Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study reports the absorption, dose-linearity and pharmacokinetics of a novel antiangiogenic agent KR-31831 in rats after i.v. and oral administration at doses of 5, 10 and 25 mg/kg on both occasions. Concentrations of KR-31831 were determined by a validated LC/MS/MS assay method. After i.v. injection, plasma concentration-time profiles showed multi-compartmental characteristics, and there were no significant differences in Cl (20.8-27.7 ml/min/kg) and dose-normalized AUC (178.1-231 microg x min/ml based on the 5 mg/kg dose) as a function of dose. However, Vss was significantly increased at the 25 mg/kg dose (4931 ml/kg) compared with those (2288-2421 ml/kg) at lower doses. Subsequently, t1/2 was increased from 143-159 min at the lower doses to 304 min at the 25 mg/kg dose. The altered VSS was found to be a result of reduced plasma protein binding at relatively high concentrations. Following oral administration (doses 5-25 mg/kg), the absolute oral bioavailability ranged from 37.8% to 46.3%, and there were no significant alterations in dose-normalized AUC, Tmax, Cmax and t1/2 as a function of dose. The extent of urinary excretion was low for both i.v. (0.35%-0.54%) and oral (0.13%-0.33%) doses. Further discussions on the chemical and microsomal stability were included. In conclusion, dose-independent absorption kinetics were observed at oral doses from 5 to 25 mg/kg in rats. Orally administered KR-31831 could be eliminated mainly by the liver metabolic pathway.
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PMID:Pharmacokinetics of a novel antiangiogenic agent KR-31831 in rats. 1557 34

Microsomal membranes isolated from red beet (Beta vulgaris L.) storage tissue were found to contain high levels of ionophore-stimulated ATPase activity. The distribution of this ATPase activity on a continuous sucrose gradient showed a low density peak (1.09 grams per cubic centimeter) that was stimulated over 400% by gramicidin and coincided with a peak of NO(3) (-)-sensitive ATPase activity. At higher densities (1.16-1.18 grams per cubic centimeter) a shoulder of gramicidin-stimulated ATPase that coincided with a peak of vanadate-sensitive ATPase was apparent. A discontinuous sucrose gradient of 16/26/34/40% sucrose (w/w) was effective in routinely separating the NO(3) (-)-sensitive ATPase (16/26% interface) from the vanadate-sensitive ATPase (34/40% interface). Both membrane fractions were shown to catalyze ATP-dependent H(+) transport, with the transport process showing the same differential sensitivity to NO(3) (-) and vanadate as the ATPase activity.Characterization of the lower density ATPase (16/26% interface) indicated that it was highly stimulated by gramicidin, inhibited by KNO(3), stimulated by anions (Cl(-) > Br(-) > acetate > HCO(3) (-) > SO(4) (2-)), and largely insensitive to monovalent cations. These characteristics are very similar to those reported for tonoplast ATPase activity and a tonoplast origin for the low density membrane vesicles was supported by comparison with isolated red beet vacuoles. The membranes isolated from the vacuole preparation were found to possess an ATPase with characteristics identical to those of the low density membrane vesicles, and were shown to have a peak density of 1.09 grams per cubic centimeter. Furthermore, following osmotic lysis the vacuolar membranes apparently resealed and ATP-dependent H(+) transport could be demonstrated in these vacuole-derived membrane vesicles. This report, thus, strongly supports a tonoplast origin for the low density, anion-sensitive H(+)-ATPase and further indicates the presence of a higher density, vanadate-sensitive, H(+)-ATPase in the red beet microsomal membrane fraction, which is presumably of plasma membrane origin.
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PMID:H-ATPase Activity from Storage Tissue of Beta vulgaris: I. Identification and Characterization of an Anion-Sensitive H-ATPase. 1666 57

2,3,7,8 Tetrachlorodibenzo-p-dioxin (TCDD) is an aromatic, long-lived environmental contaminant. While the pathogenesis of TCDD-induced toxicity is poorly understood, it has been shown that the aryl hydrocarbon receptor (AHR) is required. However, the specific transcriptomic changes that lead to toxic outcomes have not yet been identified. We previously identified a panel of 33 genes that respond to TCDD treatment in two TCDD-sensitive rodent species. To identify genes involved in the onset of hepatic toxicity, we explored 25 of these in-depth using liver from two rat strains: the TCDD-resistant Han/Wistar (H/W) and the TCDD-sensitive Long-Evans (L-E). Time course and dose-response analyses of mRNA abundance following TCDD insult indicate that eight genes are similarly regulated in livers of both strains of rat, suggesting that they are not central to the severe L-E-specific TCDD-induced toxicities. The remaining 17 genes exhibited various divergent mRNA abundances between L-E and H/W strains after TCDD treatment. Several genes displayed a biphasic response where the initial response to TCDD treatment was followed by a secondary response, usually of larger magnitude in L-E liver. This secondary response was most often an exaggeration of the original TCDD-induced response. Only cytochrome b5 type A (microsomal) (Cyb5a) had equivalent TCDD sensitivity to the prototypic AHR-responsive cytochrome P450, family 1, subfamily a, polypeptide 1 (Cyp1a1), while six genes were less sensitive. Four genes showed an early inter-strain difference that was sustained throughout most of the time course (atypical chemokine receptor 3 (Ackr3), collagen, type XVIII, alpha 1 (Col18a1), Cyb5a and glutamate dehydrogenase 1 (Glud1)), and of those genes examined in this study, are most likely to represent genes involved in the pathogenesis of TCDD-induced hepatotoxicity in L-E rats.
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PMID:2,3,7,8 Tetrachlorodibenzo-p-dioxin-induced RNA abundance changes identify Ackr3, Col18a1, Cyb5a and Glud1 as candidate mediators of toxicity. 2713 98