CORD-19-Sentences  

CORD-19:5e8abc62533a447422d5ead64d4ae4991cc99052 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
TextSentencer_T1 0-220 Sentence denotes Drug Design, Development and Therapy Dovepress Xyloketal B, a marine compound, acts on a network of molecular proteins and regulates the activity and expression of rat cytochrome P450 3a: a bioinformatic and animal study
T8924 0-220 Sentence denotes Drug Design, Development and Therapy Dovepress Xyloketal B, a marine compound, acts on a network of molecular proteins and regulates the activity and expression of rat cytochrome P450 3a: a bioinformatic and animal study
TextSentencer_T2 222-230 Sentence denotes Abstract
T56599 222-230 Sentence denotes Abstract
TextSentencer_T3 231-390 Sentence denotes Natural compounds are becoming popular for the treatment of illnesses and health promotion, but the mechanisms of action and safety profiles are often unknown.
T8869 231-390 Sentence denotes Natural compounds are becoming popular for the treatment of illnesses and health promotion, but the mechanisms of action and safety profiles are often unknown.
TextSentencer_T4 391-556 Sentence denotes Xyloketal B (XKB) is a novel marine compound isolated from the mangrove fungus Xylaria sp., with potent antioxidative, neuroprotective, and cardioprotective effects.
T66753 391-556 Sentence denotes Xyloketal B (XKB) is a novel marine compound isolated from the mangrove fungus Xylaria sp., with potent antioxidative, neuroprotective, and cardioprotective effects.
TextSentencer_T5 557-641 Sentence denotes However, its molecular targets and effects on drug-metabolizing enzymes are unknown.
T1723 557-641 Sentence denotes However, its molecular targets and effects on drug-metabolizing enzymes are unknown.
TextSentencer_T6 642-893 Sentence denotes This study aimed to investigate the potential molecular targets of XKB using bioinformatic approaches and to examine the effect of XKB on the expression and activity of rat cytochrome P450 3a (Cyp3a) subfamily members using midazolam as a model probe.
T31761 642-893 Sentence denotes This study aimed to investigate the potential molecular targets of XKB using bioinformatic approaches and to examine the effect of XKB on the expression and activity of rat cytochrome P450 3a (Cyp3a) subfamily members using midazolam as a model probe.
TextSentencer_T7 894-1179 Sentence denotes DDI-CPI, a server that can predict drug-drug interactions via the chemical-protein interactome, was employed to predict the targets of XKB, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to analyze the pathways of the predicted targets of XKB.
T98917 894-1179 Sentence denotes DDI-CPI, a server that can predict drug-drug interactions via the chemical-protein interactome, was employed to predict the targets of XKB, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to analyze the pathways of the predicted targets of XKB.
TextSentencer_T8 1180-1251 Sentence denotes Homology modeling was performed using the Discovery Studio program 3.1.
T62932 1180-1251 Sentence denotes Homology modeling was performed using the Discovery Studio program 3.1.
TextSentencer_T9 1252-1393 Sentence denotes The activity and expression of rat hepatic Cyp3a were examined after the rats were treated with XKB at 7 and 14 mg/kg for 8 consecutive days.
T72960 1252-1393 Sentence denotes The activity and expression of rat hepatic Cyp3a were examined after the rats were treated with XKB at 7 and 14 mg/kg for 8 consecutive days.
TextSentencer_T10 1394-1549 Sentence denotes Rat plasma concentrations of midazolam and its metabolite 1′-OH-midazolam were determined using a validated high-performance liquid chromatographic method.
T66218 1394-1549 Sentence denotes Rat plasma concentrations of midazolam and its metabolite 1′-OH-midazolam were determined using a validated high-performance liquid chromatographic method.
TextSentencer_T11 1550-1698 Sentence denotes Bioinformatic analysis showed that there were over 324 functional proteins and 61 related signaling pathways that were potentially regulated by XKB.
T6840 1550-1698 Sentence denotes Bioinformatic analysis showed that there were over 324 functional proteins and 61 related signaling pathways that were potentially regulated by XKB.
TextSentencer_T12 1699-1861 Sentence denotes A molecular docking study showed that XKB bound to the active site of human cytochrome P450 3A4 and rat Cyp3a2 homology model via the formation of hydrogen bonds.
T81464 1699-1861 Sentence denotes A molecular docking study showed that XKB bound to the active site of human cytochrome P450 3A4 and rat Cyp3a2 homology model via the formation of hydrogen bonds.
TextSentencer_T13 1862-2145 Sentence denotes The in vivo study showed that oral administration of XKB at 14 mg/kg to rats for 8 days significantly increased the area under the plasma concentration-time curve (AUC) of midazolam, with a concomitant decrease in the plasma clearance and AUC ratio of 1′-OH-midazolam over midazolam.
T88805 1862-2145 Sentence denotes The in vivo study showed that oral administration of XKB at 14 mg/kg to rats for 8 days significantly increased the area under the plasma concentration-time curve (AUC) of midazolam, with a concomitant decrease in the plasma clearance and AUC ratio of 1′-OH-midazolam over midazolam.
TextSentencer_T14 2146-2272 Sentence denotes Further, oral administration of 14 mg/kg XKB for 8 days markedly reduced the activity and expression of hepatic Cyp3a in rats.
T95381 2146-2272 Sentence denotes Further, oral administration of 14 mg/kg XKB for 8 days markedly reduced the activity and expression of hepatic Cyp3a in rats.
TextSentencer_T15 2273-2441 Sentence denotes Taken together, the results show that XKB could regulate networks of molecular proteins and related signaling pathways and that XKB downregulated hepatic Cyp3a in rats.
T61371 2273-2441 Sentence denotes Taken together, the results show that XKB could regulate networks of molecular proteins and related signaling pathways and that XKB downregulated hepatic Cyp3a in rats.
TextSentencer_T16 2442-2543 Sentence denotes XKB might cause drug interactions through modulation of the activity and expression of Cyp3a members.
T57455 2442-2543 Sentence denotes XKB might cause drug interactions through modulation of the activity and expression of Cyp3a members.
TextSentencer_T17 2544-2718 Sentence denotes More studies are warranted to confirm the mechanisms of action of XKB and to investigate the underlying mechanism for the regulating effect of XKB on Cyp3a subfamily members.
T48382 2544-2718 Sentence denotes More studies are warranted to confirm the mechanisms of action of XKB and to investigate the underlying mechanism for the regulating effect of XKB on Cyp3a subfamily members.
TextSentencer_T18 2719-2825 Sentence denotes Drug Design, Development and Therapy 2014:8 submit your manuscript | www.dovepress.com Dovepress Dovepress
T23808 2719-2825 Sentence denotes Drug Design, Development and Therapy 2014:8 submit your manuscript | www.dovepress.com Dovepress Dovepress
TextSentencer_T19 2826-2940 Sentence denotes Su et al pharmacological activity, 1 although there is limited or sparse clinical evidence for their applications.
T21863 2826-2940 Sentence denotes Su et al pharmacological activity, 1 although there is limited or sparse clinical evidence for their applications.
TextSentencer_T20 2941-3166 Sentence denotes In particular, there is a lack of data on molecular targets, mechanisms of action, pharmacokinetics (PKs, mainly focused on absorption, distribution, metabolism and excretion [ADME]), and toxicology for most natural products.
T19193 2941-3166 Sentence denotes In particular, there is a lack of data on molecular targets, mechanisms of action, pharmacokinetics (PKs, mainly focused on absorption, distribution, metabolism and excretion [ADME]), and toxicology for most natural products.
TextSentencer_T21 3167-3369 Sentence denotes 2,3 On the other hand, many of the natural products have the ability to regulate important drug-metabolizing enzymes and drug transporters, such as the cytochrome P450 enzymes (CYPs) and P-glycoprotein.
T14913 3167-3369 Sentence denotes 2,3 On the other hand, many of the natural products have the ability to regulate important drug-metabolizing enzymes and drug transporters, such as the cytochrome P450 enzymes (CYPs) and P-glycoprotein.
TextSentencer_T22 3370-3644 Sentence denotes This has raised a safety concern regarding the use of natural products due to their modulatory effect on the activity and expression of drug-metabolizing enzymes and drug transporters, resulting in potentially harmful drug interactions and eventually adverse drug reactions.
T72023 3370-3644 Sentence denotes This has raised a safety concern regarding the use of natural products due to their modulatory effect on the activity and expression of drug-metabolizing enzymes and drug transporters, resulting in potentially harmful drug interactions and eventually adverse drug reactions.
TextSentencer_T23 3645-3761 Sentence denotes 4 Human CYPs are a superfamily consisting of 57 functional genes that oxidize over 95% of the drugs in clinical use.
T5192 3645-3761 Sentence denotes 4 Human CYPs are a superfamily consisting of 57 functional genes that oxidize over 95% of the drugs in clinical use.
TextSentencer_T24 3762-3885 Sentence denotes 5,6 The human CYP3A subfamily contains four members, with CYP3A4 being the most abundant enzyme in the liver and intestine.
T99052 3762-3885 Sentence denotes 5,6 The human CYP3A subfamily contains four members, with CYP3A4 being the most abundant enzyme in the liver and intestine.
TextSentencer_T25 3886-4213 Sentence denotes 5 Importantly, CYP3A4/5 is predisposed to induction and inhibition when exposed to a number of endogenous and exogenous factors, probably resulting in an altered PK profile of the victim drug and adverse drug reactions, in particular, for those drugs with a narrow therapeutic index, such as digoxin, warfarin, and carboplatin.
T29141 3886-4213 Sentence denotes 5 Importantly, CYP3A4/5 is predisposed to induction and inhibition when exposed to a number of endogenous and exogenous factors, probably resulting in an altered PK profile of the victim drug and adverse drug reactions, in particular, for those drugs with a narrow therapeutic index, such as digoxin, warfarin, and carboplatin.
TextSentencer_T26 4214-4278 Sentence denotes 7,8 The rat Cyp3a subfamily contains Cyp3a1, 3a2, 3a9, and 3a62.
T32550 4214-4278 Sentence denotes 7,8 The rat Cyp3a subfamily contains Cyp3a1, 3a2, 3a9, and 3a62.
TextSentencer_T27 4279-4440 Sentence denotes Both rat Cyp3a1 and 3a2 have 72% identity in amino acid sequence to human CYP3A4 and share a lot of substrate specificity and inhibitor selectivity with CYP3A4.
T36839 4279-4440 Sentence denotes Both rat Cyp3a1 and 3a2 have 72% identity in amino acid sequence to human CYP3A4 and share a lot of substrate specificity and inhibitor selectivity with CYP3A4.
TextSentencer_T28 4441-4570 Sentence denotes 9,10 Cardiovascular disease (CVD), such as coronary heart disease and stroke, is the leading cause of death throughout the world.
T51225 4441-4570 Sentence denotes 9,10 Cardiovascular disease (CVD), such as coronary heart disease and stroke, is the leading cause of death throughout the world.
TextSentencer_T29 4571-4660 Sentence denotes About 17.3 million people died from CVD in 2008, accounting for 30% of all global deaths.
T15302 4571-4660 Sentence denotes About 17.3 million people died from CVD in 2008, accounting for 30% of all global deaths.
TextSentencer_T30 4661-4782 Sentence denotes 11, 12 Of these, about 7.3 million deaths resulted from coronary heart disease and 6.2 million deaths were due to stroke.
T79825 4661-4782 Sentence denotes 11, 12 Of these, about 7.3 million deaths resulted from coronary heart disease and 6.2 million deaths were due to stroke.
TextSentencer_T31 4783-4885 Sentence denotes 11,12 The incidence of CVD is increasing, exposing individuals, family, and society to a great burden.
T60934 4783-4885 Sentence denotes 11,12 The incidence of CVD is increasing, exposing individuals, family, and society to a great burden.
TextSentencer_T32 4886-5007 Sentence denotes The pathogenesis of CVD is complicated, and oxidative stress has been proposed to be a causal factor in the pathogenesis.
T23173 4886-5007 Sentence denotes The pathogenesis of CVD is complicated, and oxidative stress has been proposed to be a causal factor in the pathogenesis.
TextSentencer_T33 5008-5110 Sentence denotes 13,14 Reducing oxidative stress has been reported to be a promising strategy for the treatment of CVD.
T8231 5008-5110 Sentence denotes 13,14 Reducing oxidative stress has been reported to be a promising strategy for the treatment of CVD.
TextSentencer_T34 5111-5443 Sentence denotes 13 A number of natural products show potent antioxidative effects, and coadministration of natural products with cardiovascular drugs has gained increasing popularity because of these effects, although there is a lack of systematic preclinical and clinical data on their PKs, molecular targets, mechanisms of action, and toxicology.
T88860 5111-5443 Sentence denotes 13 A number of natural products show potent antioxidative effects, and coadministration of natural products with cardiovascular drugs has gained increasing popularity because of these effects, although there is a lack of systematic preclinical and clinical data on their PKs, molecular targets, mechanisms of action, and toxicology.
TextSentencer_T35 5444-5514 Sentence denotes 15, 16 Marine organisms are an attractive source for drug development.
T81198 5444-5514 Sentence denotes 15, 16 Marine organisms are an attractive source for drug development.
TextSentencer_T36 5515-5690 Sentence denotes Numerous compounds have been isolated from marine organisms, with a wide range of pharmacological activity, including antioxidative, anti-inflammatory, and anticancer effects.
T6052 5515-5690 Sentence denotes Numerous compounds have been isolated from marine organisms, with a wide range of pharmacological activity, including antioxidative, anti-inflammatory, and anticancer effects.
TextSentencer_T37 5691-5724 Sentence denotes 17-18 Xyloketal B (XKB, Figure 1)
T9339 5691-5724 Sentence denotes 17-18 Xyloketal B (XKB, Figure 1)
TextSentencer_T38 5726-5748 Sentence denotes Ketoconazole Midazolam
T28128 5726-5748 Sentence denotes Ketoconazole Midazolam
TextSentencer_T39 5749-5769 Sentence denotes Probucol Xyloketal B
T27691 5749-5769 Sentence denotes Probucol Xyloketal B
TextSentencer_T40 5770-6031 Sentence denotes Following target prediction, the Database for Annotation, Visualization and Integrated Discovery version 6.7 (DAVID, http://david.abcc.ncifcrf.gov/) was used to provide a biological functional interpretation of the potential targets of XKB derived from DDI-CPI.
T21928 5770-6031 Sentence denotes Following target prediction, the Database for Annotation, Visualization and Integrated Discovery version 6.7 (DAVID, http://david.abcc.ncifcrf.gov/) was used to provide a biological functional interpretation of the potential targets of XKB derived from DDI-CPI.
TextSentencer_T41 6032-6223 Sentence denotes The protein IDs of these targets from UniProtKB, National Center for Biotechnology Information, and other sources were converted into gene lists by using the Gene ID conversion tool in DAVID.
T26479 6032-6223 Sentence denotes The protein IDs of these targets from UniProtKB, National Center for Biotechnology Information, and other sources were converted into gene lists by using the Gene ID conversion tool in DAVID.
TextSentencer_T42 6224-6437 Sentence denotes DAVID adds biological function annotation including gene ontology, pathway, proteinprotein interactions, functional groups of genes (ie, clustering), and disease associations derived from main public data sources.
T38188 6224-6437 Sentence denotes DAVID adds biological function annotation including gene ontology, pathway, proteinprotein interactions, functional groups of genes (ie, clustering), and disease associations derived from main public data sources.
TextSentencer_T43 6438-6548 Sentence denotes The genes of interest were visualized using BioCarta and Kyoto Encyclopedia of Genes and Genomes pathway maps.
T8355 6438-6548 Sentence denotes The genes of interest were visualized using BioCarta and Kyoto Encyclopedia of Genes and Genomes pathway maps.
TextSentencer_T44 6549-6637 Sentence denotes The highest classification stringency was selected for functional annotation clustering.
T61473 6549-6637 Sentence denotes The highest classification stringency was selected for functional annotation clustering.
TextSentencer_T45 6638-6850 Sentence denotes Enrichment scores and Fisher's Exact test P-values (and the corresponding false discovery rate) were then calculated to identify which functional-related gene groups are significantly enriched in the target list.
T68854 6638-6850 Sentence denotes Enrichment scores and Fisher's Exact test P-values (and the corresponding false discovery rate) were then calculated to identify which functional-related gene groups are significantly enriched in the target list.
TextSentencer_T46 6851-6974 Sentence denotes These significant enriched gene groups could provide clues on how XKB interacts with molecular targets in a systematic way.
T90944 6851-6974 Sentence denotes These significant enriched gene groups could provide clues on how XKB interacts with molecular targets in a systematic way.
TextSentencer_T47 6975-7081 Sentence denotes Drug Design, Development and Therapy 2014:8 submit your manuscript | www.dovepress.com Dovepress Dovepress
T18118 6975-7081 Sentence denotes Drug Design, Development and Therapy 2014:8 submit your manuscript | www.dovepress.com Dovepress Dovepress
TextSentencer_T48 7082-7273 Sentence denotes Su et al and probucol, the duplicate chemical structures were deleted and ionization change, tautomer or isomer generation, Lipinski filter, and three-dimensional generator were all set true.
T354 7082-7273 Sentence denotes Su et al and probucol, the duplicate chemical structures were deleted and ionization change, tautomer or isomer generation, Lipinski filter, and three-dimensional generator were all set true.
TextSentencer_T49 7274-7427 Sentence denotes After ligand preparation, XKB, midazolam, ketoconazole, and probucol were docked into the active sites of the human CYP3A4 and rat Cyp3a2 homology model.
T44071 7274-7427 Sentence denotes After ligand preparation, XKB, midazolam, ketoconazole, and probucol were docked into the active sites of the human CYP3A4 and rat Cyp3a2 homology model.
TextSentencer_T50 7428-7517 Sentence denotes Electrostatic energy and van der Waals forces were considered during the docking process.
T63605 7428-7517 Sentence denotes Electrostatic energy and van der Waals forces were considered during the docking process.
TextSentencer_T51 7518-7615 Sentence denotes A harmonic potential with a force constant of 300 kcal/mol was applied outside the grid boundary.
T59709 7518-7615 Sentence denotes A harmonic potential with a force constant of 300 kcal/mol was applied outside the grid boundary.
TextSentencer_T52 7616-7618 Sentence denotes 28
T34164 7616-7618 Sentence denotes 28
TextSentencer_T53 7619-7696 Sentence denotes Prediction of ADME and toxicity of XKB, midazolam, ketoconazole, and probucol
T82578 7619-7696 Sentence denotes Prediction of ADME and toxicity of XKB, midazolam, ketoconazole, and probucol
TextSentencer_T54 7697-7862 Sentence denotes Using the Discovery Studio program 3.1 designed by Accelrys Inc, the ADME and toxicity (ADMET) profiles of XKB, midazolam, ketoconazole, and probucol were predicted.
T46643 7697-7862 Sentence denotes Using the Discovery Studio program 3.1 designed by Accelrys Inc, the ADME and toxicity (ADMET) profiles of XKB, midazolam, ketoconazole, and probucol were predicted.
TextSentencer_T55 7863-7996 Sentence denotes Briefly, the chemical structures of XKB, midazolam, ketoconazole, and probucol were retrieved from the PubChem database ( Figure 1 ).
T32581 7863-7996 Sentence denotes Briefly, the chemical structures of XKB, midazolam, ketoconazole, and probucol were retrieved from the PubChem database ( Figure 1 ).
TextSentencer_T56 7997-8079 Sentence denotes All the structures were introduced into the Discovery Studio program and prepared.
T43357 7997-8079 Sentence denotes All the structures were introduced into the Discovery Studio program and prepared.
TextSentencer_T57 8080-8292 Sentence denotes During preparation of these structures, the duplicate chemical structures were deleted and the ionization change, tautomer or isomer generation, Lipinski filter, and three-dimensional generator were all set true.
T16569 8080-8292 Sentence denotes During preparation of these structures, the duplicate chemical structures were deleted and the ionization change, tautomer or isomer generation, Lipinski filter, and three-dimensional generator were all set true.
TextSentencer_T58 8293-8443 Sentence denotes Following preparation of the structures, XKB, midazolam, ketoconazole, and probucol were subject to ADMET evaluation using the ADMET Predictor module.
T61792 8293-8443 Sentence denotes Following preparation of the structures, XKB, midazolam, ketoconazole, and probucol were subject to ADMET evaluation using the ADMET Predictor module.
TextSentencer_T59 8444-8618 Sentence denotes Parameters including solubility, absorption, permeability across the blood-brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding were predicted.
T77058 8444-8618 Sentence denotes Parameters including solubility, absorption, permeability across the blood-brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding were predicted.
TextSentencer_T60 8619-8767 Sentence denotes There are four different ADMET absorption levels, ranging from 0, 1, 2, to 3, indicating good, moderate, low, and very low absorption, respectively.
T26877 8619-8767 Sentence denotes There are four different ADMET absorption levels, ranging from 0, 1, 2, to 3, indicating good, moderate, low, and very low absorption, respectively.
TextSentencer_T61 8768-8813 Sentence denotes The ADMET aqueous solubility level is classi-
T52629 8768-8813 Sentence denotes The ADMET aqueous solubility level is classi-
TextSentencer_T62 8815-9135 Sentence denotes There is an increasing prevalence of natural products, including marine products, that are used to improve body function and manage various ailments due to their diverse is a novel marine compound isolated from the mangrove fungus Xylaria sp., and has potent antioxidative, neuroprotective, and cardioprotective effects.
T57095 8815-9135 Sentence denotes There is an increasing prevalence of natural products, including marine products, that are used to improve body function and manage various ailments due to their diverse is a novel marine compound isolated from the mangrove fungus Xylaria sp., and has potent antioxidative, neuroprotective, and cardioprotective effects.
TextSentencer_T63 9136-9306 Sentence denotes 19 , 20 We have found that XKB has a relaxing effect on blood vessels and protects endothelial cells against oxidative injury induced by oxidized low-density lipoprotein.
T20711 9136-9306 Sentence denotes 19 , 20 We have found that XKB has a relaxing effect on blood vessels and protects endothelial cells against oxidative injury induced by oxidized low-density lipoprotein.
TextSentencer_T64 9307-9466 Sentence denotes 10 It directly scavenged the free radical-generating compound 1,1-diphenyl-2-picrylhydrazyl and protected PC12 cells against oxygen-glucose deprivation injury.
T91661 9307-9466 Sentence denotes 10 It directly scavenged the free radical-generating compound 1,1-diphenyl-2-picrylhydrazyl and protected PC12 cells against oxygen-glucose deprivation injury.
TextSentencer_T65 9467-9537 Sentence denotes 9 Further, it has a strong inhibitory effect on the L-calcium channel.
T94852 9467-9537 Sentence denotes 9 Further, it has a strong inhibitory effect on the L-calcium channel.
TextSentencer_T66 9538-9690 Sentence denotes 21 The potent antioxidative effect of XKB suggests that it is a promising agent in the treatment of oxidative stress-associated conditions, such as CVD.
T9807 9538-9690 Sentence denotes 21 The potent antioxidative effect of XKB suggests that it is a promising agent in the treatment of oxidative stress-associated conditions, such as CVD.
TextSentencer_T67 9691-9809 Sentence denotes To establish the dose-response and dose-toxicity relationships of XKB, we investigated its metabolism and PKs in rats.
T17309 9691-9809 Sentence denotes To establish the dose-response and dose-toxicity relationships of XKB, we investigated its metabolism and PKs in rats.
TextSentencer_T68 9810-9925 Sentence denotes In vivo, the plasma PKs of XKB followed a two-compartment model with a distribution phase and an elimination phase.
T45977 9810-9925 Sentence denotes In vivo, the plasma PKs of XKB followed a two-compartment model with a distribution phase and an elimination phase.
TextSentencer_T69 9926-10071 Sentence denotes 22 XKB showed a short elimination half-life (22-27 minutes) , suggesting that it was rapidly distributed in the body and also rapidly eliminated.
T60173 9926-10071 Sentence denotes 22 XKB showed a short elimination half-life (22-27 minutes) , suggesting that it was rapidly distributed in the body and also rapidly eliminated.
TextSentencer_T70 10072-10209 Sentence denotes However, the molecular targets in response to XKB treatment and the effect of XKB on regulation of drug-metabolizing enzymes are unknown.
T33303 10072-10209 Sentence denotes However, the molecular targets in response to XKB treatment and the effect of XKB on regulation of drug-metabolizing enzymes are unknown.
TextSentencer_T71 10210-10583 Sentence denotes In the present study, in order to investigate the molecular targets of XKB, we predicted these targets using a bioinformatic platform, analyzed the interactions between XKB and rat Cyp3a2 using a homology model followed by molecular docking, and examined the effect of oral XKB on the activity and expression of hepatic Cyp3a in rats using midazolam as the model substrate.
T37612 10210-10583 Sentence denotes In the present study, in order to investigate the molecular targets of XKB, we predicted these targets using a bioinformatic platform, analyzed the interactions between XKB and rat Cyp3a2 using a homology model followed by molecular docking, and examined the effect of oral XKB on the activity and expression of hepatic Cyp3a in rats using midazolam as the model substrate.
TextSentencer_T72 10584-10741 Sentence denotes The interactome of XKB was predicted using the DDI-CPI tool, a web-based server that can predict drug-drug interactions via the chemical-protein interactome.
T25444 10584-10741 Sentence denotes The interactome of XKB was predicted using the DDI-CPI tool, a web-based server that can predict drug-drug interactions via the chemical-protein interactome.
TextSentencer_T73 10742-10839 Sentence denotes 23, 24 Protein targets were obtained from a third-party protein structure database named PDBbind.
T40748 10742-10839 Sentence denotes 23, 24 Protein targets were obtained from a third-party protein structure database named PDBbind.
TextSentencer_T74 10840-11088 Sentence denotes 25 There is a total of 1,780 Protein Data Bank (PDB) entries for human proteins available in PDBbind, and a total of 301 nonredundant PDBs corresponding to 353 ligand binding pockets were identified, 86% of which have resolutions of less than 2.5Å.
T88121 10840-11088 Sentence denotes 25 There is a total of 1,780 Protein Data Bank (PDB) entries for human proteins available in PDBbind, and a total of 301 nonredundant PDBs corresponding to 353 ligand binding pockets were identified, 86% of which have resolutions of less than 2.5Å.
TextSentencer_T75 11089-11273 Sentence denotes The docking boxes for each of the pockets were defined by expanding the circumscribed cube of the pocket with a margin of 8Å in six directions (up, down, front, back, left, and right).
T25483 11089-11273 Sentence denotes The docking boxes for each of the pockets were defined by expanding the circumscribed cube of the pocket with a margin of 8Å in six directions (up, down, front, back, left, and right).
TextSentencer_T76 11274-11367 Sentence denotes For preparation of XKB, the two-dimensional structure of the XKB was downloaded from PubChem.
T12527 11274-11367 Sentence denotes For preparation of XKB, the two-dimensional structure of the XKB was downloaded from PubChem.
TextSentencer_T77 11368-11473 Sentence denotes The hydrogen and Gasteiger charge were added and the file format was transformed into mol2 using Vega ZZ.
T15746 11368-11473 Sentence denotes The hydrogen and Gasteiger charge were added and the file format was transformed into mol2 using Vega ZZ.
TextSentencer_T78 11474-11607 Sentence denotes The docking program AutoDock 4.2 was used to dock the XKB molecule into all 353 pockets, generating a score vector of 353 dimensions.
T27122 11474-11607 Sentence denotes The docking program AutoDock 4.2 was used to dock the XKB molecule into all 353 pockets, generating a score vector of 353 dimensions.
TextSentencer_T79 11608-11679 Sentence denotes Z'-scores were then calculated using methodologies described elsewhere.
T71992 11608-11679 Sentence denotes Z'-scores were then calculated using methodologies described elsewhere.
TextSentencer_T80 11680-11828 Sentence denotes 23, 26, 27 Herein, an empirical threshold of -0.6 for the Z'-score was set to indicate that the binding of XKB to this target was likely to be true.
T96506 11680-11828 Sentence denotes 23, 26, 27 Herein, an empirical threshold of -0.6 for the Z'-score was set to indicate that the binding of XKB to this target was likely to be true.
TextSentencer_T81 11829-12094 Sentence denotes We employed the Discovery Studio program 3.1 designed by Accelrys Inc (San Diego, CA, USA) to dock XKB, midazolam, ketoconazole, and probucol into the active site of human CYP3A4 and rat Cyp3a2 homology model as previously described, 28 but with some modifications.
T63142 11829-12094 Sentence denotes We employed the Discovery Studio program 3.1 designed by Accelrys Inc (San Diego, CA, USA) to dock XKB, midazolam, ketoconazole, and probucol into the active site of human CYP3A4 and rat Cyp3a2 homology model as previously described, 28 but with some modifications.
TextSentencer_T82 12095-12293 Sentence denotes Due to the lack of availability of a crystal structure for rat hepatic Cyp3a2, we built a homology model based on the reported human CYP3A4 crystal structure (PDB ID 4K9W; http://www.rcsb.org/pdb/).
T38002 12095-12293 Sentence denotes Due to the lack of availability of a crystal structure for rat hepatic Cyp3a2, we built a homology model based on the reported human CYP3A4 crystal structure (PDB ID 4K9W; http://www.rcsb.org/pdb/).
TextSentencer_T83 12294-12534 Sentence denotes For the establishment of a homology model of rat hepatic Cyp3a2, we first retrieved the rat Cyp3a2 sequence from the National Center for Biotechnology Information (NCBI Reference Sequence NP_695224.2; http://www.ncbi.nlm.nih.gov/ protein/).
T99112 12294-12534 Sentence denotes For the establishment of a homology model of rat hepatic Cyp3a2, we first retrieved the rat Cyp3a2 sequence from the National Center for Biotechnology Information (NCBI Reference Sequence NP_695224.2; http://www.ncbi.nlm.nih.gov/ protein/).
TextSentencer_T84 12535-12608 Sentence denotes We aligned the rat Cyp3a2 sequence based on the template of human CYP3A4.
T29872 12535-12608 Sentence denotes We aligned the rat Cyp3a2 sequence based on the template of human CYP3A4.
TextSentencer_T85 12609-12751 Sentence denotes Following the establishment of this homology model, both the human CYP3A4 and rat Cyp3a2 homology models were cleaned, modified, and prepared.
T91035 12609-12751 Sentence denotes Following the establishment of this homology model, both the human CYP3A4 and rat Cyp3a2 homology models were cleaned, modified, and prepared.
TextSentencer_T86 12752-12805 Sentence denotes For the preparation for XKB, midazolam, ketoconazole,
T71675 12752-12805 Sentence denotes For the preparation for XKB, midazolam, ketoconazole,
TextSentencer_T87 12806-13046 Sentence denotes The animals were randomly divided into five groups (n=8) and treated intraperitoneally once daily with saline (blank control), soybean oil (vehicle), ketoconazole (75 mg/kg, positive control), or XKB (7 and 14 mg/kg) for 8 consecutive days.
T53626 12806-13046 Sentence denotes The animals were randomly divided into five groups (n=8) and treated intraperitoneally once daily with saline (blank control), soybean oil (vehicle), ketoconazole (75 mg/kg, positive control), or XKB (7 and 14 mg/kg) for 8 consecutive days.
TextSentencer_T88 13047-13113 Sentence denotes All animals had free access to standard laboratory food and water.
T45025 13047-13113 Sentence denotes All animals had free access to standard laboratory food and water.
TextSentencer_T89 13114-13220 Sentence denotes In order to reduce the intestinal contents, animals were fasted overnight before termination of the study.
T60773 13114-13220 Sentence denotes In order to reduce the intestinal contents, animals were fasted overnight before termination of the study.
TextSentencer_T90 13221-13300 Sentence denotes Midazolam 20 mg/kg was administered orally 12 hours after the last dose of XKB.
T22729 13221-13300 Sentence denotes Midazolam 20 mg/kg was administered orally 12 hours after the last dose of XKB.
TextSentencer_T91 13301-13453 Sentence denotes Blood samples were collected from the post ocular vein 0, 5, 15, 30, 45, 60, 90, 120, 180, 240 , 300, and 360 minutes after administration of midazolam.
T95754 13301-13453 Sentence denotes Blood samples were collected from the post ocular vein 0, 5, 15, 30, 45, 60, 90, 120, 180, 240 , 300, and 360 minutes after administration of midazolam.
TextSentencer_T92 13454-13592 Sentence denotes All blood samples were immediately centrifuged at 1,000× g for 10 minutes to obtain the plasma and stored at -20°C until further analysis.
T22272 13454-13592 Sentence denotes All blood samples were immediately centrifuged at 1,000× g for 10 minutes to obtain the plasma and stored at -20°C until further analysis.
TextSentencer_T93 13593-13761 Sentence denotes The animals were euthanized by cervical dislocation after blood collection, and liver samples were collected for further assessment of activity and expression of Cyp3a.
T4861 13593-13761 Sentence denotes The animals were euthanized by cervical dislocation after blood collection, and liver samples were collected for further assessment of activity and expression of Cyp3a.
TextSentencer_T94 13762-13821 Sentence denotes Rat liver microsomes were prepared as previously described.
T65637 13762-13821 Sentence denotes Rat liver microsomes were prepared as previously described.
TextSentencer_T95 13822-13990 Sentence denotes 29 Briefly, liver tissues were collected and washed with ice-cold KCl buffer (0.2 M, pH 7.4) until the tissues became pale or whitish, and then blotted dry and weighed.
T49531 13822-13990 Sentence denotes 29 Briefly, liver tissues were collected and washed with ice-cold KCl buffer (0.2 M, pH 7.4) until the tissues became pale or whitish, and then blotted dry and weighed.
TextSentencer_T96 13991-14034 Sentence denotes All subsequent steps were performed at 4°C.
T5265 13991-14034 Sentence denotes All subsequent steps were performed at 4°C.
TextSentencer_T97 14035-14152 Sentence denotes The liver samples were homogenized with three volumes of 0.05 M Tris⁄KCl buffer at pH 7.4 using a tissue homogenizer.
T31276 14035-14152 Sentence denotes The liver samples were homogenized with three volumes of 0.05 M Tris⁄KCl buffer at pH 7.4 using a tissue homogenizer.
TextSentencer_T98 14153-14224 Sentence denotes The liver homogenates were then centrifuged at 9,000× g for 30 minutes.
T57778 14153-14224 Sentence denotes The liver homogenates were then centrifuged at 9,000× g for 30 minutes.
TextSentencer_T99 14225-14308 Sentence denotes The supernatant was collected and centrifuged further at 105,000× g for 60 minutes.
T55347 14225-14308 Sentence denotes The supernatant was collected and centrifuged further at 105,000× g for 60 minutes.
TextSentencer_T100 14309-14494 Sentence denotes The supernatant was thereafter decanted and the microsomal pellets were resuspended in homogenization buffer and centrifuged again at 105,000× g for 60 minutes to remove the hemoglobin.
T7553 14309-14494 Sentence denotes The supernatant was thereafter decanted and the microsomal pellets were resuspended in homogenization buffer and centrifuged again at 105,000× g for 60 minutes to remove the hemoglobin.
TextSentencer_T101 14495-14690 Sentence denotes Rat liver microsomes were resuspended in 0.1 M sodium phosphate buffer (0.8 mM ethylenediamine tetraacetic acid, 1 mM dithiothreitol, and 20% glycerol; pH 7.4) and stored at -80°C until analysis.
T61916 14495-14690 Sentence denotes Rat liver microsomes were resuspended in 0.1 M sodium phosphate buffer (0.8 mM ethylenediamine tetraacetic acid, 1 mM dithiothreitol, and 20% glycerol; pH 7.4) and stored at -80°C until analysis.
TextSentencer_T102 14691-14881 Sentence denotes The protein concentration of each microsomal sample was determined using the bicinchoninic acid protein assay (Pierce Chemicals, Rockford, IL, USA) with bovine serum albumin as the standard.
T60534 14691-14881 Sentence denotes The protein concentration of each microsomal sample was determined using the bicinchoninic acid protein assay (Pierce Chemicals, Rockford, IL, USA) with bovine serum albumin as the standard.
TextSentencer_T103 14882-15027 Sentence denotes The plasma concentrations of midazolam and its metabolites 1′-OH-MDZ were measured by HPLC as previously described, 30 with slight modifications.
T64812 14882-15027 Sentence denotes The plasma concentrations of midazolam and its metabolites 1′-OH-MDZ were measured by HPLC as previously described, 30 with slight modifications.
TextSentencer_T104 15028-15576 Sentence denotes The HPLC method was validated prior to determination of the plasma PKs of midazolam as per the International Conference on Harmonization guidelines on validation of analytical procedures, including the specificity (ability to unequivocally determine the analyte), linearity (response curve of the analyte), lower limit of quantification (concentration of the analyte which has a signal to noise ratio of 3:1), precision and accuracy (results of repeatability), recovery (satisfactory accuracy and precision), and stability (degradation of analyte).
T43044 15028-15576 Sentence denotes The HPLC method was validated prior to determination of the plasma PKs of midazolam as per the International Conference on Harmonization guidelines on validation of analytical procedures, including the specificity (ability to unequivocally determine the analyte), linearity (response curve of the analyte), lower limit of quantification (concentration of the analyte which has a signal to noise ratio of 3:1), precision and accuracy (results of repeatability), recovery (satisfactory accuracy and precision), and stability (degradation of analyte).
TextSentencer_T105 15577-15703 Sentence denotes 2, 4 A 100 μL aliquot of plasma was diluted with 400 μL of 0.1 M NaOH, and diazepam 8 μg/mL was added as an internal standard.
T98903 15577-15703 Sentence denotes 2, 4 A 100 μL aliquot of plasma was diluted with 400 μL of 0.1 M NaOH, and diazepam 8 μg/mL was added as an internal standard.
TextSentencer_T106 15704-15823 Sentence denotes The mixture was extracted with 2.5 mL of dichloromethane and pentane (at a ratio of 3:7), then vortexed for 20 seconds.
T60247 15704-15823 Sentence denotes The mixture was extracted with 2.5 mL of dichloromethane and pentane (at a ratio of 3:7), then vortexed for 20 seconds.
TextSentencer_T107 15824-15932 Sentence denotes The upper organic phase was transferred into a clean glass tube and the residual liquid was extracted again.
T98552 15824-15932 Sentence denotes The upper organic phase was transferred into a clean glass tube and the residual liquid was extracted again.
TextSentencer_T108 15933-15991 Sentence denotes The upper organic phase mixture was evaporated to dryness.
T49098 15933-15991 Sentence denotes The upper organic phase mixture was evaporated to dryness.
TextSentencer_T109 15992-16199 Sentence denotes The dried residue was dissolved in 100 μL of mobile phase and centrifuged at 12,000× g for 10 minutes, and the supernatant was subjected to HPLC analysis and detected using an ultraviolet detector at 254 nm.
T21079 15992-16199 Sentence denotes The dried residue was dissolved in 100 μL of mobile phase and centrifuged at 12,000× g for 10 minutes, and the supernatant was subjected to HPLC analysis and detected using an ultraviolet detector at 254 nm.
TextSentencer_T110 16200-16343 Sentence denotes An HPLC system with a Shim-Pack 250 mm ×4.6 mm reverse phase column packed with 5 μm VP-ODS C 18 (Shimadzu Corporation, Tokyo, Japan) was used.
T75375 16200-16343 Sentence denotes An HPLC system with a Shim-Pack 250 mm ×4.6 mm reverse phase column packed with 5 μm VP-ODS C 18 (Shimadzu Corporation, Tokyo, Japan) was used.
TextSentencer_T111 16344-16383 Sentence denotes The column temperature was set at 40°C.
T293 16344-16383 Sentence denotes The column temperature was set at 40°C.
TextSentencer_T112 16384-16510 Sentence denotes The mobile phase was 10 mM ammonium acetate buffer (pH 4.5) and acetonitrile (63:37, v/v) at a flow rate of 1.0 mL per minute.
T94861 16384-16510 Sentence denotes The mobile phase was 10 mM ammonium acetate buffer (pH 4.5) and acetonitrile (63:37, v/v) at a flow rate of 1.0 mL per minute.
TextSentencer_T113 16511-16578 Sentence denotes All samples were analyzed within the validated stability timeframe.
T77334 16511-16578 Sentence denotes All samples were analyzed within the validated stability timeframe.
TextSentencer_T114 16579-16972 Sentence denotes Following determination of their plasma concentrations, the PK parameters of midazolam and 1′-OH-MDZ were calculated by single-compartmental analysis using the PKSlover program (China Pharmaceutical University, Nanjing, People's Republic of China), 31, 32 which is a freely available menu-driven add-in program for Microsoft Excel written in Visual Basic for Applications for PK data analysis.
T44269 16579-16972 Sentence denotes Following determination of their plasma concentrations, the PK parameters of midazolam and 1′-OH-MDZ were calculated by single-compartmental analysis using the PKSlover program (China Pharmaceutical University, Nanjing, People's Republic of China), 31, 32 which is a freely available menu-driven add-in program for Microsoft Excel written in Visual Basic for Applications for PK data analysis.
TextSentencer_T115 16973-17419 Sentence denotes The PK parameters calculated were the absorption rate constant (k a ), elimination rate constant (k e ), half-life of absorption (t 1/2ka ), half-life of elimination (t 1/2ke ), volume of distribution (V/F), body clearance (CL/F), maximum plasma concentration observed (C max ), time to reach C max (T max ), area under the plasma concentration-time curve (AUC 0-t ), AUC 0-inf , area under the first moment curve (AUMC), and mean residence time.
T22299 16973-17419 Sentence denotes The PK parameters calculated were the absorption rate constant (k a ), elimination rate constant (k e ), half-life of absorption (t 1/2ka ), half-life of elimination (t 1/2ke ), volume of distribution (V/F), body clearance (CL/F), maximum plasma concentration observed (C max ), time to reach C max (T max ), area under the plasma concentration-time curve (AUC 0-t ), AUC 0-inf , area under the first moment curve (AUMC), and mean residence time.
TextSentencer_T116 17420-17486 Sentence denotes The t 1/2ke was calculated using the formula t 1/2ke =0.693/ k e .
T60270 17420-17486 Sentence denotes The t 1/2ke was calculated using the formula t 1/2ke =0.693/ k e .
TextSentencer_T117 17487-17537 Sentence denotes The AUC was calculated using the trapezoidal rule.
T10304 17487-17537 Sentence denotes The AUC was calculated using the trapezoidal rule.
TextSentencer_T118 17538-17587 Sentence denotes CL was calculated by the formula CL/F = dose/AUC.
T73288 17538-17587 Sentence denotes CL was calculated by the formula CL/F = dose/AUC.
TextSentencer_T119 17588-17675 Sentence denotes The V/F following oral administration was calculated using the V/F = CL/F/k e equation.
T26166 17588-17675 Sentence denotes The V/F following oral administration was calculated using the V/F = CL/F/k e equation.
TextSentencer_T120 17676-17821 Sentence denotes The effect of XKB on rat hepatic Cyp3a activity was examined using the luminescent assay (P450-Glo) according to the manufacturer's instructions.
T82446 17676-17821 Sentence denotes The effect of XKB on rat hepatic Cyp3a activity was examined using the luminescent assay (P450-Glo) according to the manufacturer's instructions.
TextSentencer_T121 17822-17891 Sentence denotes Briefly, rat liver homogenates were prepared as described previously.
T92931 17822-17891 Sentence denotes Briefly, rat liver homogenates were prepared as described previously.
TextSentencer_T122 17892-18110 Sentence denotes 29 The reaction mixture (25 μL) was added to a 96-well microtiter plate containing microsomal protein (1 μg), Luciferin-IPA substrate (16 μM) , and 200 mM potassium phosphate buffer solution (pH 7.4), and mixed gently.
T95463 17892-18110 Sentence denotes 29 The reaction mixture (25 μL) was added to a 96-well microtiter plate containing microsomal protein (1 μg), Luciferin-IPA substrate (16 μM) , and 200 mM potassium phosphate buffer solution (pH 7.4), and mixed gently.
TextSentencer_T123 18111-18161 Sentence denotes The plate was preincubated at 37°C for 10 minutes.
T85768 18111-18161 Sentence denotes The plate was preincubated at 37°C for 10 minutes.
TextSentencer_T124 18162-18264 Sentence denotes The reaction was initiated by adding 25 μL NADPH and the mixture was incubated at 37°C for 10 minutes.
T70 18162-18264 Sentence denotes The reaction was initiated by adding 25 μL NADPH and the mixture was incubated at 37°C for 10 minutes.
TextSentencer_T125 18265-18345 Sentence denotes Next, 50 μL of reconstituted Luciferin detection reagent was added to all wells.
T17083 18265-18345 Sentence denotes Next, 50 μL of reconstituted Luciferin detection reagent was added to all wells.
TextSentencer_T126 18346-18410 Sentence denotes The reaction mixture was mixed on a plate shaker for 10 seconds.
T75071 18346-18410 Sentence denotes The reaction mixture was mixed on a plate shaker for 10 seconds.
TextSentencer_T127 18411-18463 Sentence denotes The plate was then incubated at 37°C for 20 minutes.
T8824 18411-18463 Sentence denotes The plate was then incubated at 37°C for 20 minutes.
TextSentencer_T128 18464-18516 Sentence denotes Cyp3a activity was examined by luminescence reading.
T28846 18464-18516 Sentence denotes Cyp3a activity was examined by luminescence reading.
TextSentencer_T129 18517-18591 Sentence denotes The relative Cyp3a activity was expressed as fold change over the control.
T3756 18517-18591 Sentence denotes The relative Cyp3a activity was expressed as fold change over the control.
TextSentencer_T130 18593-18703 Sentence denotes Western blotting was used to investigate the regulating effect of XKB on expression of Cyp3a in the rat liver.
T65756 18593-18703 Sentence denotes Western blotting was used to investigate the regulating effect of XKB on expression of Cyp3a in the rat liver.
TextSentencer_T131 18704-18830 Sentence denotes Briefly, rat liver microsomes (10 mg) were denatured at 95°C for 10 minutes then centrifuged at 9,000× g for 3 minutes at 4°C.
T56166 18704-18830 Sentence denotes Briefly, rat liver microsomes (10 mg) were denatured at 95°C for 10 minutes then centrifuged at 9,000× g for 3 minutes at 4°C.
TextSentencer_T132 18831-18972 Sentence denotes Protein samples were resolved in 12% sodium dodecyl sulfate-polyacrylamide gel and then transferred onto polyvinylidene difluoride membranes.
T2761 18831-18972 Sentence denotes Protein samples were resolved in 12% sodium dodecyl sulfate-polyacrylamide gel and then transferred onto polyvinylidene difluoride membranes.
TextSentencer_T133 18973-19159 Sentence denotes The membranes were blocked for one hour with 5% nonfat milk in Trisbuffered saline/0.1% Tween 20 buffer, followed by incubation overnight with their respective primary antibodies at 4°C.
T65891 18973-19159 Sentence denotes The membranes were blocked for one hour with 5% nonfat milk in Trisbuffered saline/0.1% Tween 20 buffer, followed by incubation overnight with their respective primary antibodies at 4°C.
TextSentencer_T134 19160-19297 Sentence denotes The membranes were then washed with Tris-buffered saline/0.1% Tween 20 buffer and incubated with secondary antibody for one hour at 37°C.
T26121 19160-19297 Sentence denotes The membranes were then washed with Tris-buffered saline/0.1% Tween 20 buffer and incubated with secondary antibody for one hour at 37°C.
TextSentencer_T135 19298-19387 Sentence denotes Signals were detected using the Clarity Western ECL substrate and Bio-Rad imaging system.
T60567 19298-19387 Sentence denotes Signals were detected using the Clarity Western ECL substrate and Bio-Rad imaging system.
TextSentencer_T136 19388-19495 Sentence denotes Quantification was performed using the ImageJ Analyzer 4.0 software Media (Cybernetics, Bethesda, MD, USA).
T84967 19388-19495 Sentence denotes Quantification was performed using the ImageJ Analyzer 4.0 software Media (Cybernetics, Bethesda, MD, USA).
TextSentencer_T137 19496-19637 Sentence denotes The relative expression level of Cyp3a2 in rat liver microsomes was expressed as the ratio of the intensity of Cyp3a2 blots to that of GAPDH.
T16406 19496-19637 Sentence denotes The relative expression level of Cyp3a2 in rat liver microsomes was expressed as the ratio of the intensity of Cyp3a2 blots to that of GAPDH.
TextSentencer_T138 19638-19694 Sentence denotes The data are expressed as the mean ± standard deviation.
T28518 19638-19694 Sentence denotes The data are expressed as the mean ± standard deviation.
TextSentencer_T139 19695-19803 Sentence denotes The PK parameters were compared using one-way analysis of variance, followed by Tukey's multiple comparison.
T92999 19695-19803 Sentence denotes The PK parameters were compared using one-way analysis of variance, followed by Tukey's multiple comparison.
TextSentencer_T140 19804-19869 Sentence denotes A value of P0.05 was considered to be statistically significant.
T42526 19804-19869 Sentence denotes A value of P0.05 was considered to be statistically significant.
TextSentencer_T141 19870-19952 Sentence denotes First, we predicted the molecular targets of XKB using our web-based DDI-CPI tool.
T27512 19870-19952 Sentence denotes First, we predicted the molecular targets of XKB using our web-based DDI-CPI tool.
TextSentencer_T142 19953-20570 Sentence denotes There were 324 proteins that possibly interacted with XKB (Table 1) , including those involved in redox homeostasis (eg, TXNRD1, PRDX2, TXN, RAC2, and GSTZ1), xenobiotic metabolism (eg, NR1I2, POR, ACAT1, CYB5R3, DPEP1, ADH7, and MTAP), cell proliferation (eg, LIMS1, SETD8, CLIC4, PIM1, and CHEK1), apoptosis (eg, CASP1, CASP3, CASP7, CASP8, PARP1, TRAF2, TNFRSF1A, and MAPK1), lipid metabolism (eg, FABP4, PPARA, and PPARD), signal transduction (eg, AKT1, CSNK2A1, CSNK1G2, IGF1R, GSK3B, RHOA, JAK2, JAK3, PDE5A, and RGS17), and immune and inflammatory response (eg, LILRB1, LCK, CD2, DPP4, IL1R1, CD81, and PDPK1).
T74560 19953-20570 Sentence denotes There were 324 proteins that possibly interacted with XKB (Table 1) , including those involved in redox homeostasis (eg, TXNRD1, PRDX2, TXN, RAC2, and GSTZ1), xenobiotic metabolism (eg, NR1I2, POR, ACAT1, CYB5R3, DPEP1, ADH7, and MTAP), cell proliferation (eg, LIMS1, SETD8, CLIC4, PIM1, and CHEK1), apoptosis (eg, CASP1, CASP3, CASP7, CASP8, PARP1, TRAF2, TNFRSF1A, and MAPK1), lipid metabolism (eg, FABP4, PPARA, and PPARD), signal transduction (eg, AKT1, CSNK2A1, CSNK1G2, IGF1R, GSK3B, RHOA, JAK2, JAK3, PDE5A, and RGS17), and immune and inflammatory response (eg, LILRB1, LCK, CD2, DPP4, IL1R1, CD81, and PDPK1).
TextSentencer_T143 20571-20860 Sentence denotes As shown in Table 2 , DAVID analysis identified 20 functional clusters that were significantly enriched (enrichment score 3) in the target list derived from molecular docking calculations, including energy metabolism, signal transduction, vascular regulation, and carbohydrate metabolism.
T6807 20571-20860 Sentence denotes As shown in Table 2 , DAVID analysis identified 20 functional clusters that were significantly enriched (enrichment score 3) in the target list derived from molecular docking calculations, including energy metabolism, signal transduction, vascular regulation, and carbohydrate metabolism.
TextSentencer_T144 20861-20992 Sentence denotes Further, 61 Kyoto Encyclopedia of Genes and Genomes pathways were found to be significantly enriched in the target list (Table 3 ).
T28232 20861-20992 Sentence denotes Further, 61 Kyoto Encyclopedia of Genes and Genomes pathways were found to be significantly enriched in the target list (Table 3 ).
TextSentencer_T145 20993-21133 Sentence denotes In particular, the pathways for metabolism of xenobiotics by CYPs and other enzymes were predicted to be modulated by XKB by DAVID analysis.
T49108 20993-21133 Sentence denotes In particular, the pathways for metabolism of xenobiotics by CYPs and other enzymes were predicted to be modulated by XKB by DAVID analysis.
TextSentencer_T146 21134-21401 Sentence denotes In addition, DAVID analysis revealed overlapped molecular targets between XKB and probucol (Table 4) , including CD1A, FKBP1A, PCTP, ME2, G6PD, FKBP1B, FABP7, CETP, PREP, PAK6, SIRT5, PRDX2, S100A9, SIRT5, F13A1, GM2A, CMA1, SORD, IMPDH2, GSTP1, CDA, CTSB, and GSTO1.
T5503 21134-21401 Sentence denotes In addition, DAVID analysis revealed overlapped molecular targets between XKB and probucol (Table 4) , including CD1A, FKBP1A, PCTP, ME2, G6PD, FKBP1B, FABP7, CETP, PREP, PAK6, SIRT5, PRDX2, S100A9, SIRT5, F13A1, GM2A, CMA1, SORD, IMPDH2, GSTP1, CDA, CTSB, and GSTO1.
TextSentencer_T147 21402-21548 Sentence denotes Probucol is an antihyperlipidemic drug originally developed for the treatment of coronary artery disease but withdrawn from the US market in 1995.
T84494 21402-21548 Sentence denotes Probucol is an antihyperlipidemic drug originally developed for the treatment of coronary artery disease but withdrawn from the US market in 1995.
TextSentencer_T148 21549-21667 Sentence denotes 33 The targets shared by both XKB and probucol suggest that XKB may be a promising agent for lowering of blood lipids.
T79592 21549-21667 Sentence denotes 33 The targets shared by both XKB and probucol suggest that XKB may be a promising agent for lowering of blood lipids.
TextSentencer_T149 21668-21906 Sentence denotes Given that we had predicted a number of molecular targets and related signaling pathways possibly regulated by XKB, we performed a validation study using published data after an extensive search via PubMed (from inception to August 2014).
T92805 21668-21906 Sentence denotes Given that we had predicted a number of molecular targets and related signaling pathways possibly regulated by XKB, we performed a validation study using published data after an extensive search via PubMed (from inception to August 2014).
TextSentencer_T150 21907-22219 Sentence denotes There were four published papers reporting the molecular targets and mechanisms of action of XKB. [34] [35] [36] [37] XKB reduced oxidative stress via induction of heme oxygenase-1 and suppression of NADPH oxidase activity involving the PI3K/Akt/Nrf2 signaling pathways in human umbilical vein endothelial cells.
T55240 21907-22219 Sentence denotes There were four published papers reporting the molecular targets and mechanisms of action of XKB. [34] [35] [36] [37] XKB reduced oxidative stress via induction of heme oxygenase-1 and suppression of NADPH oxidase activity involving the PI3K/Akt/Nrf2 signaling pathways in human umbilical vein endothelial cells.
TextSentencer_T151 22220-22549 Sentence denotes 37 In consistency with previous studies, [34] [35] [36] [37] our previous study also showed that XKB decreased the activity of NADPH oxidase and the expression of gp91phox and p47phox and that XKB increased the expression of Bcl-2 in human umbilical vein endothelial cells with injury induced by oxidized low-density lipoprotein.
T95284 22220-22549 Sentence denotes 37 In consistency with previous studies, [34] [35] [36] [37] our previous study also showed that XKB decreased the activity of NADPH oxidase and the expression of gp91phox and p47phox and that XKB increased the expression of Bcl-2 in human umbilical vein endothelial cells with injury induced by oxidized low-density lipoprotein.
TextSentencer_T152 22550-22725 Sentence denotes 34 XKB decreased mitochondrial superoxide, mitochondrial fragmentation, expression of GTPase dynamin-related protein 1, and the mitochondrial membrane potential in PC12 cells.
T2612 22550-22725 Sentence denotes 34 XKB decreased mitochondrial superoxide, mitochondrial fragmentation, expression of GTPase dynamin-related protein 1, and the mitochondrial membrane potential in PC12 cells.
TextSentencer_T153 22726-22862 Sentence denotes 35, 36 These data provided preliminary evidence for the validation of predicted molecular targets of XKB using a bioinformatic approach.
T34075 22726-22862 Sentence denotes 35, 36 These data provided preliminary evidence for the validation of predicted molecular targets of XKB using a bioinformatic approach.
TextSentencer_T154 22863-23180 Sentence denotes Following prediction and validation of the molecular targets, we examined the possible interactions between XKB, midazolam (a CYP3A4 probe substrate), ketoconazole (a CYP3A4 inhibitor), and probucol (an antihyperlipidemic drug) with a human CYP3A4 and rat Cyp3a2 homology model using the Discovery Studio program 3.1.
T23839 22863-23180 Sentence denotes Following prediction and validation of the molecular targets, we examined the possible interactions between XKB, midazolam (a CYP3A4 probe substrate), ketoconazole (a CYP3A4 inhibitor), and probucol (an antihyperlipidemic drug) with a human CYP3A4 and rat Cyp3a2 homology model using the Discovery Studio program 3.1.
TextSentencer_T155 23181-23200 Sentence denotes As shown in Table 5
T49307 23181-23200 Sentence denotes As shown in Table 5
TextSentencer_T156 23202-23340 Sentence denotes Tyrosine kinase plays an essential role in the selection and maturation of developing T-cells in the thymus and in mature T-cell function.
T2651 23202-23340 Sentence denotes Tyrosine kinase plays an essential role in the selection and maturation of developing T-cells in the thymus and in mature T-cell function.
TextSentencer_T157 23341-23504 Sentence denotes It is constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors and plays a key role in TCR-linked signal transduction pathways.
T57618 23341-23504 Sentence denotes It is constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors and plays a key role in TCR-linked signal transduction pathways.
TextSentencer_T158 23505-23746 Sentence denotes Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, and thereby recruits the associated LCK to the vicinity of the TCR/CD3 complex.
T57213 23505-23746 Sentence denotes Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, and thereby recruits the associated LCK to the vicinity of the TCR/CD3 complex.
TextSentencer_T159 23747-23953 Sentence denotes LCK then phosphorylates tyrosine residues within the immune receptor tyrosine-based activation motifs in the cytoplasmic tails of the TCR-γ chains and CD3 subunits, initiating the TCR/CD3 signaling pathway.
T94248 23747-23953 Sentence denotes LCK then phosphorylates tyrosine residues within the immune receptor tyrosine-based activation motifs in the cytoplasmic tails of the TCR-γ chains and CD3 subunits, initiating the TCR/CD3 signaling pathway.
TextSentencer_T160 23954-24023 Sentence denotes In addition, it contributes to signaling by other receptor molecules.
T76463 23954-24023 Sentence denotes In addition, it contributes to signaling by other receptor molecules.
TextSentencer_T161 24024-24172 Sentence denotes It associates directly with the cytoplasmic tail of CD2, and upon engagement of the CD2 molecule, LCK undergoes hyperphosphorylation and activation.
T46058 24024-24172 Sentence denotes It associates directly with the cytoplasmic tail of CD2, and upon engagement of the CD2 molecule, LCK undergoes hyperphosphorylation and activation.
TextSentencer_T162 24173-24287 Sentence denotes It also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response.
T64861 24173-24287 Sentence denotes It also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response.
TextSentencer_T163 24288-24357 Sentence denotes Binding of IL-2 to its receptor results in increased activity of LCK.
T12719 24288-24357 Sentence denotes Binding of IL-2 to its receptor results in increased activity of LCK.
TextSentencer_T164 24358-24515 Sentence denotes Is expressed at all stages of thymocyte development and is required for regulation of maturation events that are governed by both pre-TCR and mature α/β-TCR.
T89518 24358-24515 Sentence denotes Is expressed at all stages of thymocyte development and is required for regulation of maturation events that are governed by both pre-TCR and mature α/β-TCR.
TextSentencer_T165 24516-24532 Sentence denotes -34.776 -1.90347
T21536 24516-24532 Sentence denotes -34.776 -1.90347
TextSentencer_T166 24533-24739 Sentence denotes Fatty acid-binding protein, brain FABP7 B-FABP could be involved in the transport of a so far unknown hydrophobic ligand with potential morphogenic activity during development of the central nervous system.
T47552 24533-24739 Sentence denotes Fatty acid-binding protein, brain FABP7 B-FABP could be involved in the transport of a so far unknown hydrophobic ligand with potential morphogenic activity during development of the central nervous system.
TextSentencer_T167 24740-24945 Sentence denotes It is required for the establishment of the radial glial fiber system in the developing brain, a system that is necessary for the migration of immature neurons to establish cortical layers (by similarity).
T55945 24740-24945 Sentence denotes It is required for the establishment of the radial glial fiber system in the developing brain, a system that is necessary for the migration of immature neurons to establish cortical layers (by similarity).
TextSentencer_T168 24947-25094 Sentence denotes Thiol protease that cleaves IL-1β between an Asp and an Ala, releasing the mature cytokine that is involved in a variety of inflammatory processes.
T31577 24947-25094 Sentence denotes Thiol protease that cleaves IL-1β between an Asp and an Ala, releasing the mature cytokine that is involved in a variety of inflammatory processes.
TextSentencer_T169 25095-25135 Sentence denotes Important for defense against pathogens.
T93202 25095-25135 Sentence denotes Important for defense against pathogens.
TextSentencer_T170 25136-25200 Sentence denotes Cleaves and activates sterol regulatory elementbinding proteins.
T75508 25136-25200 Sentence denotes Cleaves and activates sterol regulatory elementbinding proteins.
TextSentencer_T171 25201-25228 Sentence denotes Can also promote apoptosis.
T2313 25201-25228 Sentence denotes Can also promote apoptosis.
TextSentencer_T172 25230-25276 Sentence denotes Insulin decreases blood glucose concentration.
T76684 25230-25276 Sentence denotes Insulin decreases blood glucose concentration.
TextSentencer_T173 25277-25357 Sentence denotes It increases cell permeability to monosaccharides, amino acids, and fatty acids.
T6156 25277-25357 Sentence denotes It increases cell permeability to monosaccharides, amino acids, and fatty acids.
TextSentencer_T174 25358-25446 Sentence denotes It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
T73193 25358-25446 Sentence denotes It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
TextSentencer_T175 25447-25574 Sentence denotes Binds to both poly-ubiquitin and mono-ubiquitin and regulates ligand-induced degradation of endothelial growth factor receptor.
T26039 25447-25574 Sentence denotes Binds to both poly-ubiquitin and mono-ubiquitin and regulates ligand-induced degradation of endothelial growth factor receptor.
TextSentencer_T176 25575-25621 Sentence denotes Participates in clathrin-mediated endocytosis.
T93718 25575-25621 Sentence denotes Participates in clathrin-mediated endocytosis.
TextSentencer_T177 25622-25710 Sentence denotes May be involved both in adult synaptic function and plasticity and in brain development.
T16290 25622-25710 Sentence denotes May be involved both in adult synaptic function and plasticity and in brain development.
TextSentencer_T178 25711-25752 Sentence denotes 1O6L RAC-β serine/threonineprotein kinase
T16150 25711-25752 Sentence denotes 1O6L RAC-β serine/threonineprotein kinase
TextSentencer_T179 25753-25826 Sentence denotes General protein kinase capable of phosphorylating several known proteins.
T80194 25753-25826 Sentence denotes General protein kinase capable of phosphorylating several known proteins.
TextSentencer_T180 25828-25941 Sentence denotes Receptor for brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 but not nerve growth factor.
T43787 25828-25941 Sentence denotes Receptor for brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 but not nerve growth factor.
TextSentencer_T181 25942-26011 Sentence denotes Involved in the development and/or maintenance of the nervous system.
T6219 25942-26011 Sentence denotes Involved in the development and/or maintenance of the nervous system.
TextSentencer_T182 26012-26047 Sentence denotes This is a tyrosine kinase receptor.
T7586 26012-26047 Sentence denotes This is a tyrosine kinase receptor.
TextSentencer_T183 26048-26127 Sentence denotes Known substrates for the tyrosine kinase receptors are SHC1, PI3K, and PLC-γ-1.
T5020 26048-26127 Sentence denotes Known substrates for the tyrosine kinase receptors are SHC1, PI3K, and PLC-γ-1.
TextSentencer_T184 26128-26174 Sentence denotes 1DFv Neutrophil gelatinaseassociated lipocalin
T86977 26128-26174 Sentence denotes 1DFv Neutrophil gelatinaseassociated lipocalin
TextSentencer_T185 26175-26289 Sentence denotes Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity, and renal development.
T18507 26175-26289 Sentence denotes Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity, and renal development.
TextSentencer_T186 26290-26501 Sentence denotes Binds iron through association with 2,5-dihydroxybenzoic acid, a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell, depending on the context.
T5043 26290-26501 Sentence denotes Binds iron through association with 2,5-dihydroxybenzoic acid, a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell, depending on the context.
TextSentencer_T187 26502-26685 Sentence denotes Iron-bound form (holo-24p3) is internalized following binding to the SLC22A17 (24p3R) receptor, leading to release of iron and subsequent increase of intracellular iron concentration.
T74537 26502-26685 Sentence denotes Iron-bound form (holo-24p3) is internalized following binding to the SLC22A17 (24p3R) receptor, leading to release of iron and subsequent increase of intracellular iron concentration.
TextSentencer_T188 26686-26954 Sentence denotes In contrast, association of the iron-free form (apo-24p3) with the SLC22A17 (24p3R) receptor is followed by association with an intracellular siderophore, iron chelation, and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration.
T36358 26686-26954 Sentence denotes In contrast, association of the iron-free form (apo-24p3) with the SLC22A17 (24p3R) receptor is followed by association with an intracellular siderophore, iron chelation, and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration.
TextSentencer_T189 26955-27233 Sentence denotes Involved in apoptosis due to IL-3 deprivation: iron-loaded form increases intracellular iron concentration without promoting apoptosis, while iron-free form decreases intracellular iron levels, inducing expression of the proapoptotic protein BCL2L11/BIM, resulting in apoptosis.
T28860 26955-27233 Sentence denotes Involved in apoptosis due to IL-3 deprivation: iron-loaded form increases intracellular iron concentration without promoting apoptosis, while iron-free form decreases intracellular iron levels, inducing expression of the proapoptotic protein BCL2L11/BIM, resulting in apoptosis.
TextSentencer_T190 27234-27336 Sentence denotes Involved in innate immunity, possibly by sequestering iron, leading to limitation of bacterial growth.
T17900 27234-27336 Sentence denotes Involved in innate immunity, possibly by sequestering iron, leading to limitation of bacterial growth.
TextSentencer_T191 27338-27616 Sentence denotes The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent γ-carboxylation of glutamate residues in prothrombin synthesis.
T46147 27338-27616 Sentence denotes The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent γ-carboxylation of glutamate residues in prothrombin synthesis.
TextSentencer_T192 27618-27746 Sentence denotes Rate-limiting enzyme in the de novo synthesis of guanine nucleotides and therefore is involved in the regulation of cell growth.
T18814 27618-27746 Sentence denotes Rate-limiting enzyme in the de novo synthesis of guanine nucleotides and therefore is involved in the regulation of cell growth.
TextSentencer_T193 27747-27846 Sentence denotes It may also have a role in the development of malignancy and the growth progression of some tumors.
T75044 27747-27846 Sentence denotes It may also have a role in the development of malignancy and the growth progression of some tumors.
TextSentencer_T194 27847-27864 Sentence denotes -37.7123 -1.26732
T40657 27847-27864 Sentence denotes -37.7123 -1.26732
TextSentencer_T195 27865-27907 Sentence denotes Corticosteroid 11-βdehydrogenase isozyme 1
T11542 27865-27907 Sentence denotes Corticosteroid 11-βdehydrogenase isozyme 1
TextSentencer_T196 27908-27993 Sentence denotes Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone.
T23232 27908-27993 Sentence denotes Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone.
TextSentencer_T197 27994-28077 Sentence denotes Catalyzes reversibly the conversion of 7-ketocholesterol to 7-β-hydroxycholesterol.
T85048 27994-28077 Sentence denotes Catalyzes reversibly the conversion of 7-ketocholesterol to 7-β-hydroxycholesterol.
TextSentencer_T198 28078-28201 Sentence denotes In intact cells, the reaction runs only in one direction, from 7-ketocholesterol to 7-β-hydroxycholesterol (by similarity).
T89595 28078-28201 Sentence denotes In intact cells, the reaction runs only in one direction, from 7-ketocholesterol to 7-β-hydroxycholesterol (by similarity).
TextSentencer_T199 28202-28248 Sentence denotes Can degrade neurotoxic organophosphate esters.
T81199 28202-28248 Sentence denotes Can degrade neurotoxic organophosphate esters.
TextSentencer_T200 28250-28364 Sentence denotes Serum protease that plays an important role in the activation of the complement system via mannose-binding lectin.
T49554 28250-28364 Sentence denotes Serum protease that plays an important role in the activation of the complement system via mannose-binding lectin.
TextSentencer_T201 28365-28492 Sentence denotes After activation by autocatalytic cleavage it cleaves C2 and C4, leading to their activation and to formation of C3 convertase.
T75261 28365-28492 Sentence denotes After activation by autocatalytic cleavage it cleaves C2 and C4, leading to their activation and to formation of C3 convertase.
TextSentencer_T202 28493-28558 Sentence denotes LGALS4 Galectin that binds lactose and a related range of sugars.
T31769 28493-28558 Sentence denotes LGALS4 Galectin that binds lactose and a related range of sugars.
TextSentencer_T203 28559-28613 Sentence denotes May be involved in the assembly of adherens junctions.
T55932 28559-28613 Sentence denotes May be involved in the assembly of adherens junctions.
TextSentencer_T204 28615-28732 Sentence denotes Cell surface glycoprotein receptor involved in the costimulatory signal essential for TCR-mediated T-cell activation.
T38059 28615-28732 Sentence denotes Cell surface glycoprotein receptor involved in the costimulatory signal essential for TCR-mediated T-cell activation.
TextSentencer_T205 28733-28835 Sentence denotes Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAv1, IGF-2R, and PTPRC.
T52785 28733-28835 Sentence denotes Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAv1, IGF-2R, and PTPRC.
TextSentencer_T206 28836-28959 Sentence denotes Its binding to CAv1 and CARD11 induces T-cell proliferation and NF-κB activation in a T-cell receptor/CD3-dependent manner.
T36581 28836-28959 Sentence denotes Its binding to CAv1 and CARD11 induces T-cell proliferation and NF-κB activation in a T-cell receptor/CD3-dependent manner.
TextSentencer_T207 28960-29036 Sentence denotes Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion.
T30058 28960-29036 Sentence denotes Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion.
TextSentencer_T208 29037-29216 Sentence denotes In association with FAP is involved in the pericellular proteolysis of the extracellular matrix, and the migration and invasion of endothelial cells into the extracellular matrix.
T22864 29037-29216 Sentence denotes In association with FAP is involved in the pericellular proteolysis of the extracellular matrix, and the migration and invasion of endothelial cells into the extracellular matrix.
TextSentencer_T209 29217-29320 Sentence denotes May be involved in the promotion of lymphatic endothelial cell adhesion, migration, and tube formation.
T23279 29217-29320 Sentence denotes May be involved in the promotion of lymphatic endothelial cell adhesion, migration, and tube formation.
TextSentencer_T210 29321-29398 Sentence denotes When overexpressed, enhances cell proliferation, a process inhibited by GPC3.
T84892 29321-29398 Sentence denotes When overexpressed, enhances cell proliferation, a process inhibited by GPC3.
TextSentencer_T211 29399-29646 Sentence denotes Acts also as a serine exopeptidase with dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides, and peptide hormones.
T43545 29399-29646 Sentence denotes Acts also as a serine exopeptidase with dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides, and peptide hormones.
TextSentencer_T212 29647-29788 Sentence denotes Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline.
T75928 29647-29788 Sentence denotes Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline.
TextSentencer_T213 29790-29927 Sentence denotes Required for high-affinity binding to nerve growth factor, neurotrophin-3 and neurotrophin-4/5 but not brain-derived neurotrophic factor.
T72513 29790-29927 Sentence denotes Required for high-affinity binding to nerve growth factor, neurotrophin-3 and neurotrophin-4/5 but not brain-derived neurotrophic factor.
TextSentencer_T214 29928-30007 Sentence denotes Known substrates for the tyrosine kinase receptors are SHC1, PI3K, and PLC-γ-1.
T94352 29928-30007 Sentence denotes Known substrates for the tyrosine kinase receptors are SHC1, PI3K, and PLC-γ-1.
TextSentencer_T215 30008-30155 Sentence denotes Has a crucial role in the development and function of the nociceptive reception system as well as establishment of thermal regulation via sweating.
T97053 30008-30155 Sentence denotes Has a crucial role in the development and function of the nociceptive reception system as well as establishment of thermal regulation via sweating.
TextSentencer_T216 30156-30235 Sentence denotes Activates Erk1 by either SHC1-dependent or PLC-γ-1-dependent signaling pathway.
T99136 30156-30235 Sentence denotes Activates Erk1 by either SHC1-dependent or PLC-γ-1-dependent signaling pathway.
TextSentencer_T217 30237-30297 Sentence denotes Removes the amino-terminal methionine from nascent proteins.
T36960 30237-30297 Sentence denotes Removes the amino-terminal methionine from nascent proteins.
TextSentencer_T218 30298-30353 Sentence denotes Required for normal progression through the cell cycle.
T9350 30298-30353 Sentence denotes Required for normal progression through the cell cycle.
TextSentencer_T219 30354-30370 Sentence denotes -35.184 -1.04139
T21476 30354-30370 Sentence denotes -35.184 -1.04139
TextSentencer_T220 30371-30385 Sentence denotes Interleukin-10
T77491 30371-30385 Sentence denotes Interleukin-10
TextSentencer_T221 30386-30585 Sentence denotes Inhibits the synthesis of a number of cytokines, including interferon-γ, IL-2, IL-3, TNF, and granulocyte-macrophage colony-stimulating factor produced by activated macrophages and by helper T-cells.
T89442 30386-30585 Sentence denotes Inhibits the synthesis of a number of cytokines, including interferon-γ, IL-2, IL-3, TNF, and granulocyte-macrophage colony-stimulating factor produced by activated macrophages and by helper T-cells.
TextSentencer_T222 30586-30602 Sentence denotes 1B2T Fractalkine
T1284 30586-30602 Sentence denotes 1B2T Fractalkine
TextSentencer_T223 30603-30686 Sentence denotes The soluble form is chemotactic for T-cells and monocytes, but not for neutrophils.
T39900 30603-30686 Sentence denotes The soluble form is chemotactic for T-cells and monocytes, but not for neutrophils.
TextSentencer_T224 30687-30770 Sentence denotes The membrane-bound form promotes adhesion of those leukocytes to endothelial cells.
T4431 30687-30770 Sentence denotes The membrane-bound form promotes adhesion of those leukocytes to endothelial cells.
TextSentencer_T225 30771-30863 Sentence denotes May play a role in regulating leukocyte adhesion and migration processes at the endothelium.
T26682 30771-30863 Sentence denotes May play a role in regulating leukocyte adhesion and migration processes at the endothelium.
TextSentencer_T226 30864-30880 Sentence denotes Binds to CX3CR1.
T57878 30864-30880 Sentence denotes Binds to CX3CR1.
TextSentencer_T227 30881-30903 Sentence denotes 1HP7_2 α-1-Antitrypsin
T98851 30881-30903 Sentence denotes 1HP7_2 α-1-Antitrypsin
TextSentencer_T228 30904-30934 Sentence denotes Inhibitor of serine proteases.
T31927 30904-30934 Sentence denotes Inhibitor of serine proteases.
TextSentencer_T229 30935-31028 Sentence denotes Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin.
T61793 30935-31028 Sentence denotes Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin.
TextSentencer_T230 31029-31100 Sentence denotes Irreversibly inhibits trypsin, chymotrypsin, and plasminogen activator.
T99005 31029-31100 Sentence denotes Irreversibly inhibits trypsin, chymotrypsin, and plasminogen activator.
TextSentencer_T231 31101-31266 Sentence denotes The aberrant form inhibits insulin-induced nitric oxide synthesis in platelets, decreases coagulation time, and has proteolytic activity against insulin and plasmin.
T39551 31101-31266 Sentence denotes The aberrant form inhibits insulin-induced nitric oxide synthesis in platelets, decreases coagulation time, and has proteolytic activity against insulin and plasmin.
TextSentencer_T232 31267-31329 Sentence denotes Short peptide from AAT is a reversible chymotrypsin inhibitor.
T26206 31267-31329 Sentence denotes Short peptide from AAT is a reversible chymotrypsin inhibitor.
TextSentencer_T233 31330-31373 Sentence denotes It also inhibits elastase, but not trypsin.
T7848 31330-31373 Sentence denotes It also inhibits elastase, but not trypsin.
TextSentencer_T234 31374-31604 Sentence denotes Its major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human leukocyte elastase. showing the greater ability to mobilize cytoplasmic calcium in comparison to isoform 1.
T78514 31374-31604 Sentence denotes Its major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human leukocyte elastase. showing the greater ability to mobilize cytoplasmic calcium in comparison to isoform 1.
TextSentencer_T235 31605-31753 Sentence denotes Required in brain development and mature brain function with important roles in the regulation of axon growth, axon guidance, and neurite extension.
T85601 31605-31753 Sentence denotes Required in brain development and mature brain function with important roles in the regulation of axon growth, axon guidance, and neurite extension.
TextSentencer_T236 31754-31844 Sentence denotes Blocks axon out growth and attraction induced by NTN1 by phosphorylating its receptor DDC.
T45699 31754-31844 Sentence denotes Blocks axon out growth and attraction induced by NTN1 by phosphorylating its receptor DDC.
TextSentencer_T237 31845-31951 Sentence denotes Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
T86152 31845-31951 Sentence denotes Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
TextSentencer_T238 31952-32042 Sentence denotes Catalyzes isomerization reactions that contribute to the biosynthesis of steroid hormones.
T34212 31952-32042 Sentence denotes Catalyzes isomerization reactions that contribute to the biosynthesis of steroid hormones.
TextSentencer_T239 32043-32220 Sentence denotes Efficiently catalyze obligatory double-bond isomerizations of δ(5)-androstene-3,17-dione and δ(5)-pregnene-3,20-dione, precursors to testosterone and progesterone, respectively.
T40919 32043-32220 Sentence denotes Efficiently catalyze obligatory double-bond isomerizations of δ(5)-androstene-3,17-dione and δ(5)-pregnene-3,20-dione, precursors to testosterone and progesterone, respectively.
TextSentencer_T240 32221-32321 Sentence denotes Destroys radicals that are normally produced within cells and which are toxic to biological systems.
T99662 32221-32321 Sentence denotes Destroys radicals that are normally produced within cells and which are toxic to biological systems.
TextSentencer_T241 32323-32456 Sentence denotes Desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocytes, methemoglobin reduction.
T9862 32323-32456 Sentence denotes Desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocytes, methemoglobin reduction.
TextSentencer_T242 32457-32463 Sentence denotes LGALS7
T68683 32457-32463 Sentence denotes LGALS7
TextSentencer_T243 32464-32563 Sentence denotes Could be involved in cell-cell and/or cell-matrix interactions necessary for normal growth control.
T14447 32464-32563 Sentence denotes Could be involved in cell-cell and/or cell-matrix interactions necessary for normal growth control.
TextSentencer_T244 32564-32677 Sentence denotes Proapoptotic protein that functions intracellularly upstream of Janus kinase activation and cytochrome c release.
T73693 32564-32677 Sentence denotes Proapoptotic protein that functions intracellularly upstream of Janus kinase activation and cytochrome c release.
TextSentencer_T245 32679-32785 Sentence denotes Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
T44081 32679-32785 Sentence denotes Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
TextSentencer_T246 32786-32950 Sentence denotes Binds to activated protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane.
T20146 32786-32950 Sentence denotes Binds to activated protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane.
TextSentencer_T247 32951-33063 Sentence denotes Necessary for insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues.
T76576 32951-33063 Sentence denotes Necessary for insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues.
TextSentencer_T248 33065-33268 Sentence denotes Hepatocyte growth factor HGF HGF is a potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as growth factor for a broad spectrum of tissues and cell types.
T70681 33065-33268 Sentence denotes Hepatocyte growth factor HGF HGF is a potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as growth factor for a broad spectrum of tissues and cell types.
TextSentencer_T249 33269-33308 Sentence denotes It has no detectable protease activity.
T98322 33269-33308 Sentence denotes It has no detectable protease activity.
TextSentencer_T250 33309-33338 Sentence denotes Receptor for hyaluronic acid.
T89385 33309-33338 Sentence denotes Receptor for hyaluronic acid.
TextSentencer_T251 33339-33527 Sentence denotes Mediates cell-cell and cell-matrix interactions through its affinity for hyaluronic acid, and possibly also through its affinity for other ligands such as osteopontin, collagens, and MMPs.
T41748 33339-33527 Sentence denotes Mediates cell-cell and cell-matrix interactions through its affinity for hyaluronic acid, and possibly also through its affinity for other ligands such as osteopontin, collagens, and MMPs.
TextSentencer_T252 33528-33631 Sentence denotes Adhesion with hyaluronic acid plays an important role in cell migration, tumor growth, and progression.
T42485 33528-33631 Sentence denotes Adhesion with hyaluronic acid plays an important role in cell migration, tumor growth, and progression.
TextSentencer_T253 33632-33719 Sentence denotes Also involved in lymphocyte activation, recirculation and homing, and in hematopoiesis.
T92786 33632-33719 Sentence denotes Also involved in lymphocyte activation, recirculation and homing, and in hematopoiesis.
TextSentencer_T254 33720-33792 Sentence denotes Altered expression or dysfunction causes numerous pathogenic phenotypes.
T56069 33720-33792 Sentence denotes Altered expression or dysfunction causes numerous pathogenic phenotypes.
TextSentencer_T255 33793-33901 Sentence denotes Great protein heterogeneity due to numerous alternative splicing and post-translational modification events.
T42330 33793-33901 Sentence denotes Great protein heterogeneity due to numerous alternative splicing and post-translational modification events.
TextSentencer_T256 33902-33954 Sentence denotes 1XOS cAMP-specific 3′,5′-cyclic phosphodiesterase 4B
T56041 33902-33954 Sentence denotes 1XOS cAMP-specific 3′,5′-cyclic phosphodiesterase 4B
TextSentencer_T257 33955-34060 Sentence denotes Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
T64941 33955-34060 Sentence denotes Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
TextSentencer_T258 34061-34218 Sentence denotes May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.
T28177 34061-34218 Sentence denotes May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.
TextSentencer_T259 34219-34271 Sentence denotes 1PTW cAMP-specific 3′,5′-cyclic phosphodiesterase 4D
T52000 34219-34271 Sentence denotes 1PTW cAMP-specific 3′,5′-cyclic phosphodiesterase 4D
TextSentencer_T260 34272-34377 Sentence denotes Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
T55516 34272-34377 Sentence denotes Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
TextSentencer_T261 34379-34482 Sentence denotes Can insert into membranes and form poorly selective ion channels that may also transport chloride ions.
T41651 34379-34482 Sentence denotes Can insert into membranes and form poorly selective ion channels that may also transport chloride ions.
TextSentencer_T262 34483-34518 Sentence denotes Channel activity depends on the pH.
T63296 34483-34518 Sentence denotes Channel activity depends on the pH.
TextSentencer_T263 34519-34612 Sentence denotes Membrane insertion seems to be redox-regulated and may occur only under oxidizing conditions.
T84756 34519-34612 Sentence denotes Membrane insertion seems to be redox-regulated and may occur only under oxidizing conditions.
TextSentencer_T264 34613-34654 Sentence denotes Promotes cell-surface expression of HRH3.
T91534 34613-34654 Sentence denotes Promotes cell-surface expression of HRH3.
TextSentencer_T265 34655-34812 Sentence denotes Has alternate cellular functions like a potential role in angiogenesis or in maintaining apical-basolateral membrane polarity during mitosis and cytokinesis.
T66491 34655-34812 Sentence denotes Has alternate cellular functions like a potential role in angiogenesis or in maintaining apical-basolateral membrane polarity during mitosis and cytokinesis.
TextSentencer_T266 34813-34918 Sentence denotes Could also promote endothelial cell proliferation and regulate endothelial morphogenesis (tubulogenesis).
T2861 34813-34918 Sentence denotes Could also promote endothelial cell proliferation and regulate endothelial morphogenesis (tubulogenesis).
TextSentencer_T267 34920-35217 Sentence denotes RNA exonuclease that binds to the 3′-end of histone mRNAs and degrades them, suggesting that it plays an essential role in histone mRNA decay after replication; 2′-hydroxyl and 3′-hydroxyl groups at the last nucleotide of the histone 3′-end is required for efficient degradation of RNA substrates.
T37272 34920-35217 Sentence denotes RNA exonuclease that binds to the 3′-end of histone mRNAs and degrades them, suggesting that it plays an essential role in histone mRNA decay after replication; 2′-hydroxyl and 3′-hydroxyl groups at the last nucleotide of the histone 3′-end is required for efficient degradation of RNA substrates.
TextSentencer_T268 35218-35354 Sentence denotes Also able to degrade the 3′-overhangs of small interfering RNAs in vitro, suggesting a possible role as a regulator of RNA interference.
T18086 35218-35354 Sentence denotes Also able to degrade the 3′-overhangs of small interfering RNAs in vitro, suggesting a possible role as a regulator of RNA interference.
TextSentencer_T269 35355-35432 Sentence denotes Required for binding the 5′-ACCCA-3′ sequence present in stem-loop structure.
T8721 35355-35432 Sentence denotes Required for binding the 5′-ACCCA-3′ sequence present in stem-loop structure.
TextSentencer_T270 35433-35458 Sentence denotes Able to bind other mRNAs.
T55077 35433-35458 Sentence denotes Able to bind other mRNAs.
TextSentencer_T271 35459-35500 Sentence denotes Required for 5.8 SrRNA 3′-end processing.
T66722 35459-35500 Sentence denotes Required for 5.8 SrRNA 3′-end processing.
TextSentencer_T272 35501-35534 Sentence denotes Also binds to 5.8s ribosomal RNA.
T88652 35501-35534 Sentence denotes Also binds to 5.8s ribosomal RNA.
TextSentencer_T273 35535-35629 Sentence denotes Binds with high affinity to the stem-loop structure of replicationdependent histone pre-mRNAs.
T85175 35535-35629 Sentence denotes Binds with high affinity to the stem-loop structure of replicationdependent histone pre-mRNAs.
TextSentencer_T274 35631-35910 Sentence denotes The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes, such as the vitamin K-dependent γ-carboxylation of glutamate residues in prothrombin synthesis.
T46298 35631-35910 Sentence denotes The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes, such as the vitamin K-dependent γ-carboxylation of glutamate residues in prothrombin synthesis.
TextSentencer_T275 35911-36024 Sentence denotes Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin, and Tn-C.
T40377 35911-36024 Sentence denotes Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin, and Tn-C.
TextSentencer_T276 36025-36113 Sentence denotes The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments.
T9463 36025-36113 Sentence denotes The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments.
TextSentencer_T277 36115-36145 Sentence denotes Inhibitor of serine proteases.
T14584 36115-36145 Sentence denotes Inhibitor of serine proteases.
TextSentencer_T278 36146-36239 Sentence denotes Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin.
T79848 36146-36239 Sentence denotes Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin.
TextSentencer_T279 36240-36311 Sentence denotes Irreversibly inhibits trypsin, chymotrypsin, and plasminogen activator.
T71654 36240-36311 Sentence denotes Irreversibly inhibits trypsin, chymotrypsin, and plasminogen activator.
TextSentencer_T280 36312-36477 Sentence denotes The aberrant form inhibits insulin-induced nitric oxide synthesis in platelets, decreases coagulation time, and has proteolytic activity against insulin and plasmin.
T7738 36312-36477 Sentence denotes The aberrant form inhibits insulin-induced nitric oxide synthesis in platelets, decreases coagulation time, and has proteolytic activity against insulin and plasmin.
TextSentencer_T281 36478-36544 Sentence denotes The short peptide from AAT is a reversible chymotrypsin inhibitor.
T77316 36478-36544 Sentence denotes The short peptide from AAT is a reversible chymotrypsin inhibitor.
TextSentencer_T282 36545-36588 Sentence denotes It also inhibits elastase, but not trypsin.
T18891 36545-36588 Sentence denotes It also inhibits elastase, but not trypsin.
TextSentencer_T283 36589-36731 Sentence denotes Its major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human leukocyte elastase.
T34143 36589-36731 Sentence denotes Its major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human leukocyte elastase.
TextSentencer_T284 36733-36996 Sentence denotes Renin is a highly specific endopeptidase, the only known function of which is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney.
T97738 36733-36996 Sentence denotes Renin is a highly specific endopeptidase, the only known function of which is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney.
TextSentencer_T285 36998-37122 Sentence denotes Works in concert with the 5-α/5-β-steroid reductases to convert steroid hormones into 3-α/5-α and 3-α/5-βtetrahydrosteroids.
T84461 36998-37122 Sentence denotes Works in concert with the 5-α/5-β-steroid reductases to convert steroid hormones into 3-α/5-α and 3-α/5-βtetrahydrosteroids.
TextSentencer_T286 37123-37233 Sentence denotes Catalyzes the inactivation of the most potent androgen 5-α-dihydrotestosterone to 5-αandrostane-3-α,17-β-diol.
T13031 37123-37233 Sentence denotes Catalyzes the inactivation of the most potent androgen 5-α-dihydrotestosterone to 5-αandrostane-3-α,17-β-diol.
TextSentencer_T287 37234-37266 Sentence denotes Has a high bile-binding ability.
T59167 37234-37266 Sentence denotes Has a high bile-binding ability.
TextSentencer_T288 37268-37377 Sentence denotes Plasma membrane-associated small GTPase that cycles between an active GTP-bound and inactive GDP-bound state.
T58604 37268-37377 Sentence denotes Plasma membrane-associated small GTPase that cycles between an active GTP-bound and inactive GDP-bound state.
TextSentencer_T289 37378-37560 Sentence denotes Inactive state binds to a variety of effector proteins to regulate cellular responses, such as secretory processes, phagocytosis of apoptotic cells, and epithelial cell polarization.
T26102 37378-37560 Sentence denotes Inactive state binds to a variety of effector proteins to regulate cellular responses, such as secretory processes, phagocytosis of apoptotic cells, and epithelial cell polarization.
TextSentencer_T290 37561-37629 Sentence denotes Augments the production of reactive oxygen species by NADPH oxidase.
T60001 37561-37629 Sentence denotes Augments the production of reactive oxygen species by NADPH oxidase.
TextSentencer_T291 37631-37684 Sentence denotes Initiates the extrinsic pathway of blood coagulation.
T57997 37631-37684 Sentence denotes Initiates the extrinsic pathway of blood coagulation.
TextSentencer_T292 37685-37748 Sentence denotes Serine protease that circulates in the blood in a zymogen form.
T97456 37685-37748 Sentence denotes Serine protease that circulates in the blood in a zymogen form.
TextSentencer_T293 37749-37860 Sentence denotes Factor vII is converted to factor vIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis.
T20716 37749-37860 Sentence denotes Factor vII is converted to factor vIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis.
TextSentencer_T294 37861-37983 Sentence denotes In the presence of tissue factor and calcium ions, factor vIIa then converts factor X to factor Xa by limited proteolysis.
T68462 37861-37983 Sentence denotes In the presence of tissue factor and calcium ions, factor vIIa then converts factor X to factor Xa by limited proteolysis.
TextSentencer_T295 37984-38083 Sentence denotes Factor vIIa will also convert factor IX to factor IXa in the presence of tissue factor and calcium.
T36649 37984-38083 Sentence denotes Factor vIIa will also convert factor IX to factor IXa in the presence of tissue factor and calcium.
TextSentencer_T296 38085-38236 Sentence denotes A carboxypeptidase that converts angiotensin I to angiotensin 1-9, a peptide of unknown function, and angiotensin II to angiotensin 1-7, a vasodilator.
T21198 38085-38236 Sentence denotes A carboxypeptidase that converts angiotensin I to angiotensin 1-9, a peptide of unknown function, and angiotensin II to angiotensin 1-7, a vasodilator.
TextSentencer_T297 38237-38308 Sentence denotes Also able to hydrolyze apelin-13 and dynorphin-13 with high efficiency.
T76617 38237-38308 Sentence denotes Also able to hydrolyze apelin-13 and dynorphin-13 with high efficiency.
TextSentencer_T298 38309-38357 Sentence denotes May be an important regulator of heart function.
T51613 38309-38357 Sentence denotes May be an important regulator of heart function.
TextSentencer_T299 38358-38526 Sentence denotes In case of human coronavirus severe acute respiratory syndrome and HCov-NL63 infections, serves as functional receptor for the spike glycoprotein of both coronaviruses.
T31064 38358-38526 Sentence denotes In case of human coronavirus severe acute respiratory syndrome and HCov-NL63 infections, serves as functional receptor for the spike glycoprotein of both coronaviruses.
TextSentencer_T300 38528-38573 Sentence denotes The enzyme cleaves Lys-Arg and Arg-Ser bonds.
T94369 38528-38573 Sentence denotes The enzyme cleaves Lys-Arg and Arg-Ser bonds.
TextSentencer_T301 38574-38676 Sentence denotes It activates, in a reciprocal reaction, factor XII, after its binding to a negatively charged surface.
T43326 38574-38676 Sentence denotes It activates, in a reciprocal reaction, factor XII, after its binding to a negatively charged surface.
TextSentencer_T302 38677-38814 Sentence denotes It also releases bradykinin from HMW kininogen and may also play a role in the reninangiotensin system by converting prorenin into renin.
T69640 38677-38814 Sentence denotes It also releases bradykinin from HMW kininogen and may also play a role in the reninangiotensin system by converting prorenin into renin.
TextSentencer_T303 38816-39097 Sentence denotes The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gammacarboxylation of glutamate residues in prothrombin synthesis.
T65845 38816-39097 Sentence denotes The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gammacarboxylation of glutamate residues in prothrombin synthesis.
TextSentencer_T304 39099-39202 Sentence denotes Catalyzes the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds.
T54144 39099-39202 Sentence denotes Catalyzes the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds.
TextSentencer_T305 39203-39366 Sentence denotes Sulfonation increases the water solubility of most compounds, and therefore their renal excretion, but can also result in bioactivation to form active metabolites.
T21397 39203-39366 Sentence denotes Sulfonation increases the water solubility of most compounds, and therefore their renal excretion, but can also result in bioactivation to form active metabolites.
TextSentencer_T306 39367-39420 Sentence denotes Sulfates hydroxysteroids like dehydroepiandrosterone.
T28883 39367-39420 Sentence denotes Sulfates hydroxysteroids like dehydroepiandrosterone.
TextSentencer_T307 39421-39535 Sentence denotes Isoform 1 preferentially sulfonates cholesterol, and isoform 2 avidly sulfonates pregnenolone but not cholesterol.
T48559 39421-39535 Sentence denotes Isoform 1 preferentially sulfonates cholesterol, and isoform 2 avidly sulfonates pregnenolone but not cholesterol.
TextSentencer_T308 39537-39597 Sentence denotes Removes the amino-terminal methionine from nascent proteins.
T57744 39537-39597 Sentence denotes Removes the amino-terminal methionine from nascent proteins.
TextSentencer_T309 39598-39846 Sentence denotes The catalytic activity of human METAP2 toward Metval peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N-terminal Met-val and Met-Thr sequences in vivo.
T51931 39598-39846 Sentence denotes The catalytic activity of human METAP2 toward Metval peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N-terminal Met-val and Met-Thr sequences in vivo.
TextSentencer_T310 39848-39955 Sentence denotes Plasma membrane-associated small GTPase that cycles between active GTP-bound and inactive GDP-bound states.
T31049 39848-39955 Sentence denotes Plasma membrane-associated small GTPase that cycles between active GTP-bound and inactive GDP-bound states.
TextSentencer_T311 39956-40197 Sentence denotes In its active state, binds to a variety of effector proteins to regulate cellular responses, such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization, and growth-factor induced formation of membrane ruffles.
T84961 39956-40197 Sentence denotes In its active state, binds to a variety of effector proteins to regulate cellular responses, such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization, and growth-factor induced formation of membrane ruffles.
TextSentencer_T312 40198-40347 Sentence denotes Isoform B has an accelerated GEF-independent GDP/GTP exchange and impaired GTP hydrolysis, which is restored partially by GTPase-activating proteins.
T55841 40198-40347 Sentence denotes Isoform B has an accelerated GEF-independent GDP/GTP exchange and impaired GTP hydrolysis, which is restored partially by GTPase-activating proteins.
TextSentencer_T313 40348-40533 Sentence denotes It is able to bind to the GTPase-binding domain of PAK but not full-length PAK in a GTP-dependent manner, suggesting that the insertion does not completely abolish effector interaction.
T47192 40348-40533 Sentence denotes It is able to bind to the GTPase-binding domain of PAK but not full-length PAK in a GTP-dependent manner, suggesting that the insertion does not completely abolish effector interaction.
TextSentencer_T314 40534-40541 Sentence denotes -24.458
T581 40534-40541 Sentence denotes -24.458
TextSentencer_T315 40543-40715 Sentence denotes Nonreceptor tyrosine kinase involved in various processes, such as cell cycle progression, apoptosis, mitotic recombination, genetic instability, and histone modifications.
T20737 40543-40715 Sentence denotes Nonreceptor tyrosine kinase involved in various processes, such as cell cycle progression, apoptosis, mitotic recombination, genetic instability, and histone modifications.
TextSentencer_T316 40716-41090 Sentence denotes In the cytoplasm, plays a pivotal role in signal transduction via its association with cytokine receptors, which constitutes an initiating step in signaling for many members of the cytokine receptor superfamily, including the receptors for growth hormone, prolactin, leptin, erythropoietin, granulocyte-macrophage colony-stimulating factor, thrombopoietin, and multiple ILs.
T79837 40716-41090 Sentence denotes In the cytoplasm, plays a pivotal role in signal transduction via its association with cytokine receptors, which constitutes an initiating step in signaling for many members of the cytokine receptor superfamily, including the receptors for growth hormone, prolactin, leptin, erythropoietin, granulocyte-macrophage colony-stimulating factor, thrombopoietin, and multiple ILs.
TextSentencer_T317 41091-41324 Sentence denotes Following stimulation with erythropoietin during erythropoiesis, it is autophosphorylated and activated, leading to its association with erythropoietin receptor and tyrosine phosphorylation of residues in the EPOR cytoplasmic domain.
T32506 41091-41324 Sentence denotes Following stimulation with erythropoietin during erythropoiesis, it is autophosphorylated and activated, leading to its association with erythropoietin receptor and tyrosine phosphorylation of residues in the EPOR cytoplasmic domain.
TextSentencer_T318 41325-41400 Sentence denotes Also involved in promoting the localization of EPOR to the plasma membrane.
T27629 41325-41400 Sentence denotes Also involved in promoting the localization of EPOR to the plasma membrane.
TextSentencer_T319 41401-41458 Sentence denotes Also acts downstream of some G-protein coupled receptors.
T80538 41401-41458 Sentence denotes Also acts downstream of some G-protein coupled receptors.
TextSentencer_T320 41459-41518 Sentence denotes Plays a role in the control of body weight (by similarity).
T43088 41459-41518 Sentence denotes Plays a role in the control of body weight (by similarity).
TextSentencer_T321 41519-41711 Sentence denotes In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of Tyr-41 of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1α) from chromatin.
T97955 41519-41711 Sentence denotes In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of Tyr-41 of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1α) from chromatin.
TextSentencer_T322 41713-41929 Sentence denotes In cooperation with other chaperones, heat shock protein 70s stabilizes pre-existent proteins against aggregation and mediates the folding of newly translated polypeptides in the cytosol as well as within organelles.
T29791 41713-41929 Sentence denotes In cooperation with other chaperones, heat shock protein 70s stabilizes pre-existent proteins against aggregation and mediates the folding of newly translated polypeptides in the cytosol as well as within organelles.
TextSentencer_T323 41930-42059 Sentence denotes These chaperones participate in all these processes through their ability to recognize nonnative conformations of other proteins.
T29908 41930-42059 Sentence denotes These chaperones participate in all these processes through their ability to recognize nonnative conformations of other proteins.
TextSentencer_T324 42060-42235 Sentence denotes They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage.
T36420 42060-42235 Sentence denotes They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage.
TextSentencer_T325 42236-42354 Sentence denotes In case of rotavirus A infection, serves as a postattachment receptor for the virus to facilitate entry into the cell.
T53392 42236-42354 Sentence denotes In case of rotavirus A infection, serves as a postattachment receptor for the virus to facilitate entry into the cell.
TextSentencer_T326 42356-42469 Sentence denotes Proteasome-associated deubiquitinase that releases ubiquitin from the proteasome-targeted ubiquitinated proteins.
T82833 42356-42469 Sentence denotes Proteasome-associated deubiquitinase that releases ubiquitin from the proteasome-targeted ubiquitinated proteins.
TextSentencer_T327 42470-42526 Sentence denotes Ensures the regeneration of ubiquitin at the proteasome.
T24181 42470-42526 Sentence denotes Ensures the regeneration of ubiquitin at the proteasome.
TextSentencer_T328 42527-42651 Sentence denotes Is a reversibly associated subunit of the proteasome and a large fraction of proteasome-free protein exists within the cell.
T54100 42527-42651 Sentence denotes Is a reversibly associated subunit of the proteasome and a large fraction of proteasome-free protein exists within the cell.
TextSentencer_T329 42652-42762 Sentence denotes Required for degradation of the chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis.
T3570 42652-42762 Sentence denotes Required for degradation of the chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis.
TextSentencer_T330 42763-42979 Sentence denotes Serves also as a physiological inhibitor of endoplasmic reticulum-associated degradation under the nonstressed condition by inhibiting degradation of unfolded endoplasmic reticulum proteins via interaction with ERN1.
T28988 42763-42979 Sentence denotes Serves also as a physiological inhibitor of endoplasmic reticulum-associated degradation under the nonstressed condition by inhibiting degradation of unfolded endoplasmic reticulum proteins via interaction with ERN1.
TextSentencer_T331 42980-43059 Sentence denotes Indispensable for synaptic development and function at neuromuscular junctions.
T9205 42980-43059 Sentence denotes Indispensable for synaptic development and function at neuromuscular junctions.
TextSentencer_T332 43061-43250 Sentence denotes Phosphorylates serine-rich and arginine-rich proteins of the spliceosomal complex may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing.
T14723 43061-43250 Sentence denotes Phosphorylates serine-rich and arginine-rich proteins of the spliceosomal complex may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing.
TextSentencer_T333 43251-43317 Sentence denotes Phosphorylates serines, threonines, and tyrosines (by similarity).
T64171 43251-43317 Sentence denotes Phosphorylates serines, threonines, and tyrosines (by similarity).
TextSentencer_T334 43319-43408 Sentence denotes This inhibitor acts as "bait" for tissue plasminogen activator, urokinase, and protein C.
T18389 43319-43408 Sentence denotes This inhibitor acts as "bait" for tissue plasminogen activator, urokinase, and protein C.
TextSentencer_T335 43409-43537 Sentence denotes Its rapid interaction with tissue plasminogen activator may function as a major control point in the regulation of fibrinolysis.
T10612 43409-43537 Sentence denotes Its rapid interaction with tissue plasminogen activator may function as a major control point in the regulation of fibrinolysis.
TextSentencer_T336 43539-43606 Sentence denotes Only known pyridoxal phosphate-dependent enzyme that contains heme.
T74513 43539-43606 Sentence denotes Only known pyridoxal phosphate-dependent enzyme that contains heme.
TextSentencer_T337 43607-43756 Sentence denotes Important regulator of hydrogen sulfide, especially in the brain, utilizing cysteine instead of serine to catalyze the formation of hydrogen sulfide.
T28429 43607-43756 Sentence denotes Important regulator of hydrogen sulfide, especially in the brain, utilizing cysteine instead of serine to catalyze the formation of hydrogen sulfide.
TextSentencer_T338 43757-43946 Sentence denotes Hydrogen sulfide is a gastrotransmitter with signaling and cytoprotective effects, such as acting as a neuromodulator in the brain to protect neurons against hypoxic injury (by similarity).
T47766 43757-43946 Sentence denotes Hydrogen sulfide is a gastrotransmitter with signaling and cytoprotective effects, such as acting as a neuromodulator in the brain to protect neurons against hypoxic injury (by similarity).
TextSentencer_T339 43948-44037 Sentence denotes This inhibitor acts as "bait" for tissue plasminogen activator, urokinase, and protein C.
T26279 43948-44037 Sentence denotes This inhibitor acts as "bait" for tissue plasminogen activator, urokinase, and protein C.
TextSentencer_T340 44038-44166 Sentence denotes Its rapid interaction with tissue plasminogen activator may function as a major control point in the regulation of fibrinolysis.
T27104 44038-44166 Sentence denotes Its rapid interaction with tissue plasminogen activator may function as a major control point in the regulation of fibrinolysis.
TextSentencer_T341 44167-44175 Sentence denotes -20.2158
T77126 44167-44175 Sentence denotes -20.2158
TextSentencer_T342 44176-44200 Sentence denotes 1vJ5 Epoxide hydrolase 2
T48285 44176-44200 Sentence denotes 1vJ5 Epoxide hydrolase 2
TextSentencer_T343 44201-44261 Sentence denotes Acts on epoxides (alkene oxides, oxiranes) and arene oxides.
T27610 44201-44261 Sentence denotes Acts on epoxides (alkene oxides, oxiranes) and arene oxides.
TextSentencer_T344 44262-44340 Sentence denotes Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides.
T80890 44262-44340 Sentence denotes Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides.
TextSentencer_T345 44341-44404 Sentence denotes Also determines steady-state levels of physiological mediators.
T24860 44341-44404 Sentence denotes Also determines steady-state levels of physiological mediators.
TextSentencer_T346 44405-44434 Sentence denotes Has low phosphatase activity.
T50486 44405-44434 Sentence denotes Has low phosphatase activity.
TextSentencer_T347 44435-44443 Sentence denotes -25.2152
T99432 44435-44443 Sentence denotes -25.2152
TextSentencer_T348 44444-44486 Sentence denotes 1NY3 MAP kinase-activated protein kinase 2
T46135 44444-44486 Sentence denotes 1NY3 MAP kinase-activated protein kinase 2
TextSentencer_T349 44487-44549 Sentence denotes Its physiological substrate seems to be the small HSP27/HSP25.
T44450 44487-44549 Sentence denotes Its physiological substrate seems to be the small HSP27/HSP25.
TextSentencer_T350 44550-44652 Sentence denotes In vitro can phosphorylate glycogen synthase at Ser-7 and tyrosine hydroxylase (on Ser-19 and Ser-40).
T4855 44550-44652 Sentence denotes In vitro can phosphorylate glycogen synthase at Ser-7 and tyrosine hydroxylase (on Ser-19 and Ser-40).
TextSentencer_T351 44653-44782 Sentence denotes This kinase phosphorylates Ser in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue (by similarity).
T5487 44653-44782 Sentence denotes This kinase phosphorylates Ser in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue (by similarity).
TextSentencer_T352 44783-44851 Sentence denotes Mediates both ERK and p38 MAPK/MAPK14dependent neutrophil responses.
T84618 44783-44851 Sentence denotes Mediates both ERK and p38 MAPK/MAPK14dependent neutrophil responses.
TextSentencer_T353 44852-44933 Sentence denotes Participates in TNF α-stimulated exocytosis of secretory vesicles in neutrophils.
T50445 44852-44933 Sentence denotes Participates in TNF α-stimulated exocytosis of secretory vesicles in neutrophils.
TextSentencer_T354 44934-44998 Sentence denotes Plays a role in phagocytosis-induced respiratory burst activity.
T32337 44934-44998 Sentence denotes Plays a role in phagocytosis-induced respiratory burst activity.
TextSentencer_T355 44999-45007 Sentence denotes -27.0738
T43648 44999-45007 Sentence denotes -27.0738
TextSentencer_T356 45008-45147 Sentence denotes 1F5F Sex hormone-binding globulin SHBG Functions as an androgen transport protein, but may also be involved in receptor-mediated processes.
T65768 45008-45147 Sentence denotes 1F5F Sex hormone-binding globulin SHBG Functions as an androgen transport protein, but may also be involved in receptor-mediated processes.
TextSentencer_T357 45148-45189 Sentence denotes Each dimer binds one molecule of steroid.
T24942 45148-45189 Sentence denotes Each dimer binds one molecule of steroid.
TextSentencer_T358 45190-45261 Sentence denotes Specific for 5-α-dihydrotestosterone, testosterone, and 17-β-estradiol.
T83034 45190-45261 Sentence denotes Specific for 5-α-dihydrotestosterone, testosterone, and 17-β-estradiol.
TextSentencer_T359 45262-45371 Sentence denotes Regulates the plasma metabolic clearance rate of steroid hormones by controlling their plasma concentrations.
T56527 45262-45371 Sentence denotes Regulates the plasma metabolic clearance rate of steroid hormones by controlling their plasma concentrations.
TextSentencer_T360 45373-45435 Sentence denotes Catalyzes the conversion of aldehydes and ketones to alcohols.
T11841 45373-45435 Sentence denotes Catalyzes the conversion of aldehydes and ketones to alcohols.
TextSentencer_T361 45436-45591 Sentence denotes Catalyzes the reduction of prostaglandin D2, prostaglandin H2, and phenanthrenequinone, and the oxidation of 9-α,11-β-prostaglandin F2 to prostaglandin D2.
T96537 45436-45591 Sentence denotes Catalyzes the reduction of prostaglandin D2, prostaglandin H2, and phenanthrenequinone, and the oxidation of 9-α,11-β-prostaglandin F2 to prostaglandin D2.
TextSentencer_T362 45592-45670 Sentence denotes Functions as a bidirectional 3-α-, 17-β-and 20-α hydroxysteroid dehydrogenase.
T44165 45592-45670 Sentence denotes Functions as a bidirectional 3-α-, 17-β-and 20-α hydroxysteroid dehydrogenase.
TextSentencer_T363 45671-45772 Sentence denotes Can interconvert active androgens, estrogens, and progestins with their cognate inactive metabolites.
T61123 45671-45772 Sentence denotes Can interconvert active androgens, estrogens, and progestins with their cognate inactive metabolites.
TextSentencer_T364 45773-45838 Sentence denotes Preferentially transforms rostenedione (4-dione) to testosterone.
T80843 45773-45838 Sentence denotes Preferentially transforms rostenedione (4-dione) to testosterone.
TextSentencer_T365 45840-45910 Sentence denotes Hydrolyzes ITP and dITP to their respective monophosphate derivatives.
T27521 45840-45910 Sentence denotes Hydrolyzes ITP and dITP to their respective monophosphate derivatives.
TextSentencer_T366 45911-45968 Sentence denotes Xanthosine 5′-triphosphate is also a potential substrate.
T14770 45911-45968 Sentence denotes Xanthosine 5′-triphosphate is also a potential substrate.
TextSentencer_T367 45969-46047 Sentence denotes May be the major enzyme responsible for regulating ITP concentration in cells.
T61396 45969-46047 Sentence denotes May be the major enzyme responsible for regulating ITP concentration in cells.
TextSentencer_T368 46049-46229 Sentence denotes Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca 2+
T90656 46049-46229 Sentence denotes Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca 2+
TextSentencer_T369 46230-46268 Sentence denotes ions, phospholipids, and factor vIIIa.
T30252 46230-46268 Sentence denotes ions, phospholipids, and factor vIIIa.
TextSentencer_T370 46269-46388 Sentence denotes CDOCKER interaction energy ranged from 25 to 46 kcal/mol between CYP3A4 and XKB, midazolam, ketoconazole, and probucol.
T28725 46269-46388 Sentence denotes CDOCKER interaction energy ranged from 25 to 46 kcal/mol between CYP3A4 and XKB, midazolam, ketoconazole, and probucol.
TextSentencer_T371 46389-46489 Sentence denotes XKB formed a hydrogen bond with Gly481 at the active site of human CYP3A4 (PDB ID 4K9W; Figure 2A ).
T29187 46389-46489 Sentence denotes XKB formed a hydrogen bond with Gly481 at the active site of human CYP3A4 (PDB ID 4K9W; Figure 2A ).
TextSentencer_T372 46490-46644 Sentence denotes Both midazolam and ketoconazole bound to the active site of human CYP3A4 via π-π stacking with Phe108 ( Figure 2B ) and Arg105 (Figure 2C ), respectively.
T12316 46490-46644 Sentence denotes Both midazolam and ketoconazole bound to the active site of human CYP3A4 via π-π stacking with Phe108 ( Figure 2B ) and Arg105 (Figure 2C ), respectively.
TextSentencer_T373 46645-46769 Sentence denotes However, probucol did not show hydrogen bond formation, π-π stacking, or charge interaction with human CYP3A4 ( Figure 2D ).
T95811 46645-46769 Sentence denotes However, probucol did not show hydrogen bond formation, π-π stacking, or charge interaction with human CYP3A4 ( Figure 2D ).
TextSentencer_T374 46770-46880 Sentence denotes Further, we built a homology model of rat Cyp3a2 based on the crystal structure of human CYP3A4 (PDB ID 4K9W).
T90449 46770-46880 Sentence denotes Further, we built a homology model of rat Cyp3a2 based on the crystal structure of human CYP3A4 (PDB ID 4K9W).
TextSentencer_T375 46881-47007 Sentence denotes The sequence similarity and identity between the human CYP3A4 and rat Cyp3a2 homology model was 83.3% and 68.4%, respectively.
T20743 46881-47007 Sentence denotes The sequence similarity and identity between the human CYP3A4 and rat Cyp3a2 homology model was 83.3% and 68.4%, respectively.
TextSentencer_T376 47008-47081 Sentence denotes The CDOCKER interaction energy ranged from 23 to 34 kcal/mol ( Table 5 ).
T54729 47008-47081 Sentence denotes The CDOCKER interaction energy ranged from 23 to 34 kcal/mol ( Table 5 ).
TextSentencer_T377 47082-47225 Sentence denotes The docking results showed that XKB bound to the active site of rat Cyp3a2 homology model by hydrogen bond formation with Ala482 ( Figure 3A) .
T92607 47082-47225 Sentence denotes The docking results showed that XKB bound to the active site of rat Cyp3a2 homology model by hydrogen bond formation with Ala482 ( Figure 3A) .
TextSentencer_T378 47226-47351 Sentence denotes Midazolam was readily docked into the active site of the rat Cyp3a2 homology model by π-π stacking with Phe305 ( Figure 3B ).
T69050 47226-47351 Sentence denotes Midazolam was readily docked into the active site of the rat Cyp3a2 homology model by π-π stacking with Phe305 ( Figure 3B ).
TextSentencer_T379 47352-47476 Sentence denotes Ketoconazole bound with Arg105 by hydrogen bond formation at the active site of the rat Cyp3a2 homology model ( Figure 3C ).
T76685 47352-47476 Sentence denotes Ketoconazole bound with Arg105 by hydrogen bond formation at the active site of the rat Cyp3a2 homology model ( Figure 3C ).
TextSentencer_T380 47477-47625 Sentence denotes However, there was no hydrogen bond formation, π-π stacking, or charge interaction between probucol and the rat Cyp3a2 homology model ( Figure 3D ).
T3484 47477-47625 Sentence denotes However, there was no hydrogen bond formation, π-π stacking, or charge interaction between probucol and the rat Cyp3a2 homology model ( Figure 3D ).
TextSentencer_T381 47626-47791 Sentence denotes The compound-CYP complexes with the highest CDOCKER interaction energy were selected, and two-dimensional and three-dimensional images were taken (Figures 2 and 3) .
T43464 47626-47791 Sentence denotes The compound-CYP complexes with the highest CDOCKER interaction energy were selected, and two-dimensional and three-dimensional images were taken (Figures 2 and 3) .
TextSentencer_T382 47792-47946 Sentence denotes Taken together, the results showed that XKB could bind to the active sites of human CYP3A4 and rat Cyp3a2 via hydrogen bond formation and/or π-π stacking.
T49703 47792-47946 Sentence denotes Taken together, the results showed that XKB could bind to the active sites of human CYP3A4 and rat Cyp3a2 via hydrogen bond formation and/or π-π stacking.
TextSentencer_T383 47947-48014 Sentence denotes XKB may serve as a substrate and/or inhibitor of these two enzymes.
T43802 47947-48014 Sentence denotes XKB may serve as a substrate and/or inhibitor of these two enzymes.
TextSentencer_T384 48015-48087 Sentence denotes Predicted ADMET properties of XKB, midazolam, ketoconazole, and probucol
T33219 48015-48087 Sentence denotes Predicted ADMET properties of XKB, midazolam, ketoconazole, and probucol
TextSentencer_T385 48088-48187 Sentence denotes The predicted ADMET properties of XKB, midazolam, ketoconazole, and probucol are shown in Table 6 .
T76786 48088-48187 Sentence denotes The predicted ADMET properties of XKB, midazolam, ketoconazole, and probucol are shown in Table 6 .
TextSentencer_T386 48188-48275 Sentence denotes The aqueous solubility value (log [molar solubility]) of XKB was between -6.0 and -4.0.
T16766 48188-48275 Sentence denotes The aqueous solubility value (log [molar solubility]) of XKB was between -6.0 and -4.0.
TextSentencer_T387 48276-48384 Sentence denotes XKB showed a moderate ability to penetrate the blood-brain barrier and a good intestinal absorption profile.
T42718 48276-48384 Sentence denotes XKB showed a moderate ability to penetrate the blood-brain barrier and a good intestinal absorption profile.
TextSentencer_T388 48385-48562 Sentence denotes All properties and optimal prediction space components of XKB were within the expected ranges with regard to the CYP2D6 ligand, hepatotoxicity, and plasma protein binding level.
T21425 48385-48562 Sentence denotes All properties and optimal prediction space components of XKB were within the expected ranges with regard to the CYP2D6 ligand, hepatotoxicity, and plasma protein binding level.
TextSentencer_T389 48563-48654 Sentence denotes Midazolam and ketoconazole showed similar ADMET profiles to XKB, except for hepatotoxicity.
T15851 48563-48654 Sentence denotes Midazolam and ketoconazole showed similar ADMET profiles to XKB, except for hepatotoxicity.
TextSentencer_T390 48655-48878 Sentence denotes ADMET Predictor showed that the optimal prediction space PC25 values for midazolam and optimal prediction space PC30 values for ketoconazole were out of range, suggesting that both compounds might be hepatotoxic (Table 6 ).
T44346 48655-48878 Sentence denotes ADMET Predictor showed that the optimal prediction space PC25 values for midazolam and optimal prediction space PC30 values for ketoconazole were out of range, suggesting that both compounds might be hepatotoxic (Table 6 ).
TextSentencer_T391 48879-49028 Sentence denotes Probucol had very low aqueous solubility and very low intestinal absorption, which are in agreement with the data reported for this drug ( Table 6 ).
T21345 48879-49028 Sentence denotes Probucol had very low aqueous solubility and very low intestinal absorption, which are in agreement with the data reported for this drug ( Table 6 ).
TextSentencer_T392 49029-49259 Sentence denotes The logP value for probucol is 10.91, 38 and its oral bioavailability is only about 10%, but can be improved using nanotechnology. [39] [40] [41] validation of HPLC method for determination of midazolam and 1′-OH-MDZ in rat plasma
T7864 49029-49259 Sentence denotes The logP value for probucol is 10.91, 38 and its oral bioavailability is only about 10%, but can be improved using nanotechnology. [39] [40] [41] validation of HPLC method for determination of midazolam and 1′-OH-MDZ in rat plasma
TextSentencer_T393 49260-49380 Sentence denotes Validation of the HPLC method was performed prior to determination of the plasma PKs of midazolam and 1′-OH-MDZ in rats.
T75732 49260-49380 Sentence denotes Validation of the HPLC method was performed prior to determination of the plasma PKs of midazolam and 1′-OH-MDZ in rats.
TextSentencer_T394 49381-49513 Sentence denotes This included an examination of specificity, linearity, lower limit of quantification, precision, accuracy, recovery, and stability.
T73002 49381-49513 Sentence denotes This included an examination of specificity, linearity, lower limit of quantification, precision, accuracy, recovery, and stability.
TextSentencer_T395 49514-49643 Sentence denotes Figure 4 shows the representative chromatogram of blank rat plasma and rat plasma spiked with midazolam, 1′-OH-MDZ, and diazepam.
T54427 49514-49643 Sentence denotes Figure 4 shows the representative chromatogram of blank rat plasma and rat plasma spiked with midazolam, 1′-OH-MDZ, and diazepam.
TextSentencer_T396 49644-49833 Sentence denotes The results indicate that midazolam, 1′-OH-MDZ, and diazepam were separated completely under the assay conditions and no endogenous interfering peaks were observed at their retention times.
T88875 49644-49833 Sentence denotes The results indicate that midazolam, 1′-OH-MDZ, and diazepam were separated completely under the assay conditions and no endogenous interfering peaks were observed at their retention times.
TextSentencer_T397 49835-50028 Sentence denotes The precision and accuracy of the method were determined using quality control samples at three concentrations of midazolam (0.075, 0.30, and 4.80 μg/mL) and 1′-OH-MDZ (0.05, 0.40, 3.20 μg/mL).
T6711 49835-50028 Sentence denotes The precision and accuracy of the method were determined using quality control samples at three concentrations of midazolam (0.075, 0.30, and 4.80 μg/mL) and 1′-OH-MDZ (0.05, 0.40, 3.20 μg/mL).
TextSentencer_T398 50029-50154 Sentence denotes The precision of the assay was expressed by the relative standard deviation of the mean value from the nominal concentration.
T34386 50029-50154 Sentence denotes The precision of the assay was expressed by the relative standard deviation of the mean value from the nominal concentration.
TextSentencer_T399 50155-50256 Sentence denotes Accuracy was expressed as the percentage of the mean value calculated from the nominal concentration.
T42327 50155-50256 Sentence denotes Accuracy was expressed as the percentage of the mean value calculated from the nominal concentration.
TextSentencer_T400 50257-50291 Sentence denotes The results are shown in Table 7 .
T30398 50257-50291 Sentence denotes The results are shown in Table 7 .
TextSentencer_T401 50292-50489 Sentence denotes These values were within the acceptable range, indicating that the developed method was reproducible, accurate, and reliable for quantitative determination of midazolam and 1′-OH-MDZ in rat plasma.
T5295 50292-50489 Sentence denotes These values were within the acceptable range, indicating that the developed method was reproducible, accurate, and reliable for quantitative determination of midazolam and 1′-OH-MDZ in rat plasma.
TextSentencer_T402 50490-50493 Sentence denotes The
T68891 50490-50493 Sentence denotes The
TextSentencer_T403 50495-50635 Sentence denotes Stability tests were performed at low, medium, and high concentrations of the quality control samples and the results are shown in Table 8 .
T12222 50495-50635 Sentence denotes Stability tests were performed at low, medium, and high concentrations of the quality control samples and the results are shown in Table 8 .
TextSentencer_T404 50636-50733 Sentence denotes Stock solutions of midazolam and 1′-OH-MDZ were stable for at least 30 days when stored at -20°C.
T58098 50636-50733 Sentence denotes Stock solutions of midazolam and 1′-OH-MDZ were stable for at least 30 days when stored at -20°C.
TextSentencer_T405 50734-50915 Sentence denotes Further, the concentrations of midazolam and 1′-OH-MDZ did not change significantly after exposure of the samples at room temperature for 2 and 12 hours or three freeze-thaw cycles.
T4922 50734-50915 Sentence denotes Further, the concentrations of midazolam and 1′-OH-MDZ did not change significantly after exposure of the samples at room temperature for 2 and 12 hours or three freeze-thaw cycles.
TextSentencer_T406 50916-51050 Sentence denotes The results indicate that midazolam and 1′-OH-MDZ are stable enough to be analyzed using this method within a predetermined timeframe.
T38430 50916-51050 Sentence denotes The results indicate that midazolam and 1′-OH-MDZ are stable enough to be analyzed using this method within a predetermined timeframe.
TextSentencer_T407 51051-51198 Sentence denotes Given that we had observed potential interactions between XKB and rat Cyp3a2, we then examined the effect of XKB on Cyp3a-mediated drug metabolism.
T41862 51051-51198 Sentence denotes Given that we had observed potential interactions between XKB and rat Cyp3a2, we then examined the effect of XKB on Cyp3a-mediated drug metabolism.
TextSentencer_T408 51199-51283 Sentence denotes Successive oral administration of XKB was scheduled using midazolam as a probe drug.
T70166 51199-51283 Sentence denotes Successive oral administration of XKB was scheduled using midazolam as a probe drug.
TextSentencer_T409 51284-51437 Sentence denotes Midazolam is a well-known probe substrate for human CYP3A4/5, but it is unclear if it is an appropriate probe for determining rat Cyp3a activity in vivo.
T38299 51284-51437 Sentence denotes Midazolam is a well-known probe substrate for human CYP3A4/5, but it is unclear if it is an appropriate probe for determining rat Cyp3a activity in vivo.
TextSentencer_T410 51438-51495 Sentence denotes The major metabolite of midazolam in humans is 1′-OH-MDZ.
T74037 51438-51495 Sentence denotes The major metabolite of midazolam in humans is 1′-OH-MDZ.
TextSentencer_T411 51496-51643 Sentence denotes 42 The mean plasma profiles of midazolam and 1′-OH-MDZ after 8 consecutive days of treatment with XKB are shown for each group in Figures 5 and 6 .
T38947 51496-51643 Sentence denotes 42 The mean plasma profiles of midazolam and 1′-OH-MDZ after 8 consecutive days of treatment with XKB are shown for each group in Figures 5 and 6 .
TextSentencer_T412 51644-51700 Sentence denotes The associated PK parameters are listed in Tables 9-11 .
T58062 51644-51700 Sentence denotes The associated PK parameters are listed in Tables 9-11 .
TextSentencer_T413 51701-51837 Sentence denotes The results indicate there were significant changes in the PK parameters of midazolam and 1′-OH-MDZ in rats treated with XKB for 8 days.
T53357 51701-51837 Sentence denotes The results indicate there were significant changes in the PK parameters of midazolam and 1′-OH-MDZ in rats treated with XKB for 8 days.
TextSentencer_T414 51838-52041 Sentence denotes In comparison with vehicle-treated rats, treatment with 14 mg/kg XKB increased the C max , AUC 0-t , AUC 0-inf , and AUMC of midazolam by 2.9fold, 2.7-fold, 2.6-fold, and 2.0-fold, respectively (P0.05).
T90531 51838-52041 Sentence denotes In comparison with vehicle-treated rats, treatment with 14 mg/kg XKB increased the C max , AUC 0-t , AUC 0-inf , and AUMC of midazolam by 2.9fold, 2.7-fold, 2.6-fold, and 2.0-fold, respectively (P0.05).
TextSentencer_T415 52042-52210 Sentence denotes In contrast, the CL/F and V/F of midazolam were decreased by 63.0% and 84.0% in rats treated with 14 mg/kg XKB, respectively, compared with rats receiving vehicle only.
T90337 52042-52210 Sentence denotes In contrast, the CL/F and V/F of midazolam were decreased by 63.0% and 84.0% in rats treated with 14 mg/kg XKB, respectively, compared with rats receiving vehicle only.
TextSentencer_T416 52211-52365 Sentence denotes The k a , k e , t 1/2ka , t 1/2ke , T max , and mean residence time for midazolam remained unchanged after rats were given 14 mg/kg XKB orally for 8 days.
T36373 52211-52365 Sentence denotes The k a , k e , t 1/2ka , t 1/2ke , T max , and mean residence time for midazolam remained unchanged after rats were given 14 mg/kg XKB orally for 8 days.
TextSentencer_T417 52366-52689 Sentence denotes Our data also show that oral administration of XKB at 7 mg/kg significantly changed the AUC 0-t of midazolam, with a 1. oral administration of XKB 7 mg/kg significantly increased AUC 0-t , AUC 0-inf , and AUMC by 1.5-fold, 1.6-fold, and 1.9-fold, respectively, when compared with the control rats treated with vehicle only.
T69418 52366-52689 Sentence denotes Our data also show that oral administration of XKB at 7 mg/kg significantly changed the AUC 0-t of midazolam, with a 1. oral administration of XKB 7 mg/kg significantly increased AUC 0-t , AUC 0-inf , and AUMC by 1.5-fold, 1.6-fold, and 1.9-fold, respectively, when compared with the control rats treated with vehicle only.
TextSentencer_T418 52690-52879 Sentence denotes Similarly, there was a 1.4-fold, 1.5-fold, and 2-fold increase in AUC 0-t , AUC 0-inf , and AUMC, respectively, in rats treated with XKB 14 mg/kg for 8 days when compared with control rats.
T27482 52690-52879 Sentence denotes Similarly, there was a 1.4-fold, 1.5-fold, and 2-fold increase in AUC 0-t , AUC 0-inf , and AUMC, respectively, in rats treated with XKB 14 mg/kg for 8 days when compared with control rats.
TextSentencer_T419 52880-53054 Sentence denotes Compared with vehicletreated rats, the ratio of plasma AUC for 1′-OH-MDZ over that of midazolam was significantly decreased by 42.6% in rats treated orally with XKB 14 mg/kg.
T37951 52880-53054 Sentence denotes Compared with vehicletreated rats, the ratio of plasma AUC for 1′-OH-MDZ over that of midazolam was significantly decreased by 42.6% in rats treated orally with XKB 14 mg/kg.
TextSentencer_T420 53055-53162 Sentence denotes However, treatment of XKB at either dose did not change the CL/F and V/F of midazolam or 1′-OH-MDZ in rats.
T91514 53055-53162 Sentence denotes However, treatment of XKB at either dose did not change the CL/F and V/F of midazolam or 1′-OH-MDZ in rats.
TextSentencer_T421 53163-53460 Sentence denotes In addition, compared with normal saline or soybean oil, a single dose of ketoconazole 75 mg/kg significantly increased the C max , AUC 0-t , and AUC 0-inf of midazolam by 3.5-fold, 3.6-fold, and 3.6-fold, respectively, and decreased the V/F and CL/F of midazolam by 75.2% and 73.7%, respectively.
T9430 53163-53460 Sentence denotes In addition, compared with normal saline or soybean oil, a single dose of ketoconazole 75 mg/kg significantly increased the C max , AUC 0-t , and AUC 0-inf of midazolam by 3.5-fold, 3.6-fold, and 3.6-fold, respectively, and decreased the V/F and CL/F of midazolam by 75.2% and 73.7%, respectively.
TextSentencer_T422 53461-53657 Sentence denotes Further, compared with vehicle-treated rats, the ratio of the plasma AUC of 1′-OH-MDZ over that of midazolam was significantly decreased by 66.2% in rats treated orally with ketoconazole 75 mg/kg.
T555 53461-53657 Sentence denotes Further, compared with vehicle-treated rats, the ratio of the plasma AUC of 1′-OH-MDZ over that of midazolam was significantly decreased by 66.2% in rats treated orally with ketoconazole 75 mg/kg.
TextSentencer_T423 53658-53856 Sentence denotes Collectively, the above results show that XKB 7 or 14 mg/kg significantly reduced the metabolism of midazolam in rats without marked dose dependence, probably due to the decreased activity of Cyp3a.
T23722 53658-53856 Sentence denotes Collectively, the above results show that XKB 7 or 14 mg/kg significantly reduced the metabolism of midazolam in rats without marked dose dependence, probably due to the decreased activity of Cyp3a.
TextSentencer_T424 53857-54031 Sentence denotes Since the total clearance and distribution of midazolam and its metabolite were not altered by XKB, the possibility of modulation of other pathways by XKB cannot be excluded.
T94173 53857-54031 Sentence denotes Since the total clearance and distribution of midazolam and its metabolite were not altered by XKB, the possibility of modulation of other pathways by XKB cannot be excluded.
TextSentencer_T425 54032-54212 Sentence denotes Following observation of the reduced metabolism of the probe substrate, hepatic Cyp3a activity was measured using a luminescent assay after the rats were dosed with XKB for 8 days.
T44317 54032-54212 Sentence denotes Following observation of the reduced metabolism of the probe substrate, hepatic Cyp3a activity was measured using a luminescent assay after the rats were dosed with XKB for 8 days.
TextSentencer_T426 54213-54305 Sentence denotes As shown in Figure 7 , the activity of rat hepatic Cyp3a was significantly inhibited by XKB.
T99873 54213-54305 Sentence denotes As shown in Figure 7 , the activity of rat hepatic Cyp3a was significantly inhibited by XKB.
TextSentencer_T427 54306-54499 Sentence denotes In comparison with the vehicle group (soybean oil), there was a 6.27% (P0.05) and 29.27% (P0.001) decline in the activity of Cyp3a when rats were treated with 7 or 14 mg/kg XKB, respectively.
T27908 54306-54499 Sentence denotes In comparison with the vehicle group (soybean oil), there was a 6.27% (P0.05) and 29.27% (P0.001) decline in the activity of Cyp3a when rats were treated with 7 or 14 mg/kg XKB, respectively.
TextSentencer_T428 54500-54638 Sentence denotes Ketoconazole also showed significantly inhibited Cyp3a activity, with a 48.79% reduction (P0.001) compared with the saline-treated group.
T25637 54500-54638 Sentence denotes Ketoconazole also showed significantly inhibited Cyp3a activity, with a 48.79% reduction (P0.001) compared with the saline-treated group.
TextSentencer_T429 54639-54763 Sentence denotes To examine further the regulatory effect of XKB on Cyp3a levels, Cyp3a2 expression was determined by Western blotting assay.
T59570 54639-54763 Sentence denotes To examine further the regulatory effect of XKB on Cyp3a levels, Cyp3a2 expression was determined by Western blotting assay.
TextSentencer_T430 54764-54882 Sentence denotes As shown in Figure 8 , administration of XKB for 8 days significantly inhibited expression of Cyp3a2 in the rat liver.
T32070 54764-54882 Sentence denotes As shown in Figure 8 , administration of XKB for 8 days significantly inhibited expression of Cyp3a2 in the rat liver.
TextSentencer_T431 54883-55063 Sentence denotes Compared with the vehicle group (soybean oil), there was a 19.58% and 28.97% (P0.001) decrease in expression of Cyp3a2 when rats were treated with 7 or 14 mg/kg XKB, respectively.
T71408 54883-55063 Sentence denotes Compared with the vehicle group (soybean oil), there was a 19.58% and 28.97% (P0.001) decrease in expression of Cyp3a2 when rats were treated with 7 or 14 mg/kg XKB, respectively.
TextSentencer_T432 55064-55154 Sentence denotes However, administration of ketoconazole did not change Cyp3a2 expression in the rat liver.
T29214 55064-55154 Sentence denotes However, administration of ketoconazole did not change Cyp3a2 expression in the rat liver.
TextSentencer_T433 55155-55257 Sentence denotes Taken together, XKB has a potent inhibitory effect on Cyp3a2 expression and activity in the rat liver.
T31066 55155-55257 Sentence denotes Taken together, XKB has a potent inhibitory effect on Cyp3a2 expression and activity in the rat liver.
TextSentencer_T434 55258-55348 Sentence denotes The mechanisms for the downregulating effect of XKB on hepatic Cyp3a2 in rats are unknown.
T86970 55258-55348 Sentence denotes The mechanisms for the downregulating effect of XKB on hepatic Cyp3a2 in rats are unknown.
TextSentencer_T435 55349-55505 Sentence denotes XKB is a potent antioxidant with great potential for the treatment of CVD but its molecular targets and effects on drug-metabolizing enzymes remain unknown.
T13721 55349-55505 Sentence denotes XKB is a potent antioxidant with great potential for the treatment of CVD but its molecular targets and effects on drug-metabolizing enzymes remain unknown.
TextSentencer_T436 55506-55610 Sentence denotes 37 Human CYP3A is a major CYP subfamily that metabolizes over 60% of endogenous and exogenous materials.
T83503 55506-55610 Sentence denotes 37 Human CYP3A is a major CYP subfamily that metabolizes over 60% of endogenous and exogenous materials.
TextSentencer_T437 55611-55739 Sentence denotes 6 Modulation of the activity and expression of CYP3A would cause substantial changes in drug metabolism in the clinical setting.
T63540 55611-55739 Sentence denotes 6 Modulation of the activity and expression of CYP3A would cause substantial changes in drug metabolism in the clinical setting.
TextSentencer_T438 55740-55853 Sentence denotes In the present study, we predicted over 324 molecular targets and 61 related signaling pathways regulated by XKB.
T62710 55740-55853 Sentence denotes In the present study, we predicted over 324 molecular targets and 61 related signaling pathways regulated by XKB.
TextSentencer_T439 55854-55954 Sentence denotes We found that XKB interacted with the rat hepatic Cyp3a2 homology model via hydrogen bond formation.
T22637 55854-55954 Sentence denotes We found that XKB interacted with the rat hepatic Cyp3a2 homology model via hydrogen bond formation.
TextSentencer_T440 55955-56121 Sentence denotes Further, we found that XKB increased the AUC 0-t and C max of midazolam, and inhibited the activity and expression level of Cyp3a in rats treated with XKB for 8 days.
T82031 55955-56121 Sentence denotes Further, we found that XKB increased the AUC 0-t and C max of midazolam, and inhibited the activity and expression level of Cyp3a in rats treated with XKB for 8 days.
TextSentencer_T441 56122-56385 Sentence denotes Our findings indicate that the beneficial effects of XKB can be attributed to regulation of a network of molecular targets and signaling pathways and that XKB can regulate Cyp3a-mediated drug metabolism by suppressing the activity and expression of Cyp3a in vivo.
T21926 56122-56385 Sentence denotes Our findings indicate that the beneficial effects of XKB can be attributed to regulation of a network of molecular targets and signaling pathways and that XKB can regulate Cyp3a-mediated drug metabolism by suppressing the activity and expression of Cyp3a in vivo.
TextSentencer_T442 56386-56651 Sentence denotes Bioinformatic approaches have become a valuable way of predicting the interactome of a chemical molecule, so we used a DDI-CPI tool to predict the potential targets and employed DAVID to analyze the molecular targets and related signaling pathways regulated by XKB.
T21310 56386-56651 Sentence denotes Bioinformatic approaches have become a valuable way of predicting the interactome of a chemical molecule, so we used a DDI-CPI tool to predict the potential targets and employed DAVID to analyze the molecular targets and related signaling pathways regulated by XKB.
TextSentencer_T443 56652-56755 Sentence denotes Our findings show that XKB can modulate a number of functional proteins and related signaling pathways.
T83972 56652-56755 Sentence denotes Our findings show that XKB can modulate a number of functional proteins and related signaling pathways.
TextSentencer_T444 56756-56997 Sentence denotes These proteins and signaling pathways have important roles in the regulation of redox homeostasis, cell proliferation, apoptosis, energy metabolism, metabolism of xenobiotics, lipid and carbohydrate metabolism, and the inflammatory response.
T62627 56756-56997 Sentence denotes These proteins and signaling pathways have important roles in the regulation of redox homeostasis, cell proliferation, apoptosis, energy metabolism, metabolism of xenobiotics, lipid and carbohydrate metabolism, and the inflammatory response.
TextSentencer_T445 56998-57265 Sentence denotes Interestingly, XKB shared a number of molecular targets with probucol, which was initially developed as an antihyperlipidemic drug for the treatment of coronary artery diseases but was removed from the USA market in 1995 after it was found to prolong the QT interval.
T62709 56998-57265 Sentence denotes Interestingly, XKB shared a number of molecular targets with probucol, which was initially developed as an antihyperlipidemic drug for the treatment of coronary artery diseases but was removed from the USA market in 1995 after it was found to prolong the QT interval.
TextSentencer_T446 57266-57388 Sentence denotes 33, 43 The overlapped molecular targets suggest that XKB can regulate the same targets and signaling pathways as probucol.
T70239 57266-57388 Sentence denotes 33, 43 The overlapped molecular targets suggest that XKB can regulate the same targets and signaling pathways as probucol.
TextSentencer_T447 57389-57589 Sentence denotes Probucol has been reported to lower cholesterol levels in the blood by increasing the rate of low-density lipoprotein catabolism, inhibiting cholesterol synthesis, and delaying cholesterol absorption.
T98990 57389-57589 Sentence denotes Probucol has been reported to lower cholesterol levels in the blood by increasing the rate of low-density lipoprotein catabolism, inhibiting cholesterol synthesis, and delaying cholesterol absorption.
TextSentencer_T448 57590-57698 Sentence denotes 44 It is also a potent antioxidant that suppresses the oxidation of cholesterol in low-density lipoproteins.
T87918 57590-57698 Sentence denotes 44 It is also a potent antioxidant that suppresses the oxidation of cholesterol in low-density lipoproteins.
TextSentencer_T449 57699-57777 Sentence denotes The cholesterol efflux regulatory protein ABCA1 is considered its main target.
T84028 57699-57777 Sentence denotes The cholesterol efflux regulatory protein ABCA1 is considered its main target.
TextSentencer_T450 57778-57940 Sentence denotes 45 As a natural marine compound, XKB may be a promising agent for the treatment of CVD when its potential cardiovascular side effects can be minimized or avoided.
T84574 57778-57940 Sentence denotes 45 As a natural marine compound, XKB may be a promising agent for the treatment of CVD when its potential cardiovascular side effects can be minimized or avoided.
TextSentencer_T451 57941-58005 Sentence denotes Notes: values are shown as the mean ± standard deviation, (n=5).
T39943 57941-58005 Sentence denotes Notes: values are shown as the mean ± standard deviation, (n=5).
TextSentencer_T452 58006-58070 Sentence denotes Abbreviations: RSD, relative standard deviation; MDZ, midazolam.
T9639 58006-58070 Sentence denotes Abbreviations: RSD, relative standard deviation; MDZ, midazolam.
TextSentencer_T453 58071-58454 Sentence denotes The DDI-CPI approach provides a rapid and inexpensive strategy to predict potential targets, identify drug repositioning potential, and evaluate and determine adverse drug reactions of a chemical/drug via molecular docking of small compound across human proteome, 23, 24, 27, 46, 47 although this web-based program has several limitations that may affect the accuracy of the outcome.
T7436 58071-58454 Sentence denotes The DDI-CPI approach provides a rapid and inexpensive strategy to predict potential targets, identify drug repositioning potential, and evaluate and determine adverse drug reactions of a chemical/drug via molecular docking of small compound across human proteome, 23, 24, 27, 46, 47 although this web-based program has several limitations that may affect the accuracy of the outcome.
TextSentencer_T454 58455-58596 Sentence denotes 24 For example, DDI-CPI is able to fully reveal potential targets due to the lack of a human protein structure and the assessment stringency.
T79558 58455-58596 Sentence denotes 24 For example, DDI-CPI is able to fully reveal potential targets due to the lack of a human protein structure and the assessment stringency.
TextSentencer_T455 58597-58874 Sentence denotes 24 XKB has shown potent antioxidative, anti-inflammatory, and anticancer effects in preclinical studies. [17] [18] This is supported by our prediction that XKB can target multiple pathways associated with oxidative stress, redox homoeostasis, cell proliferation, and apoptosis.
T40301 58597-58874 Sentence denotes 24 XKB has shown potent antioxidative, anti-inflammatory, and anticancer effects in preclinical studies. [17] [18] This is supported by our prediction that XKB can target multiple pathways associated with oxidative stress, redox homoeostasis, cell proliferation, and apoptosis.
TextSentencer_T456 58875-59047 Sentence denotes In order to characterize the role of XKB in the regulation of CYPs, we next performed a homology modeling experiment to examine the interactions between XKB and rat Cyp3a2.
T54705 58875-59047 Sentence denotes In order to characterize the role of XKB in the regulation of CYPs, we next performed a homology modeling experiment to examine the interactions between XKB and rat Cyp3a2.
TextSentencer_T457 59048-59124 Sentence denotes The rat Cyp3a2 homology model was built based on human CYP3A4 (PDB ID 4K9W).
T70749 59048-59124 Sentence denotes The rat Cyp3a2 homology model was built based on human CYP3A4 (PDB ID 4K9W).
TextSentencer_T458 59125-59244 Sentence denotes Our data show that the rat Cyp3a2 homology model shared 83.3% sequence similarity and 68.4% identity with human CYP3A4.
T80694 59125-59244 Sentence denotes Our data show that the rat Cyp3a2 homology model shared 83.3% sequence similarity and 68.4% identity with human CYP3A4.
TextSentencer_T459 59245-59342 Sentence denotes It has been reported that rat Cyp3a2 exhibits a 73% homology amino acid sequence to human CYP3A4.
T11835 59245-59342 Sentence denotes It has been reported that rat Cyp3a2 exhibits a 73% homology amino acid sequence to human CYP3A4.
TextSentencer_T460 59343-59416 Sentence denotes 48 This difference may affect the interaction between XKB and rat Cyp3a2.
T61354 59343-59416 Sentence denotes 48 This difference may affect the interaction between XKB and rat Cyp3a2.
TextSentencer_T461 59417-59577 Sentence denotes Indeed, our findings show that XKB interacted with the rat Cyp3a2 homology model via hydrogen bond formation at Ala482 located in the active site of the enzyme.
T63432 59417-59577 Sentence denotes Indeed, our findings show that XKB interacted with the rat Cyp3a2 homology model via hydrogen bond formation at Ala482 located in the active site of the enzyme.
TextSentencer_T462 59578-59687 Sentence denotes However, there was no interaction between XKB and human CYP3A4 Ala482 located in the active site, but Gly481.
T77700 59578-59687 Sentence denotes However, there was no interaction between XKB and human CYP3A4 Ala482 located in the active site, but Gly481.
TextSentencer_T463 59688-59813 Sentence denotes Collectively, our modeling study shows that XKB can act as a substrate and/or inhibitor for both rat Cyp3a2 and human CYP3A4.
T85387 59688-59813 Sentence denotes Collectively, our modeling study shows that XKB can act as a substrate and/or inhibitor for both rat Cyp3a2 and human CYP3A4.
TextSentencer_T464 59814-60012 Sentence denotes However, when we extrapolate these results to humans, we should bear in mind that Cyp3a2 and CYP3A4 share a certain degree of sequence similarity identity, so functional validation is always needed.
T7305 59814-60012 Sentence denotes However, when we extrapolate these results to humans, we should bear in mind that Cyp3a2 and CYP3A4 share a certain degree of sequence similarity identity, so functional validation is always needed.
TextSentencer_T465 60013-60346 Sentence denotes The ADMET Predictor showed that XKB had moderate water solubility and oral absorption and that probucol had very low water solubility and oral absorption, which is consistent with previously reported data. [38] [39] [40] [41] The predicted ADMET profiles show that XKB might be a better oral agent than probucol for drug development.
T90003 60013-60346 Sentence denotes The ADMET Predictor showed that XKB had moderate water solubility and oral absorption and that probucol had very low water solubility and oral absorption, which is consistent with previously reported data. [38] [39] [40] [41] The predicted ADMET profiles show that XKB might be a better oral agent than probucol for drug development.
TextSentencer_T466 60347-60481 Sentence denotes Midazolam is a probe substrate for CYP3A with sedative, amnesic, anxiolytic, muscle relaxant, and anticonvulsant properties in humans.
T47815 60347-60481 Sentence denotes Midazolam is a probe substrate for CYP3A with sedative, amnesic, anxiolytic, muscle relaxant, and anticonvulsant properties in humans.
TextSentencer_T467 60482-60720 Sentence denotes It has been widely used to examine the degree of drug interaction and inhibitory effect of xenobiotics on the activity and function of CYP3A4/5 via evaluation of urinary and/or plasma levels of midazolam and its main metabolite 1′-OH-MDZ.
T47847 60482-60720 Sentence denotes It has been widely used to examine the degree of drug interaction and inhibitory effect of xenobiotics on the activity and function of CYP3A4/5 via evaluation of urinary and/or plasma levels of midazolam and its main metabolite 1′-OH-MDZ.
TextSentencer_T468 60721-60986 Sentence denotes 49, 50 In our study, plasma concentrations of midazolam and 1′-OH-MDZ were determined using a validated HPLC method with a high specificity, linearity, precision, accuracy, and recovery rate for midazolam and 1′-OH-MDZ, and the tested samples showed high stability.
T12816 60721-60986 Sentence denotes 49, 50 In our study, plasma concentrations of midazolam and 1′-OH-MDZ were determined using a validated HPLC method with a high specificity, linearity, precision, accuracy, and recovery rate for midazolam and 1′-OH-MDZ, and the tested samples showed high stability.
TextSentencer_T469 60987-61103 Sentence denotes This indicates that the HPLC method is reliable for determining the plasma concentration of midazolam and 1′-OH-MDZ.
T41630 60987-61103 Sentence denotes This indicates that the HPLC method is reliable for determining the plasma concentration of midazolam and 1′-OH-MDZ.
TextSentencer_T470 61104-61264 Sentence denotes Our present findings show that oral administration of XKB 14 kg/mg for 8 days significantly elevated the AUC 0-t and C max of midazolam, but decreased its CL/F.
T97972 61104-61264 Sentence denotes Our present findings show that oral administration of XKB 14 kg/mg for 8 days significantly elevated the AUC 0-t and C max of midazolam, but decreased its CL/F.
TextSentencer_T471 61265-61380 Sentence denotes XKB also showed an inhibitory effect on the metabolism of midazolam similar to that seen with ketoconazole in vivo.
T31671 61265-61380 Sentence denotes XKB also showed an inhibitory effect on the metabolism of midazolam similar to that seen with ketoconazole in vivo.
TextSentencer_T472 61381-61523 Sentence denotes However, there were not remarkable changes in the k a , k e , t 1/2ka , t 1/2ke , and V/F of midazolam and 1′-OH-MDZ in rats treated with XKB.
T70602 61381-61523 Sentence denotes However, there were not remarkable changes in the k a , k e , t 1/2ka , t 1/2ke , and V/F of midazolam and 1′-OH-MDZ in rats treated with XKB.
TextSentencer_T473 61524-61644 Sentence denotes Collectively, the data strongly suggest that XKB decreased Cyp3a-mediated metabolism and clearance of midazolam in rats.
T25785 61524-61644 Sentence denotes Collectively, the data strongly suggest that XKB decreased Cyp3a-mediated metabolism and clearance of midazolam in rats.
TextSentencer_T474 61645-61852 Sentence denotes Notably, it has been reported that midazolam has inducing effects on expression of Cyp3a1 and Cyp2b in rat hepatocytes, 51 which in turn may affect its own metabolism and that of other Cyp3a substrate drugs.
T8487 61645-61852 Sentence denotes Notably, it has been reported that midazolam has inducing effects on expression of Cyp3a1 and Cyp2b in rat hepatocytes, 51 which in turn may affect its own metabolism and that of other Cyp3a substrate drugs.
TextSentencer_T475 61853-62109 Sentence denotes Further, we found that oral administration of XKB for 8 days significantly reduced the expression and activity of hepatic Cyp3a via unknown mechanisms, but probably due Effect of oral administration of XKB on hepatic Cyp3a activity in rat liver microsomes.
T89835 61853-62109 Sentence denotes Further, we found that oral administration of XKB for 8 days significantly reduced the expression and activity of hepatic Cyp3a via unknown mechanisms, but probably due Effect of oral administration of XKB on hepatic Cyp3a activity in rat liver microsomes.
TextSentencer_T476 62110-62116 Sentence denotes Notes:
T77549 62110-62116 Sentence denotes Notes:
TextSentencer_T477 62117-62179 Sentence denotes Rats were treated with XKB orally at 7 or 14 mg/kg for 8 days.
T68939 62117-62179 Sentence denotes Rats were treated with XKB orally at 7 or 14 mg/kg for 8 days.
TextSentencer_T478 62180-62268 Sentence denotes The rats were sacrificed, the livers were collected, and liver microsomes were prepared.
T61672 62180-62268 Sentence denotes The rats were sacrificed, the livers were collected, and liver microsomes were prepared.
TextSentencer_T479 62269-62335 Sentence denotes Cyp3a activity was measured using a luminescent assay (P450-Glo™).
T56076 62269-62335 Sentence denotes Cyp3a activity was measured using a luminescent assay (P450-Glo™).
TextSentencer_T480 62336-62391 Sentence denotes The bars represent the mean ± standard deviation (n=8).
T19451 62336-62391 Sentence denotes The bars represent the mean ± standard deviation (n=8).
TextSentencer_T481 62392-62536 Sentence denotes KTZ (as the positive control) showed significant inhibition of Cyp3a activity by 48.79% (P0.001) compared with the normal saline-treated group.
T17136 62392-62536 Sentence denotes KTZ (as the positive control) showed significant inhibition of Cyp3a activity by 48.79% (P0.001) compared with the normal saline-treated group.
TextSentencer_T482 62537-62694 Sentence denotes Treatment of XKB at 7 or 14 mg/kg decreased Cyp3a2 activity by 6.27% (P0.05) and 29.27% (P0.001), respectively. ***P0.001 by one-way analysis of variance.
T46231 62537-62694 Sentence denotes Treatment of XKB at 7 or 14 mg/kg decreased Cyp3a2 activity by 6.27% (P0.05) and 29.27% (P0.001), respectively. ***P0.001 by one-way analysis of variance.
TextSentencer_T483 62695-62813 Sentence denotes Abbreviations: CYP, cytochrome P450; XKB, Xyloketal B; KTZ, ketoconazole. with toxicity-associated targets (eg, hERG).
T39110 62695-62813 Sentence denotes Abbreviations: CYP, cytochrome P450; XKB, Xyloketal B; KTZ, ketoconazole. with toxicity-associated targets (eg, hERG).
TextSentencer_T484 62814-62913 Sentence denotes The potential interactions between XKB and CYP3A4/Cyp3a2 may lead to unfavorable drug interactions.
T26761 62814-62913 Sentence denotes The potential interactions between XKB and CYP3A4/Cyp3a2 may lead to unfavorable drug interactions.
TextSentencer_T485 62914-63087 Sentence denotes In addition, the short elimination half-life of XKB may negatively affect its concentration at the site of action and compromise the therapeutic effect in clinical practice.
T53103 62914-63087 Sentence denotes In addition, the short elimination half-life of XKB may negatively affect its concentration at the site of action and compromise the therapeutic effect in clinical practice.
TextSentencer_T486 63088-63402 Sentence denotes Therefore, these findings provide clues for further XKB-based drug development and clinical use, including structural modification or nanotechnology-based formulations to minimize or avoid its potential side effects and prolong its elimination half-life to achieve therapeutic concentrations at the site of action.
T11493 63088-63402 Sentence denotes Therefore, these findings provide clues for further XKB-based drug development and clinical use, including structural modification or nanotechnology-based formulations to minimize or avoid its potential side effects and prolong its elimination half-life to achieve therapeutic concentrations at the site of action.
TextSentencer_T487 63403-63723 Sentence denotes In summary, we found that the medicinal effects of XKB could be ascribed to modulation of the networks of functional proteins and the related signaling pathways, and that XKB significantly inhibited the Cyp3a-mediated metabolism of midazolam in rats in vivo via reduction of the activity and expression of hepatic Cyp3a.
T29040 63403-63723 Sentence denotes In summary, we found that the medicinal effects of XKB could be ascribed to modulation of the networks of functional proteins and the related signaling pathways, and that XKB significantly inhibited the Cyp3a-mediated metabolism of midazolam in rats in vivo via reduction of the activity and expression of hepatic Cyp3a.
TextSentencer_T488 63724-63910 Sentence denotes Our findings suggest that XKB may behave as a CYP3A4/Cyp3a2 substrate and/or inhibitor, probably altering the PK profile of coadministered drugs metabolized by CYP3A4/Cyp3a2 in the body.
T35617 63724-63910 Sentence denotes Our findings suggest that XKB may behave as a CYP3A4/Cyp3a2 substrate and/or inhibitor, probably altering the PK profile of coadministered drugs metabolized by CYP3A4/Cyp3a2 in the body.
TextSentencer_T489 63911-64046 Sentence denotes The molecular targets and modulating effects of XKB on human CYPs need to be further examined and functionally validated in the future.
T65310 63911-64046 Sentence denotes The molecular targets and modulating effects of XKB on human CYPs need to be further examined and functionally validated in the future.