ] ], "normalized": [] }, { "id": "23183374_T5", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 1101, 1102 ] ], "normalized": [] }, { "id": "23183374_T6", "type": "CHEMICAL", "text": [ "cytidine" ], "offsets": [ [ 74, 82 ] ], "normalized": [] }, { "id": "23183374_T7", "type": "GENE-Y", "text": [ "Activation-induced cytidine deaminase" ], "offsets": [ [ 140, 177 ] ], "normalized": [] }, { "id": "23183374_T8", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 241, 244 ] ], "normalized": [] }, { "id": "23183374_T9", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 1207, 1210 ] ], "normalized": [] }, { "id": "23183374_T10", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 1364, 1367 ] ], "normalized": [] }, { "id": "23183374_T11", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 1486, 1489 ] ], "normalized": [] }, { "id": "23183374_T12", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 1544, 1547 ] ], "normalized": [] }, { "id": "23183374_T13", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 1717, 1720 ] ], "normalized": [] }, { "id": "23183374_T14", "type": "GENE-N", "text": [ "immunoglobulin" ], "offsets": [ [ 360, 374 ] ], "normalized": [] }, { "id": "23183374_T15", "type": "GENE-N", "text": [ "Ig" ], "offsets": [ [ 376, 378 ] ], "normalized": [] }, { "id": "23183374_T16", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 492, 495 ] ], "normalized": [] }, { "id": "23183374_T17", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 179, 182 ] ], "normalized": [] }, { "id": "23183374_T18", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 558, 561 ] ], "normalized": [] }, { "id": "23183374_T19", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 711, 714 ] ], "normalized": [] }, { "id": "23183374_T20", "type": "GENE-N", "text": [ "nuclear localization signal motif" ], "offsets": [ [ 820, 853 ] ], "normalized": [] }, { "id": "23183374_T21", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 867, 870 ] ], "normalized": [] }, { "id": "23183374_T22", "type": "GENE-Y", "text": [ "catenin-β-like 1" ], "offsets": [ [ 934, 950 ] ], "normalized": [] }, { "id": "23183374_T23", "type": "GENE-Y", "text": [ "CTNNBL1" ], "offsets": [ [ 952, 959 ] ], "normalized": [] }, { "id": "23183374_T24", "type": "GENE-Y", "text": [ "nucleolin" ], "offsets": [ [ 993, 1002 ] ], "normalized": [] }, { "id": "23183374_T25", "type": "GENE-Y", "text": [ "nucleophosmin" ], "offsets": [ [ 1007, 1020 ] ], "normalized": [] }, { "id": "23183374_T26", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 1063, 1066 ] ], "normalized": [] }, { "id": "23183374_T27", "type": "GENE-N", "text": [ "immunoglobulin" ], "offsets": [ [ 108, 122 ] ], "normalized": [] }, { "id": "23183374_T28", "type": "GENE-N", "text": [ "nuclear and nucleolar localization motif" ], "offsets": [ [ 11, 51 ] ], "normalized": [] }, { "id": "23183374_T29", "type": "GENE-Y", "text": [ "activation-induced cytidine deaminase" ], "offsets": [ [ 55, 92 ] ], "normalized": [] }, { "id": "23183374_T30", "type": "GENE-Y", "text": [ "AID" ], "offsets": [ [ 94, 97 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23183374_0", "type": "SUBSTRATE", "arg1_id": "23183374_T2", "arg2_id": "23183374_T8", "normalized": [] }, { "id": "23183374_1", "type": "PRODUCT-OF", "arg1_id": "23183374_T4", "arg2_id": "23183374_T8", "normalized": [] }, { "id": "23183374_2", "type": "PART-OF", "arg1_id": "23183374_T5", "arg2_id": "23183374_T26", "normalized": [] }, { "id": "23183374_3", "type": "SUBSTRATE", "arg1_id": "23183374_T1", "arg2_id": "23183374_T11", "normalized": [] } ]

[ { "id": "22982445_title", "type": "title", "text": [ "Leukotriene D4 induces cognitive impairment through enhancement of CysLT₁ R-mediated amyloid-β generation in mice." ], "offsets": [ [ 0, 114 ] ] }, { "id": "22982445_abstract", "type": "abstract", "text": [ "Amyloid plaques in the extracellular parenchyma mainly consist of amyloid-β peptides (Aβ), one of the pathological hallmarks in Alzheimer's disease (AD). In the present study, we examined neuroinflammation, amyloidogenesis, and memory performance following intracerebral infusions of leukotriene D4 (LTD4) in mice. The results demonstrated that intracerebral infusions of LTD4 (1 ng/mouse) produced memory impairment as determined by Morris water maze test and Y-maze test in mice, and caused the accumulation of Aβ1-40 and Aβ1-42 in the hippocampus and cortex through increased activity of β- and γ-secretases accompanied with increased expression of amyloid precursor protein (APP). LTD4 also induced expression of cysteinyl leukotriene receptor 1 (CysLT(1)R) and NF-κB p65 in the hippocampus and cortex. Pretreatment with pranlukast (1.5 ng/mouse, intracerebroventricularly), a CysLT(1)R antagonist, blocked LTD4-induced amyloidogenesis, memory deficits. Pranlukast (0.6 μM) also prevented LTD4 (20 nM)-induced amyloidogenesis in the cultured neurons in vitro. Moreover, LTD4-induced increases in CysLT(1)R and NF-κB p65 in the brain were also attenuated by pranlukast. These results suggest that LTD4 increases Aβ peptide burden via activation of CysLT(1)R, which further affects APP levels and activity of β- and γ-secretases via the NF-κB pathway. Our findings identify CysLT(1)R signaling as a novel proinflammatory and proamyloidogenic pathway, and suggest a rationale for development of therapeutics targeting the CysLT(1)R in neuroinflammatory diseases such as AD." ], "offsets": [ [ 115, 1689 ] ] } ]

[ { "id": "22982445_T1", "type": "CHEMICAL", "text": [ "LTD4" ], "offsets": [ [ 1189, 1193 ] ], "normalized": [] }, { "id": "22982445_T2", "type": "CHEMICAL", "text": [ "pranlukast" ], "offsets": [ [ 1276, 1286 ] ], "normalized": [] }, { "id": "22982445_T3", "type": "CHEMICAL", "text": [ "LTD4" ], "offsets": [ [ 1315, 1319 ] ], "normalized": [] }, { "id": "22982445_T4", "type": "CHEMICAL", "text": [ "leukotriene D4" ], "offsets": [ [ 399, 413 ] ], "normalized": [] }, { "id": "22982445_T5", "type": "CHEMICAL", "text": [ "LTD4" ], "offsets": [ [ 415, 419 ] ], "normalized": [] }, { "id": "22982445_T6", "type": "CHEMICAL", "text": [ "LTD4" ], "offsets": [ [ 487, 491 ] ], "normalized": [] }, { "id": "22982445_T7", "type": "CHEMICAL", "text": [ "LTD4" ], "offsets": [ [ 800, 804 ] ], "normalized": [] }, { "id": "22982445_T8", "type": "CHEMICAL", "text": [ "cysteinyl leukotriene" ], "offsets": [ [ 832, 853 ] ], "normalized": [] }, { "id": "22982445_T9", "type": "CHEMICAL", "text": [ "pranlukast" ], "offsets": [ [ 940, 950 ] ], "normalized": [] }, { "id": "22982445_T10", "type": "CHEMICAL", "text": [ "LTD4" ], "offsets": [ [ 1026, 1030 ] ], "normalized": [] }, { "id": "22982445_T11", "type": "CHEMICAL", "text": [ "Pranlukast" ], "offsets": [ [ 1073, 1083 ] ], "normalized": [] }, { "id": "22982445_T12", "type": "CHEMICAL", "text": [ "LTD4" ], "offsets": [ [ 1108, 1112 ] ], "normalized": [] }, { "id": "22982445_T13", "type": "CHEMICAL", "text": [ "Leukotriene D4" ], "offsets": [ [ 0, 14 ] ], "normalized": [] }, { "id": "22982445_T14", "type": "GENE-Y", "text": [ "Amyloid" ], "offsets": [ [ 115, 122 ] ], "normalized": [] }, { "id": "22982445_T15", "type": "GENE-Y", "text": [ "CysLT(1)R" ], "offsets": [ [ 1215, 1224 ] ], "normalized": [] }, { "id": "22982445_T16", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 1229, 1234 ] ], "normalized": [] }, { "id": "22982445_T17", "type": "GENE-Y", "text": [ "p65" ], "offsets": [ [ 1235, 1238 ] ], "normalized": [] }, { "id": "22982445_T18", "type": "GENE-Y", "text": [ "Aβ peptide" ], "offsets": [ [ 1330, 1340 ] ], "normalized": [] }, { "id": "22982445_T19", "type": "GENE-Y", "text": [ "CysLT(1)R" ], "offsets": [ [ 1366, 1375 ] ], "normalized": [] }, { "id": "22982445_T20", "type": "GENE-Y", "text": [ "APP" ], "offsets": [ [ 1399, 1402 ] ], "normalized": [] }, { "id": "22982445_T21", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 1454, 1459 ] ], "normalized": [] }, { "id": "22982445_T22", "type": "GENE-Y", "text": [ "CysLT(1)R" ], "offsets": [ [ 1491, 1500 ] ], "normalized": [] }, { "id": "22982445_T23", "type": "GENE-Y", "text": [ "CysLT(1)R" ], "offsets": [ [ 1638, 1647 ] ], "normalized": [] }, { "id": "22982445_T24", "type": "GENE-Y", "text": [ "Aβ1-40" ], "offsets": [ [ 628, 634 ] ], "normalized": [] }, { "id": "22982445_T25", "type": "GENE-Y", "text": [ "Aβ1-42" ], "offsets": [ [ 639, 645 ] ], "normalized": [] }, { "id": "22982445_T26", "type": "GENE-Y", "text": [ "amyloid precursor protein" ], "offsets": [ [ 767, 792 ] ], "normalized": [] }, { "id": "22982445_T27", "type": "GENE-Y", "text": [ "amyloid-β peptides" ], "offsets": [ [ 181, 199 ] ], "normalized": [] }, { "id": "22982445_T28", "type": "GENE-Y", "text": [ "APP" ], "offsets": [ [ 794, 797 ] ], "normalized": [] }, { "id": "22982445_T29", "type": "GENE-Y", "text": [ "cysteinyl leukotriene receptor 1" ], "offsets": [ [ 832, 864 ] ], "normalized": [] }, { "id": "22982445_T30", "type": "GENE-Y", "text": [ "CysLT(1)R" ], "offsets": [ [ 866, 875 ] ], "normalized": [] }, { "id": "22982445_T31", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 881, 886 ] ], "normalized": [] }, { "id": "22982445_T32", "type": "GENE-Y", "text": [ "p65" ], "offsets": [ [ 887, 890 ] ], "normalized": [] }, { "id": "22982445_T33", "type": "GENE-Y", "text": [ "Aβ" ], "offsets": [ [ 201, 203 ] ], "normalized": [] }, { "id": "22982445_T34", "type": "GENE-Y", "text": [ "CysLT(1)R" ], "offsets": [ [ 996, 1005 ] ], "normalized": [] }, { "id": "22982445_T35", "type": "GENE-Y", "text": [ "CysLT₁ R" ], "offsets": [ [ 67, 75 ] ], "normalized": [] }, { "id": "22982445_T36", "type": "GENE-Y", "text": [ "amyloid-β" ], "offsets": [ [ 85, 94 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "11340119_title", "type": "title", "text": [ "Stability of vitamin B-6-dependent aminotransferase activity in frozen packed erythrocytes is dependent on storage temperature." ], "offsets": [ [ 0, 127 ] ] }, { "id": "11340119_abstract", "type": "abstract", "text": [ "Pyridoxal 5'-phosphate (PLP) stimulation of erythrocyte alanine and aspartate aminotransferase (EALT, EAST) activities is a frequently used functional measure of vitamin B-6 status. Stability of enzyme activities and activity coefficients (AC, stimulated / unstimulated) was assessed in packed erythrocytes frozen at -20, -80 degrees C and under liquid nitrogen (-196 degrees C). Activities of EALT and EAST, with and without added PLP, were determined in fresh erythrocytes (d 0) and frozen samples on d 1, 7, 14, 28, 58 and 84. In -20 degrees C samples, EALT basal activity decreased 17 and 22% (P < or = 0.05 for both) by d 58 and 84, respectively, and EAST basal activity decreased 40% (P < or = 0.05) by d 58. In -80 and -196 degrees C samples, EALT and EAST basal activities did not change significantly. Activity coefficients did not differ significantly from d 0 at any storage temperature, but EAST-AC increased 9-19% (nonsignificant) in samples stored at -20 and -80 degrees C for 7 to 84 d. Additionally, EAST-AC was significantly higher in -20 than -80 and -196 degrees C samples on d 1 and 58, respectively. Erythrocytes may be frozen for 28 d at -20 degrees C and 84 d at -80 degrees C before analysis for EALT; for EAST, activity should be measured on fresh erythrocytes." ], "offsets": [ [ 128, 1414 ] ] } ]

[ { "id": "11340119_T1", "type": "CHEMICAL", "text": [ "Pyridoxal 5'-phosphate" ], "offsets": [ [ 128, 150 ] ], "normalized": [] }, { "id": "11340119_T2", "type": "CHEMICAL", "text": [ "vitamin B-6" ], "offsets": [ [ 290, 301 ] ], "normalized": [] }, { "id": "11340119_T3", "type": "CHEMICAL", "text": [ "PLP" ], "offsets": [ [ 152, 155 ] ], "normalized": [] }, { "id": "11340119_T4", "type": "CHEMICAL", "text": [ "nitrogen" ], "offsets": [ [ 481, 489 ] ], "normalized": [] }, { "id": "11340119_T5", "type": "CHEMICAL", "text": [ "PLP" ], "offsets": [ [ 560, 563 ] ], "normalized": [] }, { "id": "11340119_T6", "type": "CHEMICAL", "text": [ "alanine" ], "offsets": [ [ 184, 191 ] ], "normalized": [] }, { "id": "11340119_T7", "type": "CHEMICAL", "text": [ "aspartate" ], "offsets": [ [ 196, 205 ] ], "normalized": [] }, { "id": "11340119_T8", "type": "CHEMICAL", "text": [ "vitamin B-6" ], "offsets": [ [ 13, 24 ] ], "normalized": [] }, { "id": "11340119_T9", "type": "GENE-Y", "text": [ "EAST" ], "offsets": [ [ 1144, 1148 ] ], "normalized": [] }, { "id": "11340119_T10", "type": "GENE-Y", "text": [ "EAST" ], "offsets": [ [ 230, 234 ] ], "normalized": [] }, { "id": "11340119_T11", "type": "GENE-N", "text": [ "EALT" ], "offsets": [ [ 1348, 1352 ] ], "normalized": [] }, { "id": "11340119_T12", "type": "GENE-Y", "text": [ "EAST" ], "offsets": [ [ 1358, 1362 ] ], "normalized": [] }, { "id": "11340119_T13", "type": "GENE-N", "text": [ "EALT" ], "offsets": [ [ 522, 526 ] ], "normalized": [] }, { "id": "11340119_T14", "type": "GENE-Y", "text": [ "EAST" ], "offsets": [ [ 531, 535 ] ], "normalized": [] }, { "id": "11340119_T15", "type": "GENE-N", "text": [ "erythrocyte alanine and aspartate aminotransferase" ], "offsets": [ [ 172, 222 ] ], "normalized": [] }, { "id": "11340119_T16", "type": "GENE-N", "text": [ "EALT" ], "offsets": [ [ 684, 688 ] ], "normalized": [] }, { "id": "11340119_T17", "type": "GENE-Y", "text": [ "EAST" ], "offsets": [ [ 784, 788 ] ], "normalized": [] }, { "id": "11340119_T18", "type": "GENE-N", "text": [ "EALT" ], "offsets": [ [ 878, 882 ] ], "normalized": [] }, { "id": "11340119_T19", "type": "GENE-Y", "text": [ "EAST" ], "offsets": [ [ 887, 891 ] ], "normalized": [] }, { "id": "11340119_T20", "type": "GENE-Y", "text": [ "EAST" ], "offsets": [ [ 1031, 1035 ] ], "normalized": [] }, { "id": "11340119_T21", "type": "GENE-N", "text": [ "EALT" ], "offsets": [ [ 224, 228 ] ], "normalized": [] }, { "id": "11340119_T22", "type": "GENE-N", "text": [ "vitamin B-6-dependent aminotransferase" ], "offsets": [ [ 13, 51 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "15199474_title", "type": "title", "text": [ "P2Y12, a new platelet ADP receptor, target of clopidogrel." ], "offsets": [ [ 0, 58 ] ] }, { "id": "15199474_abstract", "type": "abstract", "text": [ "Clopidogrel is a potent antithrombotic drug that inhibits ADP-induced platelet aggregation. The results of large clinical trials have demonstrated an overall benefit of clopidogrel over aspirin in the prevention of vascular ischemic events (myocardial infarction, stroke, vascular death) in patients with a history of symptomatic atherosclerotic disease. The antiaggregating effect of clopidogrel is attributed to an irreversible inhibition of ADP binding to a purinergic receptor present at the platelet surface. Clopidogrel is not active in vitro and can be considered a precursor of an active metabolite formed in the liver. The chemical structure of this active metabolite and its biological activity have been described recently. Several purinergic receptors have been described on platelets; P2X (1), a calcium channel, and P2Y1 a Gq-coupled seven-transmembrane domain receptor, have been found not to be antagonized by clopidogrel. Another Gi (2)-coupled receptor (named P2Y12) has been recently cloned and stably expressed in CHO cells. These cells displayed a strong affinity for (33)P-2MeS-ADP, a stable analogue of ADP, the binding characteristics of which corresponded in all points to those observed on platelets. The binding of (33)P-2MeS-ADP to these cells was strongly inhibited by the active metabolite of clopidogrel with a potency that was consistent with that observed for this compound on platelets. In these transfected CHO cells, as in platelets, ADP and 2MeS-ADP induced adenylyl cyclase downregulation, an effect that was inhibited by the active metabolite of clopidogrel. These results demonstrate that this receptor corresponds to the previously called \"P2t\" platelet receptor and show that the active metabolite of clopidogrel binds in a covalent manner to this receptor, thus explaining how it blocks the aggregating effect of ADP on platelets." ], "offsets": [ [ 59, 1932 ] ] } ]

[ { "id": "15199474_T1", "type": "CHEMICAL", "text": [ "Clopidogrel" ], "offsets": [ [ 59, 70 ] ], "normalized": [] }, { "id": "15199474_T2", "type": "CHEMICAL", "text": [ "(33)P-2MeS-ADP" ], "offsets": [ [ 1148, 1162 ] ], "normalized": [] }, { "id": "15199474_T3", "type": "CHEMICAL", "text": [ "ADP" ], "offsets": [ [ 1185, 1188 ] ], "normalized": [] }, { "id": "15199474_T4", "type": "CHEMICAL", "text": [ "(33)P-2MeS-ADP" ], "offsets": [ [ 1301, 1315 ] ], "normalized": [] }, { "id": "15199474_T5", "type": "CHEMICAL", "text": [ "clopidogrel" ], "offsets": [ [ 1382, 1393 ] ], "normalized": [] }, { "id": "15199474_T6", "type": "CHEMICAL", "text": [ "ADP" ], "offsets": [ [ 1529, 1532 ] ], "normalized": [] }, { "id": "15199474_T7", "type": "CHEMICAL", "text": [ "2MeS-ADP" ], "offsets": [ [ 1537, 1545 ] ], "normalized": [] }, { "id": "15199474_T8", "type": "CHEMICAL", "text": [ "adenylyl" ], "offsets": [ [ 1554, 1562 ] ], "normalized": [] }, { "id": "15199474_T9", "type": "CHEMICAL", "text": [ "clopidogrel" ], "offsets": [ [ 1644, 1655 ] ], "normalized": [] }, { "id": "15199474_T10", "type": "CHEMICAL", "text": [ "clopidogrel" ], "offsets": [ [ 228, 239 ] ], "normalized": [] }, { "id": "15199474_T11", "type": "CHEMICAL", "text": [ "clopidogrel" ], "offsets": [ [ 1802, 1813 ] ], "normalized": [] }, { "id": "15199474_T12", "type": "CHEMICAL", "text": [ "ADP" ], "offsets": [ [ 1915, 1918 ] ], "normalized": [] }, { "id": "15199474_T13", "type": "CHEMICAL", "text": [ "aspirin" ], "offsets": [ [ 245, 252 ] ], "normalized": [] }, { "id": "15199474_T14", "type": "CHEMICAL", "text": [ "clopidogrel" ], "offsets": [ [ 444, 455 ] ], "normalized": [] }, { "id": "15199474_T15", "type": "CHEMICAL", "text": [ "ADP" ], "offsets": [ [ 503, 506 ] ], "normalized": [] }, { "id": "15199474_T16", "type": "CHEMICAL", "text": [ "Clopidogrel" ], "offsets": [ [ 573, 584 ] ], "normalized": [] }, { "id": "15199474_T17", "type": "CHEMICAL", "text": [ "ADP" ], "offsets": [ [ 117, 120 ] ], "normalized": [] }, { "id": "15199474_T18", "type": "CHEMICAL", "text": [ "calcium" ], "offsets": [ [ 868, 875 ] ], "normalized": [] }, { "id": "15199474_T19", "type": "CHEMICAL", "text": [ "clopidogrel" ], "offsets": [ [ 985, 996 ] ], "normalized": [] }, { "id": "15199474_T20", "type": "CHEMICAL", "text": [ "ADP" ], "offsets": [ [ 22, 25 ] ], "normalized": [] }, { "id": "15199474_T21", "type": "CHEMICAL", "text": [ "clopidogrel" ], "offsets": [ [ 46, 57 ] ], "normalized": [] }, { "id": "15199474_T22", "type": "GENE-Y", "text": [ "P2t" ], "offsets": [ [ 1740, 1743 ] ], "normalized": [] }, { "id": "15199474_T23", "type": "GENE-N", "text": [ "platelet receptor" ], "offsets": [ [ 1745, 1762 ] ], "normalized": [] }, { "id": "15199474_T24", "type": "GENE-N", "text": [ "purinergic receptor" ], "offsets": [ [ 520, 539 ] ], "normalized": [] }, { "id": "15199474_T25", "type": "GENE-N", "text": [ "purinergic receptors" ], "offsets": [ [ 802, 822 ] ], "normalized": [] }, { "id": "15199474_T26", "type": "GENE-Y", "text": [ "P2X (1)" ], "offsets": [ [ 857, 864 ] ], "normalized": [] }, { "id": "15199474_T27", "type": "GENE-N", "text": [ "calcium channel" ], "offsets": [ [ 868, 883 ] ], "normalized": [] }, { "id": "15199474_T28", "type": "GENE-Y", "text": [ "P2Y1" ], "offsets": [ [ 889, 893 ] ], "normalized": [] }, { "id": "15199474_T29", "type": "GENE-N", "text": [ "Gq-coupled seven-transmembrane domain receptor" ], "offsets": [ [ 896, 942 ] ], "normalized": [] }, { "id": "15199474_T30", "type": "GENE-N", "text": [ "Gi (2)-coupled receptor" ], "offsets": [ [ 1006, 1029 ] ], "normalized": [] }, { "id": "15199474_T31", "type": "GENE-Y", "text": [ "P2Y12" ], "offsets": [ [ 1037, 1042 ] ], "normalized": [] }, { "id": "15199474_T32", "type": "GENE-Y", "text": [ "P2Y12" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "15199474_T33", "type": "GENE-N", "text": [ "ADP receptor" ], "offsets": [ [ 22, 34 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "16395286_title", "type": "title", "text": [ "Dose-response effect of tetracyclines on cerebral matrix metalloproteinase-9 after vascular endothelial growth factor hyperstimulation." ], "offsets": [ [ 0, 135 ] ] }, { "id": "16395286_abstract", "type": "abstract", "text": [ "Brain arteriovenous malformations (BAVMs) are a potentially life-threatening disorder. Matrix metalloproteinase (MMP)-9 activity was greatly increased in BAVM tissue specimens. Doxycycline was shown to decrease cerebral MMP-9 activities and angiogenesis induced by vascular endothelial growth factor (VEGF). In the present study, we determined the dose-response effects of doxycycline and minocycline on cerebral MMP-9 using our mouse model with VEGF focal hyperstimulation delivered with adenoviral vector (AdVEGF) in the brain. Mice were treated with doxycycline or minocycline, respectively, at 1, 5, 10, 30, 50, or 100 mg/kg/day through drinking water for 1 week. Our results have shown that MMP-9 messenger ribonucleic acid (mRNA) expression was inhibited by doxycycline starting at 10 mg/kg/day (P<0.02). Minocycline showed more potent inhibition on MMP-9 mRNA expression, starting at 1 (P<0.005) and further at more than 30 (P<0.001) mg/kg/day. At the enzymatic activity level, doxycycline started to suppress MMP-9 activity at 5 mg/kg/day (P<0.001), while minocycline had an effect at a lower dose, 1 mg/kg/day (P<0.02). The inhibition of cerebral MMP-9 mRNA and activity were highly correlated with drug levels in the brain tissue. We also assessed the potential relevant signaling pathway in vitro to elucidate the mechanisms underlying the MMP-9 inhibition by tetracyclines. In vitro, minocycline, but not doxycycline, inhibits MMP-9, at least in part, via the extracellular signaling-related kinase 1/2 (ERK1/2)-mediated pathway. This study provided the evidence that the tetracyclines inhibit stimulated cerebral MMP-9 at multiple levels and are effective at very low doses, offering great potential for therapeutic use." ], "offsets": [ [ 136, 1869 ] ] } ]

[ { "id": "16395286_T1", "type": "CHEMICAL", "text": [ "minocycline" ], "offsets": [ [ 1200, 1211 ] ], "normalized": [] }, { "id": "16395286_T2", "type": "CHEMICAL", "text": [ "tetracyclines" ], "offsets": [ [ 1507, 1520 ] ], "normalized": [] }, { "id": "16395286_T3", "type": "CHEMICAL", "text": [ "minocycline" ], "offsets": [ [ 1532, 1543 ] ], "normalized": [] }, { "id": "16395286_T4", "type": "CHEMICAL", "text": [ "doxycycline" ], "offsets": [ [ 1553, 1564 ] ], "normalized": [] }, { "id": "16395286_T5", "type": "CHEMICAL", "text": [ "tetracyclines" ], "offsets": [ [ 1720, 1733 ] ], "normalized": [] }, { "id": "16395286_T6", "type": "CHEMICAL", "text": [ "Doxycycline" ], "offsets": [ [ 313, 324 ] ], "normalized": [] }, { "id": "16395286_T7", "type": "CHEMICAL", "text": [ "doxycycline" ], "offsets": [ [ 509, 520 ] ], "normalized": [] }, { "id": "16395286_T8", "type": "CHEMICAL", "text": [ "minocycline" ], "offsets": [ [ 525, 536 ] ], "normalized": [] }, { "id": "16395286_T9", "type": "CHEMICAL", "text": [ "doxycycline" ], "offsets": [ [ 689, 700 ] ], "normalized": [] }, { "id": "16395286_T10", "type": "CHEMICAL", "text": [ "minocycline" ], "offsets": [ [ 704, 715 ] ], "normalized": [] }, { "id": "16395286_T11", "type": "CHEMICAL", "text": [ "doxycycline" ], "offsets": [ [ 900, 911 ] ], "normalized": [] }, { "id": "16395286_T12", "type": "CHEMICAL", "text": [ "Minocycline" ], "offsets": [ [ 947, 958 ] ], "normalized": [] }, { "id": "16395286_T13", "type": "CHEMICAL", "text": [ "doxycycline" ], "offsets": [ [ 1121, 1132 ] ], "normalized": [] }, { "id": "16395286_T14", "type": "CHEMICAL", "text": [ "tetracyclines" ], "offsets": [ [ 24, 37 ] ], "normalized": [] }, { "id": "16395286_T15", "type": "GENE-Y", "text": [ "MMP-9" ], "offsets": [ [ 1153, 1158 ] ], "normalized": [] }, { "id": "16395286_T16", "type": "GENE-Y", "text": [ "MMP-9" ], "offsets": [ [ 1292, 1297 ] ], "normalized": [] }, { "id": "16395286_T17", "type": "GENE-Y", "text": [ "MMP-9" ], "offsets": [ [ 1487, 1492 ] ], "normalized": [] }, { "id": "16395286_T18", "type": "GENE-Y", "text": [ "MMP-9" ], "offsets": [ [ 1575, 1580 ] ], "normalized": [] }, { "id": "16395286_T19", "type": "GENE-N", "text": [ "extracellular signaling-related kinase 1/2" ], "offsets": [ [ 1608, 1650 ] ], "normalized": [] }, { "id": "16395286_T20", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 1652, 1658 ] ], "normalized": [] }, { "id": "16395286_T21", "type": "GENE-Y", "text": [ "MMP-9" ], "offsets": [ [ 1762, 1767 ] ], "normalized": [] }, { "id": "16395286_T22", "type": "GENE-Y", "text": [ "MMP-9" ], "offsets": [ [ 356, 361 ] ], "normalized": [] }, { "id": "16395286_T23", "type": "GENE-Y", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 401, 435 ] ], "normalized": [] }, { "id": "16395286_T24", "type": "GENE-Y", "text": [ "VEGF" ], "offsets": [ [ 437, 441 ] ], "normalized": [] }, { "id": "16395286_T25", "type": "GENE-Y", "text": [ "MMP-9" ], "offsets": [ [ 549, 554 ] ], "normalized": [] }, { "id": "16395286_T26", "type": "GENE-Y", "text": [ "VEGF" ], "offsets": [ [ 582, 586 ] ], "normalized": [] }, { "id": "16395286_T27", "type": "GENE-Y", "text": [ "VEGF" ], "offsets": [ [ 646, 650 ] ], "normalized": [] }, { "id": "16395286_T28", "type": "GENE-Y", "text": [ "MMP-9" ], "offsets": [ [ 832, 837 ] ], "normalized": [] }, { "id": "16395286_T29", "type": "GENE-Y", "text": [ "MMP-9" ], "offsets": [ [ 992, 997 ] ], "normalized": [] }, { "id": "16395286_T30", "type": "GENE-Y", "text": [ "Matrix metalloproteinase (MMP)-9" ], "offsets": [ [ 223, 255 ] ], "normalized": [] }, { "id": "16395286_T31", "type": "GENE-Y", "text": [ "matrix metalloproteinase-9" ], "offsets": [ [ 50, 76 ] ], "normalized": [] }, { "id": "16395286_T32", "type": "GENE-Y", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 83, 117 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "8484964_title", "type": "title", "text": [ "Purification of nonantibiotic insulinase inhibitors from bacitracin." ], "offsets": [ [ 0, 68 ] ] }, { "id": "8484964_abstract", "type": "abstract", "text": [ "Bacitracin is commonly used in metabolic studies as an insulinase inhibitor. The many isoforms of the commercial preparation were fractionated by charge and size in order to find the most active rat-muscle insulinase inhibitors. CM-Sepharose chromatography revealed that most of the inhibitory activity was contained in a fraction (CM-Inh) that amounted to less than 5% of the mixture. The CM-Inh fraction could be further separated by size on Bio-Gel P4 columns. Six subgroups, each with characteristic specific activity, were isolated. The most potent inhibitor fractions have no antibiotic activity and have molecular weights about twice that of bacitracin A. The peaks isolated by means of Bio-Gel P4 chromatography can be further fractionated by reversed phase HPLC on a C8 column, and by electrophoresis on nonreducing acrylamide gels." ], "offsets": [ [ 69, 910 ] ] } ]

[ { "id": "8484964_T1", "type": "CHEMICAL", "text": [ "Bacitracin" ], "offsets": [ [ 69, 79 ] ], "normalized": [] }, { "id": "8484964_T2", "type": "CHEMICAL", "text": [ "bacitracin A" ], "offsets": [ [ 718, 730 ] ], "normalized": [] }, { "id": "8484964_T3", "type": "CHEMICAL", "text": [ "acrylamide" ], "offsets": [ [ 894, 904 ] ], "normalized": [] }, { "id": "8484964_T4", "type": "CHEMICAL", "text": [ "bacitracin" ], "offsets": [ [ 57, 67 ] ], "normalized": [] }, { "id": "8484964_T5", "type": "GENE-Y", "text": [ "insulinase" ], "offsets": [ [ 275, 285 ] ], "normalized": [] }, { "id": "8484964_T6", "type": "GENE-N", "text": [ "insulinase" ], "offsets": [ [ 124, 134 ] ], "normalized": [] }, { "id": "8484964_T7", "type": "GENE-N", "text": [ "insulinase" ], "offsets": [ [ 30, 40 ] ], "normalized": [] } ]

[]

[]

[ { "id": "8484964_0", "type": "INHIBITOR", "arg1_id": "8484964_T4", "arg2_id": "8484964_T7", "normalized": [] }, { "id": "8484964_1", "type": "INHIBITOR", "arg1_id": "8484964_T1", "arg2_id": "8484964_T6", "normalized": [] } ]

[ { "id": "19549602_title", "type": "title", "text": [ "Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity." ], "offsets": [ [ 0, 130 ] ] }, { "id": "19549602_abstract", "type": "abstract", "text": [ "Neurotrophins, the cognate ligands for the Trk receptors, are homodimers and induce Trk dimerization through a symmetric bivalent mechanism. We report here that amitriptyline, an antidepressant drug, directly binds TrkA and TrkB and triggers their dimerization and activation. Amitriptyline, but not any other tricyclic or selective serotonin reuptake inhibitor antidepressants, promotes TrkA autophosphorylation in primary neurons and induces neurite outgrowth in PC12 cells. Amitriptyline binds the extracellular domain of both TrkA and TrkB and promotes TrkA-TrkB receptor heterodimerization. Truncation of amitriptyline binding motif on TrkA abrogates the receptor dimerization by amitriptyline. Administration of amitriptyline to mice activates both receptors and significantly reduces kainic acid-triggered neuronal cell death. Inhibition of TrkA, but not TrkB, abolishes amitriptyline's neuroprotective effect without impairing its antidepressant activity. Thus, amitriptyline acts as a TrkA and TrkB agonist and possesses marked neurotrophic activity." ], "offsets": [ [ 131, 1190 ] ] } ]

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[]

[]

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[ { "id": "12517247_title", "type": "title", "text": [ "Eprosartan for the treatment of hypertension." ], "offsets": [ [ 0, 45 ] ] }, { "id": "12517247_abstract", "type": "abstract", "text": [ "Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure. The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile. Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT(1)) receptors, and reduce the pressor effects of AII in the vasculature. By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure. However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P. Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action. Eprosartan acts at vascular AT(1) receptors (postsynaptically) and at presynaptic AT(1) receptors, where it inhibits sympathetically stimulated noradrenaline release. Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs. In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects. Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide." ], "offsets": [ [ 46, 1799 ] ] } ]

[ { "id": "12517247_T1", "type": "CHEMICAL", "text": [ "Eprosartan" ], "offsets": [ [ 1082, 1092 ] ], "normalized": [] }, { "id": "12517247_T2", "type": "CHEMICAL", "text": [ "noradrenaline" ], "offsets": [ [ 1226, 1239 ] ], "normalized": [] }, { "id": "12517247_T3", "type": "CHEMICAL", "text": [ "eprosartan" ], "offsets": [ [ 1460, 1470 ] ], "normalized": [] }, { "id": "12517247_T4", "type": "CHEMICAL", "text": [ "enalapril" ], "offsets": [ [ 1569, 1578 ] ], "normalized": [] }, { "id": "12517247_T5", "type": "CHEMICAL", "text": [ "Eprosartan" ], "offsets": [ [ 1622, 1632 ] ], "normalized": [] }, { "id": "12517247_T6", "type": "CHEMICAL", "text": [ "hydrochlorothiazide" ], "offsets": [ [ 1779, 1798 ] ], "normalized": [] }, { "id": "12517247_T7", "type": "CHEMICAL", "text": [ "Angiotensin II" ], "offsets": [ [ 290, 304 ] ], "normalized": [] }, { "id": "12517247_T8", "type": "CHEMICAL", "text": [ "AII" ], "offsets": [ [ 306, 309 ] ], "normalized": [] }, { "id": "12517247_T9", "type": "CHEMICAL", "text": [ "AII" ], "offsets": [ [ 396, 399 ] ], "normalized": [] }, { "id": "12517247_T10", "type": "CHEMICAL", "text": [ "AII" ], "offsets": [ [ 460, 463 ] ], "normalized": [] }, { "id": "12517247_T11", "type": "CHEMICAL", "text": [ "angiotensin" ], "offsets": [ [ 561, 572 ] ], "normalized": [] }, { "id": "12517247_T12", "type": "CHEMICAL", "text": [ "AII" ], "offsets": [ [ 661, 664 ] ], "normalized": [] }, { "id": "12517247_T13", "type": "CHEMICAL", "text": [ "bradykinin" ], "offsets": [ [ 801, 811 ] ], "normalized": [] }, { "id": "12517247_T14", "type": "CHEMICAL", "text": [ "substance P" ], "offsets": [ [ 839, 850 ] ], "normalized": [] }, { "id": "12517247_T15", "type": "CHEMICAL", "text": [ "AII" ], "offsets": [ [ 872, 875 ] ], "normalized": [] }, { "id": "12517247_T16", "type": "CHEMICAL", "text": [ "eprosartan" ], "offsets": [ [ 886, 896 ] ], "normalized": [] }, { "id": "12517247_T17", "type": "CHEMICAL", "text": [ "biphenyl" ], "offsets": [ [ 990, 998 ] ], "normalized": [] }, { "id": "12517247_T18", "type": "CHEMICAL", "text": [ "tetrazole" ], "offsets": [ [ 1004, 1013 ] ], "normalized": [] }, { "id": "12517247_T19", "type": "CHEMICAL", "text": [ "Eprosartan" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "12517247_T20", "type": "GENE-Y", "text": [ "AT(1) receptors" ], "offsets": [ [ 1110, 1125 ] ], "normalized": [] }, { "id": "12517247_T21", "type": "GENE-Y", "text": [ "AT(1) receptors" ], "offsets": [ [ 1164, 1179 ] ], "normalized": [] }, { "id": "12517247_T22", "type": "GENE-N", "text": [ "cytochrome P450" ], "offsets": [ [ 1275, 1290 ] ], "normalized": [] }, { "id": "12517247_T23", "type": "GENE-Y", "text": [ "ACE" ], "offsets": [ [ 1555, 1558 ] ], "normalized": [] }, { "id": "12517247_T24", "type": "GENE-N", "text": [ "Angiotensin II (AII) receptor" ], "offsets": [ [ 290, 319 ] ], "normalized": [] }, { "id": "12517247_T25", "type": "GENE-Y", "text": [ "AII Type 1 (AT(1)) receptors" ], "offsets": [ [ 396, 424 ] ], "normalized": [] }, { "id": "12517247_T26", "type": "GENE-Y", "text": [ "AII" ], "offsets": [ [ 460, 463 ] ], "normalized": [] }, { "id": "12517247_T27", "type": "GENE-Y", "text": [ "angiotensin-converting enzyme" ], "offsets": [ [ 561, 590 ] ], "normalized": [] }, { "id": "12517247_T28", "type": "GENE-Y", "text": [ "ACE" ], "offsets": [ [ 592, 595 ] ], "normalized": [] }, { "id": "12517247_T29", "type": "GENE-N", "text": [ "AII receptor" ], "offsets": [ [ 661, 673 ] ], "normalized": [] }, { "id": "12517247_T30", "type": "GENE-Y", "text": [ "ACE" ], "offsets": [ [ 695, 698 ] ], "normalized": [] }, { "id": "12517247_T31", "type": "GENE-Y", "text": [ "bradykinin" ], "offsets": [ [ 801, 811 ] ], "normalized": [] }, { "id": "12517247_T32", "type": "GENE-Y", "text": [ "ubstance P" ], "offsets": [ [ 840, 850 ] ], "normalized": [] }, { "id": "12517247_T33", "type": "GENE-Y", "text": [ "AII" ], "offsets": [ [ 872, 875 ] ], "normalized": [] } ]

[]

[]

[ { "id": "12517247_0", "type": "INHIBITOR", "arg1_id": "12517247_T16", "arg2_id": "12517247_T33", "normalized": [] }, { "id": "12517247_1", "type": "INHIBITOR", "arg1_id": "12517247_T4", "arg2_id": "12517247_T23", "normalized": [] } ]

[ { "id": "23578968_title", "type": "title", "text": [ "Evaluation of a predictive in vitro Leydig cell assay for anti-androgenicity of phthalate esters in the rat." ], "offsets": [ [ 0, 108 ] ] }, { "id": "23578968_abstract", "type": "abstract", "text": [ "An in vitro assay using the rat Leydig cell line R2C was evaluated for its ability to quantitatively predict inhibition of testosterone synthesis. Results obtained for endocrine active phthalates (MEHP, MBP), and inactive phthalates (MMP and MEP) were highly consistent with in vivo results based on tissue and media concentrations. Statistically significant inhibition of testosterone synthesis (p<0.05, 1-way ANOVA) was observed at 1μM MBP and 3μM MEHP, while MEP and MMP did not affect inhibition of testosterone synthesis until much higher concentrations (≫100μM). Concentrations causing 50% inhibition of testosterone synthesis for MBP and MEHP (3 and 6μM respectively), were similar to in vivo values (3 and 7μM). The R2C assay was used to determine the relative potency of 14 structurally diverse monoesters and oxidative metabolites of MEHP. Monoesters with alkyl chains 4-5 carbons in length had the highest potency for testosterone inhibition, while 0-2 carbon alkyl chains were least potent. Phase I metabolism did not completely inactivate MEHP, underscoring the need for metabolism data when interpreting in vitro pharmacodynamic data. This steroid inhibition assay provides a predictive in vitro alternative to expensive and timeconsuming developmental rat studies for phthalate-induced antiandrogenicity." ], "offsets": [ [ 109, 1428 ] ] } ]

[ { "id": "23578968_T1", "type": "CHEMICAL", "text": [ "MEHP" ], "offsets": [ [ 1161, 1165 ] ], "normalized": [] }, { "id": "23578968_T2", "type": "CHEMICAL", "text": [ "steroid" ], "offsets": [ [ 1263, 1270 ] ], "normalized": [] }, { "id": "23578968_T3", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 232, 244 ] ], "normalized": [] }, { "id": "23578968_T4", "type": "CHEMICAL", "text": [ "phthalate" ], "offsets": [ [ 1392, 1401 ] ], "normalized": [] }, { "id": "23578968_T5", "type": "CHEMICAL", "text": [ "phthalates" ], "offsets": [ [ 294, 304 ] ], "normalized": [] }, { "id": "23578968_T6", "type": "CHEMICAL", "text": [ "MEHP" ], "offsets": [ [ 306, 310 ] ], "normalized": [] }, { "id": "23578968_T7", "type": "CHEMICAL", "text": [ "MBP" ], "offsets": [ [ 312, 315 ] ], "normalized": [] }, { "id": "23578968_T8", "type": "CHEMICAL", "text": [ "phthalates" ], "offsets": [ [ 331, 341 ] ], "normalized": [] }, { "id": "23578968_T9", "type": "CHEMICAL", "text": [ "MMP" ], "offsets": [ [ 343, 346 ] ], "normalized": [] }, { "id": "23578968_T10", "type": "CHEMICAL", "text": [ "MEP" ], "offsets": [ [ 351, 354 ] ], "normalized": [] }, { "id": "23578968_T11", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 482, 494 ] ], "normalized": [] }, { "id": "23578968_T12", "type": "CHEMICAL", "text": [ "MBP" ], "offsets": [ [ 547, 550 ] ], "normalized": [] }, { "id": "23578968_T13", "type": "CHEMICAL", "text": [ "MEHP" ], "offsets": [ [ 559, 563 ] ], "normalized": [] }, { "id": "23578968_T14", "type": "CHEMICAL", "text": [ "MEP" ], "offsets": [ [ 571, 574 ] ], "normalized": [] }, { "id": "23578968_T15", "type": "CHEMICAL", "text": [ "MMP" ], "offsets": [ [ 579, 582 ] ], "normalized": [] }, { "id": "23578968_T16", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 612, 624 ] ], "normalized": [] }, { "id": "23578968_T17", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 719, 731 ] ], "normalized": [] }, { "id": "23578968_T18", "type": "CHEMICAL", "text": [ "MBP" ], "offsets": [ [ 746, 749 ] ], "normalized": [] }, { "id": "23578968_T19", "type": "CHEMICAL", "text": [ "MEHP" ], "offsets": [ [ 754, 758 ] ], "normalized": [] }, { "id": "23578968_T20", "type": "CHEMICAL", "text": [ "monoesters" ], "offsets": [ [ 913, 923 ] ], "normalized": [] }, { "id": "23578968_T21", "type": "CHEMICAL", "text": [ "MEHP" ], "offsets": [ [ 953, 957 ] ], "normalized": [] }, { "id": "23578968_T22", "type": "CHEMICAL", "text": [ "Monoesters" ], "offsets": [ [ 959, 969 ] ], "normalized": [] }, { "id": "23578968_T23", "type": "CHEMICAL", "text": [ "carbons" ], "offsets": [ [ 992, 999 ] ], "normalized": [] }, { "id": "23578968_T24", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 1038, 1050 ] ], "normalized": [] }, { "id": "23578968_T25", "type": "CHEMICAL", "text": [ "carbon" ], "offsets": [ [ 1073, 1079 ] ], "normalized": [] }, { "id": "23578968_T26", "type": "CHEMICAL", "text": [ "phthalate esters" ], "offsets": [ [ 80, 96 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "15546741_title", "type": "title", "text": [ "9-cis-retinoic acid analogues with bulky hydrophobic rings: new RXR-selective agonists." ], "offsets": [ [ 0, 87 ] ] }, { "id": "15546741_abstract", "type": "abstract", "text": [ "Stille cross-coupling of aryltriflates 10 and dienylstannane 11, oxidation and Horner-Wadsworth-Emmons reaction afforded stereoselectively retinoates 15. Saponification provided the carboxylic acids 8a and 8b, retinoids that incorporate a bulky hydrophobic ring while preserving the 9-cis-geometry of the parent system. In contrast to the pan-RAR/RXR agonistic profile of the lower homologue of 8a, compound 7 (LG100567), retinoids 8 showed selective binding and transactivation of RXR, devoid of significant RAR activation. In PLB985 leukemia cells that require RXR agonists for differentiation compounds 8 induced maturation in the presence of the RAR-selective pan-agonist TTNPB; this effect was blocked by an RXR-selective antagonist." ], "offsets": [ [ 88, 826 ] ] } ]

[ { "id": "15546741_T1", "type": "CHEMICAL", "text": [ "carboxylic acids" ], "offsets": [ [ 270, 286 ] ], "normalized": [] }, { "id": "15546741_T2", "type": "CHEMICAL", "text": [ "retinoids" ], "offsets": [ [ 298, 307 ] ], "normalized": [] }, { "id": "15546741_T3", "type": "CHEMICAL", "text": [ "aryltriflates" ], "offsets": [ [ 113, 126 ] ], "normalized": [] }, { "id": "15546741_T4", "type": "CHEMICAL", "text": [ "LG100567" ], "offsets": [ [ 499, 507 ] ], "normalized": [] }, { "id": "15546741_T5", "type": "CHEMICAL", "text": [ "retinoids" ], "offsets": [ [ 510, 519 ] ], "normalized": [] }, { "id": "15546741_T6", "type": "CHEMICAL", "text": [ "dienylstannane" ], "offsets": [ [ 134, 148 ] ], "normalized": [] }, { "id": "15546741_T7", "type": "CHEMICAL", "text": [ "9-cis-retinoic acid" ], "offsets": [ [ 0, 19 ] ], "normalized": [] }, { "id": "15546741_T8", "type": "GENE-N", "text": [ "RAR" ], "offsets": [ [ 431, 434 ] ], "normalized": [] }, { "id": "15546741_T9", "type": "GENE-N", "text": [ "RXR" ], "offsets": [ [ 435, 438 ] ], "normalized": [] }, { "id": "15546741_T10", "type": "GENE-N", "text": [ "RXR" ], "offsets": [ [ 570, 573 ] ], "normalized": [] }, { "id": "15546741_T11", "type": "GENE-N", "text": [ "RAR" ], "offsets": [ [ 597, 600 ] ], "normalized": [] }, { "id": "15546741_T12", "type": "GENE-N", "text": [ "RXR" ], "offsets": [ [ 651, 654 ] ], "normalized": [] }, { "id": "15546741_T13", "type": "GENE-N", "text": [ "RAR" ], "offsets": [ [ 738, 741 ] ], "normalized": [] }, { "id": "15546741_T14", "type": "GENE-N", "text": [ "RXR" ], "offsets": [ [ 801, 804 ] ], "normalized": [] }, { "id": "15546741_T15", "type": "GENE-N", "text": [ "RXR" ], "offsets": [ [ 64, 67 ] ], "normalized": [] } ]

[]

[]

[ { "id": "15546741_0", "type": "AGONIST", "arg1_id": "15546741_T7", "arg2_id": "15546741_T15", "normalized": [] }, { "id": "15546741_1", "type": "AGONIST", "arg1_id": "15546741_T4", "arg2_id": "15546741_T9", "normalized": [] }, { "id": "15546741_2", "type": "AGONIST", "arg1_id": "15546741_T4", "arg2_id": "15546741_T8", "normalized": [] }, { "id": "15546741_3", "type": "DIRECT-REGULATOR", "arg1_id": "15546741_T5", "arg2_id": "15546741_T10", "normalized": [] }, { "id": "15546741_4", "type": "ACTIVATOR", "arg1_id": "15546741_T5", "arg2_id": "15546741_T10", "normalized": [] } ]

[ { "id": "18773878_title", "type": "title", "text": [ "DNA damage and homologous recombination signaling induced by thymidylate deprivation." ], "offsets": [ [ 0, 85 ] ] }, { "id": "18773878_abstract", "type": "abstract", "text": [ "DNA damage is accepted as a consequence of thymidylate deprivation induced by chemotherapeutic inhibitors of thymidylate synthase (TS), but the types of damage and signaling responses remain incompletely understood. Thymidylate deprivation increases dUTP and uracil in DNA, which is removed by base excision repair (BER). Because BER requires a synthesis step, strand break intermediates presumably accumulate. Thymidylate deprivation also induces cell cycle arrest during replication. Homologous recombination (HR) is a means of repairing persistent BER intermediates and collapsed replication forks. There are also intimate links between HR and S-phase checkpoint pathways. In this study, the goals were to determine the involvement of HR-associated proteins and DNA damage signaling responses to thymidylate deprivation. When RAD51, which is a central component of HR, was depleted by siRNA cells were sensitized to raltitrexed (RTX), which specifically inhibits TS. To our knowledge, this is the first demonstration in mammalian cells that depletion of RAD51 causes sensitivity to thymidylate deprivation. Activation of DNA damage signaling responses was examined following treatment with RTX. Phosphorylation of replication protein A (RPA2 subunit) and formation of damage-induced foci were strikingly evident following IC(50) doses of RTX. Induction was much more striking following RTX treatment than with hydroxyurea, which is commonly used to inhibit replication. RTX treatment also induced foci of RAD51, gamma-H2AX, phospho-Chk1, and phospho-NBS1, although the extent of co-localization with RPA2 foci varied. Collectively, the results suggest that HR and S-phase checkpoint signaling processes are invoked by thymidylate deprivation and influence cellular resistance to thymidylate deprivation." ], "offsets": [ [ 86, 1892 ] ] } ]

[ { "id": "18773878_T1", "type": "CHEMICAL", "text": [ "thymidylate" ], "offsets": [ [ 1171, 1182 ] ], "normalized": [] }, { "id": "18773878_T2", "type": "CHEMICAL", "text": [ "thymidylate" ], "offsets": [ [ 195, 206 ] ], "normalized": [] }, { "id": "18773878_T3", "type": "CHEMICAL", "text": [ "RTX" ], "offsets": [ [ 1279, 1282 ] ], "normalized": [] }, { "id": "18773878_T4", "type": "CHEMICAL", "text": [ "RTX" ], "offsets": [ [ 1427, 1430 ] ], "normalized": [] }, { "id": "18773878_T5", "type": "CHEMICAL", "text": [ "RTX" ], "offsets": [ [ 1475, 1478 ] ], "normalized": [] }, { "id": "18773878_T6", "type": "CHEMICAL", "text": [ "hydroxyurea" ], "offsets": [ [ 1499, 1510 ] ], "normalized": [] }, { "id": "18773878_T7", "type": "CHEMICAL", "text": [ "RTX" ], "offsets": [ [ 1559, 1562 ] ], "normalized": [] }, { "id": "18773878_T8", "type": "CHEMICAL", "text": [ "thymidylate" ], "offsets": [ [ 1807, 1818 ] ], "normalized": [] }, { "id": "18773878_T9", "type": "CHEMICAL", "text": [ "thymidylate" ], "offsets": [ [ 1868, 1879 ] ], "normalized": [] }, { "id": "18773878_T10", "type": "CHEMICAL", "text": [ "Thymidylate" ], "offsets": [ [ 302, 313 ] ], "normalized": [] }, { "id": "18773878_T11", "type": "CHEMICAL", "text": [ "uracil" ], "offsets": [ [ 345, 351 ] ], "normalized": [] }, { "id": "18773878_T12", "type": "CHEMICAL", "text": [ "Thymidylate" ], "offsets": [ [ 497, 508 ] ], "normalized": [] }, { "id": "18773878_T13", "type": "CHEMICAL", "text": [ "thymidylate" ], "offsets": [ [ 129, 140 ] ], "normalized": [] }, { "id": "18773878_T14", "type": "CHEMICAL", "text": [ "thymidylate" ], "offsets": [ [ 885, 896 ] ], "normalized": [] }, { "id": "18773878_T15", "type": "CHEMICAL", "text": [ "raltitrexed" ], "offsets": [ [ 1005, 1016 ] ], "normalized": [] }, { "id": "18773878_T16", "type": "CHEMICAL", "text": [ "RTX" ], "offsets": [ [ 1018, 1021 ] ], "normalized": [] }, { "id": "18773878_T17", "type": "CHEMICAL", "text": [ "thymidylate" ], "offsets": [ [ 61, 72 ] ], "normalized": [] }, { "id": "18773878_T18", "type": "GENE-Y", "text": [ "RAD51" ], "offsets": [ [ 1143, 1148 ] ], "normalized": [] }, { "id": "18773878_T19", "type": "GENE-Y", "text": [ "thymidylate synthase" ], "offsets": [ [ 195, 215 ] ], "normalized": [] }, { "id": "18773878_T20", "type": "GENE-N", "text": [ "replication protein A" ], "offsets": [ [ 1303, 1324 ] ], "normalized": [] }, { "id": "18773878_T21", "type": "GENE-Y", "text": [ "RPA2" ], "offsets": [ [ 1326, 1330 ] ], "normalized": [] }, { "id": "18773878_T22", "type": "GENE-Y", "text": [ "TS" ], "offsets": [ [ 217, 219 ] ], "normalized": [] }, { "id": "18773878_T23", "type": "GENE-Y", "text": [ "RAD51" ], "offsets": [ [ 1594, 1599 ] ], "normalized": [] }, { "id": "18773878_T24", "type": "GENE-Y", "text": [ "gamma-H2AX" ], "offsets": [ [ 1601, 1611 ] ], "normalized": [] }, { "id": "18773878_T25", "type": "GENE-Y", "text": [ "phospho-Chk1" ], "offsets": [ [ 1613, 1625 ] ], "normalized": [] }, { "id": "18773878_T26", "type": "GENE-Y", "text": [ "phospho-NBS1" ], "offsets": [ [ 1631, 1643 ] ], "normalized": [] }, { "id": "18773878_T27", "type": "GENE-Y", "text": [ "RPA2" ], "offsets": [ [ 1689, 1693 ] ], "normalized": [] }, { "id": "18773878_T28", "type": "GENE-Y", "text": [ "RAD51" ], "offsets": [ [ 915, 920 ] ], "normalized": [] }, { "id": "18773878_T29", "type": "GENE-Y", "text": [ "TS" ], "offsets": [ [ 1052, 1054 ] ], "normalized": [] } ]

[]

[]

[ { "id": "18773878_0", "type": "PRODUCT-OF", "arg1_id": "18773878_T13", "arg2_id": "18773878_T19", "normalized": [] }, { "id": "18773878_1", "type": "PRODUCT-OF", "arg1_id": "18773878_T13", "arg2_id": "18773878_T22", "normalized": [] }, { "id": "18773878_2", "type": "INHIBITOR", "arg1_id": "18773878_T16", "arg2_id": "18773878_T29", "normalized": [] }, { "id": "18773878_3", "type": "INDIRECT-UPREGULATOR", "arg1_id": "18773878_T7", "arg2_id": "18773878_T23", "normalized": [] }, { "id": "18773878_4", "type": "INDIRECT-UPREGULATOR", "arg1_id": "18773878_T7", "arg2_id": "18773878_T24", "normalized": [] }, { "id": "18773878_5", "type": "INDIRECT-UPREGULATOR", "arg1_id": "18773878_T7", "arg2_id": "18773878_T25", "normalized": [] }, { "id": "18773878_6", "type": "INDIRECT-UPREGULATOR", "arg1_id": "18773878_T7", "arg2_id": "18773878_T26", "normalized": [] } ]

[ { "id": "23489521_title", "type": "title", "text": [ "The use of insulin analogues in pregnancy." ], "offsets": [ [ 0, 42 ] ] }, { "id": "23489521_abstract", "type": "abstract", "text": [ "Excellent glycaemic control is essential in pregnancy to optimise maternal and foetal outcomes. The aim of this review is to assess the efficacy and safety of insulin analogues in pregnancy. Insulin lispro and insulin aspart are safe in pregnancy and may improve post-prandial glycaemic control in women with type 1 diabetes. However, a lack of data indicating improved foetal outcomes would suggest that there is no imperative to switch to a short-acting analogue where the woman's diabetes is well controlled with human insulin. There are no reports of the use of insulin glulisine in pregnancy and so its use cannot be recommended. Most studies of insulin glargine in pregnancy are small, retrospective and include women with pre-existing diabetes and gestational diabetes. There appear to be no major safety concerns and so it seems reasonable to continue insulin glargine if required to achieve excellent glycaemic control. A head-to-head comparison between insulin detemir and NPH insulin in women with type 1 diabetes showed that while foetal outcomes did not differ, fasting plasma glucose improved with insulin detemir without an increased incidence of hypoglycaemia. The greater evidence base supports the use of insulin detemir as the first line long-acting analogue in pregnancy but the lack of definitive foetal benefits means that there is no strong need to switch a woman who is well controlled on NPH insulin. There seems little justification in using long acting insulin analogues in women with gestational diabetes or type 2 diabetes where the risk of hypoglycaemia is low." ], "offsets": [ [ 43, 1634 ] ] } ]

[ { "id": "23489521_T1", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 1133, 1140 ] ], "normalized": [] }, { "id": "23489521_T2", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 1155, 1162 ] ], "normalized": [] }, { "id": "23489521_T3", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 1266, 1273 ] ], "normalized": [] }, { "id": "23489521_T4", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 1460, 1467 ] ], "normalized": [] }, { "id": "23489521_T5", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 1523, 1530 ] ], "normalized": [] }, { "id": "23489521_T6", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 202, 209 ] ], "normalized": [] }, { "id": "23489521_T7", "type": "GENE-Y", "text": [ "Insulin" ], "offsets": [ [ 234, 241 ] ], "normalized": [] }, { "id": "23489521_T8", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 253, 260 ] ], "normalized": [] }, { "id": "23489521_T9", "type": "GENE-Y", "text": [ "human insulin" ], "offsets": [ [ 559, 572 ] ], "normalized": [] }, { "id": "23489521_T10", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 609, 616 ] ], "normalized": [] }, { "id": "23489521_T11", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 694, 701 ] ], "normalized": [] }, { "id": "23489521_T12", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 903, 910 ] ], "normalized": [] }, { "id": "23489521_T13", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 1006, 1013 ] ], "normalized": [] }, { "id": "23489521_T14", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 1030, 1037 ] ], "normalized": [] }, { "id": "23489521_T15", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 11, 18 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23489521_0", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23489521_T1", "arg2_id": "23489521_T2", "normalized": [] } ]

[ { "id": "23572520_title", "type": "title", "text": [ "S-nitrosation of glutathione transferase P1-1 is controlled by the conformation of a dynamic active-site helix." ], "offsets": [ [ 0, 111 ] ] }, { "id": "23572520_abstract", "type": "abstract", "text": [ "S-nitrosation is a post-translational modification of protein cysteine residues which occurs in response to cellular oxidative stress. Although it is increasingly being linked to physiologically important processes, the molecular basis for protein regulation by this modification remains poorly understood. We used transient kinetic methods to determine a minimal mechanism for spontaneous GSNO-mediated transnitrosation of human glutathione transferase (GST) P1-1, a major detoxification enzyme and key regulator of cell proliferation. C47 of GSTP1-1 is S-nitrosated in two steps, with the chemical step limited by a pre-equilibrium between the open and closed conformations of helix α2 at the active site. C101, in contrast, is S-nitrosated in a single step but is subject to negative cooperativity due to steric hindrance at the dimer interface. Despite the presence of a GSNO binding site at the active site of GSTP1-1, isothermal titration calorimetry as well as nitrosation experiments using CysNO demonstrate that GSNO binding does not precede S-nitrosation of GSTP1-1. Kinetics experiments using the cellular reductant GSH show that C101-NO is substantially more resistant to denitrosation than C47-NO, suggesting a potential role for C101-NO in long term nitric oxide storage or transfer. These results constitute the first report of the molecular mechanism of spontaneous protein transnitrosation, providing insight into the post-translational control of GSTP1-1 as well as the process of protein transnitrosation in general." ], "offsets": [ [ 112, 1647 ] ] } ]

[ { "id": "23572520_T1", "type": "CHEMICAL", "text": [ "S" ], "offsets": [ [ 112, 113 ] ], "normalized": [] }, { "id": "23572520_T2", "type": "CHEMICAL", "text": [ "S" ], "offsets": [ [ 1163, 1164 ] ], "normalized": [] }, { "id": "23572520_T3", "type": "CHEMICAL", "text": [ "GSH" ], "offsets": [ [ 1239, 1242 ] ], "normalized": [] }, { "id": "23572520_T4", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 1258, 1260 ] ], "normalized": [] }, { "id": "23572520_T5", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 1319, 1321 ] ], "normalized": [] }, { "id": "23572520_T6", "type": "CHEMICAL", "text": [ "NO" ], "offsets": [ [ 1360, 1362 ] ], "normalized": [] }, { "id": "23572520_T7", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 1376, 1388 ] ], "normalized": [] }, { "id": "23572520_T8", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 542, 553 ] ], "normalized": [] }, { "id": "23572520_T9", "type": "CHEMICAL", "text": [ "S" ], "offsets": [ [ 667, 668 ] ], "normalized": [] }, { "id": "23572520_T10", "type": "CHEMICAL", "text": [ "cysteine" ], "offsets": [ [ 174, 182 ] ], "normalized": [] }, { "id": "23572520_T11", "type": "CHEMICAL", "text": [ "S" ], "offsets": [ [ 842, 843 ] ], "normalized": [] }, { "id": "23572520_T12", "type": "CHEMICAL", "text": [ "CysNO" ], "offsets": [ [ 1110, 1115 ] ], "normalized": [] }, { "id": "23572520_T13", "type": "CHEMICAL", "text": [ "S" ], "offsets": [ [ 0, 1 ] ], "normalized": [] }, { "id": "23572520_T14", "type": "CHEMICAL", "text": [ "glutathione" ], "offsets": [ [ 17, 28 ] ], "normalized": [] }, { "id": "23572520_T15", "type": "GENE-Y", "text": [ "GSTP1-1" ], "offsets": [ [ 1180, 1187 ] ], "normalized": [] }, { "id": "23572520_T16", "type": "GENE-Y", "text": [ "GSTP1-1" ], "offsets": [ [ 1577, 1584 ] ], "normalized": [] }, { "id": "23572520_T17", "type": "GENE-Y", "text": [ "human glutathione transferase (GST) P1-1" ], "offsets": [ [ 536, 576 ] ], "normalized": [] }, { "id": "23572520_T18", "type": "GENE-Y", "text": [ "GSTP1-1" ], "offsets": [ [ 656, 663 ] ], "normalized": [] }, { "id": "23572520_T19", "type": "GENE-N", "text": [ "GSNO binding site" ], "offsets": [ [ 987, 1004 ] ], "normalized": [] }, { "id": "23572520_T20", "type": "GENE-Y", "text": [ "GSTP1-1" ], "offsets": [ [ 1027, 1034 ] ], "normalized": [] }, { "id": "23572520_T21", "type": "GENE-Y", "text": [ "glutathione transferase P1-1" ], "offsets": [ [ 17, 45 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23572520_0", "type": "PART-OF", "arg1_id": "23572520_T13", "arg2_id": "23572520_T21", "normalized": [] }, { "id": "23572520_1", "type": "PART-OF", "arg1_id": "23572520_T9", "arg2_id": "23572520_T18", "normalized": [] }, { "id": "23572520_2", "type": "PART-OF", "arg1_id": "23572520_T2", "arg2_id": "23572520_T15", "normalized": [] } ]

[ { "id": "1600046_title", "type": "title", "text": [ "Review article: 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications." ], "offsets": [ [ 0, 145 ] ] }, { "id": "1600046_abstract", "type": "abstract", "text": [ "Serotonin (5-hydroxytryptamine; 5-HT) is found in the enteric nervous system where it has been implicated in controlling gastrointestinal motor function. A number of receptor or recognition sites have been identified in the gut, but recently most attention has focused on the 5-HT3 and 5-HT4 receptors. The functional role of the 5-HT3 receptor remains incompletely understood, but it is probably involved in the modulation of colonic motility and visceral pain in the gut. A number of selective 5-HT3 antagonists have been developed including ondansetron, granisetron, tropisetron renzapride and zacopride. While the substituted benzamide prokinetics (for example, metoclopramide, cisapride) also block 5-HT3 receptors in high concentrations, their prokinetic action is believed to be on the basis of their agonist effects on the putative 5-HT4 receptor. Some 5-HT3 antagonists have 5-HT4 agonist activity (for example, renzapride, zacopride) and others do not (for example, ondansetron, granisetron), while tropisetron in high concentrations is a 5-HT4 antagonist. Based on the pharmacological data, it has been suggested that specific 5-HT antagonists and agonists may prove to be beneficial in a number of gastrointestinal disorders including the irritable bowel syndrome, functional dyspepsia, non-cardiac chest pain, gastrooesophageal reflux and refractory nausea. In this review, the rationale for the use of these compounds is discussed, and the available experimental evidence is summarized." ], "offsets": [ [ 146, 1646 ] ] } ]

[ { "id": "1600046_T1", "type": "CHEMICAL", "text": [ "Serotonin" ], "offsets": [ [ 146, 155 ] ], "normalized": [] }, { "id": "1600046_T2", "type": "CHEMICAL", "text": [ "tropisetron" ], "offsets": [ [ 1155, 1166 ] ], "normalized": [] }, { "id": "1600046_T3", "type": "CHEMICAL", "text": [ "5-hydroxytryptamine" ], "offsets": [ [ 157, 176 ] ], "normalized": [] }, { "id": "1600046_T4", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 1284, 1288 ] ], "normalized": [] }, { "id": "1600046_T5", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 178, 182 ] ], "normalized": [] }, { "id": "1600046_T6", "type": "CHEMICAL", "text": [ "ondansetron" ], "offsets": [ [ 690, 701 ] ], "normalized": [] }, { "id": "1600046_T7", "type": "CHEMICAL", "text": [ "granisetron" ], "offsets": [ [ 703, 714 ] ], "normalized": [] }, { "id": "1600046_T8", "type": "CHEMICAL", "text": [ "tropisetron" ], "offsets": [ [ 716, 727 ] ], "normalized": [] }, { "id": "1600046_T9", "type": "CHEMICAL", "text": [ "renzapride" ], "offsets": [ [ 728, 738 ] ], "normalized": [] }, { "id": "1600046_T10", "type": "CHEMICAL", "text": [ "zacopride" ], "offsets": [ [ 743, 752 ] ], "normalized": [] }, { "id": "1600046_T11", "type": "CHEMICAL", "text": [ "benzamide" ], "offsets": [ [ 776, 785 ] ], "normalized": [] }, { "id": "1600046_T12", "type": "CHEMICAL", "text": [ "metoclopramide" ], "offsets": [ [ 812, 826 ] ], "normalized": [] }, { "id": "1600046_T13", "type": "CHEMICAL", "text": [ "cisapride" ], "offsets": [ [ 828, 837 ] ], "normalized": [] }, { "id": "1600046_T14", "type": "CHEMICAL", "text": [ "renzapride" ], "offsets": [ [ 1067, 1077 ] ], "normalized": [] }, { "id": "1600046_T15", "type": "CHEMICAL", "text": [ "zacopride" ], "offsets": [ [ 1079, 1088 ] ], "normalized": [] }, { "id": "1600046_T16", "type": "CHEMICAL", "text": [ "ondansetron" ], "offsets": [ [ 1122, 1133 ] ], "normalized": [] }, { "id": "1600046_T17", "type": "CHEMICAL", "text": [ "granisetron" ], "offsets": [ [ 1135, 1146 ] ], "normalized": [] }, { "id": "1600046_T18", "type": "CHEMICAL", "text": [ "5-hydroxytryptamine" ], "offsets": [ [ 16, 35 ] ], "normalized": [] }, { "id": "1600046_T19", "type": "GENE-Y", "text": [ "5-HT4" ], "offsets": [ [ 1195, 1200 ] ], "normalized": [] }, { "id": "1600046_T20", "type": "GENE-Y", "text": [ "5-HT3" ], "offsets": [ [ 422, 427 ] ], "normalized": [] }, { "id": "1600046_T21", "type": "GENE-Y", "text": [ "5-HT4" ], "offsets": [ [ 432, 437 ] ], "normalized": [] }, { "id": "1600046_T22", "type": "GENE-Y", "text": [ "5-HT3" ], "offsets": [ [ 476, 481 ] ], "normalized": [] }, { "id": "1600046_T23", "type": "GENE-Y", "text": [ "5-HT3" ], "offsets": [ [ 642, 647 ] ], "normalized": [] }, { "id": "1600046_T24", "type": "GENE-Y", "text": [ "5-HT3" ], "offsets": [ [ 850, 855 ] ], "normalized": [] }, { "id": "1600046_T25", "type": "GENE-Y", "text": [ "5-HT4" ], "offsets": [ [ 986, 991 ] ], "normalized": [] }, { "id": "1600046_T26", "type": "GENE-Y", "text": [ "5-HT3" ], "offsets": [ [ 1007, 1012 ] ], "normalized": [] }, { "id": "1600046_T27", "type": "GENE-Y", "text": [ "5-HT4" ], "offsets": [ [ 1030, 1035 ] ], "normalized": [] } ]

[]

[]

[ { "id": "1600046_0", "type": "ANTAGONIST", "arg1_id": "1600046_T6", "arg2_id": "1600046_T23", "normalized": [] }, { "id": "1600046_1", "type": "ANTAGONIST", "arg1_id": "1600046_T7", "arg2_id": "1600046_T23", "normalized": [] }, { "id": "1600046_2", "type": "ANTAGONIST", "arg1_id": "1600046_T8", "arg2_id": "1600046_T23", "normalized": [] }, { "id": "1600046_3", "type": "ANTAGONIST", "arg1_id": "1600046_T9", "arg2_id": "1600046_T23", "normalized": [] }, { "id": "1600046_4", "type": "ANTAGONIST", "arg1_id": "1600046_T10", "arg2_id": "1600046_T23", "normalized": [] }, { "id": "1600046_5", "type": "INHIBITOR", "arg1_id": "1600046_T11", "arg2_id": "1600046_T24", "normalized": [] }, { "id": "1600046_6", "type": "INHIBITOR", "arg1_id": "1600046_T12", "arg2_id": "1600046_T24", "normalized": [] }, { "id": "1600046_7", "type": "INHIBITOR", "arg1_id": "1600046_T13", "arg2_id": "1600046_T24", "normalized": [] }, { "id": "1600046_8", "type": "ANTAGONIST", "arg1_id": "1600046_T14", "arg2_id": "1600046_T26", "normalized": [] }, { "id": "1600046_9", "type": "AGONIST", "arg1_id": "1600046_T14", "arg2_id": "1600046_T27", "normalized": [] }, { "id": "1600046_10", "type": "ANTAGONIST", "arg1_id": "1600046_T15", "arg2_id": "1600046_T26", "normalized": [] }, { "id": "1600046_11", "type": "AGONIST", "arg1_id": "1600046_T15", "arg2_id": "1600046_T27", "normalized": [] }, { "id": "1600046_12", "type": "ANTAGONIST", "arg1_id": "1600046_T2", "arg2_id": "1600046_T19", "normalized": [] }, { "id": "1600046_13", "type": "AGONIST", "arg1_id": "1600046_T11", "arg2_id": "1600046_T25", "normalized": [] }, { "id": "1600046_14", "type": "AGONIST", "arg1_id": "1600046_T12", "arg2_id": "1600046_T25", "normalized": [] }, { "id": "1600046_15", "type": "AGONIST", "arg1_id": "1600046_T13", "arg2_id": "1600046_T25", "normalized": [] } ]

[ { "id": "15606893_title", "type": "title", "text": [ "Characterization of an allosteric citalopram-binding site at the serotonin transporter." ], "offsets": [ [ 0, 87 ] ] }, { "id": "15606893_abstract", "type": "abstract", "text": [ "The serotonin transporter (SERT), which belongs to a family of sodium/chloride-dependent transporters, is the major pharmacological target in the treatment of several clinical disorders, including depression and anxiety. In the present study we show that the dissociation rate, of [3H]S-citalopram from human SERT, is retarded by the presence of serotonin, as well as by several antidepressants, when present in the dissociation buffer. Dissociation of [3H]S-citalopram from SERT is most potently inhibited by S-citalopram followed by R-citalopram, sertraline, serotonin and paroxetine. EC50 values for S- and R-citalopram are 3.6 +/- 0.4 microm and 19.4 +/- 2.3 microm, respectively. Fluoxetine, venlafaxine and duloxetine have no significant effect on the dissociation of [3H]S-citalopram. Allosteric modulation of dissociation is independent of temperature, or the presence of Na+ in the dissociation buffer. Dissociation of [3H]S-citalopram from a complex with the SERT double-mutant, N208Q/N217Q, which has been suggested to be unable to self-assemble into oligomeric complexes, is retarded to an extent similar to that found with the wild-type, raising the possibility that the allosteric mechanism is mediated within a single subunit. A species-scanning mutagenesis study comparing human and bovine SERT revealed that Met180, Tyr495 and Ser513 are important residues in mediating the allosteric effect, as well as contributing to high-affinity binding at the primary site." ], "offsets": [ [ 88, 1567 ] ] } ]

[ { "id": "15606893_T1", "type": "CHEMICAL", "text": [ "[3H]S-citalopram" ], "offsets": [ [ 369, 385 ] ], "normalized": [] }, { "id": "15606893_T2", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 434, 443 ] ], "normalized": [] }, { "id": "15606893_T3", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 92, 101 ] ], "normalized": [] }, { "id": "15606893_T4", "type": "CHEMICAL", "text": [ "[3H]S-citalopram" ], "offsets": [ [ 541, 557 ] ], "normalized": [] }, { "id": "15606893_T5", "type": "CHEMICAL", "text": [ "S-citalopram" ], "offsets": [ [ 598, 610 ] ], "normalized": [] }, { "id": "15606893_T6", "type": "CHEMICAL", "text": [ "R-citalopram" ], "offsets": [ [ 623, 635 ] ], "normalized": [] }, { "id": "15606893_T7", "type": "CHEMICAL", "text": [ "sertraline" ], "offsets": [ [ 637, 647 ] ], "normalized": [] }, { "id": "15606893_T8", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 649, 658 ] ], "normalized": [] }, { "id": "15606893_T9", "type": "CHEMICAL", "text": [ "paroxetine" ], "offsets": [ [ 663, 673 ] ], "normalized": [] }, { "id": "15606893_T10", "type": "CHEMICAL", "text": [ "S- and R-citalopram" ], "offsets": [ [ 691, 710 ] ], "normalized": [] }, { "id": "15606893_T11", "type": "CHEMICAL", "text": [ "sodium" ], "offsets": [ [ 151, 157 ] ], "normalized": [] }, { "id": "15606893_T12", "type": "CHEMICAL", "text": [ "Fluoxetine" ], "offsets": [ [ 773, 783 ] ], "normalized": [] }, { "id": "15606893_T13", "type": "CHEMICAL", "text": [ "venlafaxine" ], "offsets": [ [ 785, 796 ] ], "normalized": [] }, { "id": "15606893_T14", "type": "CHEMICAL", "text": [ "chloride" ], "offsets": [ [ 158, 166 ] ], "normalized": [] }, { "id": "15606893_T15", "type": "CHEMICAL", "text": [ "duloxetine" ], "offsets": [ [ 801, 811 ] ], "normalized": [] }, { "id": "15606893_T16", "type": "CHEMICAL", "text": [ "[3H]S-citalopram" ], "offsets": [ [ 862, 878 ] ], "normalized": [] }, { "id": "15606893_T17", "type": "CHEMICAL", "text": [ "Na+" ], "offsets": [ [ 968, 971 ] ], "normalized": [] }, { "id": "15606893_T18", "type": "CHEMICAL", "text": [ "[3H]S-citalopram" ], "offsets": [ [ 1016, 1032 ] ], "normalized": [] }, { "id": "15606893_T19", "type": "CHEMICAL", "text": [ "citalopram" ], "offsets": [ [ 34, 44 ] ], "normalized": [] }, { "id": "15606893_T20", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 65, 74 ] ], "normalized": [] }, { "id": "15606893_T21", "type": "GENE-N", "text": [ "human and bovine SERT" ], "offsets": [ [ 1377, 1398 ] ], "normalized": [] }, { "id": "15606893_T22", "type": "GENE-Y", "text": [ "SERT" ], "offsets": [ [ 115, 119 ] ], "normalized": [] }, { "id": "15606893_T23", "type": "GENE-Y", "text": [ "human SERT" ], "offsets": [ [ 391, 401 ] ], "normalized": [] }, { "id": "15606893_T24", "type": "GENE-Y", "text": [ "serotonin transporter" ], "offsets": [ [ 92, 113 ] ], "normalized": [] }, { "id": "15606893_T25", "type": "GENE-Y", "text": [ "SERT" ], "offsets": [ [ 563, 567 ] ], "normalized": [] }, { "id": "15606893_T26", "type": "GENE-N", "text": [ "sodium/chloride-dependent transporters" ], "offsets": [ [ 151, 189 ] ], "normalized": [] }, { "id": "15606893_T27", "type": "GENE-Y", "text": [ "SERT" ], "offsets": [ [ 1057, 1061 ] ], "normalized": [] }, { "id": "15606893_T28", "type": "GENE-N", "text": [ "N208Q" ], "offsets": [ [ 1077, 1082 ] ], "normalized": [] }, { "id": "15606893_T29", "type": "GENE-N", "text": [ "N217Q" ], "offsets": [ [ 1083, 1088 ] ], "normalized": [] }, { "id": "15606893_T30", "type": "GENE-Y", "text": [ "serotonin transporter" ], "offsets": [ [ 65, 86 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23266271_title", "type": "title", "text": [ "Radioprotection by two phenolic compounds: chlorogenic and quinic acid, on X-ray induced DNA damage in human blood lymphocytes in vitro." ], "offsets": [ [ 0, 136 ] ] }, { "id": "23266271_abstract", "type": "abstract", "text": [ "The present study was designed to determine the radioprotective effect of two phytochemicals, namely, quinic acid and chlorogenic acid, against X-ray irradiation-induced genomic instability in non-tumorigenic human blood lymphocytes. The protective ability of two phenolic acids against radiation-induced DNA damage was assessed using the alkaline comet assay in human blood lymphocytes isolated from two healthy human donors. A Siemens Mevatron MD2 (Siemens AG, USA, 1994) linear accelerator was used for irradiation. The results of the alkaline comet assay revealed that quinic acid and chlorogenic acid decreased the DNA damage induced by X-ray irradiation and provided a significant radioprotective effect. Quinic acid decreased the presence of irradiation-induced DNA damage by 5.99-53.57% and chlorogenic acid by 4.49-48.15%, as determined by the alkaline comet assay. The results show that quinic acid and chlorogenic acid may act as radioprotective compounds. Future studies should focus on determining the mechanism by which these phenolic acids provide radioprotection." ], "offsets": [ [ 137, 1216 ] ] } ]

[ { "id": "23266271_T1", "type": "CHEMICAL", "text": [ "quinic acid" ], "offsets": [ [ 239, 250 ] ], "normalized": [] }, { "id": "23266271_T2", "type": "CHEMICAL", "text": [ "phenolic acids" ], "offsets": [ [ 1177, 1191 ] ], "normalized": [] }, { "id": "23266271_T3", "type": "CHEMICAL", "text": [ "chlorogenic acid" ], "offsets": [ [ 255, 271 ] ], "normalized": [] }, { "id": "23266271_T4", "type": "CHEMICAL", "text": [ "phenolic acids" ], "offsets": [ [ 401, 415 ] ], "normalized": [] }, { "id": "23266271_T5", "type": "CHEMICAL", "text": [ "quinic acid" ], "offsets": [ [ 710, 721 ] ], "normalized": [] }, { "id": "23266271_T6", "type": "CHEMICAL", "text": [ "chlorogenic acid" ], "offsets": [ [ 726, 742 ] ], "normalized": [] }, { "id": "23266271_T7", "type": "CHEMICAL", "text": [ "Quinic acid" ], "offsets": [ [ 848, 859 ] ], "normalized": [] }, { "id": "23266271_T8", "type": "CHEMICAL", "text": [ "chlorogenic acid" ], "offsets": [ [ 936, 952 ] ], "normalized": [] }, { "id": "23266271_T9", "type": "CHEMICAL", "text": [ "quinic acid" ], "offsets": [ [ 1034, 1045 ] ], "normalized": [] }, { "id": "23266271_T10", "type": "CHEMICAL", "text": [ "chlorogenic acid" ], "offsets": [ [ 1050, 1066 ] ], "normalized": [] }, { "id": "23266271_T11", "type": "CHEMICAL", "text": [ "phenolic" ], "offsets": [ [ 23, 31 ] ], "normalized": [] }, { "id": "23266271_T12", "type": "CHEMICAL", "text": [ "chlorogenic and quinic acid" ], "offsets": [ [ 43, 70 ] ], "normalized": [] } ]

[]

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[ { "id": "15680473_title", "type": "title", "text": [ "Cocaine- and amphetamine-regulated transcript peptide potentiates spinal glutamatergic sympathoexcitation in anesthetized rats." ], "offsets": [ [ 0, 127 ] ] }, { "id": "15680473_abstract", "type": "abstract", "text": [ "Cocaine- and amphetamine-regulated transcript (CART) is widely expressed in the rat central nervous system, notably in areas involved in control of autonomic and neuroendocrine functions. The aim of this study was to evaluate the effects of CART peptide fragment 55-102, referred to herein as CARTp, by intrathecal injection on blood pressure (BP) and heart rate (HR) before and after intrathecal glutamate in urethane-anesthetized male Sprague-Dawley rats. CARTp (0.1-10 nmol) administered intrathecally caused no or a small, statistically insignificant increase of blood pressure and heart rate, except at the concentration of 10 nmol, which caused a significant increase of blood pressure and heart rate. Intrathecal glutamate (0.1-10 nmol) produced a dose-dependent increase in arterial pressure and heart rate. Pretreatment with CARTp dose-dependently potentiated the pressor effects of glutamate (1 nmol), which by itself elicited a moderate increase of blood pressure and heart rate. Further, CARTp significantly potentiated the tachycardic effect of glutamate at 1 and 5 nmol, but attenuated the response at 10 nmol. The effect of CARTp was long-lasting, as it enhanced glutamatergic responses up to 90 min after administration. Prior injection of CARTp antiserum (1:500) but not normal rabbit serum nullified the potentiating effect of CARTp on glutamatergic responses. The result suggests that CARTp, whose immunoreactivity is detectable in sympathetic preganglionic neurons as well as in fibers projecting into the intermediolateral cell column, augments spinal sympathetic outflow elicited by glutamate at lower concentrations and may directly excite neurons in the intermediolateral cell column at higher concentrations." ], "offsets": [ [ 128, 1861 ] ] } ]

[ { "id": "15680473_T1", "type": "CHEMICAL", "text": [ "Cocaine" ], "offsets": [ [ 128, 135 ] ], "normalized": [] }, { "id": "15680473_T2", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 1186, 1195 ] ], "normalized": [] }, { "id": "15680473_T3", "type": "CHEMICAL", "text": [ "amphetamine" ], "offsets": [ [ 141, 152 ] ], "normalized": [] }, { "id": "15680473_T4", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 1733, 1742 ] ], "normalized": [] }, { "id": "15680473_T5", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 525, 534 ] ], "normalized": [] }, { "id": "15680473_T6", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 848, 857 ] ], "normalized": [] }, { "id": "15680473_T7", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 1020, 1029 ] ], "normalized": [] }, { "id": "15680473_T8", "type": "CHEMICAL", "text": [ "Cocaine" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "15680473_T9", "type": "CHEMICAL", "text": [ "amphetamine" ], "offsets": [ [ 13, 24 ] ], "normalized": [] }, { "id": "15680473_T10", "type": "GENE-Y", "text": [ "Cocaine- and amphetamine-regulated transcript" ], "offsets": [ [ 128, 173 ] ], "normalized": [] }, { "id": "15680473_T11", "type": "GENE-Y", "text": [ "CARTp" ], "offsets": [ [ 1128, 1133 ] ], "normalized": [] }, { "id": "15680473_T12", "type": "GENE-Y", "text": [ "CARTp" ], "offsets": [ [ 1267, 1272 ] ], "normalized": [] }, { "id": "15680473_T13", "type": "GENE-Y", "text": [ "CARTp" ], "offsets": [ [ 1384, 1389 ] ], "normalized": [] }, { "id": "15680473_T14", "type": "GENE-Y", "text": [ "CARTp" ], "offsets": [ [ 1473, 1478 ] ], "normalized": [] }, { "id": "15680473_T15", "type": "GENE-Y", "text": [ "CARTp" ], "offsets": [ [ 1532, 1537 ] ], "normalized": [] }, { "id": "15680473_T16", "type": "GENE-Y", "text": [ "CART peptide" ], "offsets": [ [ 369, 381 ] ], "normalized": [] }, { "id": "15680473_T17", "type": "GENE-Y", "text": [ "CARTp" ], "offsets": [ [ 421, 426 ] ], "normalized": [] }, { "id": "15680473_T18", "type": "GENE-Y", "text": [ "CARTp" ], "offsets": [ [ 586, 591 ] ], "normalized": [] }, { "id": "15680473_T19", "type": "GENE-Y", "text": [ "CART" ], "offsets": [ [ 175, 179 ] ], "normalized": [] }, { "id": "15680473_T20", "type": "GENE-Y", "text": [ "CARTp" ], "offsets": [ [ 962, 967 ] ], "normalized": [] }, { "id": "15680473_T21", "type": "GENE-Y", "text": [ "Cocaine- and amphetamine-regulated transcript peptide" ], "offsets": [ [ 0, 53 ] ], "normalized": [] } ]

[]

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[ { "id": "10864881_title", "type": "title", "text": [ "Betaxolol, a beta(1)-adrenoceptor antagonist, reduces Na(+) influx into cortical synaptosomes by direct interaction with Na(+) channels: comparison with other beta-adrenoceptor antagonists." ], "offsets": [ [ 0, 189 ] ] }, { "id": "10864881_abstract", "type": "abstract", "text": [ "Betaxolol, a beta(1)-adrenoceptor antagonist used for the treatment of glaucoma, is known to be neuroprotective in paradigms of ischaemia/excitotoxicity. In this study, we examined whether betaxolol and other beta-adrenoceptor antagonists interact directly with neurotoxin binding to sites 1 and 2 of the voltage-sensitive sodium channel (Na(+) channel) in rat cerebrocortical synaptosomes. Betaxolol inhibited specific [(3)H]-batrachotoxinin-A 20-alpha-benzoate ([(3)H]-BTX-B) binding to neurotoxin site 2 in a concentration-dependent manner with an IC(50) value of 9.8 microM. Comparison of all the beta-adrenoceptor antagonists tested revealed a potency order of propranolol>betaxolol approximately levobetaxolol>levobunolol approximately carteolol>/=timolol>atenolol. None of the drugs caused a significant inhibition of [(3)H]-saxitoxin binding to neurotoxin receptor site 1, even at concentrations as high as 250 microM. Saturation experiments showed that betaxolol increased the K(D) of [(3)H]-BTX-B binding but had no effect on the B(max). The association kinetics of [(3)H]-BTX-B were unaffected by betaxolol, but the drug significantly accelerated the dissociation rate of the radioligand. These findings argue for a competitive, indirect, allosteric mode of inhibition of [(3)H]-BTX-B binding by betaxolol. Betaxolol inhibited veratridine-stimulated Na(+) influx in rat cortical synaptosomes with an IC(50) value of 28. 3 microM. Carteolol, levobunolol, timolol and atenolol were significantly less effective than betaxolol at reducing veratridine-evoked Na(+) influx. The ability of betaxolol to interact with neurotoxin site 2 of the Na(+) channel and inhibit Na(+) influx may have a role in its neuroprotective action in paradigms of excitotoxicity/ischaemia and in its therapeutic effect in glaucoma." ], "offsets": [ [ 190, 2005 ] ] } ]

[ { "id": "10864881_T1", "type": "CHEMICAL", "text": [ "Betaxolol" ], "offsets": [ [ 190, 199 ] ], "normalized": [] }, { "id": "10864881_T2", "type": "CHEMICAL", "text": [ "[(3)H]-BTX-B" ], "offsets": [ [ 1266, 1278 ] ], "normalized": [] }, { "id": "10864881_T3", "type": "CHEMICAL", "text": [ "betaxolol" ], "offsets": [ [ 1298, 1307 ] ], "normalized": [] }, { "id": "10864881_T4", "type": "CHEMICAL", "text": [ "[(3)H]-BTX-B" ], "offsets": [ [ 1473, 1485 ] ], "normalized": [] }, { "id": "10864881_T5", "type": "CHEMICAL", "text": [ "betaxolol" ], "offsets": [ [ 1497, 1506 ] ], "normalized": [] }, { "id": "10864881_T6", "type": "CHEMICAL", "text": [ "Betaxolol" ], "offsets": [ [ 1508, 1517 ] ], "normalized": [] }, { "id": "10864881_T7", "type": "CHEMICAL", "text": [ "veratridine" ], "offsets": [ [ 1528, 1539 ] ], "normalized": [] }, { "id": "10864881_T8", "type": "CHEMICAL", "text": [ "Na(+)" ], "offsets": [ [ 1551, 1556 ] ], "normalized": [] }, { "id": "10864881_T9", "type": "CHEMICAL", "text": [ "Carteolol" ], "offsets": [ [ 1631, 1640 ] ], "normalized": [] }, { "id": "10864881_T10", "type": "CHEMICAL", "text": [ "levobunolol" ], "offsets": [ [ 1642, 1653 ] ], "normalized": [] }, { "id": "10864881_T11", "type": "CHEMICAL", "text": [ "timolol" ], "offsets": [ [ 1655, 1662 ] ], "normalized": [] }, { "id": "10864881_T12", "type": "CHEMICAL", "text": [ "atenolol" ], "offsets": [ [ 1667, 1675 ] ], "normalized": [] }, { "id": "10864881_T13", "type": "CHEMICAL", "text": [ "betaxolol" ], "offsets": [ [ 1715, 1724 ] ], "normalized": [] }, { "id": "10864881_T14", "type": "CHEMICAL", "text": [ "veratridine" ], "offsets": [ [ 1737, 1748 ] ], "normalized": [] }, { "id": "10864881_T15", "type": "CHEMICAL", "text": [ "Na(+)" ], "offsets": [ [ 1756, 1761 ] ], "normalized": [] }, { "id": "10864881_T16", "type": "CHEMICAL", "text": [ "betaxolol" ], "offsets": [ [ 1785, 1794 ] ], "normalized": [] }, { "id": "10864881_T17", "type": "CHEMICAL", "text": [ "Na(+)" ], "offsets": [ [ 1837, 1842 ] ], "normalized": [] }, { "id": "10864881_T18", "type": "CHEMICAL", "text": [ "Na(+)" ], "offsets": [ [ 1863, 1868 ] ], "normalized": [] }, { "id": "10864881_T19", "type": "CHEMICAL", "text": [ "betaxolol" ], "offsets": [ [ 379, 388 ] ], "normalized": [] }, { "id": "10864881_T20", "type": "CHEMICAL", "text": [ "sodium" ], "offsets": [ [ 513, 519 ] ], "normalized": [] }, { "id": "10864881_T21", "type": "CHEMICAL", "text": [ "Na(+)" ], "offsets": [ [ 529, 534 ] ], "normalized": [] }, { "id": "10864881_T22", "type": "CHEMICAL", "text": [ "Betaxolol" ], "offsets": [ [ 581, 590 ] ], "normalized": [] }, { "id": "10864881_T23", "type": "CHEMICAL", "text": [ "[(3)H]-batrachotoxinin-A 20-alpha-benzoate" ], "offsets": [ [ 610, 652 ] ], "normalized": [] }, { "id": "10864881_T24", "type": "CHEMICAL", "text": [ "[(3)H]-BTX-B" ], "offsets": [ [ 654, 666 ] ], "normalized": [] }, { "id": "10864881_T25", "type": "CHEMICAL", "text": [ "propranolol" ], "offsets": [ [ 856, 867 ] ], "normalized": [] }, { "id": "10864881_T26", "type": "CHEMICAL", "text": [ "betaxolol" ], "offsets": [ [ 868, 877 ] ], "normalized": [] }, { "id": "10864881_T27", "type": "CHEMICAL", "text": [ "levobetaxolol" ], "offsets": [ [ 892, 905 ] ], "normalized": [] }, { "id": "10864881_T28", "type": "CHEMICAL", "text": [ "levobunolol" ], "offsets": [ [ 906, 917 ] ], "normalized": [] }, { "id": "10864881_T29", "type": "CHEMICAL", "text": [ "carteolol" ], "offsets": [ [ 932, 941 ] ], "normalized": [] }, { "id": "10864881_T30", "type": "CHEMICAL", "text": [ "timolol" ], "offsets": [ [ 944, 951 ] ], "normalized": [] }, { "id": "10864881_T31", "type": "CHEMICAL", "text": [ "atenolol" ], "offsets": [ [ 952, 960 ] ], "normalized": [] }, { "id": "10864881_T32", "type": "CHEMICAL", "text": [ "[(3)H]-saxitoxin" ], "offsets": [ [ 1015, 1031 ] ], "normalized": [] }, { "id": "10864881_T33", "type": "CHEMICAL", "text": [ "betaxolol" ], "offsets": [ [ 1152, 1161 ] ], "normalized": [] }, { "id": "10864881_T34", "type": "CHEMICAL", "text": [ "[(3)H]-BTX-B" ], "offsets": [ [ 1184, 1196 ] ], "normalized": [] }, { "id": "10864881_T35", "type": "CHEMICAL", "text": [ "Betaxolol" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "10864881_T36", "type": "CHEMICAL", "text": [ "Na(+)" ], "offsets": [ [ 121, 126 ] ], "normalized": [] }, { "id": "10864881_T37", "type": "CHEMICAL", "text": [ "Na(+)" ], "offsets": [ [ 54, 59 ] ], "normalized": [] }, { "id": "10864881_T38", "type": "GENE-Y", "text": [ "beta(1)-adrenoceptor" ], "offsets": [ [ 203, 223 ] ], "normalized": [] }, { "id": "10864881_T39", "type": "GENE-N", "text": [ "Na(+) channel" ], "offsets": [ [ 1837, 1850 ] ], "normalized": [] }, { "id": "10864881_T40", "type": "GENE-N", "text": [ "beta-adrenoceptor" ], "offsets": [ [ 399, 416 ] ], "normalized": [] }, { "id": "10864881_T41", "type": "GENE-N", "text": [ "voltage-sensitive sodium channel" ], "offsets": [ [ 495, 527 ] ], "normalized": [] }, { "id": "10864881_T42", "type": "GENE-N", "text": [ "Na(+) channel" ], "offsets": [ [ 529, 542 ] ], "normalized": [] }, { "id": "10864881_T43", "type": "GENE-N", "text": [ "neurotoxin site 2" ], "offsets": [ [ 679, 696 ] ], "normalized": [] }, { "id": "10864881_T44", "type": "GENE-N", "text": [ "beta-adrenoceptor" ], "offsets": [ [ 791, 808 ] ], "normalized": [] }, { "id": "10864881_T45", "type": "GENE-N", "text": [ "neurotoxin receptor site 1" ], "offsets": [ [ 1043, 1069 ] ], "normalized": [] }, { "id": "10864881_T46", "type": "GENE-N", "text": [ "Na(+) channels" ], "offsets": [ [ 121, 135 ] ], "normalized": [] }, { "id": "10864881_T47", "type": "GENE-Y", "text": [ "beta(1)-adrenoceptor" ], "offsets": [ [ 13, 33 ] ], "normalized": [] }, { "id": "10864881_T48", "type": "GENE-N", "text": [ "beta-adrenoceptor" ], "offsets": [ [ 159, 176 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "11078056_title", "type": "title", "text": [ "Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia." ], "offsets": [ [ 0, 96 ] ] }, { "id": "11078056_abstract", "type": "abstract", "text": [ "Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers." ], "offsets": [ [ 97, 2208 ] ] } ]

[ { "id": "11078056_T1", "type": "CHEMICAL", "text": [ "rofecoxib" ], "offsets": [ [ 1105, 1114 ] ], "normalized": [] }, { "id": "11078056_T2", "type": "CHEMICAL", "text": [ "MK-0966" ], "offsets": [ [ 1116, 1123 ] ], "normalized": [] }, { "id": "11078056_T3", "type": "CHEMICAL", "text": [ "meloxicam" ], "offsets": [ [ 1233, 1242 ] ], "normalized": [] }, { "id": "11078056_T4", "type": "CHEMICAL", "text": [ "NS-398" ], "offsets": [ [ 1401, 1407 ] ], "normalized": [] }, { "id": "11078056_T5", "type": "CHEMICAL", "text": [ "flurbiprofen" ], "offsets": [ [ 1742, 1754 ] ], "normalized": [] }, { "id": "11078056_T6", "type": "CHEMICAL", "text": [ "prostaglandins" ], "offsets": [ [ 303, 317 ] ], "normalized": [] }, { "id": "11078056_T7", "type": "CHEMICAL", "text": [ "prostaglandin" ], "offsets": [ [ 420, 433 ] ], "normalized": [] }, { "id": "11078056_T8", "type": "CHEMICAL", "text": [ "aspirin" ], "offsets": [ [ 579, 586 ] ], "normalized": [] }, { "id": "11078056_T9", "type": "CHEMICAL", "text": [ "sulindac" ], "offsets": [ [ 620, 628 ] ], "normalized": [] }, { "id": "11078056_T10", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 633, 645 ] ], "normalized": [] }, { "id": "11078056_T11", "type": "CHEMICAL", "text": [ "meloxicam" ], "offsets": [ [ 1068, 1077 ] ], "normalized": [] }, { "id": "11078056_T12", "type": "CHEMICAL", "text": [ "celecoxib" ], "offsets": [ [ 1079, 1088 ] ], "normalized": [] }, { "id": "11078056_T13", "type": "CHEMICAL", "text": [ "SC-58635" ], "offsets": [ [ 1090, 1098 ] ], "normalized": [] }, { "id": "11078056_T14", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1198, 1203 ] ], "normalized": [] }, { "id": "11078056_T15", "type": "GENE-Y", "text": [ "COX-1" ], "offsets": [ [ 1212, 1217 ] ], "normalized": [] }, { "id": "11078056_T16", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1327, 1332 ] ], "normalized": [] }, { "id": "11078056_T17", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1394, 1399 ] ], "normalized": [] }, { "id": "11078056_T18", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1429, 1434 ] ], "normalized": [] }, { "id": "11078056_T19", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1542, 1547 ] ], "normalized": [] }, { "id": "11078056_T20", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 251, 256 ] ], "normalized": [] }, { "id": "11078056_T21", "type": "GENE-Y", "text": [ "Bcl-2" ], "offsets": [ [ 1666, 1671 ] ], "normalized": [] }, { "id": "11078056_T22", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1756, 1761 ] ], "normalized": [] }, { "id": "11078056_T23", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1771, 1776 ] ], "normalized": [] }, { "id": "11078056_T24", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1921, 1926 ] ], "normalized": [] }, { "id": "11078056_T25", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 288, 293 ] ], "normalized": [] }, { "id": "11078056_T26", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 2078, 2083 ] ], "normalized": [] }, { "id": "11078056_T27", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 396, 401 ] ], "normalized": [] }, { "id": "11078056_T28", "type": "GENE-Y", "text": [ "cyclooxygenase (COX) -2" ], "offsets": [ [ 139, 162 ] ], "normalized": [] }, { "id": "11078056_T29", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 725, 730 ] ], "normalized": [] }, { "id": "11078056_T30", "type": "GENE-Y", "text": [ "COX-1" ], "offsets": [ [ 780, 785 ] ], "normalized": [] }, { "id": "11078056_T31", "type": "GENE-Y", "text": [ "COX-1" ], "offsets": [ [ 171, 176 ] ], "normalized": [] }, { "id": "11078056_T32", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 950, 955 ] ], "normalized": [] }, { "id": "11078056_T33", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 1042, 1047 ] ], "normalized": [] }, { "id": "11078056_T34", "type": "GENE-Y", "text": [ "cyclooxygenase (COX)-2" ], "offsets": [ [ 16, 38 ] ], "normalized": [] }, { "id": "11078056_T35", "type": "GENE-Y", "text": [ "COX-2" ], "offsets": [ [ 77, 82 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "9145928_title", "type": "title", "text": [ "Study of the interaction between aryloxypropanolamines and Asn386 in helix VII of the human 5-hydroxytryptamine1A receptor." ], "offsets": [ [ 0, 123 ] ] }, { "id": "9145928_abstract", "type": "abstract", "text": [ "We studied the stereoselective interaction between aryloxypropanolamines and the human 5-hydroxytryptamine1A (5-HT1A) receptor. R- and S-enantiomers of propranolol, penbutolol, and alprenolol were investigated for their ability to bind to human 5-HT1A wild-type and Asn386Val mutant receptors. Asn386 seemed to act as a chiral discriminator. Although both aryloxypropanol enantiomers displayed lower affinity for the mutant receptors, the affinities for the S-enantiomers were more affected. Receptor affinities of other structurally unrelated 5-HT1A ligands were not decreased by the mutation of Asn386 to valine. In addition, a series of analogues of propranolol with structural variation in the oxypropanolamine moiety was synthesized, and affinities for wild-type and Asn386Val mutant 5-HT1A receptors were determined. Both the hydroxyl and the ether oxygen atoms of the oxypropanol moiety seem to be required for binding at wild-type 5-HT1A receptors. The hydroxyl group of propranolol probably directly interacts with Asn386. The ether oxygen atom may be important for steric reasons but can also be involved in a direct interaction with Asn386. These findings are in agreement with the interactions of aryloxypropanolamines with Asn386 in rat 5-HT1A receptors that we previously proposed. The loss of affinity for propranolol by the Asn386Val mutation could be regained by replacement of the hydroxyl group of the ligand by a methoxy group. This modification of the propranolol structure has no effect on the affinity of both enantiomers for the wild-type 5-HT1A receptor, which provides an alternative hypothesis for the interaction of Asn386 with the oxypropanol oxygen atoms. According to this novel hypothesis, the oxypropanol oxygen atoms may both act as hydrogen bond acceptors from the NH2 group of Asn386." ], "offsets": [ [ 124, 1944 ] ] } ]

[ { "id": "9145928_T1", "type": "CHEMICAL", "text": [ "oxygen" ], "offsets": [ [ 1166, 1172 ] ], "normalized": [] }, { "id": "9145928_T2", "type": "CHEMICAL", "text": [ "aryloxypropanolamines" ], "offsets": [ [ 1333, 1354 ] ], "normalized": [] }, { "id": "9145928_T3", "type": "CHEMICAL", "text": [ "R- and S-enantiomers of propranolol" ], "offsets": [ [ 252, 287 ] ], "normalized": [] }, { "id": "9145928_T4", "type": "CHEMICAL", "text": [ "propranolol" ], "offsets": [ [ 1445, 1456 ] ], "normalized": [] }, { "id": "9145928_T5", "type": "CHEMICAL", "text": [ "hydroxyl" ], "offsets": [ [ 1523, 1531 ] ], "normalized": [] }, { "id": "9145928_T6", "type": "CHEMICAL", "text": [ "methoxy" ], "offsets": [ [ 1557, 1564 ] ], "normalized": [] }, { "id": "9145928_T7", "type": "CHEMICAL", "text": [ "propranolol" ], "offsets": [ [ 1597, 1608 ] ], "normalized": [] }, { "id": "9145928_T8", "type": "CHEMICAL", "text": [ "penbutolol" ], "offsets": [ [ 289, 299 ] ], "normalized": [] }, { "id": "9145928_T9", "type": "CHEMICAL", "text": [ "oxypropanol" ], "offsets": [ [ 1784, 1795 ] ], "normalized": [] }, { "id": "9145928_T10", "type": "CHEMICAL", "text": [ "oxygen" ], "offsets": [ [ 1796, 1802 ] ], "normalized": [] }, { "id": "9145928_T11", "type": "CHEMICAL", "text": [ "oxypropanol" ], "offsets": [ [ 1850, 1861 ] ], "normalized": [] }, { "id": "9145928_T12", "type": "CHEMICAL", "text": [ "oxygen" ], "offsets": [ [ 1862, 1868 ] ], "normalized": [] }, { "id": "9145928_T13", "type": "CHEMICAL", "text": [ "hydrogen" ], "offsets": [ [ 1891, 1899 ] ], "normalized": [] }, { "id": "9145928_T14", "type": "CHEMICAL", "text": [ "NH2" ], "offsets": [ [ 1924, 1927 ] ], "normalized": [] }, { "id": "9145928_T15", "type": "CHEMICAL", "text": [ "alprenolol" ], "offsets": [ [ 305, 315 ] ], "normalized": [] }, { "id": "9145928_T16", "type": "CHEMICAL", "text": [ "aryloxypropanol" ], "offsets": [ [ 480, 495 ] ], "normalized": [] }, { "id": "9145928_T17", "type": "CHEMICAL", "text": [ "aryloxypropanolamines" ], "offsets": [ [ 175, 196 ] ], "normalized": [] }, { "id": "9145928_T18", "type": "CHEMICAL", "text": [ "valine" ], "offsets": [ [ 731, 737 ] ], "normalized": [] }, { "id": "9145928_T19", "type": "CHEMICAL", "text": [ "propranolol" ], "offsets": [ [ 777, 788 ] ], "normalized": [] }, { "id": "9145928_T20", "type": "CHEMICAL", "text": [ "oxypropanolamine" ], "offsets": [ [ 822, 838 ] ], "normalized": [] }, { "id": "9145928_T21", "type": "CHEMICAL", "text": [ "hydroxyl" ], "offsets": [ [ 956, 964 ] ], "normalized": [] }, { "id": "9145928_T22", "type": "CHEMICAL", "text": [ "oxygen" ], "offsets": [ [ 979, 985 ] ], "normalized": [] }, { "id": "9145928_T23", "type": "CHEMICAL", "text": [ "oxypropanol" ], "offsets": [ [ 999, 1010 ] ], "normalized": [] }, { "id": "9145928_T24", "type": "CHEMICAL", "text": [ "hydroxyl" ], "offsets": [ [ 1085, 1093 ] ], "normalized": [] }, { "id": "9145928_T25", "type": "CHEMICAL", "text": [ "propranolol" ], "offsets": [ [ 1103, 1114 ] ], "normalized": [] }, { "id": "9145928_T26", "type": "CHEMICAL", "text": [ "aryloxypropanolamines" ], "offsets": [ [ 33, 54 ] ], "normalized": [] }, { "id": "9145928_T27", "type": "GENE-Y", "text": [ "rat 5-HT1A" ], "offsets": [ [ 1370, 1380 ] ], "normalized": [] }, { "id": "9145928_T28", "type": "GENE-N", "text": [ "Asn386Val" ], "offsets": [ [ 1464, 1473 ] ], "normalized": [] }, { "id": "9145928_T29", "type": "GENE-Y", "text": [ "5-HT1A" ], "offsets": [ [ 1687, 1693 ] ], "normalized": [] }, { "id": "9145928_T30", "type": "GENE-Y", "text": [ "human 5-HT1A" ], "offsets": [ [ 363, 375 ] ], "normalized": [] }, { "id": "9145928_T31", "type": "GENE-N", "text": [ "Asn386Val" ], "offsets": [ [ 390, 399 ] ], "normalized": [] }, { "id": "9145928_T32", "type": "GENE-Y", "text": [ "5-HT1A" ], "offsets": [ [ 668, 674 ] ], "normalized": [] }, { "id": "9145928_T33", "type": "GENE-N", "text": [ "Asn386 to valine" ], "offsets": [ [ 721, 737 ] ], "normalized": [] }, { "id": "9145928_T34", "type": "GENE-N", "text": [ "Asn386Val mutant" ], "offsets": [ [ 896, 912 ] ], "normalized": [] }, { "id": "9145928_T35", "type": "GENE-Y", "text": [ "5-HT1A" ], "offsets": [ [ 913, 919 ] ], "normalized": [] }, { "id": "9145928_T36", "type": "GENE-Y", "text": [ "human 5-hydroxytryptamine1A (5-HT1A) receptor" ], "offsets": [ [ 205, 250 ] ], "normalized": [] }, { "id": "9145928_T37", "type": "GENE-Y", "text": [ "5-HT1A" ], "offsets": [ [ 1063, 1069 ] ], "normalized": [] }, { "id": "9145928_T38", "type": "GENE-Y", "text": [ "human 5-hydroxytryptamine1A" ], "offsets": [ [ 86, 113 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23493374_title", "type": "title", "text": [ "Creb1-Mecp2-(m)CpG complex transactivates postnatal murine neuronal glucose transporter isoform 3 expression." ], "offsets": [ [ 0, 109 ] ] }, { "id": "23493374_abstract", "type": "abstract", "text": [ "The murine neuronal facilitative glucose transporter isoform 3 (Glut3) is developmentally regulated, peaking in expression at postnatal day (PN)14. In the present study, we characterized a canonical CpG island spanning the 5'-flanking region of the glut3 gene. Methylation-specific PCR and bisulfite sequencing identified methylation of this CpG ((m)CpG) island of the glut3 gene, frequency of methylation increasing 2.5-fold with a 1.6-fold increase in DNA methyl transferase 3a concentrations noted with advancing postnatal age (PN14 vs PN3). 5'-flanking region of glut3-luciferase reporter transient transfection in HT22 hippocampal neurons demonstrated that (m)CpGs inhibit glut3 transcription. Contrary to this biological function, glut3 expression rises synchronously with (m)CpGs in PN14 vs PN3 neurons. Chromatin immunoprecipitation (IP) revealed that methyl-CpG binding protein 2 (Mecp2) bound the glut3-(m)CpGs. Depending on association with specific coregulators, Mecp2, a dual regulator of gene transcription, may repress or activate a downstream gene. Sequential chromatin IP uncovered the glut3-(m)CpGs to bind Mecp2 exponentially upon recruitment of Creb1 rather than histone deacetylase 1. Co-IP and coimmunolocalization confirmed that Creb1 associated with Mecp2 and cotransfection with glut3-(m)CpG in HT22 cells enhanced glut3 transcription. Separate 5-aza-2'-deoxycytidine pretreatment or in combination with trichostatin A reduced (m)CpG and specific small interference RNAs targeting Mecp2 and Creb1 separately or together depleting Mecp2 and/or Creb1 binding of glut3-(m)CpGs reduced glut3 expression in HT22 cells. We conclude that Glut3 is a methylation-sensitive neuronal gene that recruits Mecp2. Recruitment of Creb1-Mecp2 by glut3-(m)CpG contributes towards transactivation, formulating an escape from (m)CpG-induced gene suppression, and thereby promoting developmental neuronal glut3 gene transcription and expression." ], "offsets": [ [ 110, 2059 ] ] } ]

[ { "id": "23493374_T1", "type": "CHEMICAL", "text": [ "(m)CpGs" ], "offsets": [ [ 1219, 1226 ] ], "normalized": [] }, { "id": "23493374_T2", "type": "CHEMICAL", "text": [ "(m)CpG" ], "offsets": [ [ 1420, 1426 ] ], "normalized": [] }, { "id": "23493374_T3", "type": "CHEMICAL", "text": [ "5-aza-2'-deoxycytidine" ], "offsets": [ [ 1480, 1502 ] ], "normalized": [] }, { "id": "23493374_T4", "type": "CHEMICAL", "text": [ "trichostatin A" ], "offsets": [ [ 1539, 1553 ] ], "normalized": [] }, { "id": "23493374_T5", "type": "CHEMICAL", "text": [ "(m)CpG" ], "offsets": [ [ 1562, 1568 ] ], "normalized": [] }, { "id": "23493374_T6", "type": "CHEMICAL", "text": [ "(m)CpGs" ], "offsets": [ [ 1701, 1708 ] ], "normalized": [] }, { "id": "23493374_T7", "type": "CHEMICAL", "text": [ "(m)CpG" ], "offsets": [ [ 1870, 1876 ] ], "normalized": [] }, { "id": "23493374_T8", "type": "CHEMICAL", "text": [ "(m)CpG" ], "offsets": [ [ 1941, 1947 ] ], "normalized": [] }, { "id": "23493374_T9", "type": "CHEMICAL", "text": [ "CpG" ], "offsets": [ [ 309, 312 ] ], "normalized": [] }, { "id": "23493374_T10", "type": "CHEMICAL", "text": [ "bisulfite" ], "offsets": [ [ 400, 409 ] ], "normalized": [] }, { "id": "23493374_T11", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 143, 150 ] ], "normalized": [] }, { "id": "23493374_T12", "type": "CHEMICAL", "text": [ "CpG" ], "offsets": [ [ 452, 455 ] ], "normalized": [] }, { "id": "23493374_T13", "type": "CHEMICAL", "text": [ "(m)CpG" ], "offsets": [ [ 457, 463 ] ], "normalized": [] }, { "id": "23493374_T14", "type": "CHEMICAL", "text": [ "(m)CpGs" ], "offsets": [ [ 772, 779 ] ], "normalized": [] }, { "id": "23493374_T15", "type": "CHEMICAL", "text": [ "(m)CpGs" ], "offsets": [ [ 889, 896 ] ], "normalized": [] }, { "id": "23493374_T16", "type": "CHEMICAL", "text": [ "methyl" ], "offsets": [ [ 970, 976 ] ], "normalized": [] }, { "id": "23493374_T17", "type": "CHEMICAL", "text": [ "(m)CpGs" ], "offsets": [ [ 1023, 1030 ] ], "normalized": [] }, { "id": "23493374_T18", "type": "CHEMICAL", "text": [ "(m)CpG" ], "offsets": [ [ 12, 18 ] ], "normalized": [] }, { "id": "23493374_T19", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 68, 75 ] ], "normalized": [] }, { "id": "23493374_T20", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 1213, 1218 ] ], "normalized": [] }, { "id": "23493374_T21", "type": "GENE-Y", "text": [ "Mecp2" ], "offsets": [ [ 1235, 1240 ] ], "normalized": [] }, { "id": "23493374_T22", "type": "GENE-Y", "text": [ "Creb1" ], "offsets": [ [ 1275, 1280 ] ], "normalized": [] }, { "id": "23493374_T23", "type": "GENE-Y", "text": [ "histone deacetylase 1" ], "offsets": [ [ 1293, 1314 ] ], "normalized": [] }, { "id": "23493374_T24", "type": "GENE-Y", "text": [ "Creb1" ], "offsets": [ [ 1362, 1367 ] ], "normalized": [] }, { "id": "23493374_T25", "type": "GENE-Y", "text": [ "Mecp2" ], "offsets": [ [ 1384, 1389 ] ], "normalized": [] }, { "id": "23493374_T26", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 1414, 1419 ] ], "normalized": [] }, { "id": "23493374_T27", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 1450, 1455 ] ], "normalized": [] }, { "id": "23493374_T28", "type": "GENE-Y", "text": [ "Mecp2" ], "offsets": [ [ 1616, 1621 ] ], "normalized": [] }, { "id": "23493374_T29", "type": "GENE-Y", "text": [ "Creb1" ], "offsets": [ [ 1626, 1631 ] ], "normalized": [] }, { "id": "23493374_T30", "type": "GENE-Y", "text": [ "Mecp2" ], "offsets": [ [ 1665, 1670 ] ], "normalized": [] }, { "id": "23493374_T31", "type": "GENE-Y", "text": [ "Creb1" ], "offsets": [ [ 1678, 1683 ] ], "normalized": [] }, { "id": "23493374_T32", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 1695, 1700 ] ], "normalized": [] }, { "id": "23493374_T33", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 1717, 1722 ] ], "normalized": [] }, { "id": "23493374_T34", "type": "GENE-Y", "text": [ "Glut3" ], "offsets": [ [ 1766, 1771 ] ], "normalized": [] }, { "id": "23493374_T35", "type": "GENE-Y", "text": [ "Mecp2" ], "offsets": [ [ 1827, 1832 ] ], "normalized": [] }, { "id": "23493374_T36", "type": "GENE-Y", "text": [ "Creb1" ], "offsets": [ [ 1849, 1854 ] ], "normalized": [] }, { "id": "23493374_T37", "type": "GENE-Y", "text": [ "Mecp2" ], "offsets": [ [ 1855, 1860 ] ], "normalized": [] }, { "id": "23493374_T38", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 1864, 1869 ] ], "normalized": [] }, { "id": "23493374_T39", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 2019, 2024 ] ], "normalized": [] }, { "id": "23493374_T40", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 359, 364 ] ], "normalized": [] }, { "id": "23493374_T41", "type": "GENE-Y", "text": [ "glucose transporter isoform 3" ], "offsets": [ [ 143, 172 ] ], "normalized": [] }, { "id": "23493374_T42", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 479, 484 ] ], "normalized": [] }, { "id": "23493374_T43", "type": "GENE-Y", "text": [ "DNA methyl transferase 3a" ], "offsets": [ [ 564, 589 ] ], "normalized": [] }, { "id": "23493374_T44", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 677, 682 ] ], "normalized": [] }, { "id": "23493374_T45", "type": "GENE-Y", "text": [ "Glut3" ], "offsets": [ [ 174, 179 ] ], "normalized": [] }, { "id": "23493374_T46", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 788, 793 ] ], "normalized": [] }, { "id": "23493374_T47", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 847, 852 ] ], "normalized": [] }, { "id": "23493374_T48", "type": "GENE-Y", "text": [ "methyl-CpG binding protein 2" ], "offsets": [ [ 970, 998 ] ], "normalized": [] }, { "id": "23493374_T49", "type": "GENE-Y", "text": [ "Mecp2" ], "offsets": [ [ 1000, 1005 ] ], "normalized": [] }, { "id": "23493374_T50", "type": "GENE-Y", "text": [ "glut3" ], "offsets": [ [ 1017, 1022 ] ], "normalized": [] }, { "id": "23493374_T51", "type": "GENE-Y", "text": [ "Mecp2" ], "offsets": [ [ 1085, 1090 ] ], "normalized": [] }, { "id": "23493374_T52", "type": "GENE-Y", "text": [ "Creb1" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "23493374_T53", "type": "GENE-Y", "text": [ "Mecp2" ], "offsets": [ [ 6, 11 ] ], "normalized": [] }, { "id": "23493374_T54", "type": "GENE-Y", "text": [ "glucose transporter isoform 3" ], "offsets": [ [ 68, 97 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "15126366_title", "type": "title", "text": [ "Characterization of the interaction of ingenol 3-angelate with protein kinase C." ], "offsets": [ [ 0, 80 ] ] }, { "id": "15126366_abstract", "type": "abstract", "text": [ "Ingenol 3-angelate (I3A) is one of the active ingredients in Euphorbia peplus, which has been used in traditional medicine. Here, we report the initial characterization of I3A as a protein kinase C (PKC) ligand. I3A bound to PKC-alpha in the presence of phosphatidylserine with high affinity; however, under these assay conditions, little PKC isoform selectivity was observed. PKC isoforms did show different sensitivity and selectivity for down-regulation by I3A and phorbol 12-myristate 13-acetate (PMA) in WEHI-231, HOP-92, and Colo-205 cells. In all of the three cell types, I3A inhibited cell proliferation with somewhat lower potency than did PMA. In intact CHO-K1 cells, I3A was able to translocate different green fluorescent protein-tagged PKC isoforms, visualized by confocal microscopy, with equal or higher potency than PMA. PKC-delta in particular showed a different pattern of translocation in response to I3A and PMA. I3A induced a higher level of secretion of the inflammatory cytokine interleukin 6 compared with PMA in the WEHI-231 cells and displayed a marked biphasic dose-response curve for the induction. I3A was unable to cause the same extent of association of the C1b domain of PKC-delta with lipids, compared with PMA or the physiological regulator diacylglycerol, and was able to partially block the association induced by these agents, measured by surface plasmon resonance. The in vitro kinase activity of PKC-alpha induced by I3A was lower than that induced by PMA. The novel pattern of behavior of I3A makes it of great interest for further evaluation." ], "offsets": [ [ 81, 1664 ] ] } ]

[ { "id": "15126366_T1", "type": "CHEMICAL", "text": [ "Ingenol 3-angelate" ], "offsets": [ [ 81, 99 ] ], "normalized": [] }, { "id": "15126366_T2", "type": "CHEMICAL", "text": [ "PMA" ], "offsets": [ [ 1111, 1114 ] ], "normalized": [] }, { "id": "15126366_T3", "type": "CHEMICAL", "text": [ "I3A" ], "offsets": [ [ 1208, 1211 ] ], "normalized": [] }, { "id": "15126366_T4", "type": "CHEMICAL", "text": [ "PMA" ], "offsets": [ [ 1321, 1324 ] ], "normalized": [] }, { "id": "15126366_T5", "type": "CHEMICAL", "text": [ "diacylglycerol" ], "offsets": [ [ 1356, 1370 ] ], "normalized": [] }, { "id": "15126366_T6", "type": "CHEMICAL", "text": [ "I3A" ], "offsets": [ [ 1537, 1540 ] ], "normalized": [] }, { "id": "15126366_T7", "type": "CHEMICAL", "text": [ "PMA" ], "offsets": [ [ 1572, 1575 ] ], "normalized": [] }, { "id": "15126366_T8", "type": "CHEMICAL", "text": [ "I3A" ], "offsets": [ [ 1610, 1613 ] ], "normalized": [] }, { "id": "15126366_T9", "type": "CHEMICAL", "text": [ "I3A" ], "offsets": [ [ 253, 256 ] ], "normalized": [] }, { "id": "15126366_T10", "type": "CHEMICAL", "text": [ "I3A" ], "offsets": [ [ 101, 104 ] ], "normalized": [] }, { "id": "15126366_T11", "type": "CHEMICAL", "text": [ "I3A" ], "offsets": [ [ 293, 296 ] ], "normalized": [] }, { "id": "15126366_T12", "type": "CHEMICAL", "text": [ "phosphatidylserine" ], "offsets": [ [ 335, 353 ] ], "normalized": [] }, { "id": "15126366_T13", "type": "CHEMICAL", "text": [ "I3A" ], "offsets": [ [ 541, 544 ] ], "normalized": [] }, { "id": "15126366_T14", "type": "CHEMICAL", "text": [ "phorbol 12-myristate 13-acetate" ], "offsets": [ [ 549, 580 ] ], "normalized": [] }, { "id": "15126366_T15", "type": "CHEMICAL", "text": [ "PMA" ], "offsets": [ [ 582, 585 ] ], "normalized": [] }, { "id": "15126366_T16", "type": "CHEMICAL", "text": [ "I3A" ], "offsets": [ [ 660, 663 ] ], "normalized": [] }, { "id": "15126366_T17", "type": "CHEMICAL", "text": [ "PMA" ], "offsets": [ [ 730, 733 ] ], "normalized": [] }, { "id": "15126366_T18", "type": "CHEMICAL", "text": [ "I3A" ], "offsets": [ [ 759, 762 ] ], "normalized": [] }, { "id": "15126366_T19", "type": "CHEMICAL", "text": [ "PMA" ], "offsets": [ [ 913, 916 ] ], "normalized": [] }, { "id": "15126366_T20", "type": "CHEMICAL", "text": [ "I3A" ], "offsets": [ [ 1001, 1004 ] ], "normalized": [] }, { "id": "15126366_T21", "type": "CHEMICAL", "text": [ "PMA" ], "offsets": [ [ 1009, 1012 ] ], "normalized": [] }, { "id": "15126366_T22", "type": "CHEMICAL", "text": [ "I3A" ], "offsets": [ [ 1014, 1017 ] ], "normalized": [] }, { "id": "15126366_T23", "type": "CHEMICAL", "text": [ "ingenol 3-angelate" ], "offsets": [ [ 39, 57 ] ], "normalized": [] }, { "id": "15126366_T24", "type": "GENE-Y", "text": [ "interleukin 6" ], "offsets": [ [ 1083, 1096 ] ], "normalized": [] }, { "id": "15126366_T25", "type": "GENE-N", "text": [ "C1b domain" ], "offsets": [ [ 1270, 1280 ] ], "normalized": [] }, { "id": "15126366_T26", "type": "GENE-Y", "text": [ "PKC-delta" ], "offsets": [ [ 1284, 1293 ] ], "normalized": [] }, { "id": "15126366_T27", "type": "GENE-Y", "text": [ "PKC-alpha" ], "offsets": [ [ 1516, 1525 ] ], "normalized": [] }, { "id": "15126366_T28", "type": "GENE-N", "text": [ "protein kinase C" ], "offsets": [ [ 262, 278 ] ], "normalized": [] }, { "id": "15126366_T29", "type": "GENE-N", "text": [ "PKC" ], "offsets": [ [ 280, 283 ] ], "normalized": [] }, { "id": "15126366_T30", "type": "GENE-Y", "text": [ "PKC-alpha" ], "offsets": [ [ 306, 315 ] ], "normalized": [] }, { "id": "15126366_T31", "type": "GENE-N", "text": [ "PKC" ], "offsets": [ [ 420, 423 ] ], "normalized": [] }, { "id": "15126366_T32", "type": "GENE-N", "text": [ "PKC" ], "offsets": [ [ 458, 461 ] ], "normalized": [] }, { "id": "15126366_T33", "type": "GENE-Y", "text": [ "green fluorescent protein" ], "offsets": [ [ 797, 822 ] ], "normalized": [] }, { "id": "15126366_T34", "type": "GENE-N", "text": [ "PKC" ], "offsets": [ [ 830, 833 ] ], "normalized": [] }, { "id": "15126366_T35", "type": "GENE-Y", "text": [ "PKC-delta" ], "offsets": [ [ 918, 927 ] ], "normalized": [] }, { "id": "15126366_T36", "type": "GENE-N", "text": [ "cytokine" ], "offsets": [ [ 1074, 1082 ] ], "normalized": [] }, { "id": "15126366_T37", "type": "GENE-N", "text": [ "protein kinase C" ], "offsets": [ [ 63, 79 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23301860_title", "type": "title", "text": [ "Single-walled carbon nanotube surface control of complement recognition and activation." ], "offsets": [ [ 0, 87 ] ] }, { "id": "23301860_abstract", "type": "abstract", "text": [ "Carbon nanotubes (CNTs) are receiving considerable attention in site-specific drug and nucleic acid delivery, photodynamic therapy, and photoacoustic molecular imaging. Despite these advances, nanotubes may activate the complement system (an integral part of innate immunity), which can induce clinically significant anaphylaxis. We demonstrate that single-walled CNTs coated with human serum albumin activate the complement system through C1q-mediated classical and the alternative pathways. Surface coating with methoxypoly(ethylene glycol)-based amphiphiles, which confers solubility and prolongs circulation profiles of CNTs, activates the complement system differently, depending on the amphiphile structure. CNTs with linear poly(ethylene glycol) amphiphiles trigger the lectin pathway of the complement through both L-ficolin and mannan-binding lectin recognition. The lectin pathway activation, however, did not trigger the amplification loop of the alternative pathway. An amphiphile with branched poly(ethylene glycol) architecture also activated the lectin pathway but only through L-ficolin recognition. Importantly, this mode of activation neither generated anaphylatoxins nor induced triggering of the effector arm of the complement system. These observations provide a major step toward nanomaterial surface modification with polymers that have the properties to significantly improve innate immunocompatibility by limiting the formation of complement C3 and C5 convertases." ], "offsets": [ [ 88, 1577 ] ] } ]

[ { "id": "23301860_T1", "type": "CHEMICAL", "text": [ "Carbon" ], "offsets": [ [ 88, 94 ] ], "normalized": [] }, { "id": "23301860_T2", "type": "CHEMICAL", "text": [ "poly(ethylene glycol)" ], "offsets": [ [ 1095, 1116 ] ], "normalized": [] }, { "id": "23301860_T3", "type": "CHEMICAL", "text": [ "methoxypoly(ethylene glycol)" ], "offsets": [ [ 602, 630 ] ], "normalized": [] }, { "id": "23301860_T4", "type": "CHEMICAL", "text": [ "poly(ethylene glycol)" ], "offsets": [ [ 819, 840 ] ], "normalized": [] }, { "id": "23301860_T5", "type": "CHEMICAL", "text": [ "carbon" ], "offsets": [ [ 14, 20 ] ], "normalized": [] }, { "id": "23301860_T6", "type": "GENE-N", "text": [ "lectin" ], "offsets": [ [ 1149, 1155 ] ], "normalized": [] }, { "id": "23301860_T7", "type": "GENE-N", "text": [ "C3 and C5 convertases" ], "offsets": [ [ 1555, 1576 ] ], "normalized": [] }, { "id": "23301860_T8", "type": "GENE-Y", "text": [ "human serum albumin" ], "offsets": [ [ 469, 488 ] ], "normalized": [] }, { "id": "23301860_T9", "type": "GENE-N", "text": [ "lectin" ], "offsets": [ [ 865, 871 ] ], "normalized": [] }, { "id": "23301860_T10", "type": "GENE-N", "text": [ "lectin" ], "offsets": [ [ 940, 946 ] ], "normalized": [] }, { "id": "23301860_T11", "type": "GENE-N", "text": [ "lectin" ], "offsets": [ [ 964, 970 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23301860_0", "type": "ACTIVATOR", "arg1_id": "23301860_T2", "arg2_id": "23301860_T6", "normalized": [] } ]

[ { "id": "23363575_title", "type": "title", "text": [ "TCDD and corticosterone on testicular steroidogenesis and antioxidant system of epididymal sperm in rats." ], "offsets": [ [ 0, 105 ] ] }, { "id": "23363575_abstract", "type": "abstract", "text": [ "2,3,7,8-Tetrachloro dibenzo-p-dioxin (TCDD), an endocrine-disrupting environmental pollutant, has been found to cause male reproductive toxicity. Glucocorticoids have been found to influence the metabolic pathway of TCDD. Stress, which affects the male reproductive function, is marked by an increase in the level and activity of glucocorticoids in the body. The present study was carried out to understand the effect of TCDD on testicular steroidogenesis and sperm antioxidant system under the influence of increased level of corticosterone in the body. Adult male rats were treated with either TCDD (100 ng/kg bw/ day) or corticosterone (3 mg/kg bw/day) or both for 15 days. Treatment with either TCDD or corticosterone was found to suppress the levels of steroidogenic acute regulatory protein and androgen-binding protein and reduce the activities of steroidogenic enzymes in testis while increasing oxidative stress in ventral prostate, seminal vesicles and epididymal sperm. In rats treated with both TCDD and corticosterone, the suppression of testicular steroidogenesis and increase in oxidative stress observed in ventral prostate, seminal vesicles and epididymal sperm were significant as compared to TCDD alone treated rats. The levels of Fas and FasL proteins were also increased in rats subjected to either TCDD or corticosterone treatment. In rats treated with both compounds, the increase observed in testicular levels of Fas and FasL was significant as compared to TCDD alone treated rats. Effect of TCDD on testicular steroidogenesis and antioxidant system of epididymal sperm may get enhanced under increased level of glucocorticoids in the body." ], "offsets": [ [ 106, 1770 ] ] } ]

[ { "id": "23363575_T1", "type": "CHEMICAL", "text": [ "2,3,7,8-Tetrachloro dibenzo-p-dioxin" ], "offsets": [ [ 106, 142 ] ], "normalized": [] }, { "id": "23363575_T2", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 1113, 1117 ] ], "normalized": [] }, { "id": "23363575_T3", "type": "CHEMICAL", "text": [ "corticosterone" ], "offsets": [ [ 1122, 1136 ] ], "normalized": [] }, { "id": "23363575_T4", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 1317, 1321 ] ], "normalized": [] }, { "id": "23363575_T5", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 1426, 1430 ] ], "normalized": [] }, { "id": "23363575_T6", "type": "CHEMICAL", "text": [ "corticosterone" ], "offsets": [ [ 1434, 1448 ] ], "normalized": [] }, { "id": "23363575_T7", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 1587, 1591 ] ], "normalized": [] }, { "id": "23363575_T8", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 1622, 1626 ] ], "normalized": [] }, { "id": "23363575_T9", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 322, 326 ] ], "normalized": [] }, { "id": "23363575_T10", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 144, 148 ] ], "normalized": [] }, { "id": "23363575_T11", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 527, 531 ] ], "normalized": [] }, { "id": "23363575_T12", "type": "CHEMICAL", "text": [ "corticosterone" ], "offsets": [ [ 633, 647 ] ], "normalized": [] }, { "id": "23363575_T13", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 702, 706 ] ], "normalized": [] }, { "id": "23363575_T14", "type": "CHEMICAL", "text": [ "corticosterone" ], "offsets": [ [ 730, 744 ] ], "normalized": [] }, { "id": "23363575_T15", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 805, 809 ] ], "normalized": [] }, { "id": "23363575_T16", "type": "CHEMICAL", "text": [ "TCDD" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "23363575_T17", "type": "CHEMICAL", "text": [ "corticosterone" ], "offsets": [ [ 9, 23 ] ], "normalized": [] }, { "id": "23363575_T18", "type": "GENE-Y", "text": [ "Fas" ], "offsets": [ [ 1356, 1359 ] ], "normalized": [] }, { "id": "23363575_T19", "type": "GENE-Y", "text": [ "FasL" ], "offsets": [ [ 1364, 1368 ] ], "normalized": [] }, { "id": "23363575_T20", "type": "GENE-Y", "text": [ "Fas" ], "offsets": [ [ 1543, 1546 ] ], "normalized": [] }, { "id": "23363575_T21", "type": "GENE-Y", "text": [ "FasL" ], "offsets": [ [ 1551, 1555 ] ], "normalized": [] }, { "id": "23363575_T22", "type": "GENE-Y", "text": [ "steroidogenic acute regulatory protein" ], "offsets": [ [ 864, 902 ] ], "normalized": [] }, { "id": "23363575_T23", "type": "GENE-Y", "text": [ "androgen-binding protein" ], "offsets": [ [ 907, 931 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "23349524_title", "type": "title", "text": [ "The role of GH in adipose tissue: lessons from adipose-specific GH receptor gene-disrupted mice." ], "offsets": [ [ 0, 96 ] ] }, { "id": "23349524_abstract", "type": "abstract", "text": [ "GH receptor (GHR) gene-disrupted mice (GHR-/-) have provided countless discoveries as to the numerous actions of GH. Many of these discoveries highlight the importance of GH in adipose tissue. For example GHR-/- mice are insulin sensitive yet obese with preferential enlargement of the sc adipose depot. GHR-/- mice also have elevated levels of leptin, resistin, and adiponectin, compared with controls leading some to suggest that GH may negatively regulate certain adipokines. To help clarify the role that GH exerts specifically on adipose tissue in vivo, we selectively disrupted GHR in adipose tissue to produce Fat GHR Knockout (FaGHRKO) mice. Surprisingly, FaGHRKOs shared only a few characteristics with global GHR-/- mice. Like the GHR-/- mice, FaGHRKO mice are obese with increased total body fat and increased adipocyte size. However, FaGHRKO mice have increases in all adipose depots with no improvements in measures of glucose homeostasis. Furthermore, resistin and adiponectin levels in FaGHRKO mice are similar to controls (or slightly decreased) unlike the increased levels found in GHR-/- mice, suggesting that GH does not regulate these adipokines directly in adipose tissue in vivo. Other features of FaGHRKO mice include decreased levels of adipsin, a near-normal GH/IGF-1 axis, and minimal changes to a large assortment of circulating factors that were measured such as IGF-binding proteins. In conclusion, specific removal of GHR in adipose tissue is sufficient to increase adipose tissue and decrease circulating adipsin. However, removal of GHR in adipose tissue alone is not sufficient to increase levels of resistin or adiponectin and does not alter glucose metabolism." ], "offsets": [ [ 97, 1792 ] ] } ]

[ { "id": "23349524_T1", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 1773, 1780 ] ], "normalized": [] }, { "id": "23349524_T2", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 1029, 1036 ] ], "normalized": [] }, { "id": "23349524_T3", "type": "GENE-Y", "text": [ "GH receptor" ], "offsets": [ [ 97, 108 ] ], "normalized": [] }, { "id": "23349524_T4", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 1100, 1103 ] ], "normalized": [] }, { "id": "23349524_T5", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 1196, 1199 ] ], "normalized": [] }, { "id": "23349524_T6", "type": "GENE-Y", "text": [ "GH" ], "offsets": [ [ 1225, 1227 ] ], "normalized": [] }, { "id": "23349524_T7", "type": "GENE-Y", "text": [ "GH" ], "offsets": [ [ 210, 212 ] ], "normalized": [] }, { "id": "23349524_T8", "type": "GENE-N", "text": [ "adipokines" ], "offsets": [ [ 1252, 1262 ] ], "normalized": [] }, { "id": "23349524_T9", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 1319, 1322 ] ], "normalized": [] }, { "id": "23349524_T10", "type": "GENE-Y", "text": [ "adipsin" ], "offsets": [ [ 1358, 1365 ] ], "normalized": [] }, { "id": "23349524_T11", "type": "GENE-Y", "text": [ "GH" ], "offsets": [ [ 1381, 1383 ] ], "normalized": [] }, { "id": "23349524_T12", "type": "GENE-Y", "text": [ "IGF-1" ], "offsets": [ [ 1384, 1389 ] ], "normalized": [] }, { "id": "23349524_T13", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 110, 113 ] ], "normalized": [] }, { "id": "23349524_T14", "type": "GENE-N", "text": [ "IGF-binding proteins" ], "offsets": [ [ 1488, 1508 ] ], "normalized": [] }, { "id": "23349524_T15", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 1545, 1548 ] ], "normalized": [] }, { "id": "23349524_T16", "type": "GENE-Y", "text": [ "adipsin" ], "offsets": [ [ 1633, 1640 ] ], "normalized": [] }, { "id": "23349524_T17", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 1662, 1665 ] ], "normalized": [] }, { "id": "23349524_T18", "type": "GENE-Y", "text": [ "resistin" ], "offsets": [ [ 1730, 1738 ] ], "normalized": [] }, { "id": "23349524_T19", "type": "GENE-Y", "text": [ "adiponectin" ], "offsets": [ [ 1742, 1753 ] ], "normalized": [] }, { "id": "23349524_T20", "type": "GENE-Y", "text": [ "GH" ], "offsets": [ [ 268, 270 ] ], "normalized": [] }, { "id": "23349524_T21", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 302, 305 ] ], "normalized": [] }, { "id": "23349524_T22", "type": "GENE-N", "text": [ "insulin" ], "offsets": [ [ 318, 325 ] ], "normalized": [] }, { "id": "23349524_T23", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 401, 404 ] ], "normalized": [] }, { "id": "23349524_T24", "type": "GENE-Y", "text": [ "leptin" ], "offsets": [ [ 442, 448 ] ], "normalized": [] }, { "id": "23349524_T25", "type": "GENE-Y", "text": [ "resistin" ], "offsets": [ [ 450, 458 ] ], "normalized": [] }, { "id": "23349524_T26", "type": "GENE-Y", "text": [ "adiponectin" ], "offsets": [ [ 464, 475 ] ], "normalized": [] }, { "id": "23349524_T27", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 136, 139 ] ], "normalized": [] }, { "id": "23349524_T28", "type": "GENE-Y", "text": [ "GH" ], "offsets": [ [ 529, 531 ] ], "normalized": [] }, { "id": "23349524_T29", "type": "GENE-Y", "text": [ "adipokines" ], "offsets": [ [ 564, 574 ] ], "normalized": [] }, { "id": "23349524_T30", "type": "GENE-Y", "text": [ "GH" ], "offsets": [ [ 606, 608 ] ], "normalized": [] }, { "id": "23349524_T31", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 681, 684 ] ], "normalized": [] }, { "id": "23349524_T32", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 718, 721 ] ], "normalized": [] }, { "id": "23349524_T33", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 734, 737 ] ], "normalized": [] }, { "id": "23349524_T34", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 763, 766 ] ], "normalized": [] }, { "id": "23349524_T35", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 816, 819 ] ], "normalized": [] }, { "id": "23349524_T36", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 838, 841 ] ], "normalized": [] }, { "id": "23349524_T37", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 853, 856 ] ], "normalized": [] }, { "id": "23349524_T38", "type": "GENE-Y", "text": [ "GHR" ], "offsets": [ [ 945, 948 ] ], "normalized": [] }, { "id": "23349524_T39", "type": "GENE-Y", "text": [ "resistin" ], "offsets": [ [ 1063, 1071 ] ], "normalized": [] }, { "id": "23349524_T40", "type": "GENE-Y", "text": [ "adiponectin" ], "offsets": [ [ 1076, 1087 ] ], "normalized": [] }, { "id": "23349524_T41", "type": "GENE-Y", "text": [ "GH" ], "offsets": [ [ 12, 14 ] ], "normalized": [] }, { "id": "23349524_T42", "type": "GENE-Y", "text": [ "GH receptor" ], "offsets": [ [ 64, 75 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23410798_title", "type": "title", "text": [ "Spiro heterocycles as potential inhibitors of SIRT1: Pd/C-mediated synthesis of novel N-indolylmethyl spiroindoline-3,2'-quinazolines." ], "offsets": [ [ 0, 134 ] ] }, { "id": "23410798_abstract", "type": "abstract", "text": [ "Novel N-indolylmethyl substituted spiroindoline-3,2'-quinazolines were designed as potential inhibitiors of SIRT1. These compounds were synthesized in good yields by using Pd/C-Cu mediated coupling-cyclization strategy as a key step involving the reaction of 1-(prop-2-ynyl)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione with 2-iodoanilides. Some of the compounds synthesized have shown encouraging inhibition of Sir 2 protein (a yeast homologue of mammalian SIRT1) in vitro and three of them showed dose dependent inhibition of Sir 2. The docking results suggested that the benzene ring of 1,2,3,4-tetrahydroquinazolin ring system of these molecules occupied the deep hydrophobic pocket of the protein and one of the NH along with the sulfonyl group participated in strong H-bonding interaction with the amino acid residues." ], "offsets": [ [ 135, 967 ] ] } ]

[ { "id": "23410798_T1", "type": "CHEMICAL", "text": [ "Pd" ], "offsets": [ [ 307, 309 ] ], "normalized": [] }, { "id": "23410798_T2", "type": "CHEMICAL", "text": [ "C-Cu" ], "offsets": [ [ 310, 314 ] ], "normalized": [] }, { "id": "23410798_T3", "type": "CHEMICAL", "text": [ "1-(prop-2-ynyl)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione" ], "offsets": [ [ 394, 462 ] ], "normalized": [] }, { "id": "23410798_T4", "type": "CHEMICAL", "text": [ "2-iodoanilides" ], "offsets": [ [ 468, 482 ] ], "normalized": [] }, { "id": "23410798_T5", "type": "CHEMICAL", "text": [ "benzene" ], "offsets": [ [ 717, 724 ] ], "normalized": [] }, { "id": "23410798_T6", "type": "CHEMICAL", "text": [ "1,2,3,4-tetrahydroquinazolin" ], "offsets": [ [ 733, 761 ] ], "normalized": [] }, { "id": "23410798_T7", "type": "CHEMICAL", "text": [ "N-indolylmethyl substituted spiroindoline-3,2'-quinazolines" ], "offsets": [ [ 141, 200 ] ], "normalized": [] }, { "id": "23410798_T8", "type": "CHEMICAL", "text": [ "NH" ], "offsets": [ [ 860, 862 ] ], "normalized": [] }, { "id": "23410798_T9", "type": "CHEMICAL", "text": [ "sulfonyl" ], "offsets": [ [ 878, 886 ] ], "normalized": [] }, { "id": "23410798_T10", "type": "CHEMICAL", "text": [ "H" ], "offsets": [ [ 916, 917 ] ], "normalized": [] }, { "id": "23410798_T11", "type": "CHEMICAL", "text": [ "amino acid" ], "offsets": [ [ 947, 957 ] ], "normalized": [] }, { "id": "23410798_T12", "type": "CHEMICAL", "text": [ "Pd" ], "offsets": [ [ 53, 55 ] ], "normalized": [] }, { "id": "23410798_T13", "type": "CHEMICAL", "text": [ "C" ], "offsets": [ [ 56, 57 ] ], "normalized": [] }, { "id": "23410798_T14", "type": "CHEMICAL", "text": [ "N-indolylmethyl spiroindoline-3,2'-quinazolines" ], "offsets": [ [ 86, 133 ] ], "normalized": [] }, { "id": "23410798_T15", "type": "GENE-Y", "text": [ "SIRT1" ], "offsets": [ [ 243, 248 ] ], "normalized": [] }, { "id": "23410798_T16", "type": "GENE-Y", "text": [ "Sir 2" ], "offsets": [ [ 555, 560 ] ], "normalized": [] }, { "id": "23410798_T17", "type": "GENE-N", "text": [ "mammalian SIRT1" ], "offsets": [ [ 591, 606 ] ], "normalized": [] }, { "id": "23410798_T18", "type": "GENE-Y", "text": [ "Sir 2" ], "offsets": [ [ 671, 676 ] ], "normalized": [] }, { "id": "23410798_T19", "type": "GENE-Y", "text": [ "SIRT1" ], "offsets": [ [ 46, 51 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23410798_0", "type": "INHIBITOR", "arg1_id": "23410798_T14", "arg2_id": "23410798_T19", "normalized": [] }, { "id": "23410798_1", "type": "INHIBITOR", "arg1_id": "23410798_T7", "arg2_id": "23410798_T15", "normalized": [] } ]

[ { "id": "17662248_title", "type": "title", "text": [ "Stimulation of N-methyl-D-aspartate receptors modulates Jurkat T cell growth and adhesion to fibronectin." ], "offsets": [ [ 0, 105 ] ] }, { "id": "17662248_abstract", "type": "abstract", "text": [ "The aims of this study were to investigate the expression and the functional roles of N-methyl-d-aspartate (NMDA) receptors in leukemic Jurkat T cells. RT-PCR and immunofluorescence/confocal microscopy analysis showed that Jurkat T cells express the NR1 and NR2B subunits of the NMDA receptors. Exposure of Jurkat cells to either (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine [(+)-MK 801] or D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5), two selective NMDA receptor antagonists, limited cell growth by inhibiting cell cycle progression and inducing apoptosis, whereas l-glutamate (1 microM) and NMDA (10 microM) significantly increased (137.2+/-22.0%; P<0.01) Jurkat T cell adhesion to fibronectin. In conclusion, our results demonstrate that Jurkat T cells express NMDA receptors functionally active in controlling cell growth and adhesion to fibronectin." ], "offsets": [ [ 106, 993 ] ] } ]

[ { "id": "17662248_T1", "type": "CHEMICAL", "text": [ "NMDA" ], "offsets": [ [ 214, 218 ] ], "normalized": [] }, { "id": "17662248_T2", "type": "CHEMICAL", "text": [ "NMDA" ], "offsets": [ [ 385, 389 ] ], "normalized": [] }, { "id": "17662248_T3", "type": "CHEMICAL", "text": [ "(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine" ], "offsets": [ [ 436, 509 ] ], "normalized": [] }, { "id": "17662248_T4", "type": "CHEMICAL", "text": [ "(+)-MK 801" ], "offsets": [ [ 511, 521 ] ], "normalized": [] }, { "id": "17662248_T5", "type": "CHEMICAL", "text": [ "D-(-)-2-amino-5-phosphonopentanoic acid" ], "offsets": [ [ 526, 565 ] ], "normalized": [] }, { "id": "17662248_T6", "type": "CHEMICAL", "text": [ "D-AP5" ], "offsets": [ [ 567, 572 ] ], "normalized": [] }, { "id": "17662248_T7", "type": "CHEMICAL", "text": [ "NMDA" ], "offsets": [ [ 589, 593 ] ], "normalized": [] }, { "id": "17662248_T8", "type": "CHEMICAL", "text": [ "l-glutamate" ], "offsets": [ [ 705, 716 ] ], "normalized": [] }, { "id": "17662248_T9", "type": "CHEMICAL", "text": [ "NMDA" ], "offsets": [ [ 732, 736 ] ], "normalized": [] }, { "id": "17662248_T10", "type": "CHEMICAL", "text": [ "NMDA" ], "offsets": [ [ 903, 907 ] ], "normalized": [] }, { "id": "17662248_T11", "type": "CHEMICAL", "text": [ "N-methyl-d-aspartate" ], "offsets": [ [ 192, 212 ] ], "normalized": [] }, { "id": "17662248_T12", "type": "CHEMICAL", "text": [ "N-methyl-D-aspartate" ], "offsets": [ [ 15, 35 ] ], "normalized": [] }, { "id": "17662248_T13", "type": "GENE-Y", "text": [ "NR1" ], "offsets": [ [ 356, 359 ] ], "normalized": [] }, { "id": "17662248_T14", "type": "GENE-Y", "text": [ "NR2B" ], "offsets": [ [ 364, 368 ] ], "normalized": [] }, { "id": "17662248_T15", "type": "GENE-N", "text": [ "NMDA receptors" ], "offsets": [ [ 385, 399 ] ], "normalized": [] }, { "id": "17662248_T16", "type": "GENE-N", "text": [ "NMDA receptor" ], "offsets": [ [ 589, 602 ] ], "normalized": [] }, { "id": "17662248_T17", "type": "GENE-Y", "text": [ "fibronectin" ], "offsets": [ [ 823, 834 ] ], "normalized": [] }, { "id": "17662248_T18", "type": "GENE-N", "text": [ "NMDA receptors" ], "offsets": [ [ 903, 917 ] ], "normalized": [] }, { "id": "17662248_T19", "type": "GENE-N", "text": [ "N-methyl-d-aspartate (NMDA) receptors" ], "offsets": [ [ 192, 229 ] ], "normalized": [] }, { "id": "17662248_T20", "type": "GENE-Y", "text": [ "fibronectin" ], "offsets": [ [ 981, 992 ] ], "normalized": [] }, { "id": "17662248_T21", "type": "GENE-N", "text": [ "N-methyl-D-aspartate receptors" ], "offsets": [ [ 15, 45 ] ], "normalized": [] }, { "id": "17662248_T22", "type": "GENE-Y", "text": [ "fibronectin" ], "offsets": [ [ 93, 104 ] ], "normalized": [] } ]

[]

[]

[ { "id": "17662248_0", "type": "ANTAGONIST", "arg1_id": "17662248_T3", "arg2_id": "17662248_T16", "normalized": [] }, { "id": "17662248_1", "type": "ANTAGONIST", "arg1_id": "17662248_T4", "arg2_id": "17662248_T16", "normalized": [] }, { "id": "17662248_2", "type": "ANTAGONIST", "arg1_id": "17662248_T5", "arg2_id": "17662248_T16", "normalized": [] }, { "id": "17662248_3", "type": "ANTAGONIST", "arg1_id": "17662248_T6", "arg2_id": "17662248_T16", "normalized": [] } ]

[ { "id": "12826271_title", "type": "title", "text": [ "Diclofenac inhibits proliferation and differentiation of neural stem cells." ], "offsets": [ [ 0, 75 ] ] }, { "id": "12826271_abstract", "type": "abstract", "text": [ "Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in clinical situations as anti-inflammatory, analgesic and antipyretic drugs. However, it is still unknown whether NSAIDs have effects on the development of the central nervous system. In the present study, we investigated the effects of NSAIDs on neural stem cell (NSC) proliferation and differentiation into neurons. In contrast to aspirin, naproxen, indomethacin and ibuprofen, treatment with diclofenac (10 microM) for 2 days induced the death of NSCs in a concentration-dependent manner. Diclofenac also inhibited the proliferation of NSCs and their differentiation into neurons. Treatment with diclofenac resulted in nuclear condensation (a morphological change due to apoptosis of NSCs) 24hr after the treatment and activated caspase-3 after 6 hr, indicating that diclofenac may cause apoptosis of neuronal cells via activation of the caspase cascade. These results suggest that diclofenac may affect the development of the central nervous system." ], "offsets": [ [ 76, 1092 ] ] } ]

[ { "id": "12826271_T1", "type": "CHEMICAL", "text": [ "aspirin" ], "offsets": [ [ 472, 479 ] ], "normalized": [] }, { "id": "12826271_T2", "type": "CHEMICAL", "text": [ "naproxen" ], "offsets": [ [ 481, 489 ] ], "normalized": [] }, { "id": "12826271_T3", "type": "CHEMICAL", "text": [ "indomethacin" ], "offsets": [ [ 491, 503 ] ], "normalized": [] }, { "id": "12826271_T4", "type": "CHEMICAL", "text": [ "ibuprofen" ], "offsets": [ [ 508, 517 ] ], "normalized": [] }, { "id": "12826271_T5", "type": "CHEMICAL", "text": [ "diclofenac" ], "offsets": [ [ 534, 544 ] ], "normalized": [] }, { "id": "12826271_T6", "type": "CHEMICAL", "text": [ "Diclofenac" ], "offsets": [ [ 631, 641 ] ], "normalized": [] }, { "id": "12826271_T7", "type": "CHEMICAL", "text": [ "diclofenac" ], "offsets": [ [ 738, 748 ] ], "normalized": [] }, { "id": "12826271_T8", "type": "CHEMICAL", "text": [ "diclofenac" ], "offsets": [ [ 909, 919 ] ], "normalized": [] }, { "id": "12826271_T9", "type": "CHEMICAL", "text": [ "diclofenac" ], "offsets": [ [ 1024, 1034 ] ], "normalized": [] }, { "id": "12826271_T10", "type": "CHEMICAL", "text": [ "Diclofenac" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "12826271_T11", "type": "GENE-Y", "text": [ "caspase-3" ], "offsets": [ [ 871, 880 ] ], "normalized": [] }, { "id": "12826271_T12", "type": "GENE-N", "text": [ "caspase" ], "offsets": [ [ 980, 987 ] ], "normalized": [] } ]

[]

[]

[ { "id": "12826271_0", "type": "ACTIVATOR", "arg1_id": "12826271_T7", "arg2_id": "12826271_T11", "normalized": [] }, { "id": "12826271_1", "type": "ACTIVATOR", "arg1_id": "12826271_T8", "arg2_id": "12826271_T12", "normalized": [] } ]

[ { "id": "16617454_title", "type": "title", "text": [ "Airway inflammation in asymptomatic children with episodic wheeze." ], "offsets": [ [ 0, 66 ] ] }, { "id": "16617454_abstract", "type": "abstract", "text": [ "Airway pathologies have been comprehensively researched in adult asthma, but in children, the extent of airway inflammation associated with episodic wheeze, often diagnosed as asthma, has not been fully characterized. It is not clear whether persistent airway inflammation is present in the absence of wheezing symptoms, and there is controversy regarding the role of age and atopy. This study assessed cellular and cytokine markers of airway inflammation in asymptomatic children with a history of episodic wheeze. Children with a history of episodic wheeze and cough (study group) and nonasthmatic patients requiring elective surgery (control group) were recruited. All subjects in the study group had a history of significant episodic wheezing (>2 episodes per year), and used only as-needed beta-agonist treatment. Bronchoalveolar lavage (BAL) was obtained using bronchoscopic lavage (study group) and nonbronchoscopic lavage (control group). Differential cell counts of BAL and flow cytometry were performed to identify T-lymphocyte phenotypes, and intracellular cytokine profiles were measured after phorbol-12-myristate 13-acetate (PMA) stimulation of BAL fluid T-cells. Twenty-one children with a history of 2-12 episodes of wheeze per year and 21 nonasthmatic subjects without respiratory symptoms were recruited. Study and control subjects were matched for age (median age, 5 years) and demographic characteristics. Study subjects had higher IgE levels, but their measurements were still within normal range. No significant differences in BAL differential cell counts were noted, and in both groups, the majority of T-cells were CD3+ CD8+, with a median CD4:CD8 ratio of 0.6. There was no significant difference in T-cell expression of the activation markers HLA-DR and CD25 (IL-2 receptor), or in PMA-induced production of the intracellular cytokines IFN-gamma, IL-2, IL-4, IL-5, and IL-10. The results of this study suggest that significant T-cell-driven airway inflammation is absent in mild or nonatopic, asymptomatic children of this age group who have episodic wheeze. Our findings support asthma management guidelines that do not recommend long-term treatment of this group of patients with anti-inflammatory medications." ], "offsets": [ [ 67, 2305 ] ] } ]

[ { "id": "16617454_T1", "type": "CHEMICAL", "text": [ "phorbol-12-myristate 13-acetate" ], "offsets": [ [ 1173, 1204 ] ], "normalized": [] }, { "id": "16617454_T2", "type": "CHEMICAL", "text": [ "PMA" ], "offsets": [ [ 1206, 1209 ] ], "normalized": [] }, { "id": "16617454_T3", "type": "CHEMICAL", "text": [ "PMA" ], "offsets": [ [ 1875, 1878 ] ], "normalized": [] }, { "id": "16617454_T4", "type": "GENE-N", "text": [ "cytokine" ], "offsets": [ [ 1135, 1143 ] ], "normalized": [] }, { "id": "16617454_T5", "type": "GENE-N", "text": [ "IgE" ], "offsets": [ [ 1519, 1522 ] ], "normalized": [] }, { "id": "16617454_T6", "type": "GENE-N", "text": [ "CD3" ], "offsets": [ [ 1706, 1709 ] ], "normalized": [] }, { "id": "16617454_T7", "type": "GENE-N", "text": [ "CD8" ], "offsets": [ [ 1711, 1714 ] ], "normalized": [] }, { "id": "16617454_T8", "type": "GENE-Y", "text": [ "CD4" ], "offsets": [ [ 1731, 1734 ] ], "normalized": [] }, { "id": "16617454_T9", "type": "GENE-N", "text": [ "CD8" ], "offsets": [ [ 1735, 1738 ] ], "normalized": [] }, { "id": "16617454_T10", "type": "GENE-N", "text": [ "HLA-DR" ], "offsets": [ [ 1836, 1842 ] ], "normalized": [] }, { "id": "16617454_T11", "type": "GENE-Y", "text": [ "CD25" ], "offsets": [ [ 1847, 1851 ] ], "normalized": [] }, { "id": "16617454_T12", "type": "GENE-Y", "text": [ "IL-2 receptor" ], "offsets": [ [ 1853, 1866 ] ], "normalized": [] }, { "id": "16617454_T13", "type": "GENE-N", "text": [ "cytokines" ], "offsets": [ [ 1919, 1928 ] ], "normalized": [] }, { "id": "16617454_T14", "type": "GENE-Y", "text": [ "IFN-gamma" ], "offsets": [ [ 1929, 1938 ] ], "normalized": [] }, { "id": "16617454_T15", "type": "GENE-Y", "text": [ "IL-2" ], "offsets": [ [ 1940, 1944 ] ], "normalized": [] }, { "id": "16617454_T16", "type": "GENE-Y", "text": [ "IL-4" ], "offsets": [ [ 1946, 1950 ] ], "normalized": [] }, { "id": "16617454_T17", "type": "GENE-Y", "text": [ "IL-5" ], "offsets": [ [ 1952, 1956 ] ], "normalized": [] }, { "id": "16617454_T18", "type": "GENE-Y", "text": [ "IL-10" ], "offsets": [ [ 1962, 1967 ] ], "normalized": [] }, { "id": "16617454_T19", "type": "GENE-N", "text": [ "cytokine" ], "offsets": [ [ 483, 491 ] ], "normalized": [] } ]

[]

[]

[ { "id": "16617454_0", "type": "INDIRECT-UPREGULATOR", "arg1_id": "16617454_T3", "arg2_id": "16617454_T13", "normalized": [] }, { "id": "16617454_1", "type": "INDIRECT-UPREGULATOR", "arg1_id": "16617454_T3", "arg2_id": "16617454_T14", "normalized": [] }, { "id": "16617454_2", "type": "INDIRECT-UPREGULATOR", "arg1_id": "16617454_T3", "arg2_id": "16617454_T15", "normalized": [] }, { "id": "16617454_3", "type": "INDIRECT-UPREGULATOR", "arg1_id": "16617454_T3", "arg2_id": "16617454_T16", "normalized": [] }, { "id": "16617454_4", "type": "INDIRECT-UPREGULATOR", "arg1_id": "16617454_T3", "arg2_id": "16617454_T17", "normalized": [] }, { "id": "16617454_5", "type": "INDIRECT-UPREGULATOR", "arg1_id": "16617454_T3", "arg2_id": "16617454_T18", "normalized": [] } ]

[ { "id": "11422746_title", "type": "title", "text": [ "Fibroblast growth factor receptors and their ligands in the adult rat kidney." ], "offsets": [ [ 0, 77 ] ] }, { "id": "11422746_abstract", "type": "abstract", "text": [ "BACKGROUND: Fibroblast growth factors (FGFs) are a family of at least 21 heparin-binding proteins involved in many biological processes, both during development and in the adult, including cell proliferation, differentiation, and angiogenesis. FGFs mediate their effects through high-affinity tyrosine kinase receptors (FGFRs), which are encoded by four genes. The aims of the present study were to localize FGFR-1 through FGFR-3 in the normal adult rat kidney and to determine which functional FGFR variants and FGFs were expressed. METHODS: Avidin-biotin-enhanced horseradish peroxidase immunohistochemistry was used on paraffin sections of rat kidney to localize FGFR-1 through FGFR-3, whereas reverse transcriptase-polymerase chain reaction was used to examine expression of the receptor variants and also of FGF-1 through FGF-10 in cortex, outer medulla, and inner medulla. RESULTS: By immunohistochemistry, each receptor was localized to distinct and overlapping nephron segments, such that one or more FGFRs were localized to all nephron and collecting duct epithelia. FGFR-1 and FGFR-3 were localized to glomeruli, FGFR-3 to proximal tubules and FGFR-1 to thin limbs. FGFR-1 through FGFR-3 were localized to distal straight tubules, with FGFR-1 and FGFR-3 localized to distal convoluted tubules. FGFR-1 and FGFR-3 were localized to medullary collecting ducts. In addition, FGFR-1 was localized to the smooth muscle of renal arteries. All seven FGFR variants were expressed in the cortex and outer medulla, with fewer FGFRs in the inner medulla. FGF-1, FGF-2, FGF-7, FGF-8, and FGF-9 were expressed in the kidney, with FGF-10 expression found only in the cortex. CONCLUSIONS: Mapping of these receptors is critical to the determination of the effects of FGF ligands in discrete regions of the kidney. The distributions of the FGFRs in the normal adult kidney and the restricted expression of FGF ligands suggest that specific FGFs have distinct and important roles in the maintenance of normal kidney structure and function." ], "offsets": [ [ 78, 2109 ] ] } ]

[ { "id": "11422746_T1", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 371, 379 ] ], "normalized": [] }, { "id": "11422746_T2", "type": "CHEMICAL", "text": [ "biotin" ], "offsets": [ [ 628, 634 ] ], "normalized": [] }, { "id": "11422746_T3", "type": "GENE-N", "text": [ "FGFRs" ], "offsets": [ [ 1087, 1092 ] ], "normalized": [] }, { "id": "11422746_T4", "type": "GENE-Y", "text": [ "FGFR-1" ], "offsets": [ [ 1154, 1160 ] ], "normalized": [] }, { "id": "11422746_T5", "type": "GENE-Y", "text": [ "FGFR-3" ], "offsets": [ [ 1165, 1171 ] ], "normalized": [] }, { "id": "11422746_T6", "type": "GENE-Y", "text": [ "FGFR-3" ], "offsets": [ [ 1201, 1207 ] ], "normalized": [] }, { "id": "11422746_T7", "type": "GENE-Y", "text": [ "FGFR-1" ], "offsets": [ [ 1232, 1238 ] ], "normalized": [] }, { "id": "11422746_T8", "type": "GENE-Y", "text": [ "FGFR-1" ], "offsets": [ [ 1254, 1260 ] ], "normalized": [] }, { "id": "11422746_T9", "type": "GENE-Y", "text": [ "FGFR-3" ], "offsets": [ [ 1269, 1275 ] ], "normalized": [] }, { "id": "11422746_T10", "type": "GENE-N", "text": [ "Fibroblast growth factors" ], "offsets": [ [ 90, 115 ] ], "normalized": [] }, { "id": "11422746_T11", "type": "GENE-Y", "text": [ "FGFR-1" ], "offsets": [ [ 1324, 1330 ] ], "normalized": [] }, { "id": "11422746_T12", "type": "GENE-Y", "text": [ "FGFR-3" ], "offsets": [ [ 1335, 1341 ] ], "normalized": [] }, { "id": "11422746_T13", "type": "GENE-Y", "text": [ "FGFR-1" ], "offsets": [ [ 1382, 1388 ] ], "normalized": [] }, { "id": "11422746_T14", "type": "GENE-Y", "text": [ "FGFR-3" ], "offsets": [ [ 1393, 1399 ] ], "normalized": [] }, { "id": "11422746_T15", "type": "GENE-Y", "text": [ "FGFR-1" ], "offsets": [ [ 1459, 1465 ] ], "normalized": [] }, { "id": "11422746_T16", "type": "GENE-N", "text": [ "FGFR" ], "offsets": [ [ 1530, 1534 ] ], "normalized": [] }, { "id": "11422746_T17", "type": "GENE-N", "text": [ "FGFRs" ], "offsets": [ [ 1603, 1608 ] ], "normalized": [] }, { "id": "11422746_T18", "type": "GENE-Y", "text": [ "FGF-1" ], "offsets": [ [ 1631, 1636 ] ], "normalized": [] }, { "id": "11422746_T19", "type": "GENE-Y", "text": [ "FGF-2" ], "offsets": [ [ 1638, 1643 ] ], "normalized": [] }, { "id": "11422746_T20", "type": "GENE-Y", "text": [ "FGF-7" ], "offsets": [ [ 1645, 1650 ] ], "normalized": [] }, { "id": "11422746_T21", "type": "GENE-Y", "text": [ "FGF-8" ], "offsets": [ [ 1652, 1657 ] ], "normalized": [] }, { "id": "11422746_T22", "type": "GENE-Y", "text": [ "FGF-9" ], "offsets": [ [ 1663, 1668 ] ], "normalized": [] }, { "id": "11422746_T23", "type": "GENE-Y", "text": [ "FGF-10" ], "offsets": [ [ 1704, 1710 ] ], "normalized": [] }, { "id": "11422746_T24", "type": "GENE-N", "text": [ "FGF" ], "offsets": [ [ 1839, 1842 ] ], "normalized": [] }, { "id": "11422746_T25", "type": "GENE-N", "text": [ "FGFRs" ], "offsets": [ [ 1911, 1916 ] ], "normalized": [] }, { "id": "11422746_T26", "type": "GENE-N", "text": [ "FGF" ], "offsets": [ [ 1977, 1980 ] ], "normalized": [] }, { "id": "11422746_T27", "type": "GENE-N", "text": [ "FGFs" ], "offsets": [ [ 2011, 2015 ] ], "normalized": [] }, { "id": "11422746_T28", "type": "GENE-N", "text": [ "FGFs" ], "offsets": [ [ 322, 326 ] ], "normalized": [] }, { "id": "11422746_T29", "type": "GENE-N", "text": [ "tyrosine kinase receptors" ], "offsets": [ [ 371, 396 ] ], "normalized": [] }, { "id": "11422746_T30", "type": "GENE-N", "text": [ "FGFRs" ], "offsets": [ [ 398, 403 ] ], "normalized": [] }, { "id": "11422746_T31", "type": "GENE-N", "text": [ "FGFs" ], "offsets": [ [ 117, 121 ] ], "normalized": [] }, { "id": "11422746_T32", "type": "GENE-Y", "text": [ "FGFR-1" ], "offsets": [ [ 486, 492 ] ], "normalized": [] }, { "id": "11422746_T33", "type": "GENE-Y", "text": [ "FGFR-3" ], "offsets": [ [ 501, 507 ] ], "normalized": [] }, { "id": "11422746_T34", "type": "GENE-N", "text": [ "FGFR" ], "offsets": [ [ 573, 577 ] ], "normalized": [] }, { "id": "11422746_T35", "type": "GENE-N", "text": [ "FGFs" ], "offsets": [ [ 591, 595 ] ], "normalized": [] }, { "id": "11422746_T36", "type": "GENE-N", "text": [ "Avidin" ], "offsets": [ [ 621, 627 ] ], "normalized": [] }, { "id": "11422746_T37", "type": "GENE-Y", "text": [ "horseradish peroxidase" ], "offsets": [ [ 644, 666 ] ], "normalized": [] }, { "id": "11422746_T38", "type": "GENE-Y", "text": [ "FGFR-1" ], "offsets": [ [ 744, 750 ] ], "normalized": [] }, { "id": "11422746_T39", "type": "GENE-Y", "text": [ "FGFR-3" ], "offsets": [ [ 759, 765 ] ], "normalized": [] }, { "id": "11422746_T40", "type": "GENE-N", "text": [ "heparin-binding proteins" ], "offsets": [ [ 151, 175 ] ], "normalized": [] }, { "id": "11422746_T41", "type": "GENE-Y", "text": [ "FGF-1" ], "offsets": [ [ 891, 896 ] ], "normalized": [] }, { "id": "11422746_T42", "type": "GENE-Y", "text": [ "FGF-10" ], "offsets": [ [ 905, 911 ] ], "normalized": [] }, { "id": "11422746_T43", "type": "GENE-N", "text": [ "Fibroblast growth factor receptors" ], "offsets": [ [ 0, 34 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11422746_0", "type": "INDIRECT-UPREGULATOR", "arg1_id": "11422746_T2", "arg2_id": "11422746_T37", "normalized": [] } ]

[ { "id": "23639192_title", "type": "title", "text": [ "Puerarin stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation." ], "offsets": [ [ 0, 169 ] ] }, { "id": "23639192_abstract", "type": "abstract", "text": [ "Puerarin, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that puerarin increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. Puerarin promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERα and ERβ. Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis." ], "offsets": [ [ 170, 1680 ] ] } ]

[ { "id": "23639192_T1", "type": "CHEMICAL", "text": [ "Puerarin" ], "offsets": [ [ 170, 178 ] ], "normalized": [] }, { "id": "23639192_T2", "type": "CHEMICAL", "text": [ "puerarin" ], "offsets": [ [ 1282, 1290 ] ], "normalized": [] }, { "id": "23639192_T3", "type": "CHEMICAL", "text": [ "puerarin" ], "offsets": [ [ 1407, 1415 ] ], "normalized": [] }, { "id": "23639192_T4", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 1586, 1594 ] ], "normalized": [] }, { "id": "23639192_T5", "type": "CHEMICAL", "text": [ "puerarin" ], "offsets": [ [ 1607, 1615 ] ], "normalized": [] }, { "id": "23639192_T6", "type": "CHEMICAL", "text": [ "isoflavone glycoside" ], "offsets": [ [ 189, 209 ] ], "normalized": [] }, { "id": "23639192_T7", "type": "CHEMICAL", "text": [ "puerarin" ], "offsets": [ [ 401, 409 ] ], "normalized": [] }, { "id": "23639192_T8", "type": "CHEMICAL", "text": [ "puerarin" ], "offsets": [ [ 542, 550 ] ], "normalized": [] }, { "id": "23639192_T9", "type": "CHEMICAL", "text": [ "puerarin" ], "offsets": [ [ 732, 740 ] ], "normalized": [] }, { "id": "23639192_T10", "type": "CHEMICAL", "text": [ "cisplatin" ], "offsets": [ [ 797, 806 ] ], "normalized": [] }, { "id": "23639192_T11", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 874, 882 ] ], "normalized": [] }, { "id": "23639192_T12", "type": "CHEMICAL", "text": [ "Puerarin" ], "offsets": [ [ 907, 915 ] ], "normalized": [] }, { "id": "23639192_T13", "type": "CHEMICAL", "text": [ "puerarin" ], "offsets": [ [ 983, 991 ] ], "normalized": [] }, { "id": "23639192_T14", "type": "CHEMICAL", "text": [ "ICI 182,780" ], "offsets": [ [ 1102, 1113 ] ], "normalized": [] }, { "id": "23639192_T15", "type": "CHEMICAL", "text": [ "puerarin" ], "offsets": [ [ 1145, 1153 ] ], "normalized": [] }, { "id": "23639192_T16", "type": "CHEMICAL", "text": [ "Puerarin" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "23639192_T17", "type": "GENE-Y", "text": [ "ERα" ], "offsets": [ [ 1359, 1362 ] ], "normalized": [] }, { "id": "23639192_T18", "type": "GENE-Y", "text": [ "ERβ" ], "offsets": [ [ 1367, 1370 ] ], "normalized": [] }, { "id": "23639192_T19", "type": "GENE-N", "text": [ "MEK" ], "offsets": [ [ 1467, 1470 ] ], "normalized": [] }, { "id": "23639192_T20", "type": "GENE-N", "text": [ "ERK" ], "offsets": [ [ 1471, 1474 ] ], "normalized": [] }, { "id": "23639192_T21", "type": "GENE-N", "text": [ "PI3K" ], "offsets": [ [ 1479, 1483 ] ], "normalized": [] }, { "id": "23639192_T22", "type": "GENE-N", "text": [ "Akt" ], "offsets": [ [ 1484, 1487 ] ], "normalized": [] }, { "id": "23639192_T23", "type": "GENE-Y", "text": [ "estrogen receptor" ], "offsets": [ [ 874, 891 ] ], "normalized": [] }, { "id": "23639192_T24", "type": "GENE-Y", "text": [ "ER" ], "offsets": [ [ 893, 895 ] ], "normalized": [] }, { "id": "23639192_T25", "type": "GENE-Y", "text": [ "Bcl-xL" ], "offsets": [ [ 1050, 1056 ] ], "normalized": [] }, { "id": "23639192_T26", "type": "GENE-Y", "text": [ "ER" ], "offsets": [ [ 1088, 1090 ] ], "normalized": [] }, { "id": "23639192_T27", "type": "GENE-Y", "text": [ "ER" ], "offsets": [ [ 124, 126 ] ], "normalized": [] }, { "id": "23639192_T28", "type": "GENE-N", "text": [ "MEK" ], "offsets": [ [ 137, 140 ] ], "normalized": [] }, { "id": "23639192_T29", "type": "GENE-N", "text": [ "ERK" ], "offsets": [ [ 141, 144 ] ], "normalized": [] }, { "id": "23639192_T30", "type": "GENE-N", "text": [ "PI3K" ], "offsets": [ [ 149, 153 ] ], "normalized": [] }, { "id": "23639192_T31", "type": "GENE-N", "text": [ "Akt" ], "offsets": [ [ 154, 157 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23301766_title", "type": "title", "text": [ "Improved self-healing of polyethylene/carbon black nanocomposites by their shape memory effect." ], "offsets": [ [ 0, 95 ] ] }, { "id": "23301766_abstract", "type": "abstract", "text": [ "In this work, the improved self-healing of cross-linked polyethylene (PE) (cPE)/carbon black (CB) nanocomposites by their shape memory effect (SME) is investigated. CB nanoparticles are found to be homogeneously dispersed in the PE matrix and significantly increase the strength of the materials. Compared with the breaking of linear PE (lPE) at the melting temperature (T(m)), the cPE and cPE/CB nanocomposites still have high strength above T(m) due to the formation of networks. The cPE and cPE/CB nanocomposites show both high strain fixity ratio (R(f)) and high strain recovery ratio (R(r)). Crystallization-induced elongation is observed for all the prepared shape memory polymer (SMP) materials and the effect becomes less remarkable with increasing volume fraction of CB nanoparticles (v(CB)). The scratch self-healing tests show that the cross-linking of PE matrix, the addition of CB nanoparticles, and the previous stretching in the direction perpendicular to the scratch favor the closure of the scratch and its complete healing. This SME-aided self-healing could have potential applications in diverse fields such as coating and structure materials." ], "offsets": [ [ 96, 1258 ] ] } ]

[ { "id": "23301766_T1", "type": "CHEMICAL", "text": [ "polyethylene" ], "offsets": [ [ 152, 164 ] ], "normalized": [] }, { "id": "23301766_T2", "type": "CHEMICAL", "text": [ "carbon black" ], "offsets": [ [ 176, 188 ] ], "normalized": [] }, { "id": "23301766_T3", "type": "CHEMICAL", "text": [ "polyethylene" ], "offsets": [ [ 25, 37 ] ], "normalized": [] }, { "id": "23301766_T4", "type": "CHEMICAL", "text": [ "carbon black" ], "offsets": [ [ 38, 50 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "16474853_title", "type": "title", "text": [ "Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment." ], "offsets": [ [ 0, 101 ] ] }, { "id": "16474853_abstract", "type": "abstract", "text": [ "Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. Sorafenib, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. Sorafenib significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated." ], "offsets": [ [ 102, 2479 ] ] } ]

[ { "id": "16474853_T1", "type": "CHEMICAL", "text": [ "sorafenib" ], "offsets": [ [ 1188, 1197 ] ], "normalized": [] }, { "id": "16474853_T2", "type": "CHEMICAL", "text": [ "sorafenib" ], "offsets": [ [ 1348, 1357 ] ], "normalized": [] }, { "id": "16474853_T3", "type": "CHEMICAL", "text": [ "sorafenib" ], "offsets": [ [ 1671, 1680 ] ], "normalized": [] }, { "id": "16474853_T4", "type": "CHEMICAL", "text": [ "sorafenib" ], "offsets": [ [ 1973, 1982 ] ], "normalized": [] }, { "id": "16474853_T5", "type": "CHEMICAL", "text": [ "sorafenib" ], "offsets": [ [ 2061, 2070 ] ], "normalized": [] }, { "id": "16474853_T6", "type": "CHEMICAL", "text": [ "Sorafenib" ], "offsets": [ [ 2098, 2107 ] ], "normalized": [] }, { "id": "16474853_T7", "type": "CHEMICAL", "text": [ "sorafenib" ], "offsets": [ [ 2259, 2268 ] ], "normalized": [] }, { "id": "16474853_T8", "type": "CHEMICAL", "text": [ "Sorafenib" ], "offsets": [ [ 552, 561 ] ], "normalized": [] }, { "id": "16474853_T9", "type": "CHEMICAL", "text": [ "bis-aryl ureas" ], "offsets": [ [ 624, 638 ] ], "normalized": [] }, { "id": "16474853_T10", "type": "CHEMICAL", "text": [ "sorafenib" ], "offsets": [ [ 815, 824 ] ], "normalized": [] }, { "id": "16474853_T11", "type": "CHEMICAL", "text": [ "sorafenib" ], "offsets": [ [ 906, 915 ] ], "normalized": [] }, { "id": "16474853_T12", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 975, 983 ] ], "normalized": [] }, { "id": "16474853_T13", "type": "CHEMICAL", "text": [ "sorafenib" ], "offsets": [ [ 71, 80 ] ], "normalized": [] }, { "id": "16474853_T14", "type": "GENE-Y", "text": [ "VEGFR-3" ], "offsets": [ [ 1102, 1109 ] ], "normalized": [] }, { "id": "16474853_T15", "type": "GENE-Y", "text": [ "platelet-derived growth factor (PDGFR)-beta" ], "offsets": [ [ 1111, 1154 ] ], "normalized": [] }, { "id": "16474853_T16", "type": "GENE-Y", "text": [ "Flt-3" ], "offsets": [ [ 1155, 1160 ] ], "normalized": [] }, { "id": "16474853_T17", "type": "GENE-Y", "text": [ "c-KIT" ], "offsets": [ [ 1166, 1171 ] ], "normalized": [] }, { "id": "16474853_T18", "type": "GENE-N", "text": [ "RAS" ], "offsets": [ [ 310, 313 ] ], "normalized": [] }, { "id": "16474853_T19", "type": "GENE-Y", "text": [ "RAF" ], "offsets": [ [ 314, 317 ] ], "normalized": [] }, { "id": "16474853_T20", "type": "GENE-N", "text": [ "Ras" ], "offsets": [ [ 490, 493 ] ], "normalized": [] }, { "id": "16474853_T21", "type": "GENE-Y", "text": [ "B-Raf" ], "offsets": [ [ 504, 509 ] ], "normalized": [] }, { "id": "16474853_T22", "type": "GENE-N", "text": [ "growth factor receptors" ], "offsets": [ [ 527, 550 ] ], "normalized": [] }, { "id": "16474853_T23", "type": "GENE-Y", "text": [ "Raf-1" ], "offsets": [ [ 726, 731 ] ], "normalized": [] }, { "id": "16474853_T24", "type": "GENE-N", "text": [ "kinase" ], "offsets": [ [ 750, 756 ] ], "normalized": [] }, { "id": "16474853_T25", "type": "GENE-N", "text": [ "V599E" ], "offsets": [ [ 855, 860 ] ], "normalized": [] }, { "id": "16474853_T26", "type": "GENE-Y", "text": [ "B-Raf" ], "offsets": [ [ 868, 873 ] ], "normalized": [] }, { "id": "16474853_T27", "type": "GENE-N", "text": [ "receptor tyrosine kinases" ], "offsets": [ [ 966, 991 ] ], "normalized": [] }, { "id": "16474853_T28", "type": "GENE-Y", "text": [ "vascular-endothelial growth factor (VEGFR)-2" ], "offsets": [ [ 1056, 1100 ] ], "normalized": [] } ]

[]

[]

[ { "id": "16474853_0", "type": "INHIBITOR", "arg1_id": "16474853_T9", "arg2_id": "16474853_T23", "normalized": [] }, { "id": "16474853_1", "type": "INHIBITOR", "arg1_id": "16474853_T9", "arg2_id": "16474853_T24", "normalized": [] }, { "id": "16474853_2", "type": "INHIBITOR", "arg1_id": "16474853_T8", "arg2_id": "16474853_T23", "normalized": [] }, { "id": "16474853_3", "type": "INHIBITOR", "arg1_id": "16474853_T8", "arg2_id": "16474853_T24", "normalized": [] }, { "id": "16474853_4", "type": "INHIBITOR", "arg1_id": "16474853_T10", "arg2_id": "16474853_T25", "normalized": [] }, { "id": "16474853_5", "type": "INHIBITOR", "arg1_id": "16474853_T10", "arg2_id": "16474853_T26", "normalized": [] } ]

[ { "id": "22750078_title", "type": "title", "text": [ "The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey." ], "offsets": [ [ 0, 135 ] ] }, { "id": "22750078_abstract", "type": "abstract", "text": [ "Phosphodiesterase 10A (PDE10A) is a novel target for the treatment of schizophrenia that may address multiple symptomatic domains associated with this disorder. PDE10A is highly expressed in the brain and functions to metabolically inactivate the important second messengers cAMP and cGMP. Here we describe effects of a potent and orally bioavailable PDE10A inhibitor [2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl](imidazo[1,5-a]pyridin-1-yl)methanone] (THPP-1) on striatal signaling pathways, in behavioral tests that predict antipsychotic potential, and assays that measure episodic-like memory in rat and executive function in rhesus monkey. THPP-1 exhibits nanomolar potency on the PDE10A enzyme, demonstrates excellent pharmacokinetic properties in multiple preclinical animal species, and is selective for PDE10A over other PDE families of enzymes. THPP-1 significantly increased phosphorylation of proteins in the striatum involved in synaptic plasticity, including the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) GluR1 subunit, extracellular receptor kinase (ERK), and cAMP-response element binding protein (CREB). THPP-1 produced dose-dependent effects in preclinical assays predictive of antipsychotic activity including attenuation of MK-801-induced psychomotor activation and condition avoidance responding in rats. At similar plasma exposures, THPP-1 significantly increased object recognition memory in rat and attenuated a ketamine-induced deficit in the object retrieval detour task in rhesus monkey. These findings suggest that PDE10A inhibitors have the potential to impact multiple symptomatic domains of schizophrenia including positive symptoms and cognitive impairment. This article is part of a Special Issue entitled 'Cognitive Enhancers'." ], "offsets": [ [ 136, 1968 ] ] } ]

[ { "id": "22750078_T1", "type": "CHEMICAL", "text": [ "a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid" ], "offsets": [ [ 1156, 1209 ] ], "normalized": [] }, { "id": "22750078_T2", "type": "CHEMICAL", "text": [ "AMPA" ], "offsets": [ [ 1220, 1224 ] ], "normalized": [] }, { "id": "22750078_T3", "type": "CHEMICAL", "text": [ "cAMP" ], "offsets": [ [ 1282, 1286 ] ], "normalized": [] }, { "id": "22750078_T4", "type": "CHEMICAL", "text": [ "THPP-1" ], "offsets": [ [ 1328, 1334 ] ], "normalized": [] }, { "id": "22750078_T5", "type": "CHEMICAL", "text": [ "MK-801" ], "offsets": [ [ 1451, 1457 ] ], "normalized": [] }, { "id": "22750078_T6", "type": "CHEMICAL", "text": [ "THPP-1" ], "offsets": [ [ 1562, 1568 ] ], "normalized": [] }, { "id": "22750078_T7", "type": "CHEMICAL", "text": [ "ketamine" ], "offsets": [ [ 1643, 1651 ] ], "normalized": [] }, { "id": "22750078_T8", "type": "CHEMICAL", "text": [ "cAMP" ], "offsets": [ [ 411, 415 ] ], "normalized": [] }, { "id": "22750078_T9", "type": "CHEMICAL", "text": [ "cGMP" ], "offsets": [ [ 420, 424 ] ], "normalized": [] }, { "id": "22750078_T10", "type": "CHEMICAL", "text": [ "2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl](imidazo[1,5-a]pyridin-1-yl)methanone" ], "offsets": [ [ 505, 630 ] ], "normalized": [] }, { "id": "22750078_T11", "type": "CHEMICAL", "text": [ "THPP-1" ], "offsets": [ [ 633, 639 ] ], "normalized": [] }, { "id": "22750078_T12", "type": "CHEMICAL", "text": [ "THPP-1" ], "offsets": [ [ 824, 830 ] ], "normalized": [] }, { "id": "22750078_T13", "type": "CHEMICAL", "text": [ "THPP-1" ], "offsets": [ [ 1034, 1040 ] ], "normalized": [] }, { "id": "22750078_T14", "type": "CHEMICAL", "text": [ "THPP-1" ], "offsets": [ [ 42, 48 ] ], "normalized": [] }, { "id": "22750078_T15", "type": "GENE-Y", "text": [ "Phosphodiesterase 10A" ], "offsets": [ [ 136, 157 ] ], "normalized": [] }, { "id": "22750078_T16", "type": "GENE-N", "text": [ "multiple symptomatic domains" ], "offsets": [ [ 237, 265 ] ], "normalized": [] }, { "id": "22750078_T17", "type": "GENE-N", "text": [ "amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor" ], "offsets": [ [ 1158, 1218 ] ], "normalized": [] }, { "id": "22750078_T18", "type": "GENE-Y", "text": [ "GluR1" ], "offsets": [ [ 1226, 1231 ] ], "normalized": [] }, { "id": "22750078_T19", "type": "GENE-N", "text": [ "extracellular receptor kinase" ], "offsets": [ [ 1241, 1270 ] ], "normalized": [] }, { "id": "22750078_T20", "type": "GENE-N", "text": [ "ERK" ], "offsets": [ [ 1272, 1275 ] ], "normalized": [] }, { "id": "22750078_T21", "type": "GENE-N", "text": [ "cAMP-response element binding protein" ], "offsets": [ [ 1282, 1319 ] ], "normalized": [] }, { "id": "22750078_T22", "type": "GENE-N", "text": [ "CREB" ], "offsets": [ [ 1321, 1325 ] ], "normalized": [] }, { "id": "22750078_T23", "type": "GENE-Y", "text": [ "PDE10A" ], "offsets": [ [ 297, 303 ] ], "normalized": [] }, { "id": "22750078_T24", "type": "GENE-Y", "text": [ "PDE10A" ], "offsets": [ [ 1750, 1756 ] ], "normalized": [] }, { "id": "22750078_T25", "type": "GENE-Y", "text": [ "PDE10A" ], "offsets": [ [ 159, 165 ] ], "normalized": [] }, { "id": "22750078_T26", "type": "GENE-Y", "text": [ "PDE10A" ], "offsets": [ [ 487, 493 ] ], "normalized": [] }, { "id": "22750078_T27", "type": "GENE-Y", "text": [ "PDE10A" ], "offsets": [ [ 865, 871 ] ], "normalized": [] }, { "id": "22750078_T28", "type": "GENE-Y", "text": [ "PDE10A" ], "offsets": [ [ 991, 997 ] ], "normalized": [] }, { "id": "22750078_T29", "type": "GENE-N", "text": [ "PDE" ], "offsets": [ [ 1009, 1012 ] ], "normalized": [] }, { "id": "22750078_T30", "type": "GENE-Y", "text": [ "phosphodiesterase 10A" ], "offsets": [ [ 10, 31 ] ], "normalized": [] } ]

[]

[]

[ { "id": "22750078_0", "type": "INHIBITOR", "arg1_id": "22750078_T14", "arg2_id": "22750078_T30", "normalized": [] }, { "id": "22750078_1", "type": "SUBSTRATE", "arg1_id": "22750078_T8", "arg2_id": "22750078_T23", "normalized": [] }, { "id": "22750078_2", "type": "SUBSTRATE", "arg1_id": "22750078_T9", "arg2_id": "22750078_T23", "normalized": [] }, { "id": "22750078_3", "type": "INHIBITOR", "arg1_id": "22750078_T10", "arg2_id": "22750078_T26", "normalized": [] }, { "id": "22750078_4", "type": "INHIBITOR", "arg1_id": "22750078_T11", "arg2_id": "22750078_T26", "normalized": [] }, { "id": "22750078_5", "type": "INHIBITOR", "arg1_id": "22750078_T12", "arg2_id": "22750078_T27", "normalized": [] }, { "id": "22750078_6", "type": "INHIBITOR", "arg1_id": "22750078_T12", "arg2_id": "22750078_T28", "normalized": [] }, { "id": "22750078_7", "type": "ACTIVATOR", "arg1_id": "22750078_T13", "arg2_id": "22750078_T17", "normalized": [] }, { "id": "22750078_8", "type": "ACTIVATOR", "arg1_id": "22750078_T13", "arg2_id": "22750078_T18", "normalized": [] }, { "id": "22750078_9", "type": "ACTIVATOR", "arg1_id": "22750078_T13", "arg2_id": "22750078_T19", "normalized": [] }, { "id": "22750078_10", "type": "ACTIVATOR", "arg1_id": "22750078_T13", "arg2_id": "22750078_T20", "normalized": [] }, { "id": "22750078_11", "type": "ACTIVATOR", "arg1_id": "22750078_T13", "arg2_id": "22750078_T21", "normalized": [] }, { "id": "22750078_12", "type": "ACTIVATOR", "arg1_id": "22750078_T13", "arg2_id": "22750078_T22", "normalized": [] } ]

[ { "id": "12407077_title", "type": "title", "text": [ "Probing an open CFTR pore with organic anion blockers." ], "offsets": [ [ 0, 54 ] ] }, { "id": "12407077_abstract", "type": "abstract", "text": [ "The cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts Cl- current. We explored the CFTR pore by studying voltage-dependent blockade of the channel by two organic anions: glibenclamide and isethionate. To simplify the kinetic analysis, a CFTR mutant, K1250A-CFTR, was used because this mutant channel, once opened, can remain open for minutes. Dose-response relationships of both blockers follow a simple Michaelis-Menten function with K(d) values that differ by three orders of magnitude. Glibenclamide blocks CFTR from the intracellular side of the membrane with slow kinetics. Both the on and off rates of glibenclamide block are voltage dependent. Removing external Cl- increases affinity of glibenclamide due to a decrease of the off rate and an increase of the on rate, suggesting the presence of a Cl- binding site external to the glibenclamide binding site. Isethionate blocks the channel from the cytoplasmic side with fast kinetics, but has no measurable effect when applied extracellularly. Increasing the internal Cl- concentration reduces isethionate block without affecting its voltage dependence, suggesting that Cl- and isethionate compete for a binding site in the pore. The voltage dependence and external Cl- concentration dependence of isethionate block are nearly identical to those of glibenclamide block, suggesting that these two blockers may bind to a common binding site, an idea further supported by kinetic studies of blocking with glibenclamide/isethionate mixtures. By comparing the physical and chemical natures of these two blockers, we propose that CFTR channel has an asymmetric pore with a wide internal entrance and a deeply embedded blocker binding site where local charges as well as hydrophobic components determine the affinity of the blockers." ], "offsets": [ [ 55, 1879 ] ] } ]

[ { "id": "12407077_T1", "type": "CHEMICAL", "text": [ "Cl-" ], "offsets": [ [ 1121, 1124 ] ], "normalized": [] }, { "id": "12407077_T2", "type": "CHEMICAL", "text": [ "isethionate" ], "offsets": [ [ 1147, 1158 ] ], "normalized": [] }, { "id": "12407077_T3", "type": "CHEMICAL", "text": [ "Cl-" ], "offsets": [ [ 1223, 1226 ] ], "normalized": [] }, { "id": "12407077_T4", "type": "CHEMICAL", "text": [ "isethionate" ], "offsets": [ [ 1231, 1242 ] ], "normalized": [] }, { "id": "12407077_T5", "type": "CHEMICAL", "text": [ "Cl-" ], "offsets": [ [ 1319, 1322 ] ], "normalized": [] }, { "id": "12407077_T6", "type": "CHEMICAL", "text": [ "isethionate" ], "offsets": [ [ 1351, 1362 ] ], "normalized": [] }, { "id": "12407077_T7", "type": "CHEMICAL", "text": [ "glibenclamide" ], "offsets": [ [ 1402, 1415 ] ], "normalized": [] }, { "id": "12407077_T8", "type": "CHEMICAL", "text": [ "glibenclamide" ], "offsets": [ [ 1555, 1568 ] ], "normalized": [] }, { "id": "12407077_T9", "type": "CHEMICAL", "text": [ "isethionate" ], "offsets": [ [ 1569, 1580 ] ], "normalized": [] }, { "id": "12407077_T10", "type": "CHEMICAL", "text": [ "glibenclamide" ], "offsets": [ [ 266, 279 ] ], "normalized": [] }, { "id": "12407077_T11", "type": "CHEMICAL", "text": [ "isethionate" ], "offsets": [ [ 284, 295 ] ], "normalized": [] }, { "id": "12407077_T12", "type": "CHEMICAL", "text": [ "Glibenclamide" ], "offsets": [ [ 585, 598 ] ], "normalized": [] }, { "id": "12407077_T13", "type": "CHEMICAL", "text": [ "glibenclamide" ], "offsets": [ [ 704, 717 ] ], "normalized": [] }, { "id": "12407077_T14", "type": "CHEMICAL", "text": [ "Cl-" ], "offsets": [ [ 765, 768 ] ], "normalized": [] }, { "id": "12407077_T15", "type": "CHEMICAL", "text": [ "glibenclamide" ], "offsets": [ [ 791, 804 ] ], "normalized": [] }, { "id": "12407077_T16", "type": "CHEMICAL", "text": [ "Cl-" ], "offsets": [ [ 900, 903 ] ], "normalized": [] }, { "id": "12407077_T17", "type": "CHEMICAL", "text": [ "glibenclamide" ], "offsets": [ [ 933, 946 ] ], "normalized": [] }, { "id": "12407077_T18", "type": "CHEMICAL", "text": [ "Isethionate" ], "offsets": [ [ 961, 972 ] ], "normalized": [] }, { "id": "12407077_T19", "type": "CHEMICAL", "text": [ "Cl-" ], "offsets": [ [ 150, 153 ] ], "normalized": [] }, { "id": "12407077_T20", "type": "GENE-Y", "text": [ "CFTR" ], "offsets": [ [ 179, 183 ] ], "normalized": [] }, { "id": "12407077_T21", "type": "GENE-Y", "text": [ "CFTR" ], "offsets": [ [ 1677, 1681 ] ], "normalized": [] }, { "id": "12407077_T22", "type": "GENE-Y", "text": [ "CFTR" ], "offsets": [ [ 333, 337 ] ], "normalized": [] }, { "id": "12407077_T23", "type": "GENE-N", "text": [ "K1250A" ], "offsets": [ [ 346, 352 ] ], "normalized": [] }, { "id": "12407077_T24", "type": "GENE-Y", "text": [ "CFTR" ], "offsets": [ [ 353, 357 ] ], "normalized": [] }, { "id": "12407077_T25", "type": "GENE-Y", "text": [ "cystic fibrosis transmembrane conductance regulator" ], "offsets": [ [ 59, 110 ] ], "normalized": [] }, { "id": "12407077_T26", "type": "GENE-Y", "text": [ "CFTR" ], "offsets": [ [ 606, 610 ] ], "normalized": [] }, { "id": "12407077_T27", "type": "GENE-Y", "text": [ "CFTR" ], "offsets": [ [ 112, 116 ] ], "normalized": [] }, { "id": "12407077_T28", "type": "GENE-N", "text": [ "ion channel" ], "offsets": [ [ 124, 135 ] ], "normalized": [] }, { "id": "12407077_T29", "type": "GENE-N", "text": [ "Cl- binding site" ], "offsets": [ [ 900, 916 ] ], "normalized": [] }, { "id": "12407077_T30", "type": "GENE-N", "text": [ "glibenclamide binding site" ], "offsets": [ [ 933, 959 ] ], "normalized": [] }, { "id": "12407077_T31", "type": "GENE-Y", "text": [ "CFTR" ], "offsets": [ [ 16, 20 ] ], "normalized": [] } ]

[]

[]

[ { "id": "12407077_0", "type": "SUBSTRATE", "arg1_id": "12407077_T19", "arg2_id": "12407077_T25", "normalized": [] }, { "id": "12407077_1", "type": "SUBSTRATE", "arg1_id": "12407077_T19", "arg2_id": "12407077_T27", "normalized": [] }, { "id": "12407077_2", "type": "SUBSTRATE", "arg1_id": "12407077_T19", "arg2_id": "12407077_T28", "normalized": [] }, { "id": "12407077_3", "type": "INHIBITOR", "arg1_id": "12407077_T12", "arg2_id": "12407077_T26", "normalized": [] }, { "id": "12407077_4", "type": "INHIBITOR", "arg1_id": "12407077_T10", "arg2_id": "12407077_T20", "normalized": [] }, { "id": "12407077_5", "type": "INHIBITOR", "arg1_id": "12407077_T11", "arg2_id": "12407077_T20", "normalized": [] } ]

[ { "id": "23583258_title", "type": "title", "text": [ "Phenolic compounds present in Sardinian wine extracts protect against the production of inflammatory cytokines induced by oxysterols in CaCo-2 human enterocyte-like cells." ], "offsets": [ [ 0, 171 ] ] }, { "id": "23583258_abstract", "type": "abstract", "text": [ "Cholesterol auto-oxidation products, namely oxysterols, are widely present in cholesterol-rich foods. They are thought to potentially interfere with homeostasis of the human digestive tract, playing a role in intestinal mucosal damage. This report concerns the marked up-regulation in differentiated CaCo-2 colonic epithelial cells of two key inflammatory interleukins, IL-6 and IL-8, caused by a mixture of oxysterols representative of a high cholesterol diet. This strong pro-inflammatory effect appeared to be dependent on the net imbalance of red-ox equilibrium with the production of excessive levels of reactive oxygen species through the colonic NADPH-oxidase NOX1 activation. Induction of NOX1 was markedly while not fully inhibited by CaCo-2 cell pre-incubation with phenolic extracts obtained from well-selected wines from typical grape varieties grown in Sardinia. Oxysterol-dependent NOX1 activation, as well as interleukin synthesis, were completely prevented by Cannonau red wine extract that contains an abundant phenolic fraction, in particular phenolic acids and flavonoids. Conversely, cell pre-treatment with Vermentino white wine extract with smaller phenolic fraction showed only a partial NOX1 down-regulation and was ineffective in interleukin synthesis induced by dietary oxysterols. It is thus likely that the effects of Sardinian wine extracts against intestinal inflammation induced by dietary oxysterols are mainly due to their high phenolic content: low doses of phenolics would be responsible only for direct scavenging oxysterol-dependent ROS production. Besides this direct activity, an excess of phenolic compounds detectable in red wine, may exert an additional indirect action by blocking oxysterol-related NOX1 induction, thus totally preventing the pro-oxidant and pro-inflammatory events triggered by dietary oxysterols." ], "offsets": [ [ 172, 2030 ] ] } ]

[ { "id": "23583258_T1", "type": "CHEMICAL", "text": [ "Cholesterol" ], "offsets": [ [ 172, 183 ] ], "normalized": [] }, { "id": "23583258_T2", "type": "CHEMICAL", "text": [ "phenolic acids" ], "offsets": [ [ 1233, 1247 ] ], "normalized": [] }, { "id": "23583258_T3", "type": "CHEMICAL", "text": [ "flavonoids" ], "offsets": [ [ 1252, 1262 ] ], "normalized": [] }, { "id": "23583258_T4", "type": "CHEMICAL", "text": [ "oxysterols" ], "offsets": [ [ 1468, 1478 ] ], "normalized": [] }, { "id": "23583258_T5", "type": "CHEMICAL", "text": [ "oxysterols" ], "offsets": [ [ 1593, 1603 ] ], "normalized": [] }, { "id": "23583258_T6", "type": "CHEMICAL", "text": [ "phenolics" ], "offsets": [ [ 1664, 1673 ] ], "normalized": [] }, { "id": "23583258_T7", "type": "CHEMICAL", "text": [ "oxysterol" ], "offsets": [ [ 1722, 1731 ] ], "normalized": [] }, { "id": "23583258_T8", "type": "CHEMICAL", "text": [ "phenolic" ], "offsets": [ [ 1801, 1809 ] ], "normalized": [] }, { "id": "23583258_T9", "type": "CHEMICAL", "text": [ "oxysterol" ], "offsets": [ [ 1896, 1905 ] ], "normalized": [] }, { "id": "23583258_T10", "type": "CHEMICAL", "text": [ "oxysterols" ], "offsets": [ [ 2019, 2029 ] ], "normalized": [] }, { "id": "23583258_T11", "type": "CHEMICAL", "text": [ "oxysterols" ], "offsets": [ [ 580, 590 ] ], "normalized": [] }, { "id": "23583258_T12", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 616, 627 ] ], "normalized": [] }, { "id": "23583258_T13", "type": "CHEMICAL", "text": [ "oxysterols" ], "offsets": [ [ 216, 226 ] ], "normalized": [] }, { "id": "23583258_T14", "type": "CHEMICAL", "text": [ "oxygen" ], "offsets": [ [ 790, 796 ] ], "normalized": [] }, { "id": "23583258_T15", "type": "CHEMICAL", "text": [ "NADPH" ], "offsets": [ [ 825, 830 ] ], "normalized": [] }, { "id": "23583258_T16", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 250, 261 ] ], "normalized": [] }, { "id": "23583258_T17", "type": "CHEMICAL", "text": [ "Oxysterol" ], "offsets": [ [ 1048, 1057 ] ], "normalized": [] }, { "id": "23583258_T18", "type": "CHEMICAL", "text": [ "Phenolic" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "23583258_T19", "type": "CHEMICAL", "text": [ "oxysterols" ], "offsets": [ [ 122, 132 ] ], "normalized": [] }, { "id": "23583258_T20", "type": "GENE-Y", "text": [ "NOX1" ], "offsets": [ [ 1383, 1387 ] ], "normalized": [] }, { "id": "23583258_T21", "type": "GENE-N", "text": [ "interleukin" ], "offsets": [ [ 1427, 1438 ] ], "normalized": [] }, { "id": "23583258_T22", "type": "GENE-Y", "text": [ "NOX1" ], "offsets": [ [ 1914, 1918 ] ], "normalized": [] }, { "id": "23583258_T23", "type": "GENE-N", "text": [ "interleukins" ], "offsets": [ [ 528, 540 ] ], "normalized": [] }, { "id": "23583258_T24", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 542, 546 ] ], "normalized": [] }, { "id": "23583258_T25", "type": "GENE-Y", "text": [ "IL-8" ], "offsets": [ [ 551, 555 ] ], "normalized": [] }, { "id": "23583258_T26", "type": "GENE-N", "text": [ "NADPH-oxidase" ], "offsets": [ [ 825, 838 ] ], "normalized": [] }, { "id": "23583258_T27", "type": "GENE-Y", "text": [ "NOX1" ], "offsets": [ [ 839, 843 ] ], "normalized": [] }, { "id": "23583258_T28", "type": "GENE-Y", "text": [ "NOX1" ], "offsets": [ [ 869, 873 ] ], "normalized": [] }, { "id": "23583258_T29", "type": "GENE-Y", "text": [ "NOX1" ], "offsets": [ [ 1068, 1072 ] ], "normalized": [] }, { "id": "23583258_T30", "type": "GENE-N", "text": [ "interleukin" ], "offsets": [ [ 1096, 1107 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23583258_0", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23583258_T11", "arg2_id": "23583258_T23", "normalized": [] }, { "id": "23583258_1", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23583258_T11", "arg2_id": "23583258_T24", "normalized": [] }, { "id": "23583258_2", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23583258_T11", "arg2_id": "23583258_T25", "normalized": [] }, { "id": "23583258_3", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23583258_T12", "arg2_id": "23583258_T23", "normalized": [] }, { "id": "23583258_4", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23583258_T12", "arg2_id": "23583258_T24", "normalized": [] }, { "id": "23583258_5", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23583258_T12", "arg2_id": "23583258_T25", "normalized": [] }, { "id": "23583258_6", "type": "ACTIVATOR", "arg1_id": "23583258_T17", "arg2_id": "23583258_T29", "normalized": [] }, { "id": "23583258_7", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23583258_T17", "arg2_id": "23583258_T30", "normalized": [] }, { "id": "23583258_8", "type": "INHIBITOR", "arg1_id": "23583258_T2", "arg2_id": "23583258_T29", "normalized": [] }, { "id": "23583258_9", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23583258_T2", "arg2_id": "23583258_T30", "normalized": [] }, { "id": "23583258_10", "type": "INHIBITOR", "arg1_id": "23583258_T3", "arg2_id": "23583258_T29", "normalized": [] }, { "id": "23583258_11", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23583258_T3", "arg2_id": "23583258_T30", "normalized": [] }, { "id": "23583258_12", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23583258_T4", "arg2_id": "23583258_T21", "normalized": [] }, { "id": "23583258_13", "type": "ACTIVATOR", "arg1_id": "23583258_T9", "arg2_id": "23583258_T22", "normalized": [] }, { "id": "23583258_14", "type": "INHIBITOR", "arg1_id": "23583258_T8", "arg2_id": "23583258_T22", "normalized": [] } ]

[ { "id": "16897483_title", "type": "title", "text": [ "Two highly divergent alcohol dehydrogenases of melon exhibit fruit ripening-specific expression and distinct biochemical characteristics." ], "offsets": [ [ 0, 137 ] ] }, { "id": "16897483_abstract", "type": "abstract", "text": [ "Alcohol dehydrogenases (ADH) participate in the biosynthetic pathway of aroma volatiles in fruit by interconverting aldehydes to alcohols and providing substrates for the formation of esters. Two highly divergent ADH genes (15% identity at the amino acid level) of Cantaloupe Charentais melon (Cucumis melo var. Cantalupensis) have been isolated. Cm-ADH1 belongs to the medium-chain zinc-binding type of ADHs and is highly similar to all ADH genes expressed in fruit isolated so far. Cm-ADH2 belongs to the short-chain type of ADHs. The two encoded proteins are enzymatically active upon expression in yeast. Cm-ADH1 has strong preference for NAPDH as a co-factor, whereas Cm-ADH2 preferentially uses NADH. Both Cm-ADH proteins are much more active as reductases with K (m)s 10-20 times lower for the conversion of aldehydes to alcohols than for the dehydrogenation of alcohols to aldehydes. They both show strong preference for aliphatic aldehydes but Cm-ADH1 is capable of reducing branched aldehydes such as 3-methylbutyraldehyde, whereas Cm-ADH2 cannot. Both Cm-ADH genes are expressed specifically in fruit and up-regulated during ripening. Gene expression as well as total ADH activity are strongly inhibited in antisense ACC oxidase melons and in melon fruit treated with the ethylene antagonist 1-methylcyclopropene (1-MCP), indicating a positive regulation by ethylene. These data suggest that each of the Cm-ADH protein plays a specific role in the regulation of aroma biosynthesis in melon fruit." ], "offsets": [ [ 138, 1645 ] ] } ]

[ { "id": "16897483_T1", "type": "CHEMICAL", "text": [ "Alcohol" ], "offsets": [ [ 138, 145 ] ], "normalized": [] }, { "id": "16897483_T2", "type": "CHEMICAL", "text": [ "3-methylbutyraldehyde" ], "offsets": [ [ 1149, 1170 ] ], "normalized": [] }, { "id": "16897483_T3", "type": "CHEMICAL", "text": [ "aldehydes" ], "offsets": [ [ 254, 263 ] ], "normalized": [] }, { "id": "16897483_T4", "type": "CHEMICAL", "text": [ "ethylene" ], "offsets": [ [ 1421, 1429 ] ], "normalized": [] }, { "id": "16897483_T5", "type": "CHEMICAL", "text": [ "alcohols" ], "offsets": [ [ 267, 275 ] ], "normalized": [] }, { "id": "16897483_T6", "type": "CHEMICAL", "text": [ "1-methylcyclopropene" ], "offsets": [ [ 1441, 1461 ] ], "normalized": [] }, { "id": "16897483_T7", "type": "CHEMICAL", "text": [ "1-MCP" ], "offsets": [ [ 1463, 1468 ] ], "normalized": [] }, { "id": "16897483_T8", "type": "CHEMICAL", "text": [ "ethylene" ], "offsets": [ [ 1507, 1515 ] ], "normalized": [] }, { "id": "16897483_T9", "type": "CHEMICAL", "text": [ "amino acid" ], "offsets": [ [ 382, 392 ] ], "normalized": [] }, { "id": "16897483_T10", "type": "CHEMICAL", "text": [ "zinc" ], "offsets": [ [ 521, 525 ] ], "normalized": [] }, { "id": "16897483_T11", "type": "CHEMICAL", "text": [ "NAPDH" ], "offsets": [ [ 781, 786 ] ], "normalized": [] }, { "id": "16897483_T12", "type": "CHEMICAL", "text": [ "NADH" ], "offsets": [ [ 839, 843 ] ], "normalized": [] }, { "id": "16897483_T13", "type": "CHEMICAL", "text": [ "aldehydes" ], "offsets": [ [ 953, 962 ] ], "normalized": [] }, { "id": "16897483_T14", "type": "CHEMICAL", "text": [ "alcohols" ], "offsets": [ [ 966, 974 ] ], "normalized": [] }, { "id": "16897483_T15", "type": "CHEMICAL", "text": [ "alcohols" ], "offsets": [ [ 1007, 1015 ] ], "normalized": [] }, { "id": "16897483_T16", "type": "CHEMICAL", "text": [ "aldehydes" ], "offsets": [ [ 1019, 1028 ] ], "normalized": [] }, { "id": "16897483_T17", "type": "CHEMICAL", "text": [ "aliphatic aldehyde" ], "offsets": [ [ 1067, 1085 ] ], "normalized": [] }, { "id": "16897483_T18", "type": "CHEMICAL", "text": [ "aldehydes" ], "offsets": [ [ 1131, 1140 ] ], "normalized": [] }, { "id": "16897483_T19", "type": "CHEMICAL", "text": [ "alcohol" ], "offsets": [ [ 21, 28 ] ], "normalized": [] }, { "id": "16897483_T20", "type": "GENE-N", "text": [ "Alcohol dehydrogenases" ], "offsets": [ [ 138, 160 ] ], "normalized": [] }, { "id": "16897483_T21", "type": "GENE-N", "text": [ "Cm-ADH2" ], "offsets": [ [ 1180, 1187 ] ], "normalized": [] }, { "id": "16897483_T22", "type": "GENE-N", "text": [ "Cm-ADH" ], "offsets": [ [ 1201, 1207 ] ], "normalized": [] }, { "id": "16897483_T23", "type": "GENE-N", "text": [ "ADH" ], "offsets": [ [ 1317, 1320 ] ], "normalized": [] }, { "id": "16897483_T24", "type": "GENE-N", "text": [ "ACC oxidase" ], "offsets": [ [ 1366, 1377 ] ], "normalized": [] }, { "id": "16897483_T25", "type": "GENE-N", "text": [ "Cm-ADH" ], "offsets": [ [ 1553, 1559 ] ], "normalized": [] }, { "id": "16897483_T26", "type": "GENE-N", "text": [ "ADH" ], "offsets": [ [ 351, 354 ] ], "normalized": [] }, { "id": "16897483_T27", "type": "GENE-N", "text": [ "ADH" ], "offsets": [ [ 162, 165 ] ], "normalized": [] }, { "id": "16897483_T28", "type": "GENE-N", "text": [ "Cm-ADH1" ], "offsets": [ [ 485, 492 ] ], "normalized": [] }, { "id": "16897483_T29", "type": "GENE-N", "text": [ "ADHs" ], "offsets": [ [ 542, 546 ] ], "normalized": [] }, { "id": "16897483_T30", "type": "GENE-N", "text": [ "ADH" ], "offsets": [ [ 576, 579 ] ], "normalized": [] }, { "id": "16897483_T31", "type": "GENE-N", "text": [ "Cm-ADH2" ], "offsets": [ [ 622, 629 ] ], "normalized": [] }, { "id": "16897483_T32", "type": "GENE-N", "text": [ "ADHs" ], "offsets": [ [ 665, 669 ] ], "normalized": [] }, { "id": "16897483_T33", "type": "GENE-N", "text": [ "Cm-ADH1" ], "offsets": [ [ 747, 754 ] ], "normalized": [] }, { "id": "16897483_T34", "type": "GENE-N", "text": [ "Cm-ADH2" ], "offsets": [ [ 811, 818 ] ], "normalized": [] }, { "id": "16897483_T35", "type": "GENE-N", "text": [ "Cm-ADH" ], "offsets": [ [ 850, 856 ] ], "normalized": [] }, { "id": "16897483_T36", "type": "GENE-N", "text": [ "Cm-ADH1" ], "offsets": [ [ 1091, 1098 ] ], "normalized": [] }, { "id": "16897483_T37", "type": "GENE-N", "text": [ "alcohol dehydrogenases" ], "offsets": [ [ 21, 43 ] ], "normalized": [] } ]

[]

[]

[ { "id": "16897483_0", "type": "SUBSTRATE", "arg1_id": "16897483_T3", "arg2_id": "16897483_T20", "normalized": [] }, { "id": "16897483_1", "type": "PRODUCT-OF", "arg1_id": "16897483_T5", "arg2_id": "16897483_T20", "normalized": [] }, { "id": "16897483_2", "type": "SUBSTRATE", "arg1_id": "16897483_T3", "arg2_id": "16897483_T27", "normalized": [] }, { "id": "16897483_3", "type": "PRODUCT-OF", "arg1_id": "16897483_T5", "arg2_id": "16897483_T27", "normalized": [] }, { "id": "16897483_4", "type": "PART-OF", "arg1_id": "16897483_T9", "arg2_id": "16897483_T26", "normalized": [] }, { "id": "16897483_5", "type": "DIRECT-REGULATOR", "arg1_id": "16897483_T10", "arg2_id": "16897483_T29", "normalized": [] }, { "id": "16897483_6", "type": "SUBSTRATE", "arg1_id": "16897483_T15", "arg2_id": "16897483_T35", "normalized": [] }, { "id": "16897483_7", "type": "PRODUCT-OF", "arg1_id": "16897483_T16", "arg2_id": "16897483_T35", "normalized": [] }, { "id": "16897483_8", "type": "SUBSTRATE", "arg1_id": "16897483_T18", "arg2_id": "16897483_T36", "normalized": [] }, { "id": "16897483_9", "type": "SUBSTRATE", "arg1_id": "16897483_T2", "arg2_id": "16897483_T36", "normalized": [] }, { "id": "16897483_10", "type": "SUBSTRATE", "arg1_id": "16897483_T17", "arg2_id": "16897483_T36", "normalized": [] }, { "id": "16897483_11", "type": "SUBSTRATE", "arg1_id": "16897483_T17", "arg2_id": "16897483_T21", "normalized": [] }, { "id": "16897483_12", "type": "INHIBITOR", "arg1_id": "16897483_T6", "arg2_id": "16897483_T23", "normalized": [] }, { "id": "16897483_13", "type": "ANTAGONIST", "arg1_id": "16897483_T7", "arg2_id": "16897483_T23", "normalized": [] }, { "id": "16897483_14", "type": "ACTIVATOR", "arg1_id": "16897483_T8", "arg2_id": "16897483_T23", "normalized": [] }, { "id": "16897483_15", "type": "ACTIVATOR", "arg1_id": "16897483_T4", "arg2_id": "16897483_T23", "normalized": [] } ]

[ { "id": "23603339_title", "type": "title", "text": [ "Dehydroepiandrosterone post-transcriptionally modifies CYP1A2 induction involving androgen receptor." ], "offsets": [ [ 0, 100 ] ] }, { "id": "23603339_abstract", "type": "abstract", "text": [ "The pharmacological dosage of dehydroepiandrosterone (DHEA) protects against chemically induced carcinogenesis. The chemoprotective activity of DHEA is attributed to its inhibitory potential for the expression of CYP1A enzymes, which are highly responsible for metabolic activation of several mutagenic and carcinogenic chemicals. The present work investigated whether the chemoprevention by DHEA was due to diminished transcriptional activation of CYP1A genes or to the post-transcriptional modulation of CYP1A expression. In primary human hepatocytes, DHEA diminished the increase in CYP1A activities (7-ethoxyresorufin O-dealkylation and phenacetin O-dealkylation) and in CYP1A2 mRNA level induced by 3-methylcholanthrene, but did not alter the amount of CYP1A1 and CYP1B1 mRNA. The androgen receptor seemed to be involved in DHEA-mediated diminishment of CYP1A2 induction, which was attenuated in the presence of bicalutamide, the androgen receptor antagonist. The potential role of the glucocorticoid receptor and estrogen receptor in DHEA-mediated decrease in CYP1A2 induction was excluded. The developed computational model of CYP1A2 induction kinetics and CYP1A2 mRNA degradation proposed that a post-transcriptional mechanism was likely to be the primary mechanism of the DHEA-mediated diminishment of CYP1A2 induction. The hypothesis was confirmed by the results of actinomycin D-chase experiments in MCF-7 and LNCaP cells, displaying that the degradation rates of CYP1A2 mRNA were significantly higher in the cells exposed to DHEA. The novel findings on DHEA-mediated modulation of CYP1A2 mRNA stability may account for the beneficial effects of DHEA by decreasing the metabolic activation of pro-carcinogenic compounds." ], "offsets": [ [ 101, 1832 ] ] } ]

[ { "id": "23603339_T1", "type": "CHEMICAL", "text": [ "estrogen" ], "offsets": [ [ 1120, 1128 ] ], "normalized": [] }, { "id": "23603339_T2", "type": "CHEMICAL", "text": [ "DHEA" ], "offsets": [ [ 1141, 1145 ] ], "normalized": [] }, { "id": "23603339_T3", "type": "CHEMICAL", "text": [ "DHEA" ], "offsets": [ [ 1382, 1386 ] ], "normalized": [] }, { "id": "23603339_T4", "type": "CHEMICAL", "text": [ "actinomycin D" ], "offsets": [ [ 1477, 1490 ] ], "normalized": [] }, { "id": "23603339_T5", "type": "CHEMICAL", "text": [ "DHEA" ], "offsets": [ [ 245, 249 ] ], "normalized": [] }, { "id": "23603339_T6", "type": "CHEMICAL", "text": [ "DHEA" ], "offsets": [ [ 1638, 1642 ] ], "normalized": [] }, { "id": "23603339_T7", "type": "CHEMICAL", "text": [ "DHEA" ], "offsets": [ [ 1666, 1670 ] ], "normalized": [] }, { "id": "23603339_T8", "type": "CHEMICAL", "text": [ "DHEA" ], "offsets": [ [ 1758, 1762 ] ], "normalized": [] }, { "id": "23603339_T9", "type": "CHEMICAL", "text": [ "dehydroepiandrosterone" ], "offsets": [ [ 131, 153 ] ], "normalized": [] }, { "id": "23603339_T10", "type": "CHEMICAL", "text": [ "DHEA" ], "offsets": [ [ 493, 497 ] ], "normalized": [] }, { "id": "23603339_T11", "type": "CHEMICAL", "text": [ "DHEA" ], "offsets": [ [ 155, 159 ] ], "normalized": [] }, { "id": "23603339_T12", "type": "CHEMICAL", "text": [ "DHEA" ], "offsets": [ [ 655, 659 ] ], "normalized": [] }, { "id": "23603339_T13", "type": "CHEMICAL", "text": [ "7-ethoxyresorufin" ], "offsets": [ [ 705, 722 ] ], "normalized": [] }, { "id": "23603339_T14", "type": "CHEMICAL", "text": [ "O" ], "offsets": [ [ 723, 724 ] ], "normalized": [] }, { "id": "23603339_T15", "type": "CHEMICAL", "text": [ "phenacetin" ], "offsets": [ [ 742, 752 ] ], "normalized": [] }, { "id": "23603339_T16", "type": "CHEMICAL", "text": [ "O" ], "offsets": [ [ 753, 754 ] ], "normalized": [] }, { "id": "23603339_T17", "type": "CHEMICAL", "text": [ "3-methylcholanthrene" ], "offsets": [ [ 805, 825 ] ], "normalized": [] }, { "id": "23603339_T18", "type": "CHEMICAL", "text": [ "androgen" ], "offsets": [ [ 887, 895 ] ], "normalized": [] }, { "id": "23603339_T19", "type": "CHEMICAL", "text": [ "DHEA" ], "offsets": [ [ 930, 934 ] ], "normalized": [] }, { "id": "23603339_T20", "type": "CHEMICAL", "text": [ "bicalutamide" ], "offsets": [ [ 1018, 1030 ] ], "normalized": [] }, { "id": "23603339_T21", "type": "CHEMICAL", "text": [ "androgen" ], "offsets": [ [ 1036, 1044 ] ], "normalized": [] }, { "id": "23603339_T22", "type": "CHEMICAL", "text": [ "Dehydroepiandrosterone" ], "offsets": [ [ 0, 22 ] ], "normalized": [] }, { "id": "23603339_T23", "type": "CHEMICAL", "text": [ "androgen" ], "offsets": [ [ 82, 90 ] ], "normalized": [] }, { "id": "23603339_T24", "type": "GENE-Y", "text": [ "estrogen receptor" ], "offsets": [ [ 1120, 1137 ] ], "normalized": [] }, { "id": "23603339_T25", "type": "GENE-Y", "text": [ "CYP1A2" ], "offsets": [ [ 1167, 1173 ] ], "normalized": [] }, { "id": "23603339_T26", "type": "GENE-Y", "text": [ "CYP1A2" ], "offsets": [ [ 1235, 1241 ] ], "normalized": [] }, { "id": "23603339_T27", "type": "GENE-Y", "text": [ "CYP1A2" ], "offsets": [ [ 1265, 1271 ] ], "normalized": [] }, { "id": "23603339_T28", "type": "GENE-Y", "text": [ "CYP1A2" ], "offsets": [ [ 1412, 1418 ] ], "normalized": [] }, { "id": "23603339_T29", "type": "GENE-Y", "text": [ "CYP1A2" ], "offsets": [ [ 1576, 1582 ] ], "normalized": [] }, { "id": "23603339_T30", "type": "GENE-Y", "text": [ "CYP1A2" ], "offsets": [ [ 1694, 1700 ] ], "normalized": [] }, { "id": "23603339_T31", "type": "GENE-N", "text": [ "CYP1A" ], "offsets": [ [ 314, 319 ] ], "normalized": [] }, { "id": "23603339_T32", "type": "GENE-N", "text": [ "CYP1A" ], "offsets": [ [ 550, 555 ] ], "normalized": [] }, { "id": "23603339_T33", "type": "GENE-N", "text": [ "CYP1A" ], "offsets": [ [ 607, 612 ] ], "normalized": [] }, { "id": "23603339_T34", "type": "GENE-N", "text": [ "CYP1A" ], "offsets": [ [ 687, 692 ] ], "normalized": [] }, { "id": "23603339_T35", "type": "GENE-Y", "text": [ "CYP1A2" ], "offsets": [ [ 776, 782 ] ], "normalized": [] }, { "id": "23603339_T36", "type": "GENE-Y", "text": [ "CYP1A1" ], "offsets": [ [ 859, 865 ] ], "normalized": [] }, { "id": "23603339_T37", "type": "GENE-Y", "text": [ "CYP1B1" ], "offsets": [ [ 870, 876 ] ], "normalized": [] }, { "id": "23603339_T38", "type": "GENE-Y", "text": [ "androgen receptor" ], "offsets": [ [ 887, 904 ] ], "normalized": [] }, { "id": "23603339_T39", "type": "GENE-Y", "text": [ "CYP1A2" ], "offsets": [ [ 960, 966 ] ], "normalized": [] }, { "id": "23603339_T40", "type": "GENE-Y", "text": [ "androgen receptor" ], "offsets": [ [ 1036, 1053 ] ], "normalized": [] }, { "id": "23603339_T41", "type": "GENE-Y", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 1092, 1115 ] ], "normalized": [] }, { "id": "23603339_T42", "type": "GENE-Y", "text": [ "CYP1A2" ], "offsets": [ [ 55, 61 ] ], "normalized": [] }, { "id": "23603339_T43", "type": "GENE-Y", "text": [ "androgen receptor" ], "offsets": [ [ 82, 99 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23603339_0", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23603339_T5", "arg2_id": "23603339_T31", "normalized": [] }, { "id": "23603339_1", "type": "INHIBITOR", "arg1_id": "23603339_T12", "arg2_id": "23603339_T34", "normalized": [] }, { "id": "23603339_2", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23603339_T12", "arg2_id": "23603339_T35", "normalized": [] }, { "id": "23603339_3", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23603339_T17", "arg2_id": "23603339_T35", "normalized": [] }, { "id": "23603339_4", "type": "SUBSTRATE", "arg1_id": "23603339_T13", "arg2_id": "23603339_T34", "normalized": [] }, { "id": "23603339_5", "type": "SUBSTRATE", "arg1_id": "23603339_T14", "arg2_id": "23603339_T34", "normalized": [] }, { "id": "23603339_6", "type": "ANTAGONIST", "arg1_id": "23603339_T20", "arg2_id": "23603339_T40", "normalized": [] }, { "id": "23603339_7", "type": "INDIRECT-DOWNREGULATOR", "arg1_id": "23603339_T6", "arg2_id": "23603339_T29", "normalized": [] } ]

[ { "id": "12421359_title", "type": "title", "text": [ "Study of the nematode putative GABA type-A receptor subunits: evidence for modulation by ivermectin." ], "offsets": [ [ 0, 100 ] ] }, { "id": "12421359_abstract", "type": "abstract", "text": [ "Two alleles of the HG1 gene, which encodes a putative GABA receptor alpha/gamma subunit, were isolated from Haemonchus contortus. These two alleles were shown previously to be associated with ivermectin susceptibility (HG1A) and resistance (HG1E), respectively. Sequence analysis indicates that they differ in four amino acids. To explore the functional properties of the two alleles, a full-length cDNA encoding the beta subunit, a key functional component of the GABA receptor, was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank locus ZC482.1) and coexpressed in Xenopus oocytes with the HG1 alleles. When gab-1 was coexpressed with either the HG1A allele or the HG1E allele in Xenopus oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different sensitivity to the agonist were formed. The effects of ivermectin on the hetero-oligomeric receptors were determined. Application of ivermectin alone had no effect on the receptors. However, when coapplied with 10 micro m GABA, ivermectin potentiated the GABA-evoked current of the GAB-1/HG1A receptor, but attenuated the GABA response of the GAB-1/HG1E receptor. We demonstrated that the coexpressed HG1 and GAB-1 receptors are GABA-responsive, and provide evidence for the possible involvement of GABA receptors in the mechanism of ivermectin resistance." ], "offsets": [ [ 101, 1447 ] ] } ]

[ { "id": "12421359_T1", "type": "CHEMICAL", "text": [ "GABA" ], "offsets": [ [ 1113, 1117 ] ], "normalized": [] }, { "id": "12421359_T2", "type": "CHEMICAL", "text": [ "ivermectin" ], "offsets": [ [ 1119, 1129 ] ], "normalized": [] }, { "id": "12421359_T3", "type": "CHEMICAL", "text": [ "GABA" ], "offsets": [ [ 1146, 1150 ] ], "normalized": [] }, { "id": "12421359_T4", "type": "CHEMICAL", "text": [ "GABA" ], "offsets": [ [ 1213, 1217 ] ], "normalized": [] }, { "id": "12421359_T5", "type": "CHEMICAL", "text": [ "GABA" ], "offsets": [ [ 1320, 1324 ] ], "normalized": [] }, { "id": "12421359_T6", "type": "CHEMICAL", "text": [ "GABA" ], "offsets": [ [ 1390, 1394 ] ], "normalized": [] }, { "id": "12421359_T7", "type": "CHEMICAL", "text": [ "ivermectin" ], "offsets": [ [ 1425, 1435 ] ], "normalized": [] }, { "id": "12421359_T8", "type": "CHEMICAL", "text": [ "ivermectin" ], "offsets": [ [ 293, 303 ] ], "normalized": [] }, { "id": "12421359_T9", "type": "CHEMICAL", "text": [ "amino acids" ], "offsets": [ [ 416, 427 ] ], "normalized": [] }, { "id": "12421359_T10", "type": "CHEMICAL", "text": [ "GABA" ], "offsets": [ [ 566, 570 ] ], "normalized": [] }, { "id": "12421359_T11", "type": "CHEMICAL", "text": [ "GABA" ], "offsets": [ [ 155, 159 ] ], "normalized": [] }, { "id": "12421359_T12", "type": "CHEMICAL", "text": [ "gamma-aminobutyric acid" ], "offsets": [ [ 825, 848 ] ], "normalized": [] }, { "id": "12421359_T13", "type": "CHEMICAL", "text": [ "GABA" ], "offsets": [ [ 850, 854 ] ], "normalized": [] }, { "id": "12421359_T14", "type": "CHEMICAL", "text": [ "ivermectin" ], "offsets": [ [ 946, 956 ] ], "normalized": [] }, { "id": "12421359_T15", "type": "CHEMICAL", "text": [ "ivermectin" ], "offsets": [ [ 1024, 1034 ] ], "normalized": [] }, { "id": "12421359_T16", "type": "CHEMICAL", "text": [ "GABA" ], "offsets": [ [ 31, 35 ] ], "normalized": [] }, { "id": "12421359_T17", "type": "CHEMICAL", "text": [ "ivermectin" ], "offsets": [ [ 89, 99 ] ], "normalized": [] }, { "id": "12421359_T18", "type": "GENE-Y", "text": [ "GAB-1" ], "offsets": [ [ 1173, 1178 ] ], "normalized": [] }, { "id": "12421359_T19", "type": "GENE-Y", "text": [ "HG1A" ], "offsets": [ [ 1179, 1183 ] ], "normalized": [] }, { "id": "12421359_T20", "type": "GENE-Y", "text": [ "GAB-1" ], "offsets": [ [ 1234, 1239 ] ], "normalized": [] }, { "id": "12421359_T21", "type": "GENE-Y", "text": [ "HG1E" ], "offsets": [ [ 1240, 1244 ] ], "normalized": [] }, { "id": "12421359_T22", "type": "GENE-Y", "text": [ "HG1" ], "offsets": [ [ 1292, 1295 ] ], "normalized": [] }, { "id": "12421359_T23", "type": "GENE-Y", "text": [ "GAB-1" ], "offsets": [ [ 1300, 1305 ] ], "normalized": [] }, { "id": "12421359_T24", "type": "GENE-N", "text": [ "GABA receptors" ], "offsets": [ [ 1390, 1404 ] ], "normalized": [] }, { "id": "12421359_T25", "type": "GENE-Y", "text": [ "HG1" ], "offsets": [ [ 120, 123 ] ], "normalized": [] }, { "id": "12421359_T26", "type": "GENE-Y", "text": [ "HG1A" ], "offsets": [ [ 320, 324 ] ], "normalized": [] }, { "id": "12421359_T27", "type": "GENE-Y", "text": [ "HG1E" ], "offsets": [ [ 342, 346 ] ], "normalized": [] }, { "id": "12421359_T28", "type": "GENE-N", "text": [ "GABA receptor" ], "offsets": [ [ 566, 579 ] ], "normalized": [] }, { "id": "12421359_T29", "type": "GENE-Y", "text": [ "gab-1" ], "offsets": [ [ 623, 628 ] ], "normalized": [] }, { "id": "12421359_T30", "type": "GENE-N", "text": [ "GABA receptor alpha/gamma" ], "offsets": [ [ 155, 180 ] ], "normalized": [] }, { "id": "12421359_T31", "type": "GENE-Y", "text": [ "GenBank locus ZC482.1" ], "offsets": [ [ 651, 672 ] ], "normalized": [] }, { "id": "12421359_T32", "type": "GENE-Y", "text": [ "HG1" ], "offsets": [ [ 718, 721 ] ], "normalized": [] }, { "id": "12421359_T33", "type": "GENE-Y", "text": [ "gab-1" ], "offsets": [ [ 736, 741 ] ], "normalized": [] }, { "id": "12421359_T34", "type": "GENE-Y", "text": [ "HG1A" ], "offsets": [ [ 774, 778 ] ], "normalized": [] }, { "id": "12421359_T35", "type": "GENE-Y", "text": [ "HG1E" ], "offsets": [ [ 793, 797 ] ], "normalized": [] }, { "id": "12421359_T36", "type": "GENE-N", "text": [ "gamma-aminobutyric acid (GABA)-responsive channels" ], "offsets": [ [ 825, 875 ] ], "normalized": [] }, { "id": "12421359_T37", "type": "GENE-N", "text": [ "GABA type-A receptor" ], "offsets": [ [ 31, 51 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "23207409_title", "type": "title", "text": [ "Combining QSAR classification models for predictive modeling of human monoamine oxidase inhibitors." ], "offsets": [ [ 0, 99 ] ] }, { "id": "23207409_abstract", "type": "abstract", "text": [ "Due to their role in the metabolism of monoamine neurotransmitters, MAO-A and MAO-B present a significant pharmacological interest. For instance the inhibitors of human MAO-B are considered useful tools for the treatment of Parkinson Disease. Therefore, the rational design and synthesis of new MAOs inhibitors is considered of great importance for the development of new and more effective treatments of Parkinson Disease. In this work, Quantitative Structure Activity Relationships (QSAR) has been developed to predict the human MAO inhibitory activity and selectivity. The first step was the selection of a suitable dataset of heterocyclic compounds that include chromones, coumarins, chalcones, thiazolylhydrazones, etc. These compounds were previously synthesized in one of our laboratories, or elsewhere, and their activities measured by the same assays and for the same laboratory staff. Applying linear discriminant analysis to data derived from a variety of molecular representations and feature selection algorithms, reliable QSAR models were built which could be used to predict for test compounds the inhibitory activity and selectivity toward human MAO. This work also showed how several QSAR models can be combined to make better predictions. The final models exhibit significant statistics, interpretability, as well as displaying predictive power on an external validation set made up of chromone derivatives with unknown activity (that are being reported here for first time) synthesized by our group, and coumarins recently reported in the literature." ], "offsets": [ [ 100, 1669 ] ] } ]

[ { "id": "23207409_T1", "type": "CHEMICAL", "text": [ "coumarins" ], "offsets": [ [ 1623, 1632 ] ], "normalized": [] }, { "id": "23207409_T2", "type": "CHEMICAL", "text": [ "chromones" ], "offsets": [ [ 766, 775 ] ], "normalized": [] }, { "id": "23207409_T3", "type": "CHEMICAL", "text": [ "coumarins" ], "offsets": [ [ 777, 786 ] ], "normalized": [] }, { "id": "23207409_T4", "type": "CHEMICAL", "text": [ "chalcones" ], "offsets": [ [ 788, 797 ] ], "normalized": [] }, { "id": "23207409_T5", "type": "CHEMICAL", "text": [ "thiazolylhydrazones" ], "offsets": [ [ 799, 818 ] ], "normalized": [] }, { "id": "23207409_T6", "type": "GENE-N", "text": [ "human MAO" ], "offsets": [ [ 1256, 1265 ] ], "normalized": [] }, { "id": "23207409_T7", "type": "GENE-Y", "text": [ "human MAO-B" ], "offsets": [ [ 263, 274 ] ], "normalized": [] }, { "id": "23207409_T8", "type": "GENE-N", "text": [ "MAOs" ], "offsets": [ [ 395, 399 ] ], "normalized": [] }, { "id": "23207409_T9", "type": "GENE-N", "text": [ "human MAO" ], "offsets": [ [ 625, 634 ] ], "normalized": [] }, { "id": "23207409_T10", "type": "GENE-Y", "text": [ "MAO-A" ], "offsets": [ [ 168, 173 ] ], "normalized": [] }, { "id": "23207409_T11", "type": "GENE-Y", "text": [ "MAO-B" ], "offsets": [ [ 178, 183 ] ], "normalized": [] }, { "id": "23207409_T12", "type": "GENE-N", "text": [ "human monoamine oxidase" ], "offsets": [ [ 64, 87 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "23395171_title", "type": "title", "text": [ "Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation." ], "offsets": [ [ 0, 84 ] ] }, { "id": "23395171_abstract", "type": "abstract", "text": [ "Osteoclast maturation and function primarily depend on receptor activator of NF-κB ligand (RANKL)-mediated induction of nuclear factor of activated T cells c1 (NFATc1), which is further activated via increased intracellular calcium ([Ca(2+)](i)) oscillation. However, the coordination mechanism that mediates Ca(2+) oscillation during osteoclastogenesis remains ill defined. Here, we identified transmembrane protein 64 (Tmem64) as a regulator of Ca(2+) oscillation during osteoclastogenesis. We found that Tmem64-deficient mice exhibit increased bone mass due in part to impaired osteoclast formation. Using in vitro osteoclast culture systems, we show here that Tmem64 interacts with sarcoplasmic endoplasmic reticulum Ca(2+) ATPase 2 (SERCA2) and modulates its activity. Consequently, Tmem64 deficiency significantly diminishes RANKL-induced [Ca(2+)](i) oscillation, which results in reduced Ca(2+)/calmodulin-dependent protein kinases (CaMK) IV and mitochondrial ROS, both of which contribute to achieving the CREB activity necessary for osteoclast formation. These data demonstrate that Tmem64 is a positive modulator of osteoclast differentiation via SERCA2-dependent Ca(2+) signaling." ], "offsets": [ [ 85, 1276 ] ] } ]

[ { "id": "23395171_T1", "type": "CHEMICAL", "text": [ "Ca(2+)" ], "offsets": [ [ 1259, 1265 ] ], "normalized": [] }, { "id": "23395171_T2", "type": "CHEMICAL", "text": [ "calcium" ], "offsets": [ [ 309, 316 ] ], "normalized": [] }, { "id": "23395171_T3", "type": "CHEMICAL", "text": [ "Ca(2+)" ], "offsets": [ [ 319, 325 ] ], "normalized": [] }, { "id": "23395171_T4", "type": "CHEMICAL", "text": [ "Ca(2+)" ], "offsets": [ [ 394, 400 ] ], "normalized": [] }, { "id": "23395171_T5", "type": "CHEMICAL", "text": [ "Ca(2+)" ], "offsets": [ [ 532, 538 ] ], "normalized": [] }, { "id": "23395171_T6", "type": "CHEMICAL", "text": [ "Ca(2+)" ], "offsets": [ [ 806, 812 ] ], "normalized": [] }, { "id": "23395171_T7", "type": "CHEMICAL", "text": [ "Ca(2+)" ], "offsets": [ [ 931, 937 ] ], "normalized": [] }, { "id": "23395171_T8", "type": "CHEMICAL", "text": [ "Ca(2+)" ], "offsets": [ [ 980, 986 ] ], "normalized": [] }, { "id": "23395171_T9", "type": "CHEMICAL", "text": [ "calcium" ], "offsets": [ [ 17, 24 ] ], "normalized": [] }, { "id": "23395171_T10", "type": "GENE-N", "text": [ "CREB" ], "offsets": [ [ 1099, 1103 ] ], "normalized": [] }, { "id": "23395171_T11", "type": "GENE-Y", "text": [ "Tmem64" ], "offsets": [ [ 1177, 1183 ] ], "normalized": [] }, { "id": "23395171_T12", "type": "GENE-Y", "text": [ "SERCA2" ], "offsets": [ [ 1242, 1248 ] ], "normalized": [] }, { "id": "23395171_T13", "type": "GENE-Y", "text": [ "nuclear factor of activated T cells c1" ], "offsets": [ [ 205, 243 ] ], "normalized": [] }, { "id": "23395171_T14", "type": "GENE-Y", "text": [ "NFATc1" ], "offsets": [ [ 245, 251 ] ], "normalized": [] }, { "id": "23395171_T15", "type": "GENE-Y", "text": [ "transmembrane protein 64" ], "offsets": [ [ 480, 504 ] ], "normalized": [] }, { "id": "23395171_T16", "type": "GENE-Y", "text": [ "Tmem64" ], "offsets": [ [ 506, 512 ] ], "normalized": [] }, { "id": "23395171_T17", "type": "GENE-Y", "text": [ "Tmem64" ], "offsets": [ [ 592, 598 ] ], "normalized": [] }, { "id": "23395171_T18", "type": "GENE-Y", "text": [ "receptor activator of NF-κB ligand" ], "offsets": [ [ 140, 174 ] ], "normalized": [] }, { "id": "23395171_T19", "type": "GENE-Y", "text": [ "Tmem64" ], "offsets": [ [ 873, 879 ] ], "normalized": [] }, { "id": "23395171_T20", "type": "GENE-Y", "text": [ "RANKL" ], "offsets": [ [ 916, 921 ] ], "normalized": [] }, { "id": "23395171_T21", "type": "GENE-Y", "text": [ "Ca(2+)/calmodulin-dependent protein kinases (CaMK) IV" ], "offsets": [ [ 980, 1033 ] ], "normalized": [] }, { "id": "23395171_T22", "type": "GENE-Y", "text": [ "RANKL" ], "offsets": [ [ 176, 181 ] ], "normalized": [] }, { "id": "23395171_T23", "type": "GENE-Y", "text": [ "Tmem64" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "23395171_T24", "type": "GENE-Y", "text": [ "RANKL" ], "offsets": [ [ 42, 47 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "23073075_title", "type": "title", "text": [ "Fingolimod protects cultured cortical neurons against excitotoxic death." ], "offsets": [ [ 0, 72 ] ] }, { "id": "23073075_abstract", "type": "abstract", "text": [ "Fingolimod (FTY720), a novel drug approved for the treatment of relapsing-remitting multiple sclerosis, activates different sphingosine-1-phosphate receptor (S1PR) subtypes. Its primary mechanism of action is to reduce the egress of T lymphocytes from secondary lymphoid organs, thus restraining neuroinflammation and autoimmunity. However, recent evidence suggests that the action of FTY720 involves S1PRs expressed by cells resident in the CNS, including neurons. Here, we examined the effect of FTY720, its active metabolite, FTY720-P, and sphingosine-1-phosphate (S1P) on neuronal viability using a classical in vitro model of excitotoxic neuronal death. Mixed cultures of mouse cortical cells were challenged with toxic concentrations of N-methyl-d-aspartate (NMDA) for 10 min, and neuronal death was assessed 20 h later. FTY720, FTY720-P, and S1P were all neuroprotective when applied 18-20 h prior to the NMDA pulse. Neuroprotection was attenuated by pertussis toxin, and inhibited by the selective type-1 S1PR (S1P1R) antagonist, W146, and by inhibitors of the mitogen associated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PtdIns-3-K) pathways. Both FTY720 and FTY720-P retained their protective activity in pure cultures of mouse or rat cortical neurons. These data offer the first direct demonstration that FTY720 and its active metabolite protect neurons against excitotoxic death." ], "offsets": [ [ 73, 1483 ] ] } ]

[ { "id": "23073075_T1", "type": "CHEMICAL", "text": [ "Fingolimod" ], "offsets": [ [ 73, 83 ] ], "normalized": [] }, { "id": "23073075_T2", "type": "CHEMICAL", "text": [ "W146" ], "offsets": [ [ 1111, 1115 ] ], "normalized": [] }, { "id": "23073075_T3", "type": "CHEMICAL", "text": [ "phosphatidylinositol" ], "offsets": [ [ 1191, 1211 ] ], "normalized": [] }, { "id": "23073075_T4", "type": "CHEMICAL", "text": [ "FTY720" ], "offsets": [ [ 1249, 1255 ] ], "normalized": [] }, { "id": "23073075_T5", "type": "CHEMICAL", "text": [ "FTY720-P" ], "offsets": [ [ 1260, 1268 ] ], "normalized": [] }, { "id": "23073075_T6", "type": "CHEMICAL", "text": [ "FTY720" ], "offsets": [ [ 85, 91 ] ], "normalized": [] }, { "id": "23073075_T7", "type": "CHEMICAL", "text": [ "sphingosine-1-phosphate" ], "offsets": [ [ 197, 220 ] ], "normalized": [] }, { "id": "23073075_T8", "type": "CHEMICAL", "text": [ "FTY720" ], "offsets": [ [ 1408, 1414 ] ], "normalized": [] }, { "id": "23073075_T9", "type": "CHEMICAL", "text": [ "FTY720" ], "offsets": [ [ 458, 464 ] ], "normalized": [] }, { "id": "23073075_T10", "type": "CHEMICAL", "text": [ "FTY720" ], "offsets": [ [ 571, 577 ] ], "normalized": [] }, { "id": "23073075_T11", "type": "CHEMICAL", "text": [ "FTY720-P" ], "offsets": [ [ 602, 610 ] ], "normalized": [] }, { "id": "23073075_T12", "type": "CHEMICAL", "text": [ "sphingosine-1-phosphate" ], "offsets": [ [ 616, 639 ] ], "normalized": [] }, { "id": "23073075_T13", "type": "CHEMICAL", "text": [ "S1P" ], "offsets": [ [ 641, 644 ] ], "normalized": [] }, { "id": "23073075_T14", "type": "CHEMICAL", "text": [ "N-methyl-d-aspartate" ], "offsets": [ [ 816, 836 ] ], "normalized": [] }, { "id": "23073075_T15", "type": "CHEMICAL", "text": [ "NMDA" ], "offsets": [ [ 838, 842 ] ], "normalized": [] }, { "id": "23073075_T16", "type": "CHEMICAL", "text": [ "FTY720" ], "offsets": [ [ 900, 906 ] ], "normalized": [] }, { "id": "23073075_T17", "type": "CHEMICAL", "text": [ "FTY720-P" ], "offsets": [ [ 908, 916 ] ], "normalized": [] }, { "id": "23073075_T18", "type": "CHEMICAL", "text": [ "S1P" ], "offsets": [ [ 922, 925 ] ], "normalized": [] }, { "id": "23073075_T19", "type": "CHEMICAL", "text": [ "NMDA" ], "offsets": [ [ 985, 989 ] ], "normalized": [] }, { "id": "23073075_T20", "type": "CHEMICAL", "text": [ "Fingolimod" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "23073075_T21", "type": "GENE-Y", "text": [ "type-1 S1PR" ], "offsets": [ [ 1079, 1090 ] ], "normalized": [] }, { "id": "23073075_T22", "type": "GENE-Y", "text": [ "S1P1R" ], "offsets": [ [ 1092, 1097 ] ], "normalized": [] }, { "id": "23073075_T23", "type": "GENE-N", "text": [ "mitogen associated protein kinase" ], "offsets": [ [ 1142, 1175 ] ], "normalized": [] }, { "id": "23073075_T24", "type": "GENE-N", "text": [ "MAPK" ], "offsets": [ [ 1177, 1181 ] ], "normalized": [] }, { "id": "23073075_T25", "type": "GENE-N", "text": [ "phosphatidylinositol-3-kinase" ], "offsets": [ [ 1191, 1220 ] ], "normalized": [] }, { "id": "23073075_T26", "type": "GENE-N", "text": [ "PtdIns-3-K" ], "offsets": [ [ 1222, 1232 ] ], "normalized": [] }, { "id": "23073075_T27", "type": "GENE-N", "text": [ "sphingosine-1-phosphate receptor" ], "offsets": [ [ 197, 229 ] ], "normalized": [] }, { "id": "23073075_T28", "type": "GENE-N", "text": [ "S1PR" ], "offsets": [ [ 231, 235 ] ], "normalized": [] }, { "id": "23073075_T29", "type": "GENE-N", "text": [ "S1PRs" ], "offsets": [ [ 474, 479 ] ], "normalized": [] }, { "id": "23073075_T30", "type": "GENE-N", "text": [ "pertussis toxin" ], "offsets": [ [ 1031, 1046 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23073075_0", "type": "ACTIVATOR", "arg1_id": "23073075_T1", "arg2_id": "23073075_T27", "normalized": [] }, { "id": "23073075_1", "type": "ACTIVATOR", "arg1_id": "23073075_T1", "arg2_id": "23073075_T28", "normalized": [] }, { "id": "23073075_2", "type": "ACTIVATOR", "arg1_id": "23073075_T6", "arg2_id": "23073075_T27", "normalized": [] }, { "id": "23073075_3", "type": "ACTIVATOR", "arg1_id": "23073075_T6", "arg2_id": "23073075_T28", "normalized": [] }, { "id": "23073075_4", "type": "ANTAGONIST", "arg1_id": "23073075_T2", "arg2_id": "23073075_T22", "normalized": [] }, { "id": "23073075_5", "type": "ANTAGONIST", "arg1_id": "23073075_T2", "arg2_id": "23073075_T21", "normalized": [] } ]

[ { "id": "23131798_title", "type": "title", "text": [ "Discovery of novel cannabinoid receptor ligands by a virtual screening approach: further development of 2,4,6-trisubstituted 1,3,5-triazines as CB2 agonists." ], "offsets": [ [ 0, 157 ] ] }, { "id": "23131798_abstract", "type": "abstract", "text": [ "3D ligand-based virtual screening was employed to identify novel scaffolds for cannabinoid receptor ligand development. A total of 112 compounds with diverse structures were purchased from commercial vendors. 12 CB1 receptor antagonists/inverse agonists and 10 CB2 receptor agonists were identified in vitro. One of the CB2 agonists, N-cyclopentyl-4-ethoxy-6-(4-methylpiperidin-1-yl)-1,3,5-triazin-2-amine (19, -logEC(50)=7.5, E(max)=255%) was selected for further development. As far as we are aware, the compound's 1,3,5-triazine scaffold represents a new core structure for CB2 agonists. A library of fifty-seven 2,4,6-trisubstituted-1,3,5-triazines was created to clarify the structure-activity relationship study of the analogs." ], "offsets": [ [ 158, 891 ] ] } ]

[ { "id": "23131798_T1", "type": "CHEMICAL", "text": [ "N-cyclopentyl-4-ethoxy-6-(4-methylpiperidin-1-yl)-1,3,5-triazin-2-amine" ], "offsets": [ [ 492, 563 ] ], "normalized": [] }, { "id": "23131798_T2", "type": "CHEMICAL", "text": [ "1,3,5-triazine" ], "offsets": [ [ 675, 689 ] ], "normalized": [] }, { "id": "23131798_T3", "type": "CHEMICAL", "text": [ "2,4,6-trisubstituted-1,3,5-triazines" ], "offsets": [ [ 774, 810 ] ], "normalized": [] }, { "id": "23131798_T4", "type": "CHEMICAL", "text": [ "2,4,6-trisubstituted 1,3,5-triazines" ], "offsets": [ [ 104, 140 ] ], "normalized": [] }, { "id": "23131798_T5", "type": "GENE-Y", "text": [ "CB1" ], "offsets": [ [ 370, 373 ] ], "normalized": [] }, { "id": "23131798_T6", "type": "GENE-Y", "text": [ "CB2" ], "offsets": [ [ 419, 422 ] ], "normalized": [] }, { "id": "23131798_T7", "type": "GENE-Y", "text": [ "CB2" ], "offsets": [ [ 478, 481 ] ], "normalized": [] }, { "id": "23131798_T8", "type": "GENE-Y", "text": [ "CB2" ], "offsets": [ [ 735, 738 ] ], "normalized": [] }, { "id": "23131798_T9", "type": "GENE-N", "text": [ "cannabinoid receptor" ], "offsets": [ [ 237, 257 ] ], "normalized": [] }, { "id": "23131798_T10", "type": "GENE-Y", "text": [ "CB2" ], "offsets": [ [ 144, 147 ] ], "normalized": [] }, { "id": "23131798_T11", "type": "GENE-N", "text": [ "cannabinoid receptor" ], "offsets": [ [ 19, 39 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23131798_0", "type": "AGONIST", "arg1_id": "23131798_T4", "arg2_id": "23131798_T10", "normalized": [] }, { "id": "23131798_1", "type": "AGONIST", "arg1_id": "23131798_T1", "arg2_id": "23131798_T7", "normalized": [] }, { "id": "23131798_2", "type": "AGONIST", "arg1_id": "23131798_T2", "arg2_id": "23131798_T8", "normalized": [] } ]

[ { "id": "23530959_title", "type": "title", "text": [ "Multipart Copolyelectrolyte Adhesive of the Sandcastle Worm, Phragmatopoma californica (Fewkes): Catechol Oxidase Catalyzed Curing through Peptidyl-DOPA." ], "offsets": [ [ 0, 153 ] ] }, { "id": "23530959_abstract", "type": "abstract", "text": [ "Tube-building sabellariid polychaetes have major impacts on the geology and ecology of shorelines worldwide. Sandcastle worms, Phragmatopoma californica (Fewkes), live along the western coast of North America. Individual sabellariid worms build tubular shells by gluing together mineral particles with a multipart polyelectrolytic adhesive. Distinct sets of oppositely charged components are packaged and stored in concentrated granules in separate cell types. Homogeneous granules contain sulfated macromolecules as counter-polyanion to polycationic Pc2 and Pc5 proteins, which become major components of the fully cured glue. Heterogeneous granules contain polyphosphoproteins, Pc3A/B, paired with divalent cations and polycationic Pc1 and Pc4 proteins. Both types of granules contain catechol oxidase that catalyzes oxidative cross-linking of L-DOPA. Co-secretion of catechol oxidase guarantees rapid and spatially homogeneous curing with limited mixing of the preassembled adhesive packets. Catechol oxidase remains active long after the glue is fully cured, perhaps providing an active cue for conspecific larval settlement." ], "offsets": [ [ 154, 1283 ] ] } ]

[ { "id": "23530959_T1", "type": "CHEMICAL", "text": [ "catechol" ], "offsets": [ [ 941, 949 ] ], "normalized": [] }, { "id": "23530959_T2", "type": "CHEMICAL", "text": [ "L-DOPA" ], "offsets": [ [ 1000, 1006 ] ], "normalized": [] }, { "id": "23530959_T3", "type": "CHEMICAL", "text": [ "catechol" ], "offsets": [ [ 1024, 1032 ] ], "normalized": [] }, { "id": "23530959_T4", "type": "CHEMICAL", "text": [ "Catechol" ], "offsets": [ [ 1149, 1157 ] ], "normalized": [] }, { "id": "23530959_T5", "type": "CHEMICAL", "text": [ "DOPA" ], "offsets": [ [ 148, 152 ] ], "normalized": [] }, { "id": "23530959_T6", "type": "CHEMICAL", "text": [ "Catechol" ], "offsets": [ [ 97, 105 ] ], "normalized": [] }, { "id": "23530959_T7", "type": "GENE-Y", "text": [ "Pc2" ], "offsets": [ [ 705, 708 ] ], "normalized": [] }, { "id": "23530959_T8", "type": "GENE-N", "text": [ "Pc5" ], "offsets": [ [ 713, 716 ] ], "normalized": [] }, { "id": "23530959_T9", "type": "GENE-N", "text": [ "Pc3A/B" ], "offsets": [ [ 834, 840 ] ], "normalized": [] }, { "id": "23530959_T10", "type": "GENE-Y", "text": [ "Pc1" ], "offsets": [ [ 888, 891 ] ], "normalized": [] }, { "id": "23530959_T11", "type": "GENE-N", "text": [ "Pc4" ], "offsets": [ [ 896, 899 ] ], "normalized": [] }, { "id": "23530959_T12", "type": "GENE-N", "text": [ "catechol oxidase" ], "offsets": [ [ 941, 957 ] ], "normalized": [] }, { "id": "23530959_T13", "type": "GENE-N", "text": [ "catechol oxidase" ], "offsets": [ [ 1024, 1040 ] ], "normalized": [] }, { "id": "23530959_T14", "type": "GENE-N", "text": [ "Catechol oxidase" ], "offsets": [ [ 1149, 1165 ] ], "normalized": [] }, { "id": "23530959_T15", "type": "GENE-N", "text": [ "Catechol Oxidase" ], "offsets": [ [ 97, 113 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23530959_0", "type": "SUBSTRATE", "arg1_id": "23530959_T2", "arg2_id": "23530959_T12", "normalized": [] } ]

[ { "id": "23085435_title", "type": "title", "text": [ "Nitrogen-containing bisphosphonates induce apoptosis of hematopoietic tumor cells via inhibition of Ras signaling pathways and Bim-mediated activation of the intrinsic apoptotic pathway." ], "offsets": [ [ 0, 186 ] ] }, { "id": "23085435_abstract", "type": "abstract", "text": [ "Nitrogen-containing bisphosphonates (N-BPs) induce apoptosis in tumor cells by inhibiting the prenylation of small G-proteins. However, the details of the apoptosis-inducing mechanism remain obscure. The present study showed that the induction of apoptosis by N-BPs in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. Furthermore, N-BPs decreased the levels of phosphorylated extracellular signal-regulated kinase (ERK) and mTOR via suppression of Ras prenylation and enhanced Bim expression. The present results indicated that N-BPs induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, and enhancing Bim expression through inhibition of the Ras/MEK/ERK and Ras/mTOR pathways. The accumulation of N-BPs in bones suggests that they may act more effectively on tumors that have spread to bones or on Ras-variable tumors. This is the first study to show that the specific molecular pathways of N-BP-induced apoptosis." ], "offsets": [ [ 187, 1304 ] ] } ]

[ { "id": "23085435_T1", "type": "CHEMICAL", "text": [ "Nitrogen" ], "offsets": [ [ 187, 195 ] ], "normalized": [] }, { "id": "23085435_T2", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 1281, 1282 ] ], "normalized": [] }, { "id": "23085435_T3", "type": "CHEMICAL", "text": [ "bisphosphonates" ], "offsets": [ [ 207, 222 ] ], "normalized": [] }, { "id": "23085435_T4", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 447, 448 ] ], "normalized": [] }, { "id": "23085435_T5", "type": "CHEMICAL", "text": [ "BPs" ], "offsets": [ [ 449, 452 ] ], "normalized": [] }, { "id": "23085435_T6", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 224, 225 ] ], "normalized": [] }, { "id": "23085435_T7", "type": "CHEMICAL", "text": [ "BPs" ], "offsets": [ [ 226, 229 ] ], "normalized": [] }, { "id": "23085435_T8", "type": "CHEMICAL", "text": [ "geranylgeranyl pyrophosphate" ], "offsets": [ [ 583, 611 ] ], "normalized": [] }, { "id": "23085435_T9", "type": "CHEMICAL", "text": [ "GGPP" ], "offsets": [ [ 613, 617 ] ], "normalized": [] }, { "id": "23085435_T10", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 646, 647 ] ], "normalized": [] }, { "id": "23085435_T11", "type": "CHEMICAL", "text": [ "BPs" ], "offsets": [ [ 648, 651 ] ], "normalized": [] }, { "id": "23085435_T12", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 843, 844 ] ], "normalized": [] }, { "id": "23085435_T13", "type": "CHEMICAL", "text": [ "BPs" ], "offsets": [ [ 845, 848 ] ], "normalized": [] }, { "id": "23085435_T14", "type": "CHEMICAL", "text": [ "N" ], "offsets": [ [ 1087, 1088 ] ], "normalized": [] }, { "id": "23085435_T15", "type": "CHEMICAL", "text": [ "BPs" ], "offsets": [ [ 1089, 1092 ] ], "normalized": [] }, { "id": "23085435_T16", "type": "CHEMICAL", "text": [ "Nitrogen" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "23085435_T17", "type": "CHEMICAL", "text": [ "bisphosphonates" ], "offsets": [ [ 20, 35 ] ], "normalized": [] }, { "id": "23085435_T18", "type": "GENE-N", "text": [ "Ras" ], "offsets": [ [ 1188, 1191 ] ], "normalized": [] }, { "id": "23085435_T19", "type": "GENE-N", "text": [ "G-proteins" ], "offsets": [ [ 302, 312 ] ], "normalized": [] }, { "id": "23085435_T20", "type": "GENE-N", "text": [ "phosphorylated extracellular signal-regulated kinase" ], "offsets": [ [ 676, 728 ] ], "normalized": [] }, { "id": "23085435_T21", "type": "GENE-N", "text": [ "ERK" ], "offsets": [ [ 730, 733 ] ], "normalized": [] }, { "id": "23085435_T22", "type": "GENE-Y", "text": [ "mTOR" ], "offsets": [ [ 739, 743 ] ], "normalized": [] }, { "id": "23085435_T23", "type": "GENE-N", "text": [ "Ras" ], "offsets": [ [ 763, 766 ] ], "normalized": [] }, { "id": "23085435_T24", "type": "GENE-Y", "text": [ "Bim" ], "offsets": [ [ 792, 795 ] ], "normalized": [] }, { "id": "23085435_T25", "type": "GENE-Y", "text": [ "caspase-9" ], "offsets": [ [ 952, 961 ] ], "normalized": [] }, { "id": "23085435_T26", "type": "GENE-Y", "text": [ "caspase-3" ], "offsets": [ [ 966, 975 ] ], "normalized": [] }, { "id": "23085435_T27", "type": "GENE-Y", "text": [ "Bim" ], "offsets": [ [ 991, 994 ] ], "normalized": [] }, { "id": "23085435_T28", "type": "GENE-N", "text": [ "Ras" ], "offsets": [ [ 1032, 1035 ] ], "normalized": [] }, { "id": "23085435_T29", "type": "GENE-N", "text": [ "MEK" ], "offsets": [ [ 1036, 1039 ] ], "normalized": [] }, { "id": "23085435_T30", "type": "GENE-N", "text": [ "ERK" ], "offsets": [ [ 1040, 1043 ] ], "normalized": [] }, { "id": "23085435_T31", "type": "GENE-N", "text": [ "Ras" ], "offsets": [ [ 1048, 1051 ] ], "normalized": [] }, { "id": "23085435_T32", "type": "GENE-Y", "text": [ "mTOR" ], "offsets": [ [ 1052, 1056 ] ], "normalized": [] }, { "id": "23085435_T33", "type": "GENE-N", "text": [ "Ras" ], "offsets": [ [ 100, 103 ] ], "normalized": [] }, { "id": "23085435_T34", "type": "GENE-Y", "text": [ "Bim" ], "offsets": [ [ 127, 130 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "15114505_title", "type": "title", "text": [ "In vitro inhibition of diacylglycerol acyltransferase by prenylflavonoids from Sophora flavescens." ], "offsets": [ [ 0, 98 ] ] }, { "id": "15114505_abstract", "type": "abstract", "text": [ "Four prenylflavonoids, kurarinone ( 1), a chalcone of 1, kuraridin ( 2), kurarinol ( 3), kushenol H ( 4) and kushenol K ( 5) isolated from the roots of Sophora flavescens were investigated for their inhibitory effects on diacylglycerol acyltransferase (DGAT). The flavonoids inhibited DGAT activity in a dose-dependent manner with IC50 values of 10.9 microM ( 1), 9.8 microM ( 2), 8.6 microM ( 3), 142.0 microM ( 4) and 250 microM ( 5). The prenylflavonoids without C3-OH ( 1, 2, 3) showed stronger inhibition than those with C3-OH ( 4, 5). On the other hand, flavonoids without side chains (hesperetin, naringenin, quercetin and kaempferol) did not inhibit the enzyme activity at a final concentration of 800 microM. These data suggest that the lavandulyl side chain and the position of the hydroxy group are important for high DGAT inhibitory activity. Compound 1 also inhibited de novo synthesis of triacylglycerol (TG) in Raji cells." ], "offsets": [ [ 99, 1036 ] ] } ]

[ { "id": "15114505_T1", "type": "CHEMICAL", "text": [ "kushenol K" ], "offsets": [ [ 208, 218 ] ], "normalized": [] }, { "id": "15114505_T2", "type": "CHEMICAL", "text": [ "diacylglycerol" ], "offsets": [ [ 320, 334 ] ], "normalized": [] }, { "id": "15114505_T3", "type": "CHEMICAL", "text": [ "kurarinone" ], "offsets": [ [ 122, 132 ] ], "normalized": [] }, { "id": "15114505_T4", "type": "CHEMICAL", "text": [ "flavonoids" ], "offsets": [ [ 363, 373 ] ], "normalized": [] }, { "id": "15114505_T5", "type": "CHEMICAL", "text": [ "chalcone" ], "offsets": [ [ 141, 149 ] ], "normalized": [] }, { "id": "15114505_T6", "type": "CHEMICAL", "text": [ "prenylflavonoids" ], "offsets": [ [ 540, 556 ] ], "normalized": [] }, { "id": "15114505_T7", "type": "CHEMICAL", "text": [ "C3-OH" ], "offsets": [ [ 565, 570 ] ], "normalized": [] }, { "id": "15114505_T8", "type": "CHEMICAL", "text": [ "prenylflavonoids" ], "offsets": [ [ 104, 120 ] ], "normalized": [] }, { "id": "15114505_T9", "type": "CHEMICAL", "text": [ "C3-OH" ], "offsets": [ [ 625, 630 ] ], "normalized": [] }, { "id": "15114505_T10", "type": "CHEMICAL", "text": [ "flavonoids" ], "offsets": [ [ 659, 669 ] ], "normalized": [] }, { "id": "15114505_T11", "type": "CHEMICAL", "text": [ "kuraridin" ], "offsets": [ [ 156, 165 ] ], "normalized": [] }, { "id": "15114505_T12", "type": "CHEMICAL", "text": [ "hesperetin" ], "offsets": [ [ 691, 701 ] ], "normalized": [] }, { "id": "15114505_T13", "type": "CHEMICAL", "text": [ "naringenin" ], "offsets": [ [ 703, 713 ] ], "normalized": [] }, { "id": "15114505_T14", "type": "CHEMICAL", "text": [ "quercetin" ], "offsets": [ [ 715, 724 ] ], "normalized": [] }, { "id": "15114505_T15", "type": "CHEMICAL", "text": [ "kaempferol" ], "offsets": [ [ 729, 739 ] ], "normalized": [] }, { "id": "15114505_T16", "type": "CHEMICAL", "text": [ "kurarinol" ], "offsets": [ [ 172, 181 ] ], "normalized": [] }, { "id": "15114505_T17", "type": "CHEMICAL", "text": [ "lavandulyl" ], "offsets": [ [ 845, 855 ] ], "normalized": [] }, { "id": "15114505_T18", "type": "CHEMICAL", "text": [ "hydroxy" ], "offsets": [ [ 891, 898 ] ], "normalized": [] }, { "id": "15114505_T19", "type": "CHEMICAL", "text": [ "kushenol H" ], "offsets": [ [ 188, 198 ] ], "normalized": [] }, { "id": "15114505_T20", "type": "CHEMICAL", "text": [ "triacylglycerol" ], "offsets": [ [ 1001, 1016 ] ], "normalized": [] }, { "id": "15114505_T21", "type": "CHEMICAL", "text": [ "TG" ], "offsets": [ [ 1018, 1020 ] ], "normalized": [] }, { "id": "15114505_T22", "type": "CHEMICAL", "text": [ "diacylglycerol" ], "offsets": [ [ 23, 37 ] ], "normalized": [] }, { "id": "15114505_T23", "type": "CHEMICAL", "text": [ "prenylflavonoids" ], "offsets": [ [ 57, 73 ] ], "normalized": [] }, { "id": "15114505_T24", "type": "GENE-Y", "text": [ "diacylglycerol acyltransferase" ], "offsets": [ [ 320, 350 ] ], "normalized": [] }, { "id": "15114505_T25", "type": "GENE-Y", "text": [ "DGAT" ], "offsets": [ [ 352, 356 ] ], "normalized": [] }, { "id": "15114505_T26", "type": "GENE-Y", "text": [ "DGAT" ], "offsets": [ [ 384, 388 ] ], "normalized": [] }, { "id": "15114505_T27", "type": "GENE-Y", "text": [ "DGAT" ], "offsets": [ [ 928, 932 ] ], "normalized": [] }, { "id": "15114505_T28", "type": "GENE-Y", "text": [ "diacylglycerol acyltransferase" ], "offsets": [ [ 23, 53 ] ], "normalized": [] } ]

[]

[]

[ { "id": "15114505_0", "type": "INHIBITOR", "arg1_id": "15114505_T23", "arg2_id": "15114505_T28", "normalized": [] }, { "id": "15114505_1", "type": "INHIBITOR", "arg1_id": "15114505_T8", "arg2_id": "15114505_T24", "normalized": [] }, { "id": "15114505_2", "type": "INHIBITOR", "arg1_id": "15114505_T3", "arg2_id": "15114505_T24", "normalized": [] }, { "id": "15114505_3", "type": "INHIBITOR", "arg1_id": "15114505_T5", "arg2_id": "15114505_T24", "normalized": [] }, { "id": "15114505_4", "type": "INHIBITOR", "arg1_id": "15114505_T11", "arg2_id": "15114505_T24", "normalized": [] }, { "id": "15114505_5", "type": "INHIBITOR", "arg1_id": "15114505_T16", "arg2_id": "15114505_T24", "normalized": [] }, { "id": "15114505_6", "type": "INHIBITOR", "arg1_id": "15114505_T19", "arg2_id": "15114505_T24", "normalized": [] }, { "id": "15114505_7", "type": "INHIBITOR", "arg1_id": "15114505_T1", "arg2_id": "15114505_T24", "normalized": [] }, { "id": "15114505_8", "type": "INHIBITOR", "arg1_id": "15114505_T8", "arg2_id": "15114505_T25", "normalized": [] }, { "id": "15114505_9", "type": "INHIBITOR", "arg1_id": "15114505_T3", "arg2_id": "15114505_T25", "normalized": [] }, { "id": "15114505_10", "type": "INHIBITOR", "arg1_id": "15114505_T5", "arg2_id": "15114505_T25", "normalized": [] }, { "id": "15114505_11", "type": "INHIBITOR", "arg1_id": "15114505_T11", "arg2_id": "15114505_T25", "normalized": [] }, { "id": "15114505_12", "type": "INHIBITOR", "arg1_id": "15114505_T16", "arg2_id": "15114505_T25", "normalized": [] }, { "id": "15114505_13", "type": "INHIBITOR", "arg1_id": "15114505_T19", "arg2_id": "15114505_T25", "normalized": [] }, { "id": "15114505_14", "type": "INHIBITOR", "arg1_id": "15114505_T1", "arg2_id": "15114505_T25", "normalized": [] }, { "id": "15114505_15", "type": "INHIBITOR", "arg1_id": "15114505_T4", "arg2_id": "15114505_T26", "normalized": [] }, { "id": "15114505_16", "type": "INHIBITOR", "arg1_id": "15114505_T17", "arg2_id": "15114505_T27", "normalized": [] }, { "id": "15114505_17", "type": "INHIBITOR", "arg1_id": "15114505_T18", "arg2_id": "15114505_T27", "normalized": [] } ]

[ { "id": "23200945_title", "type": "title", "text": [ "Bradykinetic alcohol dehydrogenases make yeast fitter for growth in the presence of allyl alcohol." ], "offsets": [ [ 0, 98 ] ] }, { "id": "23200945_abstract", "type": "abstract", "text": [ "Previous studies showed that fitter yeast (Saccharomyces cerevisiae) that can grow by fermenting glucose in the presence of allyl alcohol, which is oxidized by alcohol dehydrogenase I (ADH1) to toxic acrolein, had mutations in the ADH1 gene that led to decreased ADH activity. These yeast may grow more slowly due to slower reduction of acetaldehyde and a higher NADH/NAD(+) ratio, which should decrease the oxidation of allyl alcohol. We determined steady-state kinetic constants for three yeast ADHs with new site-directed substitutions and examined the correlation between catalytic efficiency and growth on selective media of yeast expressing six different ADHs. The H15R substitution (a test for electrostatic effects) is on the surface of ADH and has small effects on the kinetics. The H44R substitution (affecting interactions with the coenzyme pyrophosphate) was previously shown to decrease affinity for coenzymes 2-4-fold and turnover numbers (V/Et) by 4-6-fold. The W82R substitution is distant from the active site, but decreases turnover numbers by 5-6-fold, perhaps by effects on protein dynamics. The E67Q substitution near the catalytic zinc was shown previously to increase the Michaelis constant for acetaldehyde and to decrease turnover for ethanol oxidation. The W54R substitution, in the substrate binding site, increases kinetic constants (Ks, by >10-fold) while decreasing turnover numbers by 2-7-fold. Growth of yeast expressing the different ADHs on YPD plates (yeast extract, peptone and dextrose) plus antimycin to require fermentation, was positively correlated with the log of catalytic efficiency for the sequential bi reaction (V1/KiaKb=KeqV2/KpKiq, varying over 4 orders of magnitude, adjusted for different levels of ADH expression) in the order: WT≈H15R>H44R>W82R>E67Q>W54R. Growth on YPD plus 10mM allyl alcohol was inversely correlated with catalytic efficiency. The fitter yeast are \"bradytrophs\" (slow growing) because the ADHs have decreased catalytic efficiency." ], "offsets": [ [ 99, 2101 ] ] } ]

[ { "id": "23200945_T1", "type": "CHEMICAL", "text": [ "zinc" ], "offsets": [ [ 1252, 1256 ] ], "normalized": [] }, { "id": "23200945_T2", "type": "CHEMICAL", "text": [ "acetaldehyde" ], "offsets": [ [ 1317, 1329 ] ], "normalized": [] }, { "id": "23200945_T3", "type": "CHEMICAL", "text": [ "allyl alcohol" ], "offsets": [ [ 223, 236 ] ], "normalized": [] }, { "id": "23200945_T4", "type": "CHEMICAL", "text": [ "ethanol" ], "offsets": [ [ 1359, 1366 ] ], "normalized": [] }, { "id": "23200945_T5", "type": "CHEMICAL", "text": [ "dextrose" ], "offsets": [ [ 1613, 1621 ] ], "normalized": [] }, { "id": "23200945_T6", "type": "CHEMICAL", "text": [ "antimycin" ], "offsets": [ [ 1628, 1637 ] ], "normalized": [] }, { "id": "23200945_T7", "type": "CHEMICAL", "text": [ "alcohol" ], "offsets": [ [ 259, 266 ] ], "normalized": [] }, { "id": "23200945_T8", "type": "CHEMICAL", "text": [ "allyl alcohol" ], "offsets": [ [ 1932, 1945 ] ], "normalized": [] }, { "id": "23200945_T9", "type": "CHEMICAL", "text": [ "acrolein" ], "offsets": [ [ 299, 307 ] ], "normalized": [] }, { "id": "23200945_T10", "type": "CHEMICAL", "text": [ "acetaldehyde" ], "offsets": [ [ 436, 448 ] ], "normalized": [] }, { "id": "23200945_T11", "type": "CHEMICAL", "text": [ "NADH" ], "offsets": [ [ 462, 466 ] ], "normalized": [] }, { "id": "23200945_T12", "type": "CHEMICAL", "text": [ "NAD(+)" ], "offsets": [ [ 467, 473 ] ], "normalized": [] }, { "id": "23200945_T13", "type": "CHEMICAL", "text": [ "allyl alcohol" ], "offsets": [ [ 520, 533 ] ], "normalized": [] }, { "id": "23200945_T14", "type": "CHEMICAL", "text": [ "pyrophosphate" ], "offsets": [ [ 951, 964 ] ], "normalized": [] }, { "id": "23200945_T15", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 196, 203 ] ], "normalized": [] }, { "id": "23200945_T16", "type": "CHEMICAL", "text": [ "alcohol" ], "offsets": [ [ 13, 20 ] ], "normalized": [] }, { "id": "23200945_T17", "type": "CHEMICAL", "text": [ "allyl alcohol" ], "offsets": [ [ 84, 97 ] ], "normalized": [] }, { "id": "23200945_T18", "type": "GENE-N", "text": [ "E67Q" ], "offsets": [ [ 1215, 1219 ] ], "normalized": [] }, { "id": "23200945_T19", "type": "GENE-N", "text": [ "W54R" ], "offsets": [ [ 1382, 1386 ] ], "normalized": [] }, { "id": "23200945_T20", "type": "GENE-N", "text": [ "ADHs" ], "offsets": [ [ 1566, 1570 ] ], "normalized": [] }, { "id": "23200945_T21", "type": "GENE-Y", "text": [ "alcohol dehydrogenase I" ], "offsets": [ [ 259, 282 ] ], "normalized": [] }, { "id": "23200945_T22", "type": "GENE-N", "text": [ "ADH" ], "offsets": [ [ 1849, 1852 ] ], "normalized": [] }, { "id": "23200945_T23", "type": "GENE-N", "text": [ "H15R" ], "offsets": [ [ 1882, 1886 ] ], "normalized": [] }, { "id": "23200945_T24", "type": "GENE-N", "text": [ "H44R" ], "offsets": [ [ 1887, 1891 ] ], "normalized": [] }, { "id": "23200945_T25", "type": "GENE-N", "text": [ "W82R" ], "offsets": [ [ 1892, 1896 ] ], "normalized": [] }, { "id": "23200945_T26", "type": "GENE-N", "text": [ "E67Q" ], "offsets": [ [ 1897, 1901 ] ], "normalized": [] }, { "id": "23200945_T27", "type": "GENE-N", "text": [ "W54R" ], "offsets": [ [ 1902, 1906 ] ], "normalized": [] }, { "id": "23200945_T28", "type": "GENE-Y", "text": [ "ADH1" ], "offsets": [ [ 284, 288 ] ], "normalized": [] }, { "id": "23200945_T29", "type": "GENE-N", "text": [ "ADHs" ], "offsets": [ [ 2060, 2064 ] ], "normalized": [] }, { "id": "23200945_T30", "type": "GENE-Y", "text": [ "ADH1" ], "offsets": [ [ 330, 334 ] ], "normalized": [] }, { "id": "23200945_T31", "type": "GENE-N", "text": [ "ADH" ], "offsets": [ [ 362, 365 ] ], "normalized": [] }, { "id": "23200945_T32", "type": "GENE-N", "text": [ "ADHs" ], "offsets": [ [ 596, 600 ] ], "normalized": [] }, { "id": "23200945_T33", "type": "GENE-N", "text": [ "ADHs" ], "offsets": [ [ 760, 764 ] ], "normalized": [] }, { "id": "23200945_T34", "type": "GENE-N", "text": [ "H15R" ], "offsets": [ [ 770, 774 ] ], "normalized": [] }, { "id": "23200945_T35", "type": "GENE-N", "text": [ "ADH" ], "offsets": [ [ 844, 847 ] ], "normalized": [] }, { "id": "23200945_T36", "type": "GENE-N", "text": [ "H44R" ], "offsets": [ [ 891, 895 ] ], "normalized": [] }, { "id": "23200945_T37", "type": "GENE-N", "text": [ "W82R" ], "offsets": [ [ 1076, 1080 ] ], "normalized": [] }, { "id": "23200945_T38", "type": "GENE-N", "text": [ "alcohol dehydrogenases" ], "offsets": [ [ 13, 35 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23200945_0", "type": "SUBSTRATE", "arg1_id": "23200945_T3", "arg2_id": "23200945_T21", "normalized": [] }, { "id": "23200945_1", "type": "SUBSTRATE", "arg1_id": "23200945_T3", "arg2_id": "23200945_T28", "normalized": [] }, { "id": "23200945_2", "type": "SUBSTRATE", "arg1_id": "23200945_T17", "arg2_id": "23200945_T38", "normalized": [] }, { "id": "23200945_3", "type": "PRODUCT-OF", "arg1_id": "23200945_T9", "arg2_id": "23200945_T21", "normalized": [] }, { "id": "23200945_4", "type": "PRODUCT-OF", "arg1_id": "23200945_T9", "arg2_id": "23200945_T28", "normalized": [] }, { "id": "23200945_5", "type": "SUBSTRATE", "arg1_id": "23200945_T2", "arg2_id": "23200945_T18", "normalized": [] }, { "id": "23200945_6", "type": "SUBSTRATE", "arg1_id": "23200945_T4", "arg2_id": "23200945_T18", "normalized": [] }, { "id": "23200945_7", "type": "PART-OF", "arg1_id": "23200945_T1", "arg2_id": "23200945_T18", "normalized": [] } ]

[ { "id": "15133083_title", "type": "title", "text": [ "Polyamine metabolism in a member of the phylum Microspora (Encephalitozoon cuniculi): effects of polyamine analogues." ], "offsets": [ [ 0, 117 ] ] }, { "id": "15133083_abstract", "type": "abstract", "text": [ "The uptake, biosynthesis and catabolism of polyamines in the microsporidian parasite Encephalitozoon cuniculi are detailed with reference to the effects of oligoamine and arylamine analogues of polyamines. Enc. cuniculi, an intracellular parasite of mammalian cells, has both biosynthetic and catabolic enzymes of polyamine metabolism, as demonstrated in cell-free extracts of mature spores. The uptake of polyamines was measured in immature, pre-emergent spores isolated from host cells by Percoll gradient. Spermine was rapidly taken up and metabolized to spermidine and an unknown, possibly acetamidopropanal, by spermidine/spermine N(1)-acetyltransferase (SSAT) and polyamine oxidase (PAO). Most of the spermidine and the unknown product were found in the cell incubation medium, indicating they were released from the cell. bis(Ethyl) oligoamine analogues of polyamines, such as SL-11144 and SL-11158, as well as arylamine analogues [BW-1, a bis(phenylbenzyl) 3-7-3 analogue] blocked uptake and interconversion of spermine at micromolar levels and, in the case of BW-1, acted as substrate for PAO. The Enc. cuniculi PAO activity differed from that found in mammalian cells with respect to pH optimum, substrate specificity and sensitivity to known PAO inhibitors. SL-11158 inhibited SSAT activity with a mixed type of inhibition in which the analogue had a 70-fold higher affinity for the enzyme than the natural substrate, spermine. The interest in Enc. cuniculi polyamine metabolism and the biochemical effects of these polyamine analogues is warranted since they cure model infections of Enc. cuniculi in mice and are potential candidates for human clinical trials." ], "offsets": [ [ 118, 1791 ] ] } ]

[ { "id": "15133083_T1", "type": "CHEMICAL", "text": [ "spermine" ], "offsets": [ [ 1137, 1145 ] ], "normalized": [] }, { "id": "15133083_T2", "type": "CHEMICAL", "text": [ "BW-1" ], "offsets": [ [ 1187, 1191 ] ], "normalized": [] }, { "id": "15133083_T3", "type": "CHEMICAL", "text": [ "SL-11158" ], "offsets": [ [ 1387, 1395 ] ], "normalized": [] }, { "id": "15133083_T4", "type": "CHEMICAL", "text": [ "spermine" ], "offsets": [ [ 1547, 1555 ] ], "normalized": [] }, { "id": "15133083_T5", "type": "CHEMICAL", "text": [ "polyamine" ], "offsets": [ [ 1645, 1654 ] ], "normalized": [] }, { "id": "15133083_T6", "type": "CHEMICAL", "text": [ "oligoamine" ], "offsets": [ [ 274, 284 ] ], "normalized": [] }, { "id": "15133083_T7", "type": "CHEMICAL", "text": [ "arylamine" ], "offsets": [ [ 289, 298 ] ], "normalized": [] }, { "id": "15133083_T8", "type": "CHEMICAL", "text": [ "polyamines" ], "offsets": [ [ 312, 322 ] ], "normalized": [] }, { "id": "15133083_T9", "type": "CHEMICAL", "text": [ "polyamine" ], "offsets": [ [ 432, 441 ] ], "normalized": [] }, { "id": "15133083_T10", "type": "CHEMICAL", "text": [ "polyamines" ], "offsets": [ [ 524, 534 ] ], "normalized": [] }, { "id": "15133083_T11", "type": "CHEMICAL", "text": [ "polyamines" ], "offsets": [ [ 161, 171 ] ], "normalized": [] }, { "id": "15133083_T12", "type": "CHEMICAL", "text": [ "N(1)" ], "offsets": [ [ 754, 758 ] ], "normalized": [] }, { "id": "15133083_T13", "type": "CHEMICAL", "text": [ "polyamine" ], "offsets": [ [ 788, 797 ] ], "normalized": [] }, { "id": "15133083_T14", "type": "CHEMICAL", "text": [ "spermidine" ], "offsets": [ [ 825, 835 ] ], "normalized": [] }, { "id": "15133083_T15", "type": "CHEMICAL", "text": [ "bis(Ethyl) oligoamine" ], "offsets": [ [ 947, 968 ] ], "normalized": [] }, { "id": "15133083_T16", "type": "CHEMICAL", "text": [ "polyamines" ], "offsets": [ [ 982, 992 ] ], "normalized": [] }, { "id": "15133083_T17", "type": "CHEMICAL", "text": [ "SL-11144" ], "offsets": [ [ 1002, 1010 ] ], "normalized": [] }, { "id": "15133083_T18", "type": "CHEMICAL", "text": [ "SL-11158" ], "offsets": [ [ 1015, 1023 ] ], "normalized": [] }, { "id": "15133083_T19", "type": "CHEMICAL", "text": [ "arylamine" ], "offsets": [ [ 1036, 1045 ] ], "normalized": [] }, { "id": "15133083_T20", "type": "CHEMICAL", "text": [ "BW-1" ], "offsets": [ [ 1057, 1061 ] ], "normalized": [] }, { "id": "15133083_T21", "type": "CHEMICAL", "text": [ "bis(phenylbenzyl)" ], "offsets": [ [ 1065, 1082 ] ], "normalized": [] }, { "id": "15133083_T22", "type": "CHEMICAL", "text": [ "Polyamine" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "15133083_T23", "type": "CHEMICAL", "text": [ "polyamine" ], "offsets": [ [ 97, 106 ] ], "normalized": [] }, { "id": "15133083_T24", "type": "GENE-N", "text": [ "PAO" ], "offsets": [ [ 1216, 1219 ] ], "normalized": [] }, { "id": "15133083_T25", "type": "GENE-N", "text": [ "Enc. cuniculi PAO" ], "offsets": [ [ 1225, 1242 ] ], "normalized": [] }, { "id": "15133083_T26", "type": "GENE-N", "text": [ "PAO" ], "offsets": [ [ 1371, 1374 ] ], "normalized": [] }, { "id": "15133083_T27", "type": "GENE-N", "text": [ "SSAT" ], "offsets": [ [ 1406, 1410 ] ], "normalized": [] }, { "id": "15133083_T28", "type": "GENE-N", "text": [ "spermidine/spermine N(1)-acetyltransferase" ], "offsets": [ [ 734, 776 ] ], "normalized": [] }, { "id": "15133083_T29", "type": "GENE-N", "text": [ "SSAT" ], "offsets": [ [ 778, 782 ] ], "normalized": [] }, { "id": "15133083_T30", "type": "GENE-N", "text": [ "polyamine oxidase" ], "offsets": [ [ 788, 805 ] ], "normalized": [] }, { "id": "15133083_T31", "type": "GENE-N", "text": [ "PAO" ], "offsets": [ [ 807, 810 ] ], "normalized": [] } ]

[]

[]

[ { "id": "15133083_0", "type": "INHIBITOR", "arg1_id": "15133083_T3", "arg2_id": "15133083_T27", "normalized": [] }, { "id": "15133083_1", "type": "SUBSTRATE", "arg1_id": "15133083_T2", "arg2_id": "15133083_T24", "normalized": [] }, { "id": "15133083_2", "type": "DIRECT-REGULATOR", "arg1_id": "15133083_T4", "arg2_id": "15133083_T27", "normalized": [] } ]

[ { "id": "23146695_title", "type": "title", "text": [ "Puerarin mediates hepatoprotection against CCl4-induced hepatic fibrosis rats through attenuation of inflammation response and amelioration of metabolic function." ], "offsets": [ [ 0, 162 ] ] }, { "id": "23146695_abstract", "type": "abstract", "text": [ "This study was designed to evaluate the potential effects of puerarin (PR), an effective isoflavonoid compound purified from Pueraria lobata, in treating hepatic fibrosis (HF) rats induced by carbon tetrachloride (CCl(4), 2 mL kg(-1) d(-1)). Compared to model control, PR treatment effectively lowered the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (Alb), total protein (TP) in HF rats. Masson stained analysis showed that the condition of HF rats was mitigated. Meanwhile, the tumor necrosis factor alpha (TNF-α), nuclear factor-kappa B (NF-κB) expressions were significantly down-regulated at protein level by PR intervention. Additionally, the activity of superoxide dismutase (SOD) was elevated, while the content of malondialdehyde (MDA) was lessened in liver tissue. As revealed by immunohistochemistry assay, PR therapy resulted in reduced production of transforming growth factor-βl (TGF-βl). Moreover, it also was attributed to decreased mRNA level of inducible nitric oxide synthase (iNOS) using RT-PCR analysis. These findings demonstrate that puerarin successfully reverses hepatotoxicity in CCl(4)-induced HF rats via the underlying mechanisms of regulating serum enzymes and attenuating TNF-α/NF-κB pathway for anti-inflammation response, as well as improving metabolic function in liver tissue." ], "offsets": [ [ 163, 1519 ] ] } ]

[ { "id": "23146695_T1", "type": "CHEMICAL", "text": [ "nitric oxide" ], "offsets": [ [ 1181, 1193 ] ], "normalized": [] }, { "id": "23146695_T2", "type": "CHEMICAL", "text": [ "puerarin" ], "offsets": [ [ 1265, 1273 ] ], "normalized": [] }, { "id": "23146695_T3", "type": "CHEMICAL", "text": [ "CCl(4)" ], "offsets": [ [ 1314, 1320 ] ], "normalized": [] }, { "id": "23146695_T4", "type": "CHEMICAL", "text": [ "carbon tetrachloride" ], "offsets": [ [ 355, 375 ] ], "normalized": [] }, { "id": "23146695_T5", "type": "CHEMICAL", "text": [ "CCl(4)" ], "offsets": [ [ 377, 383 ] ], "normalized": [] }, { "id": "23146695_T6", "type": "CHEMICAL", "text": [ "alanine" ], "offsets": [ [ 485, 492 ] ], "normalized": [] }, { "id": "23146695_T7", "type": "CHEMICAL", "text": [ "aspartate" ], "offsets": [ [ 517, 526 ] ], "normalized": [] }, { "id": "23146695_T8", "type": "CHEMICAL", "text": [ "puerarin" ], "offsets": [ [ 224, 232 ] ], "normalized": [] }, { "id": "23146695_T9", "type": "CHEMICAL", "text": [ "superoxide" ], "offsets": [ [ 869, 879 ] ], "normalized": [] }, { "id": "23146695_T10", "type": "CHEMICAL", "text": [ "malondialdehyde" ], "offsets": [ [ 931, 946 ] ], "normalized": [] }, { "id": "23146695_T11", "type": "CHEMICAL", "text": [ "MDA" ], "offsets": [ [ 948, 951 ] ], "normalized": [] }, { "id": "23146695_T12", "type": "CHEMICAL", "text": [ "isoflavonoid" ], "offsets": [ [ 252, 264 ] ], "normalized": [] }, { "id": "23146695_T13", "type": "CHEMICAL", "text": [ "Puerarin" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "23146695_T14", "type": "CHEMICAL", "text": [ "CCl4" ], "offsets": [ [ 43, 47 ] ], "normalized": [] }, { "id": "23146695_T15", "type": "GENE-Y", "text": [ "inducible nitric oxide synthase" ], "offsets": [ [ 1171, 1202 ] ], "normalized": [] }, { "id": "23146695_T16", "type": "GENE-Y", "text": [ "iNOS" ], "offsets": [ [ 1204, 1208 ] ], "normalized": [] }, { "id": "23146695_T17", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 1411, 1416 ] ], "normalized": [] }, { "id": "23146695_T18", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 1417, 1422 ] ], "normalized": [] }, { "id": "23146695_T19", "type": "GENE-N", "text": [ "alanine aminotransferase" ], "offsets": [ [ 485, 509 ] ], "normalized": [] }, { "id": "23146695_T20", "type": "GENE-N", "text": [ "ALT" ], "offsets": [ [ 511, 514 ] ], "normalized": [] }, { "id": "23146695_T21", "type": "GENE-N", "text": [ "aspartate aminotransferase" ], "offsets": [ [ 517, 543 ] ], "normalized": [] }, { "id": "23146695_T22", "type": "GENE-N", "text": [ "AST" ], "offsets": [ [ 545, 548 ] ], "normalized": [] }, { "id": "23146695_T23", "type": "GENE-Y", "text": [ "albumin" ], "offsets": [ [ 551, 558 ] ], "normalized": [] }, { "id": "23146695_T24", "type": "GENE-Y", "text": [ "Alb" ], "offsets": [ [ 560, 563 ] ], "normalized": [] }, { "id": "23146695_T25", "type": "GENE-Y", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 688, 715 ] ], "normalized": [] }, { "id": "23146695_T26", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 717, 722 ] ], "normalized": [] }, { "id": "23146695_T27", "type": "GENE-N", "text": [ "nuclear factor-kappa B" ], "offsets": [ [ 725, 747 ] ], "normalized": [] }, { "id": "23146695_T28", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 749, 754 ] ], "normalized": [] }, { "id": "23146695_T29", "type": "GENE-N", "text": [ "superoxide dismutase" ], "offsets": [ [ 869, 889 ] ], "normalized": [] }, { "id": "23146695_T30", "type": "GENE-N", "text": [ "SOD" ], "offsets": [ [ 891, 894 ] ], "normalized": [] }, { "id": "23146695_T31", "type": "GENE-Y", "text": [ "transforming growth factor-βl" ], "offsets": [ [ 1071, 1100 ] ], "normalized": [] }, { "id": "23146695_T32", "type": "GENE-Y", "text": [ "TGF-βl" ], "offsets": [ [ 1102, 1108 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23146695_0", "type": "INHIBITOR", "arg1_id": "23146695_T2", "arg2_id": "23146695_T17", "normalized": [] }, { "id": "23146695_1", "type": "INHIBITOR", "arg1_id": "23146695_T2", "arg2_id": "23146695_T18", "normalized": [] } ]

[ { "id": "17403374_title", "type": "title", "text": [ "Regulation of gluconeogenesis by Kruppel-like factor 15." ], "offsets": [ [ 0, 56 ] ] }, { "id": "17403374_abstract", "type": "abstract", "text": [ "In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15, a member of the Kruppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective amino acid catabolism promotes the development of fasting hypoglycemia in KLF15-/- mice by limiting gluconeogenic substrate availability. KLF15-/- liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of alanine aminotransferase (ALT), which converts the critical gluconeogenic amino acid alanine into pyruvate, is decreased (approximately 50%) in KLF15-/- hepatocytes. Consistent with this observation, intraperitoneal injection of pyruvate, but not alanine, rescues fasting hypoglycemia in KLF15-/- mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis." ], "offsets": [ [ 57, 1185 ] ] } ]

[ { "id": "17403374_T1", "type": "CHEMICAL", "text": [ "amino acid" ], "offsets": [ [ 515, 525 ] ], "normalized": [] }, { "id": "17403374_T2", "type": "CHEMICAL", "text": [ "amino acid" ], "offsets": [ [ 729, 739 ] ], "normalized": [] }, { "id": "17403374_T3", "type": "CHEMICAL", "text": [ "alanine" ], "offsets": [ [ 798, 805 ] ], "normalized": [] }, { "id": "17403374_T4", "type": "CHEMICAL", "text": [ "glucose" ], "offsets": [ [ 132, 139 ] ], "normalized": [] }, { "id": "17403374_T5", "type": "CHEMICAL", "text": [ "amino acid" ], "offsets": [ [ 872, 882 ] ], "normalized": [] }, { "id": "17403374_T6", "type": "CHEMICAL", "text": [ "alanine" ], "offsets": [ [ 883, 890 ] ], "normalized": [] }, { "id": "17403374_T7", "type": "CHEMICAL", "text": [ "pyruvate" ], "offsets": [ [ 896, 904 ] ], "normalized": [] }, { "id": "17403374_T8", "type": "CHEMICAL", "text": [ "pyruvate" ], "offsets": [ [ 1027, 1035 ] ], "normalized": [] }, { "id": "17403374_T9", "type": "CHEMICAL", "text": [ "alanine" ], "offsets": [ [ 1045, 1052 ] ], "normalized": [] }, { "id": "17403374_T10", "type": "GENE-Y", "text": [ "KLF15" ], "offsets": [ [ 1086, 1091 ] ], "normalized": [] }, { "id": "17403374_T11", "type": "GENE-Y", "text": [ "KLF15" ], "offsets": [ [ 1118, 1123 ] ], "normalized": [] }, { "id": "17403374_T12", "type": "GENE-Y", "text": [ "KLF15" ], "offsets": [ [ 350, 355 ] ], "normalized": [] }, { "id": "17403374_T13", "type": "GENE-N", "text": [ "Kruppel-like" ], "offsets": [ [ 373, 385 ] ], "normalized": [] }, { "id": "17403374_T14", "type": "GENE-Y", "text": [ "KLF15" ], "offsets": [ [ 589, 594 ] ], "normalized": [] }, { "id": "17403374_T15", "type": "GENE-Y", "text": [ "KLF15" ], "offsets": [ [ 653, 658 ] ], "normalized": [] }, { "id": "17403374_T16", "type": "GENE-N", "text": [ "alanine aminotransferase" ], "offsets": [ [ 798, 822 ] ], "normalized": [] }, { "id": "17403374_T17", "type": "GENE-N", "text": [ "ALT" ], "offsets": [ [ 824, 827 ] ], "normalized": [] }, { "id": "17403374_T18", "type": "GENE-Y", "text": [ "KLF15" ], "offsets": [ [ 942, 947 ] ], "normalized": [] }, { "id": "17403374_T19", "type": "GENE-Y", "text": [ "Kruppel-like factor 15" ], "offsets": [ [ 33, 55 ] ], "normalized": [] } ]

[]

[]

[ { "id": "17403374_0", "type": "SUBSTRATE", "arg1_id": "17403374_T6", "arg2_id": "17403374_T17", "normalized": [] }, { "id": "17403374_1", "type": "PRODUCT-OF", "arg1_id": "17403374_T7", "arg2_id": "17403374_T17", "normalized": [] }, { "id": "17403374_2", "type": "SUBSTRATE", "arg1_id": "17403374_T5", "arg2_id": "17403374_T17", "normalized": [] }, { "id": "17403374_3", "type": "SUBSTRATE", "arg1_id": "17403374_T5", "arg2_id": "17403374_T16", "normalized": [] }, { "id": "17403374_4", "type": "SUBSTRATE", "arg1_id": "17403374_T6", "arg2_id": "17403374_T16", "normalized": [] }, { "id": "17403374_5", "type": "PRODUCT-OF", "arg1_id": "17403374_T7", "arg2_id": "17403374_T16", "normalized": [] } ]

[ { "id": "23534412_title", "type": "title", "text": [ "Antithrombotic activity of a newly synthesized coumarin derivative 3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-N-{2-[3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-propionylamino]-ethyl}-propionamide." ], "offsets": [ [ 0, 189 ] ] }, { "id": "23534412_abstract", "type": "abstract", "text": [ "Anti-platelet therapy is a useful strategy to prevent acute thromboembolic artery occlusions. This study was designed to assess the efficacy of seselin derivatives against murine pulmonary thromboembolism, bleeding time, platelet activation and thrombosis. Administration of C3 (16 mg/kg) offered 70% protection against collagen- and epinephrine-induced pulmonary thromboembolism and 30% protection against arachidonic acid-induced death in mice, without adversely affecting bleeding time. No significant difference was observed by C3 in ferric chloride-induced arterial thrombosis in rats. Significant reduction in thrombus weight was observed in arteriovenous shunt model. In rat PRP, C3 reduced ADP and collagen-induced platelet aggregation. In chronic hamster model of dyslipidemia, administration of C3 (16 mg/kg p.o. for 90 days) had no effect on plasma lipids, vasoreactivity and platelet adhesion. C3 fed hamsters showed reduced whole-blood aggregation response to ADP and collagen compared to HC-fed hamsters. In addition, C3 augmented thrombin time; however, time to occlusion was not increased. These results convincingly demonstrated that C3 is a novel molecule that reduces the risk of thrombosis and alleviates prothrombotic state associated with hyperlipidemia without any adverse effect on bleeding time. The high benefit/risk ratio of this compound makes it a suitable candidate for future valid studies." ], "offsets": [ [ 190, 1611 ] ] } ]

[ { "id": "23534412_T1", "type": "CHEMICAL", "text": [ "seselin" ], "offsets": [ [ 334, 341 ] ], "normalized": [] }, { "id": "23534412_T2", "type": "CHEMICAL", "text": [ "epinephrine" ], "offsets": [ [ 524, 535 ] ], "normalized": [] }, { "id": "23534412_T3", "type": "CHEMICAL", "text": [ "arachidonic acid" ], "offsets": [ [ 597, 613 ] ], "normalized": [] }, { "id": "23534412_T4", "type": "CHEMICAL", "text": [ "ferric chloride" ], "offsets": [ [ 728, 743 ] ], "normalized": [] }, { "id": "23534412_T5", "type": "CHEMICAL", "text": [ "ADP" ], "offsets": [ [ 888, 891 ] ], "normalized": [] }, { "id": "23534412_T6", "type": "CHEMICAL", "text": [ "ADP" ], "offsets": [ [ 1163, 1166 ] ], "normalized": [] }, { "id": "23534412_T7", "type": "CHEMICAL", "text": [ "coumarin" ], "offsets": [ [ 47, 55 ] ], "normalized": [] }, { "id": "23534412_T8", "type": "CHEMICAL", "text": [ "3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-N-{2-[3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-propionylamino]-ethyl}-propionamide" ], "offsets": [ [ 67, 188 ] ], "normalized": [] }, { "id": "23534412_T9", "type": "GENE-N", "text": [ "collagen" ], "offsets": [ [ 510, 518 ] ], "normalized": [] }, { "id": "23534412_T10", "type": "GENE-N", "text": [ "collagen" ], "offsets": [ [ 896, 904 ] ], "normalized": [] }, { "id": "23534412_T11", "type": "GENE-N", "text": [ "collagen" ], "offsets": [ [ 1171, 1179 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "8622118_title", "type": "title", "text": [ "Structure and pharmacological properties of a molluscan glutamate-gated cation channel and its likely role in feeding behavior." ], "offsets": [ [ 0, 127 ] ] }, { "id": "8622118_abstract", "type": "abstract", "text": [ "We describe the isolation of a molluscan (Lymnaea stagnalis) full-length complementary DNA that encodes a mature polypeptide (which we have named Lym-eGluR2) with a predicted molecular weight of 105 kDa that exhibits 44-48% identity to the mammalian kainate-selective glutamate receptor GluR5, GluR6, and GluR7 subunits. Injection of in vitro-transcribed RNA from this clone into Xenopus laevis oocytes results in the robust expression of homo-oligomeric cation channels that can be gated by L-glutamate (EC50 = 1.2 +/- 0.3 micron) and several other glutamate receptor agonists; rank order of potency: glutamate >> kainate > ibotenate > AMPA. These currents can be blocked by the mammalian non-NMDA receptor antagonists 6,7-dinitroquinoxaline-2,3-dione, 6-cyano-7-nitroquinoxaline-2,3-dione, and 1-(4-chlorobenzoyl)piperazine-2,3-dicarboxylic acid. Ionic-replacement experiments have shown that the agonist-induced current is carried entirely by sodium and potassium ions. In situ hybridization has revealed that the Lym-eGluR2 transcript is present in all 11 ganglia of the Lymnaea CNS, including the 4-cluster motorneurons within the paired buccal ganglia. The pharmacological properties and deduced location of Lym-eGluR2 are entirely consistent with it being (a component of) the receptor, which has been identified previously on buccal motorneurons, that mediates the excitatory effects of glutamate released from neurons within the feeding central pattern generator." ], "offsets": [ [ 128, 1600 ] ] } ]

[ { "id": "8622118_T1", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 1523, 1532 ] ], "normalized": [] }, { "id": "8622118_T2", "type": "CHEMICAL", "text": [ "kainate" ], "offsets": [ [ 378, 385 ] ], "normalized": [] }, { "id": "8622118_T3", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 396, 405 ] ], "normalized": [] }, { "id": "8622118_T4", "type": "CHEMICAL", "text": [ "L-glutamate" ], "offsets": [ [ 620, 631 ] ], "normalized": [] }, { "id": "8622118_T5", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 678, 687 ] ], "normalized": [] }, { "id": "8622118_T6", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 730, 739 ] ], "normalized": [] }, { "id": "8622118_T7", "type": "CHEMICAL", "text": [ "kainate" ], "offsets": [ [ 743, 750 ] ], "normalized": [] }, { "id": "8622118_T8", "type": "CHEMICAL", "text": [ "ibotenate" ], "offsets": [ [ 753, 762 ] ], "normalized": [] }, { "id": "8622118_T9", "type": "CHEMICAL", "text": [ "AMPA" ], "offsets": [ [ 765, 769 ] ], "normalized": [] }, { "id": "8622118_T10", "type": "CHEMICAL", "text": [ "NMDA" ], "offsets": [ [ 822, 826 ] ], "normalized": [] }, { "id": "8622118_T11", "type": "CHEMICAL", "text": [ "6,7-dinitroquinoxaline-2,3-dione, 6-cyano-7-nitroquinoxaline-2,3-dione, and 1-(4-chlorobenzoyl)piperazine-2,3-dicarboxylic acid" ], "offsets": [ [ 848, 975 ] ], "normalized": [] }, { "id": "8622118_T12", "type": "CHEMICAL", "text": [ "sodium" ], "offsets": [ [ 1074, 1080 ] ], "normalized": [] }, { "id": "8622118_T13", "type": "CHEMICAL", "text": [ "potassium" ], "offsets": [ [ 1085, 1094 ] ], "normalized": [] }, { "id": "8622118_T14", "type": "CHEMICAL", "text": [ "glutamate" ], "offsets": [ [ 56, 65 ] ], "normalized": [] }, { "id": "8622118_T15", "type": "GENE-N", "text": [ "Lym-eGluR2" ], "offsets": [ [ 1145, 1155 ] ], "normalized": [] }, { "id": "8622118_T16", "type": "GENE-N", "text": [ "Lym-eGluR2" ], "offsets": [ [ 1342, 1352 ] ], "normalized": [] }, { "id": "8622118_T17", "type": "GENE-N", "text": [ "Lym-eGluR2" ], "offsets": [ [ 274, 284 ] ], "normalized": [] }, { "id": "8622118_T18", "type": "GENE-N", "text": [ "mammalian kainate-selective glutamate receptor" ], "offsets": [ [ 368, 414 ] ], "normalized": [] }, { "id": "8622118_T19", "type": "GENE-Y", "text": [ "GluR5" ], "offsets": [ [ 415, 420 ] ], "normalized": [] }, { "id": "8622118_T20", "type": "GENE-Y", "text": [ "GluR6" ], "offsets": [ [ 422, 427 ] ], "normalized": [] }, { "id": "8622118_T21", "type": "GENE-Y", "text": [ "GluR7" ], "offsets": [ [ 433, 438 ] ], "normalized": [] }, { "id": "8622118_T22", "type": "GENE-N", "text": [ "glutamate receptor" ], "offsets": [ [ 678, 696 ] ], "normalized": [] }, { "id": "8622118_T23", "type": "GENE-N", "text": [ "mammalian non-NMDA receptor" ], "offsets": [ [ 808, 835 ] ], "normalized": [] }, { "id": "8622118_T24", "type": "GENE-N", "text": [ "molluscan glutamate-gated cation channel" ], "offsets": [ [ 46, 86 ] ], "normalized": [] } ]

[]

[]

[ { "id": "8622118_0", "type": "AGONIST", "arg1_id": "8622118_T6", "arg2_id": "8622118_T22", "normalized": [] }, { "id": "8622118_1", "type": "AGONIST", "arg1_id": "8622118_T7", "arg2_id": "8622118_T22", "normalized": [] }, { "id": "8622118_2", "type": "AGONIST", "arg1_id": "8622118_T8", "arg2_id": "8622118_T22", "normalized": [] }, { "id": "8622118_3", "type": "AGONIST", "arg1_id": "8622118_T9", "arg2_id": "8622118_T22", "normalized": [] }, { "id": "8622118_4", "type": "ANTAGONIST", "arg1_id": "8622118_T11", "arg2_id": "8622118_T23", "normalized": [] } ]

[ { "id": "23541434_title", "type": "title", "text": [ "Pharmacological study of a new Asp49 phospholipase A2 (Bbil-TX) isolated from Bothriopsis bilineata smargadina (forest viper) venom in vertebrate neuromuscular preparations." ], "offsets": [ [ 0, 173 ] ] }, { "id": "23541434_abstract", "type": "abstract", "text": [ "The neuromuscular activity of Bbil-TX, a PLA2 with catalytic activity isolated from Bothriopsis bilineata smargadina venom, was examined in chick biventer cervicis (BC) and mouse phrenic nerve-diaphragm (PND) preparations. In BC preparations, Bbil-TX (0.5-10 μg/ml) caused time- and concentration-dependent blockade that was not reversed by washing; the times for 50% blockade were 87 ± 7, 41 ± 7 and 19 ± 2 min (mean ± SEM; n = 4-6) for 1, 5 and 10 μg/ml, respectively. Muscle contractures to exogenous ACh and KCl were unaffected. The toxin (10 μg/ml) also did not affect the twitch-tension of directly-stimulated, curarized (10 μg/ml) BC preparations. However, Bbil-TX (10 μg/ml) produced mild morphological alterations (edematous and/or hyperchromic fibers) in BC; there was also a progressive release of CK (from 116 ± 17 IU/ml (basal) to 710 ± 91 IU/ml after 45 min). Bbil-TX (5 μg/ml)-induced blockade was markedly inhibited at 22-24 °C and pretreatment with p-bromophenacyl bromide (p-BPB) abolished the neuromuscular blockade. Bbil-TX (3-30 μg/ml, n = 4-6) caused partial time- and concentration-dependent blockade in PND preparations (52 ± 2% at the highest concentration). Bbil-TX (30 μg/ml) also markedly reduced the MEPPs frequency [from 26 ± 2.5 (basal) to 10 ± 1 after 60 min; n = 5; p < 0.05] and the quantal content [from 94 ± 14 (basal) to 24 ± 3 after 60 min; n = 5; p < 0.05] of PND preparations, but caused only minor depolarization of the membrane resting potential [from -80 ± 1 mV (basal) to -66 ± 2 mV after 120 min; n = 5; p < 0.05], with no significant change in the depolarizing response to exogenous carbachol. These results show that Bbil-TX is a presynaptic PLA2 that contributes to the neuromuscular blockade caused by B. b. smargadina venom." ], "offsets": [ [ 174, 1948 ] ] } ]

[ { "id": "23541434_T1", "type": "CHEMICAL", "text": [ "carbachol" ], "offsets": [ [ 1803, 1812 ] ], "normalized": [] }, { "id": "23541434_T2", "type": "CHEMICAL", "text": [ "ACh" ], "offsets": [ [ 678, 681 ] ], "normalized": [] }, { "id": "23541434_T3", "type": "CHEMICAL", "text": [ "KCl" ], "offsets": [ [ 686, 689 ] ], "normalized": [] }, { "id": "23541434_T4", "type": "CHEMICAL", "text": [ "p-bromophenacyl bromide" ], "offsets": [ [ 1140, 1163 ] ], "normalized": [] }, { "id": "23541434_T5", "type": "CHEMICAL", "text": [ "p-BPB" ], "offsets": [ [ 1165, 1170 ] ], "normalized": [] }, { "id": "23541434_T6", "type": "GENE-N", "text": [ "PLA2" ], "offsets": [ [ 1863, 1867 ] ], "normalized": [] }, { "id": "23541434_T7", "type": "GENE-N", "text": [ "PLA2" ], "offsets": [ [ 215, 219 ] ], "normalized": [] }, { "id": "23541434_T8", "type": "GENE-N", "text": [ "CK" ], "offsets": [ [ 983, 985 ] ], "normalized": [] }, { "id": "23541434_T9", "type": "GENE-N", "text": [ "phospholipase A2" ], "offsets": [ [ 37, 53 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "15306222_title", "type": "title", "text": [ "Carvedilol selectively inhibits oscillatory intracellular calcium changes evoked by human alpha1D- and alpha1B-adrenergic receptors." ], "offsets": [ [ 0, 132 ] ] }, { "id": "15306222_abstract", "type": "abstract", "text": [ "BACKGROUND: Increasing evidence from clinical trials indicates that carvedilol, an antagonist of alpha1- and beta-adrenergic receptors (ARs), provides an effective treatment for chronic heart failure, whereas nonselective alpha1-AR blockade has an adverse outcome in this disease. It is, however, not clear whether carvedilol exhibits a subtype-dependent impact on three distinct alpha1-adrenergic receptors (alpha1-ARs). METHODS AND RESULTS: We determined binding properties of human ARs for carvedilol using HEK293 human embryonic kidney cells expressing a single AR subtype. Our results showed that the affinities of alpha1D-AR and alpha1B-AR for carvedilol are higher than that of the beta1-AR subtype, a major target in heart failure treatment. The affinity rank order and pKi values of ARs for carvedilol were as follows: alpha1D-AR (8.9)>alpha1B-AR (8.6)>beta1-AR (8.4)>beta2-AR (8.0)>alpha1A-AR (7.9)?alpha2C-AR (5.9)>alpha2B-AR (5.5)>alpha2A-AR (5.3). Furthermore, temporal kinetics of intracellular calcium signaling mediated via alpha1D- and alpha1B-ARs, but not via alpha1A-AR (P<0.01), showed oscillatory patterns with frequencies ranging from 0.3 to 3 per minute in human smooth muscle and HEK293 cells, which were inhibited by the therapeutic concentrations of carvedilol (10 nM) in a subtype-dependent manner. When oscillatory alpha1B-AR and non-oscillatory alpha1A-AR were co-expressed and heteromer receptors were detected with bioluminescence resonance energy transfer and co-immunoprecipitation, carvedilol suppressed only oscillatory component of global cytosolic free calcium change. CONCLUSIONS: These results indicate that in addition to beta-ARs, receptor inhibition by carvedilol is directed to alpha1-ARs, preferably to alpha1D- and alpha1B-AR-mediated signaling events, including intracellular calcium oscillations in vascular smooth muscle." ], "offsets": [ [ 133, 2002 ] ] } ]

[ { "id": "15306222_T1", "type": "CHEMICAL", "text": [ "calcium" ], "offsets": [ [ 1142, 1149 ] ], "normalized": [] }, { "id": "15306222_T2", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 1409, 1419 ] ], "normalized": [] }, { "id": "15306222_T3", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 1649, 1659 ] ], "normalized": [] }, { "id": "15306222_T4", "type": "CHEMICAL", "text": [ "calcium" ], "offsets": [ [ 1723, 1730 ] ], "normalized": [] }, { "id": "15306222_T5", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 1828, 1838 ] ], "normalized": [] }, { "id": "15306222_T6", "type": "CHEMICAL", "text": [ "calcium" ], "offsets": [ [ 1955, 1962 ] ], "normalized": [] }, { "id": "15306222_T7", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 448, 458 ] ], "normalized": [] }, { "id": "15306222_T8", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 626, 636 ] ], "normalized": [] }, { "id": "15306222_T9", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 783, 793 ] ], "normalized": [] }, { "id": "15306222_T10", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 201, 211 ] ], "normalized": [] }, { "id": "15306222_T11", "type": "CHEMICAL", "text": [ "carvedilol" ], "offsets": [ [ 933, 943 ] ], "normalized": [] }, { "id": "15306222_T12", "type": "CHEMICAL", "text": [ "Carvedilol" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "15306222_T13", "type": "CHEMICAL", "text": [ "calcium" ], "offsets": [ [ 58, 65 ] ], "normalized": [] }, { "id": "15306222_T14", "type": "GENE-N", "text": [ "alpha1D- and alpha1B-ARs" ], "offsets": [ [ 1173, 1197 ] ], "normalized": [] }, { "id": "15306222_T15", "type": "GENE-Y", "text": [ "alpha1A-AR" ], "offsets": [ [ 1211, 1221 ] ], "normalized": [] }, { "id": "15306222_T16", "type": "GENE-Y", "text": [ "alpha1B-AR" ], "offsets": [ [ 1476, 1486 ] ], "normalized": [] }, { "id": "15306222_T17", "type": "GENE-Y", "text": [ "alpha1A-AR" ], "offsets": [ [ 1507, 1517 ] ], "normalized": [] }, { "id": "15306222_T18", "type": "GENE-N", "text": [ "beta-ARs" ], "offsets": [ [ 1795, 1803 ] ], "normalized": [] }, { "id": "15306222_T19", "type": "GENE-N", "text": [ "alpha1-ARs" ], "offsets": [ [ 1854, 1864 ] ], "normalized": [] }, { "id": "15306222_T20", "type": "GENE-N", "text": [ "alpha1D- and alpha1B-AR" ], "offsets": [ [ 1880, 1903 ] ], "normalized": [] }, { "id": "15306222_T21", "type": "GENE-N", "text": [ "alpha1-AR" ], "offsets": [ [ 355, 364 ] ], "normalized": [] }, { "id": "15306222_T22", "type": "GENE-N", "text": [ "human ARs" ], "offsets": [ [ 612, 621 ] ], "normalized": [] }, { "id": "15306222_T23", "type": "GENE-Y", "text": [ "alpha1D-AR" ], "offsets": [ [ 753, 763 ] ], "normalized": [] }, { "id": "15306222_T24", "type": "GENE-Y", "text": [ "alpha1B-AR" ], "offsets": [ [ 768, 778 ] ], "normalized": [] }, { "id": "15306222_T25", "type": "GENE-Y", "text": [ "beta1-AR" ], "offsets": [ [ 822, 830 ] ], "normalized": [] }, { "id": "15306222_T26", "type": "GENE-N", "text": [ "ARs" ], "offsets": [ [ 925, 928 ] ], "normalized": [] }, { "id": "15306222_T27", "type": "GENE-Y", "text": [ "alpha1D-AR" ], "offsets": [ [ 961, 971 ] ], "normalized": [] }, { "id": "15306222_T28", "type": "GENE-Y", "text": [ "alpha1B-AR" ], "offsets": [ [ 978, 988 ] ], "normalized": [] }, { "id": "15306222_T29", "type": "GENE-Y", "text": [ "beta1-AR" ], "offsets": [ [ 995, 1003 ] ], "normalized": [] }, { "id": "15306222_T30", "type": "GENE-Y", "text": [ "beta2-AR" ], "offsets": [ [ 1010, 1018 ] ], "normalized": [] }, { "id": "15306222_T31", "type": "GENE-Y", "text": [ "alpha1A-AR" ], "offsets": [ [ 1025, 1035 ] ], "normalized": [] }, { "id": "15306222_T32", "type": "GENE-Y", "text": [ "alpha2C-AR" ], "offsets": [ [ 1042, 1052 ] ], "normalized": [] }, { "id": "15306222_T33", "type": "GENE-Y", "text": [ "alpha2B-AR" ], "offsets": [ [ 1059, 1069 ] ], "normalized": [] }, { "id": "15306222_T34", "type": "GENE-Y", "text": [ "alpha2A-AR" ], "offsets": [ [ 1076, 1086 ] ], "normalized": [] }, { "id": "15306222_T35", "type": "GENE-N", "text": [ "alpha1- and beta-adrenergic receptors (ARs)" ], "offsets": [ [ 230, 273 ] ], "normalized": [] }, { "id": "15306222_T36", "type": "GENE-N", "text": [ "alpha1D- and alpha1B-adrenergic receptors" ], "offsets": [ [ 90, 131 ] ], "normalized": [] } ]

[]

[]

[ { "id": "15306222_0", "type": "ANTAGONIST", "arg1_id": "15306222_T10", "arg2_id": "15306222_T21", "normalized": [] }, { "id": "15306222_1", "type": "DIRECT-REGULATOR", "arg1_id": "15306222_T9", "arg2_id": "15306222_T23", "normalized": [] }, { "id": "15306222_2", "type": "DIRECT-REGULATOR", "arg1_id": "15306222_T9", "arg2_id": "15306222_T24", "normalized": [] }, { "id": "15306222_3", "type": "DIRECT-REGULATOR", "arg1_id": "15306222_T9", "arg2_id": "15306222_T25", "normalized": [] }, { "id": "15306222_4", "type": "DIRECT-REGULATOR", "arg1_id": "15306222_T11", "arg2_id": "15306222_T26", "normalized": [] }, { "id": "15306222_5", "type": "DIRECT-REGULATOR", "arg1_id": "15306222_T11", "arg2_id": "15306222_T27", "normalized": [] }, { "id": "15306222_6", "type": "DIRECT-REGULATOR", "arg1_id": "15306222_T11", "arg2_id": "15306222_T28", "normalized": [] }, { "id": "15306222_7", "type": "DIRECT-REGULATOR", "arg1_id": "15306222_T11", "arg2_id": "15306222_T29", "normalized": [] }, { "id": "15306222_8", "type": "DIRECT-REGULATOR", "arg1_id": "15306222_T11", "arg2_id": "15306222_T30", "normalized": [] }, { "id": "15306222_9", "type": "DIRECT-REGULATOR", "arg1_id": "15306222_T11", "arg2_id": "15306222_T31", "normalized": [] }, { "id": "15306222_10", "type": "DIRECT-REGULATOR", "arg1_id": "15306222_T11", "arg2_id": "15306222_T32", "normalized": [] }, { "id": "15306222_11", "type": "DIRECT-REGULATOR", "arg1_id": "15306222_T11", "arg2_id": "15306222_T33", "normalized": [] }, { "id": "15306222_12", "type": "DIRECT-REGULATOR", "arg1_id": "15306222_T11", "arg2_id": "15306222_T34", "normalized": [] }, { "id": "15306222_13", "type": "INHIBITOR", "arg1_id": "15306222_T3", "arg2_id": "15306222_T16", "normalized": [] }, { "id": "15306222_14", "type": "INHIBITOR", "arg1_id": "15306222_T5", "arg2_id": "15306222_T18", "normalized": [] }, { "id": "15306222_15", "type": "INHIBITOR", "arg1_id": "15306222_T5", "arg2_id": "15306222_T19", "normalized": [] } ]

[ { "id": "10480573_title", "type": "title", "text": [ "Effect of thiazinotrienomycin B, an ansamycin antibiotic, on the function of epidermal growth factor receptor in human stomach tumor cells." ], "offsets": [ [ 0, 139 ] ] }, { "id": "10480573_abstract", "type": "abstract", "text": [ "Thiazinotrienomycin B (TT-B), an ansamycin isolated from fermentation broths of Streptomyces sp. MJ672-m3, inhibited the growth in vitro of human stomach tumor SC-6 cells over 10 times more strongly than the growth of other human tumor cells, such as HeLa (cervix), T24 (bladder) and LX-1 (lung). The extent of growth inhibition by TT-B of SC-6, but not of LX-1 nor T24, was lowered in a competitive manner by raising serum concentrations in the culture medium. TT-B inhibited the cell cycle progression of SC-6 at an early stage of the progression from G0/G1 to S. The inhibition was again competitive with serum concentrations in the culture medium. No direct inhibition of DNA synthesis was observed at the concentration range which caused the cell cycle arrest. TT-B and anti-epidermal growth factor receptor (anti-EGFR) were antagonistic to each other in inhibiting the cell cycle progression of SC-6 from G0/G1 to S, suggesting that the two compounds share the same target, EGFR. The kinase activity of EGFR was little inhibited by TT-B in a cell-free system." ], "offsets": [ [ 140, 1205 ] ] } ]

[ { "id": "10480573_T1", "type": "CHEMICAL", "text": [ "Thiazinotrienomycin B" ], "offsets": [ [ 140, 161 ] ], "normalized": [] }, { "id": "10480573_T2", "type": "CHEMICAL", "text": [ "TT-B" ], "offsets": [ [ 1178, 1182 ] ], "normalized": [] }, { "id": "10480573_T3", "type": "CHEMICAL", "text": [ "TT-B" ], "offsets": [ [ 163, 167 ] ], "normalized": [] }, { "id": "10480573_T4", "type": "CHEMICAL", "text": [ "ansamycin" ], "offsets": [ [ 173, 182 ] ], "normalized": [] }, { "id": "10480573_T5", "type": "CHEMICAL", "text": [ "TT-B" ], "offsets": [ [ 602, 606 ] ], "normalized": [] }, { "id": "10480573_T6", "type": "CHEMICAL", "text": [ "TT-B" ], "offsets": [ [ 906, 910 ] ], "normalized": [] }, { "id": "10480573_T7", "type": "CHEMICAL", "text": [ "thiazinotrienomycin B" ], "offsets": [ [ 10, 31 ] ], "normalized": [] }, { "id": "10480573_T8", "type": "CHEMICAL", "text": [ "ansamycin" ], "offsets": [ [ 36, 45 ] ], "normalized": [] }, { "id": "10480573_T9", "type": "GENE-Y", "text": [ "EGFR" ], "offsets": [ [ 1149, 1153 ] ], "normalized": [] }, { "id": "10480573_T10", "type": "GENE-Y", "text": [ "epidermal growth factor receptor" ], "offsets": [ [ 920, 952 ] ], "normalized": [] }, { "id": "10480573_T11", "type": "GENE-Y", "text": [ "EGFR" ], "offsets": [ [ 959, 963 ] ], "normalized": [] }, { "id": "10480573_T12", "type": "GENE-Y", "text": [ "EGFR" ], "offsets": [ [ 1120, 1124 ] ], "normalized": [] }, { "id": "10480573_T13", "type": "GENE-N", "text": [ "kinase" ], "offsets": [ [ 1130, 1136 ] ], "normalized": [] }, { "id": "10480573_T14", "type": "GENE-Y", "text": [ "epidermal growth factor receptor" ], "offsets": [ [ 77, 109 ] ], "normalized": [] } ]

[]

[]

[ { "id": "10480573_0", "type": "INHIBITOR", "arg1_id": "10480573_T2", "arg2_id": "10480573_T9", "normalized": [] }, { "id": "10480573_1", "type": "INHIBITOR", "arg1_id": "10480573_T2", "arg2_id": "10480573_T13", "normalized": [] } ]

[ { "id": "15985434_title", "type": "title", "text": [ "Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives." ], "offsets": [ [ 0, 82 ] ] }, { "id": "15985434_abstract", "type": "abstract", "text": [ "Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or CDKs." ], "offsets": [ [ 83, 1434 ] ] } ]

[ { "id": "15985434_T1", "type": "CHEMICAL", "text": [ "Pyridoxal" ], "offsets": [ [ 83, 92 ] ], "normalized": [] }, { "id": "15985434_T2", "type": "CHEMICAL", "text": [ "pyridoxal" ], "offsets": [ [ 1093, 1102 ] ], "normalized": [] }, { "id": "15985434_T3", "type": "CHEMICAL", "text": [ "pyridoxal" ], "offsets": [ [ 1197, 1206 ] ], "normalized": [] }, { "id": "15985434_T4", "type": "CHEMICAL", "text": [ "ATP" ], "offsets": [ [ 199, 202 ] ], "normalized": [] }, { "id": "15985434_T5", "type": "CHEMICAL", "text": [ "roscovitine" ], "offsets": [ [ 1296, 1307 ] ], "normalized": [] }, { "id": "15985434_T6", "type": "CHEMICAL", "text": [ "Zn2+" ], "offsets": [ [ 207, 211 ] ], "normalized": [] }, { "id": "15985434_T7", "type": "CHEMICAL", "text": [ "roscovitine" ], "offsets": [ [ 1356, 1367 ] ], "normalized": [] }, { "id": "15985434_T8", "type": "CHEMICAL", "text": [ "pyridoxal 5'-phosphate" ], "offsets": [ [ 268, 290 ] ], "normalized": [] }, { "id": "15985434_T9", "type": "CHEMICAL", "text": [ "PLP" ], "offsets": [ [ 292, 295 ] ], "normalized": [] }, { "id": "15985434_T10", "type": "CHEMICAL", "text": [ "vitamin B6" ], "offsets": [ [ 317, 327 ] ], "normalized": [] }, { "id": "15985434_T11", "type": "CHEMICAL", "text": [ "(R)-Roscovitine" ], "offsets": [ [ 362, 377 ] ], "normalized": [] }, { "id": "15985434_T12", "type": "CHEMICAL", "text": [ "CYC202" ], "offsets": [ [ 379, 385 ] ], "normalized": [] }, { "id": "15985434_T13", "type": "CHEMICAL", "text": [ "Seliciclib" ], "offsets": [ [ 387, 397 ] ], "normalized": [] }, { "id": "15985434_T14", "type": "CHEMICAL", "text": [ "(R)-roscovitine" ], "offsets": [ [ 651, 666 ] ], "normalized": [] }, { "id": "15985434_T15", "type": "CHEMICAL", "text": [ "pyridoxal" ], "offsets": [ [ 140, 149 ] ], "normalized": [] }, { "id": "15985434_T16", "type": "CHEMICAL", "text": [ "pyridoxamine" ], "offsets": [ [ 151, 163 ] ], "normalized": [] }, { "id": "15985434_T17", "type": "CHEMICAL", "text": [ "(R)-roscovitine" ], "offsets": [ [ 785, 800 ] ], "normalized": [] }, { "id": "15985434_T18", "type": "CHEMICAL", "text": [ "N6-methyl-(R)-roscovitine" ], "offsets": [ [ 802, 827 ] ], "normalized": [] }, { "id": "15985434_T19", "type": "CHEMICAL", "text": [ "O6-(R)-roscovitine" ], "offsets": [ [ 833, 851 ] ], "normalized": [] }, { "id": "15985434_T20", "type": "CHEMICAL", "text": [ "pyridoxine" ], "offsets": [ [ 169, 179 ] ], "normalized": [] }, { "id": "15985434_T21", "type": "CHEMICAL", "text": [ "roscovitines" ], "offsets": [ [ 974, 986 ] ], "normalized": [] }, { "id": "15985434_T22", "type": "CHEMICAL", "text": [ "pyridoxal" ], "offsets": [ [ 1009, 1018 ] ], "normalized": [] }, { "id": "15985434_T23", "type": "CHEMICAL", "text": [ "ATP" ], "offsets": [ [ 1071, 1074 ] ], "normalized": [] }, { "id": "15985434_T24", "type": "CHEMICAL", "text": [ "pyridoxal" ], "offsets": [ [ 21, 30 ] ], "normalized": [] }, { "id": "15985434_T25", "type": "CHEMICAL", "text": [ "roscovitine" ], "offsets": [ [ 54, 65 ] ], "normalized": [] }, { "id": "15985434_T26", "type": "GENE-Y", "text": [ "Pyridoxal kinase" ], "offsets": [ [ 83, 99 ] ], "normalized": [] }, { "id": "15985434_T27", "type": "GENE-Y", "text": [ "PDXK" ], "offsets": [ [ 1287, 1291 ] ], "normalized": [] }, { "id": "15985434_T28", "type": "GENE-Y", "text": [ "PDXK" ], "offsets": [ [ 1421, 1425 ] ], "normalized": [] }, { "id": "15985434_T29", "type": "GENE-N", "text": [ "CDKs" ], "offsets": [ [ 1429, 1433 ] ], "normalized": [] }, { "id": "15985434_T30", "type": "GENE-Y", "text": [ "PDXK" ], "offsets": [ [ 101, 105 ] ], "normalized": [] }, { "id": "15985434_T31", "type": "GENE-N", "text": [ "cyclin-dependent kinases" ], "offsets": [ [ 438, 462 ] ], "normalized": [] }, { "id": "15985434_T32", "type": "GENE-N", "text": [ "CDKs" ], "offsets": [ [ 464, 468 ] ], "normalized": [] }, { "id": "15985434_T33", "type": "GENE-Y", "text": [ "PDXK" ], "offsets": [ [ 687, 691 ] ], "normalized": [] }, { "id": "15985434_T34", "type": "GENE-Y", "text": [ "PDXK" ], "offsets": [ [ 764, 768 ] ], "normalized": [] }, { "id": "15985434_T35", "type": "GENE-Y", "text": [ "PDXK" ], "offsets": [ [ 906, 910 ] ], "normalized": [] }, { "id": "15985434_T36", "type": "GENE-N", "text": [ "CDKs" ], "offsets": [ [ 922, 926 ] ], "normalized": [] }, { "id": "15985434_T37", "type": "GENE-Y", "text": [ "PDXK" ], "offsets": [ [ 1035, 1039 ] ], "normalized": [] }, { "id": "15985434_T38", "type": "GENE-Y", "text": [ "pyridoxal kinase" ], "offsets": [ [ 21, 37 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "11489456_title", "type": "title", "text": [ "Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors." ], "offsets": [ [ 0, 116 ] ] }, { "id": "11489456_abstract", "type": "abstract", "text": [ "The present series of studies is the first to investigate the pharmacological mechanisms underlying d-fenfluramine- and d-norfenfluramine-induced hypophagia in the rat using highly selective serotonin 5-HT2 receptor antagonists. Administration of d-fenfluramine, and its major metabolite d-norfenfluramine, suppresses food intake in animals. Both compounds stimulate the release of serotonin and are potent inhibitors of the re-uptake of 5-HT into nerve terminals. In addition, d-norfenfluramine also acts as a direct 5-HT(2B/2C) receptor agonist. Pre-treatment with the selective 5-HT2C receptor antagonist, SB-242084 (0.3-3 mg/kg), dose-dependently inhibited both d-fenfluramine- (3 mg/kg) and d-norfenfluramine-induced (2 mg/kg) hypophagia. In contrast, the hypophagic effect of d-fenfluramine and d-norfenfluramine was unaffected by prior treatment with the highly selective 5-HT2B receptor antagonists, SB-215505 (0.3-3 mg/kg) and RS-127445 (1-3 mg/kg) or the 5-HT2A receptor antagonists MDL 100,907 (0.003-0.03 mg/kg) and ketanserin (0.2, 0.5 mg/kg). In addition, the 5-HT1A receptor antagonist WAY-100635 (0.3, 1 mg/kg) and the 5-HT1B receptor antagonists GR-127935 (1, 2 mg/kg) and SB-224289 (2-10 mg/kg) did not affect d-fenfluramine-induced hypophagia. These data provide unequivocal evidence for an important role of the 5-HT2C receptor in the mediation of d-fenfluramine and d-norfenfluramine-induced hypophagia in the rat and do not support the involvement of 5-HT1A/1B/2A/2B receptors." ], "offsets": [ [ 117, 1616 ] ] } ]

[ { "id": "11489456_T1", "type": "CHEMICAL", "text": [ "d-fenfluramine" ], "offsets": [ [ 217, 231 ] ], "normalized": [] }, { "id": "11489456_T2", "type": "CHEMICAL", "text": [ "ketanserin" ], "offsets": [ [ 1145, 1155 ] ], "normalized": [] }, { "id": "11489456_T3", "type": "CHEMICAL", "text": [ "WAY-100635" ], "offsets": [ [ 1218, 1228 ] ], "normalized": [] }, { "id": "11489456_T4", "type": "CHEMICAL", "text": [ "GR-127935" ], "offsets": [ [ 1280, 1289 ] ], "normalized": [] }, { "id": "11489456_T5", "type": "CHEMICAL", "text": [ "SB-224289" ], "offsets": [ [ 1307, 1316 ] ], "normalized": [] }, { "id": "11489456_T6", "type": "CHEMICAL", "text": [ "d-norfenfluramine" ], "offsets": [ [ 237, 254 ] ], "normalized": [] }, { "id": "11489456_T7", "type": "CHEMICAL", "text": [ "d-fenfluramine" ], "offsets": [ [ 1345, 1359 ] ], "normalized": [] }, { "id": "11489456_T8", "type": "CHEMICAL", "text": [ "d-fenfluramine" ], "offsets": [ [ 1485, 1499 ] ], "normalized": [] }, { "id": "11489456_T9", "type": "CHEMICAL", "text": [ "d-norfenfluramine" ], "offsets": [ [ 1504, 1521 ] ], "normalized": [] }, { "id": "11489456_T10", "type": "CHEMICAL", "text": [ "d-fenfluramine" ], "offsets": [ [ 364, 378 ] ], "normalized": [] }, { "id": "11489456_T11", "type": "CHEMICAL", "text": [ "d-norfenfluramine" ], "offsets": [ [ 405, 422 ] ], "normalized": [] }, { "id": "11489456_T12", "type": "CHEMICAL", "text": [ "serotonin" ], "offsets": [ [ 499, 508 ] ], "normalized": [] }, { "id": "11489456_T13", "type": "CHEMICAL", "text": [ "5-HT" ], "offsets": [ [ 555, 559 ] ], "normalized": [] }, { "id": "11489456_T14", "type": "CHEMICAL", "text": [ "d-norfenfluramine" ], "offsets": [ [ 595, 612 ] ], "normalized": [] }, { "id": "11489456_T15", "type": "CHEMICAL", "text": [ "SB-242084" ], "offsets": [ [ 726, 735 ] ], "normalized": [] }, { "id": "11489456_T16", "type": "CHEMICAL", "text": [ "d-fenfluramine" ], "offsets": [ [ 783, 797 ] ], "normalized": [] }, { "id": "11489456_T17", "type": "CHEMICAL", "text": [ "d-norfenfluramine" ], "offsets": [ [ 813, 830 ] ], "normalized": [] }, { "id": "11489456_T18", "type": "CHEMICAL", "text": [ "d-fenfluramine" ], "offsets": [ [ 899, 913 ] ], "normalized": [] }, { "id": "11489456_T19", "type": "CHEMICAL", "text": [ "d-norfenfluramine" ], "offsets": [ [ 918, 935 ] ], "normalized": [] }, { "id": "11489456_T20", "type": "CHEMICAL", "text": [ "SB-215505" ], "offsets": [ [ 1025, 1034 ] ], "normalized": [] }, { "id": "11489456_T21", "type": "CHEMICAL", "text": [ "RS-127445" ], "offsets": [ [ 1053, 1062 ] ], "normalized": [] }, { "id": "11489456_T22", "type": "CHEMICAL", "text": [ "MDL 100,907" ], "offsets": [ [ 1110, 1121 ] ], "normalized": [] }, { "id": "11489456_T23", "type": "CHEMICAL", "text": [ "d-fenfluramine" ], "offsets": [ [ 36, 50 ] ], "normalized": [] }, { "id": "11489456_T24", "type": "CHEMICAL", "text": [ "d-norfenfluramine" ], "offsets": [ [ 55, 72 ] ], "normalized": [] }, { "id": "11489456_T25", "type": "GENE-Y", "text": [ "5-HT1A" ], "offsets": [ [ 1191, 1197 ] ], "normalized": [] }, { "id": "11489456_T26", "type": "GENE-Y", "text": [ "5-HT1B" ], "offsets": [ [ 1252, 1258 ] ], "normalized": [] }, { "id": "11489456_T27", "type": "GENE-Y", "text": [ "5-HT2C" ], "offsets": [ [ 1449, 1455 ] ], "normalized": [] }, { "id": "11489456_T28", "type": "GENE-N", "text": [ "5-HT1A/1B/2A/2B" ], "offsets": [ [ 1590, 1605 ] ], "normalized": [] }, { "id": "11489456_T29", "type": "GENE-N", "text": [ "5-HT2" ], "offsets": [ [ 318, 323 ] ], "normalized": [] }, { "id": "11489456_T30", "type": "GENE-N", "text": [ "5-HT(2B/2C)" ], "offsets": [ [ 635, 646 ] ], "normalized": [] }, { "id": "11489456_T31", "type": "GENE-Y", "text": [ "5-HT2C" ], "offsets": [ [ 698, 704 ] ], "normalized": [] }, { "id": "11489456_T32", "type": "GENE-Y", "text": [ "5-HT2B" ], "offsets": [ [ 996, 1002 ] ], "normalized": [] }, { "id": "11489456_T33", "type": "GENE-Y", "text": [ "5-HT2A" ], "offsets": [ [ 1082, 1088 ] ], "normalized": [] }, { "id": "11489456_T34", "type": "GENE-Y", "text": [ "5-HT2C" ], "offsets": [ [ 99, 105 ] ], "normalized": [] } ]

[]

[]

[ { "id": "11489456_0", "type": "ANTAGONIST", "arg1_id": "11489456_T15", "arg2_id": "11489456_T31", "normalized": [] }, { "id": "11489456_1", "type": "AGONIST", "arg1_id": "11489456_T16", "arg2_id": "11489456_T31", "normalized": [] }, { "id": "11489456_2", "type": "AGONIST", "arg1_id": "11489456_T17", "arg2_id": "11489456_T31", "normalized": [] }, { "id": "11489456_3", "type": "ANTAGONIST", "arg1_id": "11489456_T20", "arg2_id": "11489456_T32", "normalized": [] }, { "id": "11489456_4", "type": "ANTAGONIST", "arg1_id": "11489456_T21", "arg2_id": "11489456_T32", "normalized": [] }, { "id": "11489456_5", "type": "ANTAGONIST", "arg1_id": "11489456_T22", "arg2_id": "11489456_T33", "normalized": [] }, { "id": "11489456_6", "type": "ANTAGONIST", "arg1_id": "11489456_T2", "arg2_id": "11489456_T33", "normalized": [] }, { "id": "11489456_7", "type": "AGONIST", "arg1_id": "11489456_T18", "arg2_id": "11489456_T32", "normalized": [] }, { "id": "11489456_8", "type": "AGONIST", "arg1_id": "11489456_T19", "arg2_id": "11489456_T32", "normalized": [] }, { "id": "11489456_9", "type": "AGONIST", "arg1_id": "11489456_T18", "arg2_id": "11489456_T33", "normalized": [] }, { "id": "11489456_10", "type": "AGONIST", "arg1_id": "11489456_T19", "arg2_id": "11489456_T33", "normalized": [] }, { "id": "11489456_11", "type": "ANTAGONIST", "arg1_id": "11489456_T3", "arg2_id": "11489456_T25", "normalized": [] }, { "id": "11489456_12", "type": "ANTAGONIST", "arg1_id": "11489456_T4", "arg2_id": "11489456_T26", "normalized": [] }, { "id": "11489456_13", "type": "ANTAGONIST", "arg1_id": "11489456_T5", "arg2_id": "11489456_T26", "normalized": [] }, { "id": "11489456_14", "type": "AGONIST", "arg1_id": "11489456_T7", "arg2_id": "11489456_T25", "normalized": [] }, { "id": "11489456_15", "type": "AGONIST", "arg1_id": "11489456_T7", "arg2_id": "11489456_T26", "normalized": [] }, { "id": "11489456_16", "type": "AGONIST", "arg1_id": "11489456_T8", "arg2_id": "11489456_T27", "normalized": [] }, { "id": "11489456_17", "type": "AGONIST", "arg1_id": "11489456_T9", "arg2_id": "11489456_T27", "normalized": [] } ]

[ { "id": "16823043_title", "type": "title", "text": [ "Structure of the angiogenesis inhibitor ovalicin bound to its noncognate target, human Type 1 methionine aminopeptidase." ], "offsets": [ [ 0, 120 ] ] }, { "id": "16823043_abstract", "type": "abstract", "text": [ "Methionine aminopeptidases (MetAPs) remove the initiator methionine during protein biosynthesis. They exist in two isoforms, MetAP1 and MetAP2. The anti-angiogenic compound fumagillin binds tightly to the Type 2 MetAPs but only weakly to Type 1. High-affinity complexes of fumagillin and its relative ovalicin with Type 2 human MetAP have been reported. Here we describe the crystallographic structure of the low-affinity complex between ovalicin and Type 1 human MetAP at 1.1 A resolution. This provides the first opportunity to compare the structures of ovalicin or fumagillin bound to a Type 1 and a Type 2 MetAP. For both Type 1 and Type 2 human MetAPs the inhibitor makes a covalent adduct with a corresponding histidine. At the same time there are significant differences in the alignment of the inhibitors within the respective active sites. It has been argued that the lower affinity of ovalicin and fumagillin for the Type 1 MetAPs is due to the smaller size of their active sites relative to the Type 2 enzymes. Comparison with the uncomplexed structure of human Type 1 MetAP indicates that there is some truth to this. Several active site residues have to move \"outward\" by 0.5 Angstroms or so to accommodate the inhibitor. Other residues move \"inward.\" There are, however, other factors that come into play. In particular, the side chain of His310 rotates by 134 degrees into a different position where (together with Glu128 and Tyr195) it coordinates a metal ion not seen at this site in the native enzyme." ], "offsets": [ [ 121, 1640 ] ] } ]

[ { "id": "16823043_T1", "type": "CHEMICAL", "text": [ "Methionine" ], "offsets": [ [ 121, 131 ] ], "normalized": [] }, { "id": "16823043_T2", "type": "CHEMICAL", "text": [ "fumagillin" ], "offsets": [ [ 294, 304 ] ], "normalized": [] }, { "id": "16823043_T3", "type": "CHEMICAL", "text": [ "fumagillin" ], "offsets": [ [ 394, 404 ] ], "normalized": [] }, { "id": "16823043_T4", "type": "CHEMICAL", "text": [ "ovalicin" ], "offsets": [ [ 422, 430 ] ], "normalized": [] }, { "id": "16823043_T5", "type": "CHEMICAL", "text": [ "ovalicin" ], "offsets": [ [ 559, 567 ] ], "normalized": [] }, { "id": "16823043_T6", "type": "CHEMICAL", "text": [ "ovalicin" ], "offsets": [ [ 677, 685 ] ], "normalized": [] }, { "id": "16823043_T7", "type": "CHEMICAL", "text": [ "fumagillin" ], "offsets": [ [ 689, 699 ] ], "normalized": [] }, { "id": "16823043_T8", "type": "CHEMICAL", "text": [ "histidine" ], "offsets": [ [ 837, 846 ] ], "normalized": [] }, { "id": "16823043_T9", "type": "CHEMICAL", "text": [ "ovalicin" ], "offsets": [ [ 1016, 1024 ] ], "normalized": [] }, { "id": "16823043_T10", "type": "CHEMICAL", "text": [ "fumagillin" ], "offsets": [ [ 1029, 1039 ] ], "normalized": [] }, { "id": "16823043_T11", "type": "CHEMICAL", "text": [ "ovalicin" ], "offsets": [ [ 40, 48 ] ], "normalized": [] }, { "id": "16823043_T12", "type": "CHEMICAL", "text": [ "methionine" ], "offsets": [ [ 94, 104 ] ], "normalized": [] }, { "id": "16823043_T13", "type": "GENE-N", "text": [ "Methionine aminopeptidases" ], "offsets": [ [ 121, 147 ] ], "normalized": [] }, { "id": "16823043_T14", "type": "GENE-Y", "text": [ "human Type 1 MetAP" ], "offsets": [ [ 1188, 1206 ] ], "normalized": [] }, { "id": "16823043_T15", "type": "GENE-Y", "text": [ "MetAP1" ], "offsets": [ [ 246, 252 ] ], "normalized": [] }, { "id": "16823043_T16", "type": "GENE-Y", "text": [ "MetAP2" ], "offsets": [ [ 257, 263 ] ], "normalized": [] }, { "id": "16823043_T17", "type": "GENE-Y", "text": [ "Type 2 MetAPs" ], "offsets": [ [ 326, 339 ] ], "normalized": [] }, { "id": "16823043_T18", "type": "GENE-N", "text": [ "MetAPs" ], "offsets": [ [ 149, 155 ] ], "normalized": [] }, { "id": "16823043_T19", "type": "GENE-Y", "text": [ "Type 2 human MetAP" ], "offsets": [ [ 436, 454 ] ], "normalized": [] }, { "id": "16823043_T20", "type": "GENE-Y", "text": [ "Type 1 human MetAP" ], "offsets": [ [ 572, 590 ] ], "normalized": [] }, { "id": "16823043_T21", "type": "GENE-N", "text": [ "Type 1 and a Type 2 MetAP" ], "offsets": [ [ 711, 736 ] ], "normalized": [] }, { "id": "16823043_T22", "type": "GENE-N", "text": [ "Type 1 and Type 2 human MetAPs" ], "offsets": [ [ 747, 777 ] ], "normalized": [] }, { "id": "16823043_T23", "type": "GENE-Y", "text": [ "Type 1 MetAPs" ], "offsets": [ [ 1048, 1061 ] ], "normalized": [] }, { "id": "16823043_T24", "type": "GENE-Y", "text": [ "human Type 1 methionine aminopeptidase" ], "offsets": [ [ 81, 119 ] ], "normalized": [] } ]

[]

[]

[ { "id": "16823043_0", "type": "DIRECT-REGULATOR", "arg1_id": "16823043_T11", "arg2_id": "16823043_T24", "normalized": [] }, { "id": "16823043_1", "type": "DIRECT-REGULATOR", "arg1_id": "16823043_T2", "arg2_id": "16823043_T17", "normalized": [] }, { "id": "16823043_2", "type": "DIRECT-REGULATOR", "arg1_id": "16823043_T3", "arg2_id": "16823043_T19", "normalized": [] }, { "id": "16823043_3", "type": "DIRECT-REGULATOR", "arg1_id": "16823043_T4", "arg2_id": "16823043_T19", "normalized": [] }, { "id": "16823043_4", "type": "DIRECT-REGULATOR", "arg1_id": "16823043_T5", "arg2_id": "16823043_T20", "normalized": [] }, { "id": "16823043_5", "type": "DIRECT-REGULATOR", "arg1_id": "16823043_T9", "arg2_id": "16823043_T23", "normalized": [] }, { "id": "16823043_6", "type": "DIRECT-REGULATOR", "arg1_id": "16823043_T10", "arg2_id": "16823043_T23", "normalized": [] } ]

[ { "id": "23395667_title", "type": "title", "text": [ "Growth factor delivery from hydrogel particle aggregates to promote tubular regeneration after acute kidney injury." ], "offsets": [ [ 0, 115 ] ] }, { "id": "23395667_abstract", "type": "abstract", "text": [ "Local delivery of growth factors (GFs) can accelerate regeneration of injured tissue, but for many medical applications, injectable GF delivery systems are required for clinical success. Viscoelastic, injectable aggregates of micrometer-sized hydrogel particles made of multiarmed polyethylene glycol (starPEG) and heparin were prepared and tested for site-specific paracrine stimulation of tissue regeneration. Heparin was used as it binds, protects and releases numerous GFs. Hydrogel based delivery of basic fibroblast growth factor (bFGF) and murine epidermal growth factor (EGF) was monitored utilizing enzyme-linked immunosorbent assay (ELISA). bFGF was released slowly because of its high affinity to the heparin while the significantly higher release of the non-specific binding EGF was controlled by diffusion only. To investigate GF delivery in vivo, a hydrogel loaded with murine EGF or bFGF was injected subcapsularly into the left kidney of mice with experimental acute kidney injury caused by glycerol induced rhabdomyolysis. Visual examination confirmed sustained stability of the injected gel aggregates during the timescale of the experiment. The number of proliferating kidney tubular epithelial cells was quantified both in the injected kidney and the non-injected contralateral kidney. bFGF delivery from hydrogels induced a significant increase in cell proliferation in the injected kidney, although small effects were also seen in the non-injected kidney due to a systemic effect. EGF delivery strongly increased cell proliferation for both kidneys, but also showed a local effect on the injected kidney. The hydrogel without loaded GFs was used as a control and showed no increase in cell proliferation. Our results suggest that this novel starPEG-heparin hydrogel system can be an effective approach to deliver GFs locally." ], "offsets": [ [ 116, 1963 ] ] } ]

[ { "id": "23395667_T1", "type": "CHEMICAL", "text": [ "glycerol" ], "offsets": [ [ 1123, 1131 ] ], "normalized": [] }, { "id": "23395667_T2", "type": "CHEMICAL", "text": [ "polyethylene glycol" ], "offsets": [ [ 397, 416 ] ], "normalized": [] }, { "id": "23395667_T3", "type": "GENE-Y", "text": [ "bFGF" ], "offsets": [ [ 1422, 1426 ] ], "normalized": [] }, { "id": "23395667_T4", "type": "GENE-Y", "text": [ "EGF" ], "offsets": [ [ 1619, 1622 ] ], "normalized": [] }, { "id": "23395667_T5", "type": "GENE-Y", "text": [ "basic fibroblast growth factor" ], "offsets": [ [ 621, 651 ] ], "normalized": [] }, { "id": "23395667_T6", "type": "GENE-Y", "text": [ "bFGF" ], "offsets": [ [ 653, 657 ] ], "normalized": [] }, { "id": "23395667_T7", "type": "GENE-Y", "text": [ "murine epidermal growth factor" ], "offsets": [ [ 663, 693 ] ], "normalized": [] }, { "id": "23395667_T8", "type": "GENE-Y", "text": [ "EGF" ], "offsets": [ [ 695, 698 ] ], "normalized": [] }, { "id": "23395667_T9", "type": "GENE-Y", "text": [ "bFGF" ], "offsets": [ [ 767, 771 ] ], "normalized": [] }, { "id": "23395667_T10", "type": "GENE-Y", "text": [ "EGF" ], "offsets": [ [ 903, 906 ] ], "normalized": [] }, { "id": "23395667_T11", "type": "GENE-Y", "text": [ "murine EGF" ], "offsets": [ [ 1000, 1010 ] ], "normalized": [] }, { "id": "23395667_T12", "type": "GENE-Y", "text": [ "bFGF" ], "offsets": [ [ 1014, 1018 ] ], "normalized": [] } ]

[]

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[]

[ { "id": "23500387_title", "type": "title", "text": [ "Curcumin attenuates allergic airway inflammation by regulation of CD4(+)CD25(+) regulatory T cells (Tregs)/Th17 balance in ovalbumin-sensitized mice." ], "offsets": [ [ 0, 149 ] ] }, { "id": "23500387_abstract", "type": "abstract", "text": [ "The present study aimed to determine the protective effects and the underlying mechanisms of curcumin on ovalbumin (OVA)-induced allergic inflammation in a mouse model of allergic asthma. Asthma mice model was established by ovalbumin. A total of 60 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2mg/kg), and curcumin (50mg/kg, 100mg/kg, 200mg/kg). Airway resistance (Raw) was measured by the forced oscillation technique, differential cell count in BAL fluid (BALF) was measured by Wright-Giemsa staining, histological assessment was measured by hematoxylin and eosin (HE) staining, BALF levels of Treg/Th17 cytokines were measured by enzyme-linked immunosorbent assay, Treg cells and Th17 cells were evaluated by flow cytometry (FCM). Our study demonstrated that curcumin inhibited OVA-induced increases in eosinophil count; interleukin (IL)-17A level were recovered in bronchoalveolar lavage fluid increased IL-10 level in bronchoalveolar lavage fluid. Histological studies demonstrated that curcumin substantially inhibited OVA-induced eosinophilia in lung tissue. Flow cytometry (FCM) studies demonstrated that curcumin remarkably inhibited Th17 cells and significantly increased Treg cells. The results in vivo show ovalbumin-induced significantly broke Treg/Th17 balance; curcumin treatments markedly attenuated the inflammatory in asthma model by regulating Treg/Th17 balance. Our findings support the possible use of curcumin as a therapeutic drug for patients with allergic asthma." ], "offsets": [ [ 150, 1682 ] ] } ]

[ { "id": "23500387_T1", "type": "CHEMICAL", "text": [ "curcumin" ], "offsets": [ [ 1186, 1194 ] ], "normalized": [] }, { "id": "23500387_T2", "type": "CHEMICAL", "text": [ "curcumin" ], "offsets": [ [ 1307, 1315 ] ], "normalized": [] }, { "id": "23500387_T3", "type": "CHEMICAL", "text": [ "curcumin" ], "offsets": [ [ 1470, 1478 ] ], "normalized": [] }, { "id": "23500387_T4", "type": "CHEMICAL", "text": [ "curcumin" ], "offsets": [ [ 1617, 1625 ] ], "normalized": [] }, { "id": "23500387_T5", "type": "CHEMICAL", "text": [ "dexamethasone" ], "offsets": [ [ 472, 485 ] ], "normalized": [] }, { "id": "23500387_T6", "type": "CHEMICAL", "text": [ "curcumin" ], "offsets": [ [ 500, 508 ] ], "normalized": [] }, { "id": "23500387_T7", "type": "CHEMICAL", "text": [ "hematoxylin" ], "offsets": [ [ 738, 749 ] ], "normalized": [] }, { "id": "23500387_T8", "type": "CHEMICAL", "text": [ "eosin" ], "offsets": [ [ 754, 759 ] ], "normalized": [] }, { "id": "23500387_T9", "type": "CHEMICAL", "text": [ "curcumin" ], "offsets": [ [ 956, 964 ] ], "normalized": [] }, { "id": "23500387_T10", "type": "CHEMICAL", "text": [ "curcumin" ], "offsets": [ [ 243, 251 ] ], "normalized": [] }, { "id": "23500387_T11", "type": "CHEMICAL", "text": [ "Curcumin" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "23500387_T12", "type": "GENE-Y", "text": [ "ovalbumin" ], "offsets": [ [ 255, 264 ] ], "normalized": [] }, { "id": "23500387_T13", "type": "GENE-Y", "text": [ "OVA" ], "offsets": [ [ 1219, 1222 ] ], "normalized": [] }, { "id": "23500387_T14", "type": "GENE-Y", "text": [ "OVA" ], "offsets": [ [ 266, 269 ] ], "normalized": [] }, { "id": "23500387_T15", "type": "GENE-Y", "text": [ "ovalbumin" ], "offsets": [ [ 1413, 1422 ] ], "normalized": [] }, { "id": "23500387_T16", "type": "GENE-Y", "text": [ "ovalbumin" ], "offsets": [ [ 375, 384 ] ], "normalized": [] }, { "id": "23500387_T17", "type": "GENE-N", "text": [ "cytokines" ], "offsets": [ [ 800, 809 ] ], "normalized": [] }, { "id": "23500387_T18", "type": "GENE-Y", "text": [ "OVA" ], "offsets": [ [ 975, 978 ] ], "normalized": [] }, { "id": "23500387_T19", "type": "GENE-Y", "text": [ "interleukin (IL)-17A" ], "offsets": [ [ 1018, 1038 ] ], "normalized": [] }, { "id": "23500387_T20", "type": "GENE-Y", "text": [ "IL-10" ], "offsets": [ [ 1102, 1107 ] ], "normalized": [] }, { "id": "23500387_T21", "type": "GENE-Y", "text": [ "ovalbumin" ], "offsets": [ [ 123, 132 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23500387_0", "type": "INHIBITOR", "arg1_id": "23500387_T9", "arg2_id": "23500387_T19", "normalized": [] }, { "id": "23500387_1", "type": "INHIBITOR", "arg1_id": "23500387_T9", "arg2_id": "23500387_T18", "normalized": [] }, { "id": "23500387_2", "type": "INHIBITOR", "arg1_id": "23500387_T1", "arg2_id": "23500387_T13", "normalized": [] }, { "id": "23500387_3", "type": "INHIBITOR", "arg1_id": "23500387_T3", "arg2_id": "23500387_T15", "normalized": [] }, { "id": "23500387_4", "type": "INDIRECT-UPREGULATOR", "arg1_id": "23500387_T9", "arg2_id": "23500387_T20", "normalized": [] } ]

[ { "id": "12529935_title", "type": "title", "text": [ "Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors." ], "offsets": [ [ 0, 129 ] ] }, { "id": "12529935_abstract", "type": "abstract", "text": [ "The glucagon-like peptides include glucagon, GLP-1, and GLP-2, and exert diverse actions on nutrient intake, gastrointestinal motility, islet hormone secretion, cell proliferation and apoptosis, nutrient absorption, and nutrient assimilation. GIP, a related member of the glucagon peptide superfamily, also regulates nutrient disposal via stimulation of insulin secretion. The actions of these peptides are mediated by distinct members of the glucagon receptor superfamily of G protein-coupled receptors. These receptors exhibit unique patterns of tissue-specific expression, exhibit considerable amino acid sequence identity, and share similar structural and functional properties with respect to ligand binding and signal transduction. This article provides an overview of the biology of these receptors with an emphasis on understanding the unique actions of glucagon-related peptides through studies of the biology of their cognate receptors." ], "offsets": [ [ 130, 1076 ] ] } ]

[ { "id": "12529935_T1", "type": "CHEMICAL", "text": [ "amino acid" ], "offsets": [ [ 727, 737 ] ], "normalized": [] }, { "id": "12529935_T2", "type": "GENE-Y", "text": [ "GIP" ], "offsets": [ [ 373, 376 ] ], "normalized": [] }, { "id": "12529935_T3", "type": "GENE-Y", "text": [ "glucagon" ], "offsets": [ [ 402, 410 ] ], "normalized": [] }, { "id": "12529935_T4", "type": "GENE-Y", "text": [ "insulin" ], "offsets": [ [ 484, 491 ] ], "normalized": [] }, { "id": "12529935_T5", "type": "GENE-Y", "text": [ "glucagon" ], "offsets": [ [ 165, 173 ] ], "normalized": [] }, { "id": "12529935_T6", "type": "GENE-Y", "text": [ "glucagon-like peptides" ], "offsets": [ [ 134, 156 ] ], "normalized": [] }, { "id": "12529935_T7", "type": "GENE-Y", "text": [ "glucagon receptor" ], "offsets": [ [ 573, 590 ] ], "normalized": [] }, { "id": "12529935_T8", "type": "GENE-Y", "text": [ "GLP-1" ], "offsets": [ [ 175, 180 ] ], "normalized": [] }, { "id": "12529935_T9", "type": "GENE-N", "text": [ "G protein-coupled receptors" ], "offsets": [ [ 606, 633 ] ], "normalized": [] }, { "id": "12529935_T10", "type": "GENE-Y", "text": [ "GLP-2" ], "offsets": [ [ 186, 191 ] ], "normalized": [] }, { "id": "12529935_T11", "type": "GENE-Y", "text": [ "glucagon-related peptides" ], "offsets": [ [ 992, 1017 ] ], "normalized": [] }, { "id": "12529935_T12", "type": "GENE-Y", "text": [ "GLP-1" ], "offsets": [ [ 102, 107 ] ], "normalized": [] }, { "id": "12529935_T13", "type": "GENE-Y", "text": [ "GLP-2 receptors" ], "offsets": [ [ 113, 128 ] ], "normalized": [] }, { "id": "12529935_T14", "type": "GENE-Y", "text": [ "glucagon receptor" ], "offsets": [ [ 26, 43 ] ], "normalized": [] }, { "id": "12529935_T15", "type": "GENE-N", "text": [ "G protein-coupled receptors" ], "offsets": [ [ 54, 81 ] ], "normalized": [] }, { "id": "12529935_T16", "type": "GENE-Y", "text": [ "glucagon" ], "offsets": [ [ 87, 95 ] ], "normalized": [] }, { "id": "12529935_T17", "type": "GENE-Y", "text": [ "GIP" ], "offsets": [ [ 97, 100 ] ], "normalized": [] } ]

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[]

[ { "id": "11522647_title", "type": "title", "text": [ "Activated extracellular signal-regulated kinases: association with epidermal growth factor receptor/transforming growth factor alpha expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments." ], "offsets": [ [ 0, 247 ] ] }, { "id": "11522647_abstract", "type": "abstract", "text": [ "The expression of the activated mitogen-activated kinases/extracellular signal-regulated kinases (ERKs) ERK1 and ERK2 was characterized in 101 humanhead and neck squamous carcinoma specimens. Activated ERK1/2were detected at different levels in the majority of these tumors, as assayed by immunostaining with an antibody specific for the dually phosphorylated and activated ERK1 and ERK2. ERK1/2 activation levels were higher in tumors with advanced regional lymph node metastasis (P = 0.048) and in relapsed tumors (P = 0.021). The expression of epidermal growth factor (EGF) receptor (P = 0.037), transforming growth factor alpha (TGF-alpha; P < 0.001), and HER2 (P = 0.066; positive trend) correlated with activation of ERK1/2. In a multivariate analysis, both TGF-alpha (P < 0.0001) and HER2 (P = 0.045) were independently correlated with ERK1/2 activation. In turn, activation of ERK1/2 was associated with a higher Ki-67 proliferative index (P = 0.002). In EGF receptor-dependent model cells (A431 and DiFi), a specific EGF receptor tyrosine kinase inhibitor (\"Iressa\"; ZD1839) and a chimeric anti-EGF receptor antibody (\"Cetuximab\"; C225) inhibited ERK 1/2 activation at concentrations that inhibited autocrine cell proliferation. In patients on treatment with C225, the activation of ERK1/2 in skin, an EGF receptor-dependent tissue, was lower compared with control skin. Parallel changes were seen in keratinocyte Ki67 proliferation indexes in skin from C225-treated patients. Taken together, these studies provide support for a role of activation of ERK1/2 in head and neck squamous carcinoma and a correlation with EGF receptor/TGF-alpha expression. The inhibition of ERK1/2 activation in vitro and in vivo by compounds targeting the EGF receptor points to the interest of ERK1/2 as potential surrogate markers of EGF-receptor signaling in clinical therapeutic studies." ], "offsets": [ [ 248, 2128 ] ] } ]

[ { "id": "11522647_T1", "type": "CHEMICAL", "text": [ "tyrosine" ], "offsets": [ [ 1287, 1295 ] ], "normalized": [] }, { "id": "11522647_T2", "type": "GENE-Y", "text": [ "EGF receptor" ], "offsets": [ [ 1274, 1286 ] ], "normalized": [] }, { "id": "11522647_T3", "type": "GENE-N", "text": [ "tyrosine kinase" ], "offsets": [ [ 1287, 1302 ] ], "normalized": [] }, { "id": "11522647_T4", "type": "GENE-Y", "text": [ "ERK1" ], "offsets": [ [ 352, 356 ] ], "normalized": [] }, { "id": "11522647_T5", "type": "GENE-Y", "text": [ "EGF receptor" ], "offsets": [ [ 1352, 1364 ] ], "normalized": [] }, { "id": "11522647_T6", "type": "GENE-Y", "text": [ "ERK2" ], "offsets": [ [ 361, 365 ] ], "normalized": [] }, { "id": "11522647_T7", "type": "GENE-N", "text": [ "ERK 1/2" ], "offsets": [ [ 1404, 1411 ] ], "normalized": [] }, { "id": "11522647_T8", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 1540, 1546 ] ], "normalized": [] }, { "id": "11522647_T9", "type": "GENE-Y", "text": [ "EGF receptor" ], "offsets": [ [ 1559, 1571 ] ], "normalized": [] }, { "id": "11522647_T10", "type": "GENE-Y", "text": [ "Ki67" ], "offsets": [ [ 1671, 1675 ] ], "normalized": [] }, { "id": "11522647_T11", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 1808, 1814 ] ], "normalized": [] }, { "id": "11522647_T12", "type": "GENE-Y", "text": [ "EGF receptor" ], "offsets": [ [ 1874, 1886 ] ], "normalized": [] }, { "id": "11522647_T13", "type": "GENE-Y", "text": [ "TGF-alpha" ], "offsets": [ [ 1887, 1896 ] ], "normalized": [] }, { "id": "11522647_T14", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 1927, 1933 ] ], "normalized": [] }, { "id": "11522647_T15", "type": "GENE-Y", "text": [ "EGF receptor" ], "offsets": [ [ 1993, 2005 ] ], "normalized": [] }, { "id": "11522647_T16", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 2032, 2038 ] ], "normalized": [] }, { "id": "11522647_T17", "type": "GENE-Y", "text": [ "EGF-receptor" ], "offsets": [ [ 2073, 2085 ] ], "normalized": [] }, { "id": "11522647_T18", "type": "GENE-N", "text": [ "Activated ERK1/2" ], "offsets": [ [ 440, 456 ] ], "normalized": [] }, { "id": "11522647_T19", "type": "GENE-N", "text": [ "activated mitogen-activated kinases" ], "offsets": [ [ 270, 305 ] ], "normalized": [] }, { "id": "11522647_T20", "type": "GENE-Y", "text": [ "ERK1" ], "offsets": [ [ 622, 626 ] ], "normalized": [] }, { "id": "11522647_T21", "type": "GENE-Y", "text": [ "ERK2" ], "offsets": [ [ 631, 635 ] ], "normalized": [] }, { "id": "11522647_T22", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 637, 643 ] ], "normalized": [] }, { "id": "11522647_T23", "type": "GENE-Y", "text": [ "epidermal growth factor (EGF) receptor" ], "offsets": [ [ 795, 833 ] ], "normalized": [] }, { "id": "11522647_T24", "type": "GENE-N", "text": [ "extracellular signal-regulated kinases" ], "offsets": [ [ 306, 344 ] ], "normalized": [] }, { "id": "11522647_T25", "type": "GENE-Y", "text": [ "transforming growth factor alpha" ], "offsets": [ [ 847, 879 ] ], "normalized": [] }, { "id": "11522647_T26", "type": "GENE-Y", "text": [ "TGF-alpha" ], "offsets": [ [ 881, 890 ] ], "normalized": [] }, { "id": "11522647_T27", "type": "GENE-Y", "text": [ "HER2" ], "offsets": [ [ 908, 912 ] ], "normalized": [] }, { "id": "11522647_T28", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 971, 977 ] ], "normalized": [] }, { "id": "11522647_T29", "type": "GENE-Y", "text": [ "TGF-alpha" ], "offsets": [ [ 1012, 1021 ] ], "normalized": [] }, { "id": "11522647_T30", "type": "GENE-Y", "text": [ "HER2" ], "offsets": [ [ 1039, 1043 ] ], "normalized": [] }, { "id": "11522647_T31", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 1091, 1097 ] ], "normalized": [] }, { "id": "11522647_T32", "type": "GENE-N", "text": [ "ERK1/2" ], "offsets": [ [ 1133, 1139 ] ], "normalized": [] }, { "id": "11522647_T33", "type": "GENE-Y", "text": [ "Ki-67" ], "offsets": [ [ 1169, 1174 ] ], "normalized": [] }, { "id": "11522647_T34", "type": "GENE-Y", "text": [ "EGF receptor" ], "offsets": [ [ 1211, 1223 ] ], "normalized": [] }, { "id": "11522647_T35", "type": "GENE-N", "text": [ "ERKs" ], "offsets": [ [ 346, 350 ] ], "normalized": [] }, { "id": "11522647_T36", "type": "GENE-N", "text": [ "Activated extracellular signal-regulated kinases" ], "offsets": [ [ 0, 48 ] ], "normalized": [] }, { "id": "11522647_T37", "type": "GENE-Y", "text": [ "transforming growth factor alpha" ], "offsets": [ [ 100, 132 ] ], "normalized": [] }, { "id": "11522647_T38", "type": "GENE-Y", "text": [ "epidermal growth factor receptor" ], "offsets": [ [ 203, 235 ] ], "normalized": [] }, { "id": "11522647_T39", "type": "GENE-Y", "text": [ "epidermal growth factor receptor" ], "offsets": [ [ 67, 99 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "2889803_title", "type": "title", "text": [ "Benzodiazepine receptor binding of triazolobenzodiazepines in vivo: increased receptor number with low-dose alprazolam." ], "offsets": [ [ 0, 119 ] ] }, { "id": "2889803_abstract", "type": "abstract", "text": [ "Triazolobenzodiazepines are in clinical use as hypnotics and anxiolytics. We analyzed in vivo receptor binding and brain concentrations of alprazolam, triazolam, and estazolam. Drug concentrations measured in the cerebral cortex 1 h after administration were directly proportional to dose for all three compounds. In vivo receptor binding, as defined by the specific uptake of [3H]Ro15-1788, decreased with increasing doses of estazolam and triazolam, a finding indicating dose-related increases in receptor occupancy due to these compounds. Triazolam was substantially more potent, with an IC50 value of 16 ng/g, compared with 117 ng/g for estazolam. At higher doses of alprazolam (greater than 0.2 mg/kg), receptor binding by [3H]Ro15-1788, likewise decreased with increasing dose of the former drug. However, at lower doses of alprazolam (0.02-0.05 mg/kg), which resulted in cortex concentrations of 2-7 ng/g, receptor binding was increased above control values in cortex, hypothalamus, and hippocampus but not in several other brain regions. Binding returned to control values at doses of greater than or equal to 0.01 mg/kg. Similar results were obtained in time course studies. At 8 and 10 h after a dose of 1 mg/kg i.p., corresponding to cortex concentrations of 2.7-7 ng/g, receptor binding was increased compared with controls. Similarly, at 1, 2, and 3 h after a single dose of 0.05 mg/kg, corresponding to cortex concentrations of 3.7-5.8 ng/g, receptor binding was also increased. The apparent affinity of benzodiazepine receptors for clonazepam in mice receiving alprazolam (0.05 mg/kg) was unchanged from that in untreated control mice, an observation suggesting that low doses of alprazolam increased receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)" ], "offsets": [ [ 120, 1885 ] ] } ]

[ { "id": "2889803_T1", "type": "CHEMICAL", "text": [ "Triazolobenzodiazepines" ], "offsets": [ [ 120, 143 ] ], "normalized": [] }, { "id": "2889803_T2", "type": "CHEMICAL", "text": [ "alprazolam" ], "offsets": [ [ 259, 269 ] ], "normalized": [] }, { "id": "2889803_T3", "type": "CHEMICAL", "text": [ "triazolam" ], "offsets": [ [ 271, 280 ] ], "normalized": [] }, { "id": "2889803_T4", "type": "CHEMICAL", "text": [ "benzodiazepine" ], "offsets": [ [ 1638, 1652 ] ], "normalized": [] }, { "id": "2889803_T5", "type": "CHEMICAL", "text": [ "clonazepam" ], "offsets": [ [ 1667, 1677 ] ], "normalized": [] }, { "id": "2889803_T6", "type": "CHEMICAL", "text": [ "alprazolam" ], "offsets": [ [ 1696, 1706 ] ], "normalized": [] }, { "id": "2889803_T7", "type": "CHEMICAL", "text": [ "estazolam" ], "offsets": [ [ 286, 295 ] ], "normalized": [] }, { "id": "2889803_T8", "type": "CHEMICAL", "text": [ "alprazolam" ], "offsets": [ [ 1815, 1825 ] ], "normalized": [] }, { "id": "2889803_T9", "type": "CHEMICAL", "text": [ "[3H]Ro15-1788" ], "offsets": [ [ 497, 510 ] ], "normalized": [] }, { "id": "2889803_T10", "type": "CHEMICAL", "text": [ "estazolam" ], "offsets": [ [ 547, 556 ] ], "normalized": [] }, { "id": "2889803_T11", "type": "CHEMICAL", "text": [ "triazolam" ], "offsets": [ [ 561, 570 ] ], "normalized": [] }, { "id": "2889803_T12", "type": "CHEMICAL", "text": [ "Triazolam" ], "offsets": [ [ 662, 671 ] ], "normalized": [] }, { "id": "2889803_T13", "type": "CHEMICAL", "text": [ "estazolam" ], "offsets": [ [ 761, 770 ] ], "normalized": [] }, { "id": "2889803_T14", "type": "CHEMICAL", "text": [ "alprazolam" ], "offsets": [ [ 791, 801 ] ], "normalized": [] }, { "id": "2889803_T15", "type": "CHEMICAL", "text": [ "[3H]Ro15-1788" ], "offsets": [ [ 848, 861 ] ], "normalized": [] }, { "id": "2889803_T16", "type": "CHEMICAL", "text": [ "alprazolam" ], "offsets": [ [ 950, 960 ] ], "normalized": [] }, { "id": "2889803_T17", "type": "CHEMICAL", "text": [ "Benzodiazepine" ], "offsets": [ [ 0, 14 ] ], "normalized": [] }, { "id": "2889803_T18", "type": "CHEMICAL", "text": [ "alprazolam" ], "offsets": [ [ 108, 118 ] ], "normalized": [] }, { "id": "2889803_T19", "type": "CHEMICAL", "text": [ "triazolobenzodiazepines" ], "offsets": [ [ 35, 58 ] ], "normalized": [] }, { "id": "2889803_T20", "type": "GENE-N", "text": [ "benzodiazepine receptors" ], "offsets": [ [ 1638, 1662 ] ], "normalized": [] }, { "id": "2889803_T21", "type": "GENE-N", "text": [ "Benzodiazepine receptor" ], "offsets": [ [ 0, 23 ] ], "normalized": [] } ]

[]

[]

[ { "id": "2889803_0", "type": "DIRECT-REGULATOR", "arg1_id": "2889803_T19", "arg2_id": "2889803_T21", "normalized": [] }, { "id": "2889803_1", "type": "DIRECT-REGULATOR", "arg1_id": "2889803_T5", "arg2_id": "2889803_T20", "normalized": [] }, { "id": "2889803_2", "type": "ACTIVATOR", "arg1_id": "2889803_T8", "arg2_id": "2889803_T20", "normalized": [] } ]

[ { "id": "1327384_title", "type": "title", "text": [ "[3H]-RS-15385-197, a selective and high affinity radioligand for alpha 2-adrenoceptors: implications for receptor classification." ], "offsets": [ [ 0, 129 ] ] }, { "id": "1327384_abstract", "type": "abstract", "text": [ "1. RS-15385-197 is the most potent and selective alpha 2-adrenoceptor antagonist available. We have used [3H]-RS-15385-197 to define alpha 2-adrenoceptor subtypes. The binding of [3H]-RS-15385-197 to membranes of rat cerebral cortex, rat neonatal lung and human platelets was reversible, saturable and of high affinity. Saturation experiments indicated that [3H]-RS-15385-197 bound to a single population of sites in all 3 tissues with high affinity (0.08-0.14 nM). The density of sites labelled by [3H]-RS-15385-197 was greater in the cortex (275 fmol mg-1 protein) than in the neonate lung (174 fmol mg-1 protein) and human platelet (170 fmol mg-1 protein). The density of sites labelled with [3H]-RS-15385-197 in the cortex was significantly greater than that labelled with [3H]-yohimbine (121 fmol mg-1 protein). 2. The selective alpha 2-adrenoceptor antagonists, idazoxan, yohimbine, rauwolscine and WY 26703 displaced [3H]-RS-15385-197 binding to rat cerebral cortex in a simple manner with Hill slopes close to unity. The affinities derived for these antagonists against [3H]-RS-15385-197 were similar to the values obtained for the displacement of [3H]-yohimbine indicating the alpha 2-adrenoceptor nature of the binding site. 3. alpha 2A-Adrenoceptor selective compounds, oxymetazoline and BRL 44409, showed high affinity for [3H]-RS-15385-197 binding in the human platelet and lower affinity in the neonate lung, while the alpha 2B-selective compounds, prazosin and imiloxan, showed high affinity for [3H]-RS-15385-197 binding in the neonate lung.This suggests that [3H]-RS-15385-197 labels both alpha2A- and alpha2B-adrenoceptor subtypes.4. Prazosin and methysergide inhibited the binding of [3H]-RS-15385-197 in the rat cerebral cortex in a simple manner consistent with an interaction at a single site. Although oxymetazoline inhibited [H]-RS- 15385-197 with a Hill slope significantly different from unity, the slope was increased to unity in the presence of Gpp(NH)p, suggesting an agonist-like interaction.5. The site labelled by [3H]-RS-15385-197 in the rat cortex shows high affinity for oxymetazoline and low affinity for prazosin which could be taken as evidence for classifying the site as an alpha2A-subtype.However, the affinities of yohimbine, rauwolscine and oxymetazoline at this site do not correspond to the population of sites in the human platelet. Yohimbine and rauwolscine were 20 fold selective for the platelet alph2A-subtype, whereas phentolamine was 2 fold and imiloxan was 10 fold selective for the cortex subtype. Indeed although the site showed some similarities with the alpha2A-subtype, the highest degree of homology was observed between this site and the rat submaxillary gland and the RG20 clone,tentatively called the alpha2D-adrenoceptor subtype. We propose that the alpha2-adrenoceptor in the rat cortex may therefore correspond to the putative alpha2D-subtype of the adrenoceptor." ], "offsets": [ [ 130, 3058 ] ] } ]

[ { "id": "1327384_T1", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 235, 252 ] ], "normalized": [] }, { "id": "1327384_T2", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 1208, 1225 ] ], "normalized": [] }, { "id": "1327384_T3", "type": "CHEMICAL", "text": [ "[3H]-yohimbine" ], "offsets": [ [ 1286, 1300 ] ], "normalized": [] }, { "id": "1327384_T4", "type": "CHEMICAL", "text": [ "oxymetazoline" ], "offsets": [ [ 1411, 1424 ] ], "normalized": [] }, { "id": "1327384_T5", "type": "CHEMICAL", "text": [ "BRL 44409" ], "offsets": [ [ 1429, 1438 ] ], "normalized": [] }, { "id": "1327384_T6", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 1465, 1482 ] ], "normalized": [] }, { "id": "1327384_T7", "type": "CHEMICAL", "text": [ "prazosin" ], "offsets": [ [ 1593, 1601 ] ], "normalized": [] }, { "id": "1327384_T8", "type": "CHEMICAL", "text": [ "imiloxan" ], "offsets": [ [ 1606, 1614 ] ], "normalized": [] }, { "id": "1327384_T9", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 1641, 1658 ] ], "normalized": [] }, { "id": "1327384_T10", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 1706, 1723 ] ], "normalized": [] }, { "id": "1327384_T11", "type": "CHEMICAL", "text": [ "Prazosin" ], "offsets": [ [ 1782, 1790 ] ], "normalized": [] }, { "id": "1327384_T12", "type": "CHEMICAL", "text": [ "methysergide" ], "offsets": [ [ 1795, 1807 ] ], "normalized": [] }, { "id": "1327384_T13", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 1833, 1850 ] ], "normalized": [] }, { "id": "1327384_T14", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 309, 326 ] ], "normalized": [] }, { "id": "1327384_T15", "type": "CHEMICAL", "text": [ "oxymetazoline" ], "offsets": [ [ 1955, 1968 ] ], "normalized": [] }, { "id": "1327384_T16", "type": "CHEMICAL", "text": [ "[H]-RS- 15385-197" ], "offsets": [ [ 1979, 1996 ] ], "normalized": [] }, { "id": "1327384_T17", "type": "CHEMICAL", "text": [ "Gpp(NH)p" ], "offsets": [ [ 2103, 2111 ] ], "normalized": [] }, { "id": "1327384_T18", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 2176, 2193 ] ], "normalized": [] }, { "id": "1327384_T19", "type": "CHEMICAL", "text": [ "oxymetazoline" ], "offsets": [ [ 2236, 2249 ] ], "normalized": [] }, { "id": "1327384_T20", "type": "CHEMICAL", "text": [ "prazosin" ], "offsets": [ [ 2271, 2279 ] ], "normalized": [] }, { "id": "1327384_T21", "type": "CHEMICAL", "text": [ "yohimbine" ], "offsets": [ [ 2387, 2396 ] ], "normalized": [] }, { "id": "1327384_T22", "type": "CHEMICAL", "text": [ "rauwolscine" ], "offsets": [ [ 2398, 2409 ] ], "normalized": [] }, { "id": "1327384_T23", "type": "CHEMICAL", "text": [ "oxymetazoline" ], "offsets": [ [ 2414, 2427 ] ], "normalized": [] }, { "id": "1327384_T24", "type": "CHEMICAL", "text": [ "Yohimbine" ], "offsets": [ [ 2509, 2518 ] ], "normalized": [] }, { "id": "1327384_T25", "type": "CHEMICAL", "text": [ "rauwolscine" ], "offsets": [ [ 2523, 2534 ] ], "normalized": [] }, { "id": "1327384_T26", "type": "CHEMICAL", "text": [ "phentolamine" ], "offsets": [ [ 2599, 2611 ] ], "normalized": [] }, { "id": "1327384_T27", "type": "CHEMICAL", "text": [ "imiloxan" ], "offsets": [ [ 2627, 2635 ] ], "normalized": [] }, { "id": "1327384_T28", "type": "CHEMICAL", "text": [ "RS-15385-197" ], "offsets": [ [ 133, 145 ] ], "normalized": [] }, { "id": "1327384_T29", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 488, 505 ] ], "normalized": [] }, { "id": "1327384_T30", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 629, 646 ] ], "normalized": [] }, { "id": "1327384_T31", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 825, 842 ] ], "normalized": [] }, { "id": "1327384_T32", "type": "CHEMICAL", "text": [ "[3H]-yohimbine" ], "offsets": [ [ 907, 921 ] ], "normalized": [] }, { "id": "1327384_T33", "type": "CHEMICAL", "text": [ "idazoxan" ], "offsets": [ [ 998, 1006 ] ], "normalized": [] }, { "id": "1327384_T34", "type": "CHEMICAL", "text": [ "yohimbine" ], "offsets": [ [ 1008, 1017 ] ], "normalized": [] }, { "id": "1327384_T35", "type": "CHEMICAL", "text": [ "rauwolscine" ], "offsets": [ [ 1019, 1030 ] ], "normalized": [] }, { "id": "1327384_T36", "type": "CHEMICAL", "text": [ "WY 26703" ], "offsets": [ [ 1035, 1043 ] ], "normalized": [] }, { "id": "1327384_T37", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 1054, 1071 ] ], "normalized": [] }, { "id": "1327384_T38", "type": "CHEMICAL", "text": [ "[3H]-RS-15385-197" ], "offsets": [ [ 0, 17 ] ], "normalized": [] }, { "id": "1327384_T39", "type": "GENE-N", "text": [ "alpha 2-adrenoceptor" ], "offsets": [ [ 1316, 1336 ] ], "normalized": [] }, { "id": "1327384_T40", "type": "GENE-Y", "text": [ "alpha 2A-Adrenoceptor" ], "offsets": [ [ 1368, 1389 ] ], "normalized": [] }, { "id": "1327384_T41", "type": "GENE-N", "text": [ "alpha 2-adrenoceptor" ], "offsets": [ [ 263, 283 ] ], "normalized": [] }, { "id": "1327384_T42", "type": "GENE-N", "text": [ "alpha2A- and alpha2B" ], "offsets": [ [ 1736, 1756 ] ], "normalized": [] }, { "id": "1327384_T43", "type": "GENE-N", "text": [ "alpha2D-adrenoceptor" ], "offsets": [ [ 2893, 2913 ] ], "normalized": [] }, { "id": "1327384_T44", "type": "GENE-N", "text": [ "alpha2-adrenoceptor" ], "offsets": [ [ 2943, 2962 ] ], "normalized": [] }, { "id": "1327384_T45", "type": "GENE-N", "text": [ "alpha 2-adrenoceptor" ], "offsets": [ [ 179, 199 ] ], "normalized": [] }, { "id": "1327384_T46", "type": "GENE-N", "text": [ "alpha 2-adrenoceptor" ], "offsets": [ [ 964, 984 ] ], "normalized": [] }, { "id": "1327384_T47", "type": "GENE-N", "text": [ "alpha 2-adrenoceptors" ], "offsets": [ [ 65, 86 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23206862_title", "type": "title", "text": [ "Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile." ], "offsets": [ [ 0, 126 ] ] }, { "id": "23206862_abstract", "type": "abstract", "text": [ "Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain." ], "offsets": [ [ 127, 534 ] ] } ]

[ { "id": "23206862_T1", "type": "CHEMICAL", "text": [ "oxygen" ], "offsets": [ [ 296, 302 ] ], "normalized": [] }, { "id": "23206862_T2", "type": "CHEMICAL", "text": [ "benzimidazole" ], "offsets": [ [ 26, 39 ] ], "normalized": [] }, { "id": "23206862_T3", "type": "GENE-Y", "text": [ "NPY Y5" ], "offsets": [ [ 404, 410 ] ], "normalized": [] }, { "id": "23206862_T4", "type": "GENE-Y", "text": [ "NPY Y5 receptor" ], "offsets": [ [ 157, 172 ] ], "normalized": [] }, { "id": "23206862_T5", "type": "GENE-N", "text": [ "CYP450" ], "offsets": [ [ 191, 197 ] ], "normalized": [] }, { "id": "23206862_T6", "type": "GENE-Y", "text": [ "NPY Y5 receptor" ], "offsets": [ [ 70, 85 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23206862_0", "type": "ANTAGONIST", "arg1_id": "23206862_T2", "arg2_id": "23206862_T6", "normalized": [] } ]

[ { "id": "23123425_title", "type": "title", "text": [ "Dietary quercetin ameliorates nonalcoholic steatohepatitis induced by a high-fat diet in gerbils." ], "offsets": [ [ 0, 97 ] ] }, { "id": "23123425_abstract", "type": "abstract", "text": [ "Dietary quercetin is highly abundant in edible plants, which possesses a wide range of pharmacological properties. This study was to investigate hepatoprotective effects of quercetin in the nonalcoholic steatohepatitis (NASH) gerbils induced by a high-fat diet (HFD), and to evaluate its regulatory mechanism on hepatic inflammatory response. The gerbils were fed with HFD for 28 days to induce NASH. From 15th day to 28th day, the treated drugs were given daily to each animal, respectively. The lipid profiles and biochemical markers were determined at the end of the experiment. The expressions of Sirt1, NF-κB p65 and iNOS were detected by immunohistochemistry and Western blot analysis. The results showed that oral administration of quercetin at doses of 30-60 mg/kg to hyperlipidemia rats for 14 days were highly effective in decreasing the levels of serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). It could decrease lipid accumulation in the hepatocytes, and reduce serum levels of pro-inflammatory cytokines TNF-α and IL-6 via regulating the expressions of Sirt1, NF-κB p65 and iNOS. Thus, dietary quercetin had significant therapeutic benefits and could be explored as a potential promising candidate for the prevention of NASH." ], "offsets": [ [ 98, 1452 ] ] } ]

[ { "id": "23123425_T1", "type": "CHEMICAL", "text": [ "quercetin" ], "offsets": [ [ 1321, 1330 ] ], "normalized": [] }, { "id": "23123425_T2", "type": "CHEMICAL", "text": [ "quercetin" ], "offsets": [ [ 271, 280 ] ], "normalized": [] }, { "id": "23123425_T3", "type": "CHEMICAL", "text": [ "quercetin" ], "offsets": [ [ 837, 846 ] ], "normalized": [] }, { "id": "23123425_T4", "type": "CHEMICAL", "text": [ "quercetin" ], "offsets": [ [ 106, 115 ] ], "normalized": [] }, { "id": "23123425_T5", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 968, 979 ] ], "normalized": [] }, { "id": "23123425_T6", "type": "CHEMICAL", "text": [ "triglycerides" ], "offsets": [ [ 986, 999 ] ], "normalized": [] }, { "id": "23123425_T7", "type": "CHEMICAL", "text": [ "cholesterol" ], "offsets": [ [ 1030, 1041 ] ], "normalized": [] }, { "id": "23123425_T8", "type": "CHEMICAL", "text": [ "alanine" ], "offsets": [ [ 1051, 1058 ] ], "normalized": [] }, { "id": "23123425_T9", "type": "CHEMICAL", "text": [ "aspartate" ], "offsets": [ [ 1086, 1095 ] ], "normalized": [] }, { "id": "23123425_T10", "type": "CHEMICAL", "text": [ "quercetin" ], "offsets": [ [ 8, 17 ] ], "normalized": [] }, { "id": "23123425_T11", "type": "GENE-N", "text": [ "AST" ], "offsets": [ [ 1114, 1117 ] ], "normalized": [] }, { "id": "23123425_T12", "type": "GENE-N", "text": [ "cytokines" ], "offsets": [ [ 1221, 1230 ] ], "normalized": [] }, { "id": "23123425_T13", "type": "GENE-Y", "text": [ "TNF-α" ], "offsets": [ [ 1231, 1236 ] ], "normalized": [] }, { "id": "23123425_T14", "type": "GENE-Y", "text": [ "IL-6" ], "offsets": [ [ 1241, 1245 ] ], "normalized": [] }, { "id": "23123425_T15", "type": "GENE-N", "text": [ "Sirt1" ], "offsets": [ [ 1280, 1285 ] ], "normalized": [] }, { "id": "23123425_T16", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 1287, 1292 ] ], "normalized": [] }, { "id": "23123425_T17", "type": "GENE-N", "text": [ "p65" ], "offsets": [ [ 1293, 1296 ] ], "normalized": [] }, { "id": "23123425_T18", "type": "GENE-Y", "text": [ "iNOS" ], "offsets": [ [ 1301, 1305 ] ], "normalized": [] }, { "id": "23123425_T19", "type": "GENE-N", "text": [ "Sirt1" ], "offsets": [ [ 699, 704 ] ], "normalized": [] }, { "id": "23123425_T20", "type": "GENE-N", "text": [ "NF-κB" ], "offsets": [ [ 706, 711 ] ], "normalized": [] }, { "id": "23123425_T21", "type": "GENE-N", "text": [ "p65" ], "offsets": [ [ 712, 715 ] ], "normalized": [] }, { "id": "23123425_T22", "type": "GENE-Y", "text": [ "iNOS" ], "offsets": [ [ 720, 724 ] ], "normalized": [] }, { "id": "23123425_T23", "type": "GENE-N", "text": [ "low-density lipoprotein" ], "offsets": [ [ 1006, 1029 ] ], "normalized": [] }, { "id": "23123425_T24", "type": "GENE-N", "text": [ "LDL" ], "offsets": [ [ 1043, 1046 ] ], "normalized": [] }, { "id": "23123425_T25", "type": "GENE-N", "text": [ "alanine aminotransferase" ], "offsets": [ [ 1051, 1075 ] ], "normalized": [] }, { "id": "23123425_T26", "type": "GENE-N", "text": [ "ALT" ], "offsets": [ [ 1077, 1080 ] ], "normalized": [] }, { "id": "23123425_T27", "type": "GENE-N", "text": [ "aspartate aminotransferase" ], "offsets": [ [ 1086, 1112 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "17133434_title", "type": "title", "text": [ "Hormones and body size evolution in papionin primates." ], "offsets": [ [ 0, 54 ] ] }, { "id": "17133434_abstract", "type": "abstract", "text": [ "This study examines the evolution of size differences among papionin primates by measuring hormones that regulate size growth during ontogeny and influence ultimate adult size (insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3), growth hormone binding protein (GHBP), dehydroepiandrosterone sulfate (DHEAS), testosterone, estradiol). The analyses assess longstanding ideas about circulating hormone levels and body size. Importantly, because the consensus papionin molecular phylogeny implies at least two episodes of size increase, this study offers opportunities to determine whether or not similar hormone profiles regulate this apparent evolutionary convergence (i.e., do larger-bodied papionins have higher levels of growth-related hormones than smaller-bodied papionins?). Five hundred and sixty serum samples (from 161 individuals) from 11 papionin species were analyzed using a two-level approach to address this issue. One used mixed longitudinal samples from two papionin species to test whether, during growth, large- and small-bodied species have higher and lower hormone levels, respectively. The second compared multiple papionin species to assess whether or not hormone levels covary with size in adult animals. Result show that size and hormone levels do not covary consistently across papionins, either during growth or in adulthood. Specifically, some smaller-bodied papionin species have higher absolute hormone levels than larger-bodied species. Differences in some hormone levels appear to track phylogeny more closely than body size. In contrast to studies based on single species, we demonstrate that, while the hormones analyzed affect growth, absolute circulating hormone levels either during growth or adulthood may be decoupled from interspecific differences in body size." ], "offsets": [ [ 55, 1896 ] ] } ]

[ { "id": "17133434_T1", "type": "CHEMICAL", "text": [ "dehydroepiandrosterone sulfate" ], "offsets": [ [ 365, 395 ] ], "normalized": [] }, { "id": "17133434_T2", "type": "CHEMICAL", "text": [ "DHEAS" ], "offsets": [ [ 397, 402 ] ], "normalized": [] }, { "id": "17133434_T3", "type": "CHEMICAL", "text": [ "testosterone" ], "offsets": [ [ 405, 417 ] ], "normalized": [] }, { "id": "17133434_T4", "type": "CHEMICAL", "text": [ "estradiol" ], "offsets": [ [ 419, 428 ] ], "normalized": [] }, { "id": "17133434_T5", "type": "GENE-N", "text": [ "insulin-like growth factor-I" ], "offsets": [ [ 232, 260 ] ], "normalized": [] }, { "id": "17133434_T6", "type": "GENE-N", "text": [ "IGF-I" ], "offsets": [ [ 262, 267 ] ], "normalized": [] }, { "id": "17133434_T7", "type": "GENE-N", "text": [ "insulin-like growth factor binding protein-3" ], "offsets": [ [ 270, 314 ] ], "normalized": [] }, { "id": "17133434_T8", "type": "GENE-N", "text": [ "IGFBP-3" ], "offsets": [ [ 316, 323 ] ], "normalized": [] }, { "id": "17133434_T9", "type": "GENE-N", "text": [ "growth hormone binding protein" ], "offsets": [ [ 326, 356 ] ], "normalized": [] }, { "id": "17133434_T10", "type": "GENE-N", "text": [ "GHBP" ], "offsets": [ [ 358, 362 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "11120594_title", "type": "title", "text": [ "Cytokine production by naive and primary effector CD4+ T cells exposed to norepinephrine." ], "offsets": [ [ 0, 89 ] ] }, { "id": "11120594_abstract", "type": "abstract", "text": [ "We recently showed that clones of Th1 cells, but not Th2 cells, expressed a functional beta-2-adrenergic receptor (beta2AR) and that either norepinephrine or the beta2AR agonist terbutaline stimulated this receptor to modulate the level of Th1 cytokines produced. In the present study, we show that norepinephrine and terbutaline stimulate the beta2AR to decrease the level of IL-2 produced by freshly isolated murine splenic naive CD4+ T cells from either Balb/C or DO11.10 transgenic mice and activated polyclonally with anti-CD3 and anti-CD28 mAbs. In contrast, the level of cytokines produced by primary effector Th1 and Th2 cells were unaffected when norepinephrine, terbutaline, or cAMP analogs were added at the time of restimulation. These results suggest that a diversity exists among CD4+ T-cell subsets with respect to the level of adrenergic receptor expression, responsiveness to cAMP, stage of cell differentiation, or a combination of the above." ], "offsets": [ [ 90, 1050 ] ] } ]

[ { "id": "11120594_T1", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 230, 244 ] ], "normalized": [] }, { "id": "11120594_T2", "type": "CHEMICAL", "text": [ "terbutaline" ], "offsets": [ [ 268, 279 ] ], "normalized": [] }, { "id": "11120594_T3", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 389, 403 ] ], "normalized": [] }, { "id": "11120594_T4", "type": "CHEMICAL", "text": [ "terbutaline" ], "offsets": [ [ 408, 419 ] ], "normalized": [] }, { "id": "11120594_T5", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 746, 760 ] ], "normalized": [] }, { "id": "11120594_T6", "type": "CHEMICAL", "text": [ "terbutaline" ], "offsets": [ [ 762, 773 ] ], "normalized": [] }, { "id": "11120594_T7", "type": "CHEMICAL", "text": [ "cAMP" ], "offsets": [ [ 778, 782 ] ], "normalized": [] }, { "id": "11120594_T8", "type": "CHEMICAL", "text": [ "cAMP" ], "offsets": [ [ 983, 987 ] ], "normalized": [] }, { "id": "11120594_T9", "type": "CHEMICAL", "text": [ "norepinephrine" ], "offsets": [ [ 74, 88 ] ], "normalized": [] }, { "id": "11120594_T10", "type": "GENE-Y", "text": [ "beta2AR" ], "offsets": [ [ 205, 212 ] ], "normalized": [] }, { "id": "11120594_T11", "type": "GENE-Y", "text": [ "beta2AR" ], "offsets": [ [ 252, 259 ] ], "normalized": [] }, { "id": "11120594_T12", "type": "GENE-N", "text": [ "Th1 cytokines" ], "offsets": [ [ 330, 343 ] ], "normalized": [] }, { "id": "11120594_T13", "type": "GENE-Y", "text": [ "beta2AR" ], "offsets": [ [ 434, 441 ] ], "normalized": [] }, { "id": "11120594_T14", "type": "GENE-Y", "text": [ "IL-2" ], "offsets": [ [ 467, 471 ] ], "normalized": [] }, { "id": "11120594_T15", "type": "GENE-N", "text": [ "CD3" ], "offsets": [ [ 618, 621 ] ], "normalized": [] }, { "id": "11120594_T16", "type": "GENE-Y", "text": [ "CD28" ], "offsets": [ [ 631, 635 ] ], "normalized": [] }, { "id": "11120594_T17", "type": "GENE-N", "text": [ "cytokines" ], "offsets": [ [ 668, 677 ] ], "normalized": [] }, { "id": "11120594_T18", "type": "GENE-N", "text": [ "adrenergic receptor" ], "offsets": [ [ 933, 952 ] ], "normalized": [] }, { "id": "11120594_T19", "type": "GENE-Y", "text": [ "beta-2-adrenergic receptor" ], "offsets": [ [ 177, 203 ] ], "normalized": [] }, { "id": "11120594_T20", "type": "GENE-N", "text": [ "Cytokine" ], "offsets": [ [ 0, 8 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "23333640_title", "type": "title", "text": [ "The inhibition of HIF-2α on the ATM/Chk-2 pathway is involved in the promotion effect of arsenite on benzo(a)pyrene-induced cell transformation." ], "offsets": [ [ 0, 144 ] ] }, { "id": "23333640_abstract", "type": "abstract", "text": [ "Both arsenite and benzo(a)pyrene (BaP) are known human carcinogens. Studies on the mode-of-action of arsenite indicate that it can also act as co-carcinogen or as a cancer promoter, and that it can facilitate progression of cancers. Some studies on development of lung cancers have suggested a synergism between arsenite exposure and cigarette smoking. The mechanism of action for such an effect, however, remains obscure. In the present study, we investigated the effects of HIF-2α on arsenite- and BaP-induced cell malignant transformation as well as on signal transduction pathways in human bronchial epithelial (HBE) cells. The results show that arsenite accelerates the neoplastic transformation and migration of cells and enhances chromosomal aberrations induced by BaP. HIF-2α is involved in blocking the effects of arsenite in activating the ATM/Chk-2 pathway and in repair of DNA damage induced by BaP. Moreover, blocking of HIF-2α prevents the effects of arsenite on the neoplastic transformation, cell migration, and chromosomal aberrations caused by BaP. These results indicate that the repressive effect of HIF-2α on the ATM/Chk-2 pathway leads to genomic instability, which is involved in arsenite-accelerated, BaP-induced malignant transformation of HBE cells." ], "offsets": [ [ 145, 1420 ] ] } ]

[ { "id": "23333640_T1", "type": "CHEMICAL", "text": [ "arsenite" ], "offsets": [ [ 246, 254 ] ], "normalized": [] }, { "id": "23333640_T2", "type": "CHEMICAL", "text": [ "BaP" ], "offsets": [ [ 1207, 1210 ] ], "normalized": [] }, { "id": "23333640_T3", "type": "CHEMICAL", "text": [ "arsenite" ], "offsets": [ [ 1348, 1356 ] ], "normalized": [] }, { "id": "23333640_T4", "type": "CHEMICAL", "text": [ "BaP" ], "offsets": [ [ 1370, 1373 ] ], "normalized": [] }, { "id": "23333640_T5", "type": "CHEMICAL", "text": [ "benzo(a)pyrene" ], "offsets": [ [ 163, 177 ] ], "normalized": [] }, { "id": "23333640_T6", "type": "CHEMICAL", "text": [ "arsenite" ], "offsets": [ [ 457, 465 ] ], "normalized": [] }, { "id": "23333640_T7", "type": "CHEMICAL", "text": [ "BaP" ], "offsets": [ [ 179, 182 ] ], "normalized": [] }, { "id": "23333640_T8", "type": "CHEMICAL", "text": [ "arsenite" ], "offsets": [ [ 631, 639 ] ], "normalized": [] }, { "id": "23333640_T9", "type": "CHEMICAL", "text": [ "BaP" ], "offsets": [ [ 645, 648 ] ], "normalized": [] }, { "id": "23333640_T10", "type": "CHEMICAL", "text": [ "arsenite" ], "offsets": [ [ 150, 158 ] ], "normalized": [] }, { "id": "23333640_T11", "type": "CHEMICAL", "text": [ "arsenite" ], "offsets": [ [ 795, 803 ] ], "normalized": [] }, { "id": "23333640_T12", "type": "CHEMICAL", "text": [ "BaP" ], "offsets": [ [ 917, 920 ] ], "normalized": [] }, { "id": "23333640_T13", "type": "CHEMICAL", "text": [ "arsenite" ], "offsets": [ [ 968, 976 ] ], "normalized": [] }, { "id": "23333640_T14", "type": "CHEMICAL", "text": [ "BaP" ], "offsets": [ [ 1052, 1055 ] ], "normalized": [] }, { "id": "23333640_T15", "type": "CHEMICAL", "text": [ "arsenite" ], "offsets": [ [ 1110, 1118 ] ], "normalized": [] }, { "id": "23333640_T16", "type": "CHEMICAL", "text": [ "benzo(a)pyrene" ], "offsets": [ [ 101, 115 ] ], "normalized": [] }, { "id": "23333640_T17", "type": "CHEMICAL", "text": [ "arsenite" ], "offsets": [ [ 89, 97 ] ], "normalized": [] }, { "id": "23333640_T18", "type": "GENE-Y", "text": [ "HIF-2α" ], "offsets": [ [ 1265, 1271 ] ], "normalized": [] }, { "id": "23333640_T19", "type": "GENE-Y", "text": [ "ATM" ], "offsets": [ [ 1279, 1282 ] ], "normalized": [] }, { "id": "23333640_T20", "type": "GENE-Y", "text": [ "Chk-2" ], "offsets": [ [ 1283, 1288 ] ], "normalized": [] }, { "id": "23333640_T21", "type": "GENE-Y", "text": [ "HIF-2α" ], "offsets": [ [ 621, 627 ] ], "normalized": [] }, { "id": "23333640_T22", "type": "GENE-Y", "text": [ "HIF-2α" ], "offsets": [ [ 922, 928 ] ], "normalized": [] }, { "id": "23333640_T23", "type": "GENE-Y", "text": [ "ATM" ], "offsets": [ [ 995, 998 ] ], "normalized": [] }, { "id": "23333640_T24", "type": "GENE-Y", "text": [ "Chk-2" ], "offsets": [ [ 999, 1004 ] ], "normalized": [] }, { "id": "23333640_T25", "type": "GENE-Y", "text": [ "HIF-2α" ], "offsets": [ [ 1079, 1085 ] ], "normalized": [] }, { "id": "23333640_T26", "type": "GENE-Y", "text": [ "HIF-2α" ], "offsets": [ [ 18, 24 ] ], "normalized": [] }, { "id": "23333640_T27", "type": "GENE-Y", "text": [ "ATM" ], "offsets": [ [ 32, 35 ] ], "normalized": [] }, { "id": "23333640_T28", "type": "GENE-Y", "text": [ "Chk-2" ], "offsets": [ [ 36, 41 ] ], "normalized": [] } ]

[]

[]

[ { "id": "23333640_0", "type": "ACTIVATOR", "arg1_id": "23333640_T13", "arg2_id": "23333640_T23", "normalized": [] }, { "id": "23333640_1", "type": "ACTIVATOR", "arg1_id": "23333640_T13", "arg2_id": "23333640_T24", "normalized": [] } ]

[ { "id": "23523101_title", "type": "title", "text": [ "Activation of PPARγ is required for hydroxysafflor yellow A of Carthamus tinctorius to attenuate hepatic fibrosis induced by oxidative stress." ], "offsets": [ [ 0, 142 ] ] }, { "id": "23523101_abstract", "type": "abstract", "text": [ "Oxidative stress caused hepatic fibrosis by activating hepatic stellate cells (HSCs), which were implemented by depressing PPARγ activation. Hydroxysafflor yellow A (HSYA) as a nature active ingredient with antioxidant capacity was able to effectively attenuate oxidative stress mediated injury. So it will be very interesting to study effect of HSYA on HSCs activation and liver fibrosis, and reveal the role of PPARγ·CCl4 and H2O2 were used to mimic oxidative stress mediated hepatic injury in vitro and in vivo respectively. The anti-fibrosis effects of HSYA were evaluated and its mechanisms were disclosed by applying western blot, histopathological analysis, flow cytometry, RT-PCR and ELISA. Our results showed that HSCs activation and proliferation could be induced by oxidative stress, and the expressive levels of TGF-β1 and TIMP-1, the serum levels of ALT, AST, HA, LN, III-C and IV-C were also enhanced by oxidative stress, which is correlated with liver fibrosis (p<0.05 or p<0.01). HSYA was able to effectively inhibit oxidative stress mediated hepatic injury by increasing the activities of antioxidant enzymes, up regulating the expression of PPARγ and MMP-2, and down regulating the expression of TGF-β1 and TIMP-1, and reducing α-SMA level. The protective effect of HSYA can be significantly attenuated by GW9662 via blocking PPARγ (p<0.05 or p<0.01). Taken together, these results demonstrate that HSYA is able to significantly protect the liver from oxidative stress, which requires for HSYA to stimulate PPARγ activity, reduce cell proliferation and suppress ECM synthesis." ], "offsets": [ [ 143, 1737 ] ] } ]

[ { "id": "23523101_T1", "type": "CHEMICAL", "text": [ "HSYA" ], "offsets": [ [ 1427, 1431 ] ], "normalized": [] }, { "id": "23523101_T2", "type": "CHEMICAL", "text": [ "GW9662" ], "offsets": [ [ 1467, 1473 ] ], "normalized": [] }, { "id": "23523101_T3", "type": "CHEMICAL", "text": [ "Hydroxysafflor yellow A" ], "offsets": [ [ 284, 307 ] ], "normalized": [] }, { "id": "23523101_T4", "type": "CHEMICAL", "text": [ "HSYA" ], "offsets": [ [ 1560, 1564 ] ], "normalized": [] }, { "id": "23523101_T5", "type": "CHEMICAL", "text": [ "HSYA" ], "offsets": [ [ 1650, 1654 ] ], "normalized": [] }, { "id": "23523101_T6", "type": "CHEMICAL", "text": [ "HSYA" ], "offsets": [ [ 309, 313 ] ], "normalized": [] }, { "id": "23523101_T7", "type": "CHEMICAL", "text": [ "HSYA" ], "offsets": [ [ 489, 493 ] ], "normalized": [] }, { "id": "23523101_T8", "type": "CHEMICAL", "text": [ "CCl4" ], "offsets": [ [ 562, 566 ] ], "normalized": [] }, { "id": "23523101_T9", "type": "CHEMICAL", "text": [ "H2O2" ], "offsets": [ [ 571, 575 ] ], "normalized": [] }, { "id": "23523101_T10", "type": "CHEMICAL", "text": [ "HSYA" ], "offsets": [ [ 700, 704 ] ], "normalized": [] }, { "id": "23523101_T11", "type": "CHEMICAL", "text": [ "HSYA" ], "offsets": [ [ 1139, 1143 ] ], "normalized": [] }, { "id": "23523101_T12", "type": "CHEMICAL", "text": [ "hydroxysafflor yellow A" ], "offsets": [ [ 36, 59 ] ], "normalized": [] }, { "id": "23523101_T13", "type": "GENE-Y", "text": [ "PPARγ" ], "offsets": [ [ 1302, 1307 ] ], "normalized": [] }, { "id": "23523101_T14", "type": "GENE-Y", "text": [ "MMP-2" ], "offsets": [ [ 1312, 1317 ] ], "normalized": [] }, { "id": "23523101_T15", "type": "GENE-Y", "text": [ "TGF-β1" ], "offsets": [ [ 1357, 1363 ] ], "normalized": [] }, { "id": "23523101_T16", "type": "GENE-Y", "text": [ "TIMP-1" ], "offsets": [ [ 1368, 1374 ] ], "normalized": [] }, { "id": "23523101_T17", "type": "GENE-Y", "text": [ "PPARγ" ], "offsets": [ [ 266, 271 ] ], "normalized": [] }, { "id": "23523101_T18", "type": "GENE-Y", "text": [ "α-SMA" ], "offsets": [ [ 1389, 1394 ] ], "normalized": [] }, { "id": "23523101_T19", "type": "GENE-Y", "text": [ "PPARγ" ], "offsets": [ [ 1487, 1492 ] ], "normalized": [] }, { "id": "23523101_T20", "type": "GENE-Y", "text": [ "PPARγ" ], "offsets": [ [ 1668, 1673 ] ], "normalized": [] }, { "id": "23523101_T21", "type": "GENE-Y", "text": [ "PPARγ" ], "offsets": [ [ 556, 561 ] ], "normalized": [] }, { "id": "23523101_T22", "type": "GENE-Y", "text": [ "TGF-β1" ], "offsets": [ [ 967, 973 ] ], "normalized": [] }, { "id": "23523101_T23", "type": "GENE-Y", "text": [ "TIMP-1" ], "offsets": [ [ 978, 984 ] ], "normalized": [] }, { "id": "23523101_T24", "type": "GENE-N", "text": [ "ALT" ], "offsets": [ [ 1006, 1009 ] ], "normalized": [] }, { "id": "23523101_T25", "type": "GENE-N", "text": [ "AST" ], "offsets": [ [ 1011, 1014 ] ], "normalized": [] }, { "id": "23523101_T26", "type": "GENE-N", "text": [ "LN" ], "offsets": [ [ 1020, 1022 ] ], "normalized": [] }, { "id": "23523101_T27", "type": "GENE-Y", "text": [ "III-C" ], "offsets": [ [ 1024, 1029 ] ], "normalized": [] }, { "id": "23523101_T28", "type": "GENE-N", "text": [ "IV-C" ], "offsets": [ [ 1034, 1038 ] ], "normalized": [] }, { "id": "23523101_T29", "type": "GENE-Y", "text": [ "PPARγ" ], "offsets": [ [ 14, 19 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "12200198_title", "type": "title", "text": [ "Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes." ], "offsets": [ [ 0, 119 ] ] }, { "id": "12200198_abstract", "type": "abstract", "text": [ "In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT." ], "offsets": [ [ 120, 1677 ] ] } ]

[ { "id": "12200198_T1", "type": "CHEMICAL", "text": [ "Rasagiline" ], "offsets": [ [ 1138, 1148 ] ], "normalized": [] }, { "id": "12200198_T2", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 227, 235 ] ], "normalized": [] }, { "id": "12200198_T3", "type": "CHEMICAL", "text": [ "propargylamines" ], "offsets": [ [ 1359, 1374 ] ], "normalized": [] }, { "id": "12200198_T4", "type": "CHEMICAL", "text": [ "superoxide" ], "offsets": [ [ 1433, 1443 ] ], "normalized": [] }, { "id": "12200198_T5", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 1505, 1513 ] ], "normalized": [] }, { "id": "12200198_T6", "type": "CHEMICAL", "text": [ "Rasagiline" ], "offsets": [ [ 1523, 1533 ] ], "normalized": [] }, { "id": "12200198_T7", "type": "CHEMICAL", "text": [ "propargylamines" ], "offsets": [ [ 1546, 1561 ] ], "normalized": [] }, { "id": "12200198_T8", "type": "CHEMICAL", "text": [ "dopamine" ], "offsets": [ [ 1586, 1594 ] ], "normalized": [] }, { "id": "12200198_T9", "type": "CHEMICAL", "text": [ "monoamine" ], "offsets": [ [ 312, 321 ] ], "normalized": [] }, { "id": "12200198_T10", "type": "CHEMICAL", "text": [ "(-)deprenyl" ], "offsets": [ [ 339, 350 ] ], "normalized": [] }, { "id": "12200198_T11", "type": "CHEMICAL", "text": [ "selegiline" ], "offsets": [ [ 352, 362 ] ], "normalized": [] }, { "id": "12200198_T12", "type": "CHEMICAL", "text": [ "selegiline" ], "offsets": [ [ 512, 522 ] ], "normalized": [] }, { "id": "12200198_T13", "type": "CHEMICAL", "text": [ "selegiline" ], "offsets": [ [ 563, 573 ] ], "normalized": [] }, { "id": "12200198_T14", "type": "CHEMICAL", "text": [ "propargylamines" ], "offsets": [ [ 582, 597 ] ], "normalized": [] }, { "id": "12200198_T15", "type": "CHEMICAL", "text": [ "(R)(+)-N-propargyl-1-aminoindan" ], "offsets": [ [ 599, 630 ] ], "normalized": [] }, { "id": "12200198_T16", "type": "CHEMICAL", "text": [ "rasagiline" ], "offsets": [ [ 632, 642 ] ], "normalized": [] }, { "id": "12200198_T17", "type": "CHEMICAL", "text": [ "rasagiline" ], "offsets": [ [ 786, 796 ] ], "normalized": [] }, { "id": "12200198_T18", "type": "CHEMICAL", "text": [ "N-methyl(R)salsolinol" ], "offsets": [ [ 917, 938 ] ], "normalized": [] }, { "id": "12200198_T19", "type": "CHEMICAL", "text": [ "NM(R)Sal" ], "offsets": [ [ 940, 948 ] ], "normalized": [] }, { "id": "12200198_T20", "type": "CHEMICAL", "text": [ "NM(R)Sal" ], "offsets": [ [ 951, 959 ] ], "normalized": [] }, { "id": "12200198_T21", "type": "CHEMICAL", "text": [ "propargylamines" ], "offsets": [ [ 19, 34 ] ], "normalized": [] }, { "id": "12200198_T22", "type": "GENE-Y", "text": [ "Bcl-2" ], "offsets": [ [ 1246, 1251 ] ], "normalized": [] }, { "id": "12200198_T23", "type": "GENE-N", "text": [ "neurotrophic factor" ], "offsets": [ [ 1258, 1277 ] ], "normalized": [] }, { "id": "12200198_T24", "type": "GENE-Y", "text": [ "glial cell line-derived neurotrophic factor" ], "offsets": [ [ 1279, 1322 ] ], "normalized": [] }, { "id": "12200198_T25", "type": "GENE-Y", "text": [ "GDNF" ], "offsets": [ [ 1324, 1328 ] ], "normalized": [] }, { "id": "12200198_T26", "type": "GENE-N", "text": [ "superoxide dismutase" ], "offsets": [ [ 1433, 1453 ] ], "normalized": [] }, { "id": "12200198_T27", "type": "GENE-N", "text": [ "SOD" ], "offsets": [ [ 1455, 1458 ] ], "normalized": [] }, { "id": "12200198_T28", "type": "GENE-Y", "text": [ "catalase" ], "offsets": [ [ 1464, 1472 ] ], "normalized": [] }, { "id": "12200198_T29", "type": "GENE-Y", "text": [ "type B monoamine oxidase" ], "offsets": [ [ 305, 329 ] ], "normalized": [] }, { "id": "12200198_T30", "type": "GENE-Y", "text": [ "MAO-B" ], "offsets": [ [ 331, 336 ] ], "normalized": [] } ]

[]

[]

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