Objective:To explore the glucuronic acid metabolism of acacetin in human liver and intestinal microsomes to better characterize human uridine 5'-diphospho (UDP)-glucuronosyltransferase (UGT) isoforms.In addition,i...Objective:To explore the glucuronic acid metabolism of acacetin in human liver and intestinal microsomes to better characterize human uridine 5'-diphospho (UDP)-glucuronosyltransferase (UGT) isoforms.In addition,interspecies comparisons were performed to identify the most appropriate experimental animal model for an in vivo study.Methods:Liquid chromatography tandem mass spectrometry (LC-MS/MS) and nuclear magnetic resonance (NMR) were used to confirm the successful biosynthesis of acacetin-7-O-glucuronide.Human isoforms of UGT and isozyme-specific chemical inhibitors were used for recombinant assays.Acacetin glucuronidation kinetics were assessed by combining acacetin with recombinant human UGT isoforms or with microsomes from humans or experimental animals.Kinetic differences between species were assessed in vitro using the same approach.Results:We identified multiple UGT isoforms that facilitated acacetin glucuronidation,and found that UGT1A1 was the major isoform that catalyzed this process.Acacetin-7-O-glucuronide formation exhibited clear substrate inhibition kinetics when combined with recombinant UGTs or with liver/intestinal microsomes derived from humans,monkeys,rats,mice,dogs,or pigs.Intrinsic metabolic clearance values of human intestinal microsomes were two-fold greater than those of human liver microsomes.Among the evaluated species,the Km value of dog microsomes (0.86 μM) was greatest in acacetin glucuronidation,while mice exhibited the highest CLint value,5.05 mL/min/mg.The CLint values of microsomes derived from monkeys and minipigs were 1.99 mL/min/mg and 2.12 mL/min/mg,respectively,exhibiting similar intrinsic metabolic clearance activity to that observed in humans.Conclusion:Monkey may represent a suitable model for experimental studies of acacetin pharmacokinetics owing to a high sequence homology of UGT1A1 and similar UGT1A1 glucuronidation activity to humans.展开更多
Objective:To uncover and identify the hot topic and frontier of Chinese medicines treatment of type 2 diabetes mellitus(T2DM).Methods:Web of Science TM was searched for published articles for Chinese medicines treatme...Objective:To uncover and identify the hot topic and frontier of Chinese medicines treatment of type 2 diabetes mellitus(T2DM).Methods:Web of Science TM was searched for published articles for Chinese medicines treatment of T2DM ranging from January 1st,2002 to July 6th,2016.Knowledge maps of the international Chinese medicines treatment of T2DM are visualized by using document cooccurrence analysis and word frequency analysis(Institution and Journal),co-citation clustering analysis(Co-reference),keyword co-occurrence clustering analysis with CiteSpac III,a tool of scientometrics.Results:Universidad Nacional Autonoma de Mexico is the institution with the highest number of published papers that had been cited in this field,while China has four institutions among the top 10.The journal of the highest frequency of co-cited journal was Diabetes Care,a core one in the field.Keywords co-occurrence network was composed of 185 nodes,541 lines,and divided into 10 clusters.Co-citation network of co-reference was composed of 407 nodes,1199 lines,and divided into 20 clusters.Using Chinese medicine to improve insulin resistance and Chinese medicine research on blood glucose control are the hot topics.The frontier contains two aspects:new drugs development and application of intestinal insulin treatment and development and use of traditional Chinese medicine antidiabetic plants.Conclusion:Institutions from China still plays a major role in TCM-focused T2DM studies.The effect of TCM herbs on insulin resistance is the hot topic of the domain.Developing new TCM herbal medicine that regulates incretin effect is the domain frontier.Research on the Chinese medicines treatment of T2DM needs more high-quality evidence to support,and its mechanism requires further exploration.展开更多
基金the National Natural Science Foundation of China(81473800).
文摘Objective:To explore the glucuronic acid metabolism of acacetin in human liver and intestinal microsomes to better characterize human uridine 5'-diphospho (UDP)-glucuronosyltransferase (UGT) isoforms.In addition,interspecies comparisons were performed to identify the most appropriate experimental animal model for an in vivo study.Methods:Liquid chromatography tandem mass spectrometry (LC-MS/MS) and nuclear magnetic resonance (NMR) were used to confirm the successful biosynthesis of acacetin-7-O-glucuronide.Human isoforms of UGT and isozyme-specific chemical inhibitors were used for recombinant assays.Acacetin glucuronidation kinetics were assessed by combining acacetin with recombinant human UGT isoforms or with microsomes from humans or experimental animals.Kinetic differences between species were assessed in vitro using the same approach.Results:We identified multiple UGT isoforms that facilitated acacetin glucuronidation,and found that UGT1A1 was the major isoform that catalyzed this process.Acacetin-7-O-glucuronide formation exhibited clear substrate inhibition kinetics when combined with recombinant UGTs or with liver/intestinal microsomes derived from humans,monkeys,rats,mice,dogs,or pigs.Intrinsic metabolic clearance values of human intestinal microsomes were two-fold greater than those of human liver microsomes.Among the evaluated species,the Km value of dog microsomes (0.86 μM) was greatest in acacetin glucuronidation,while mice exhibited the highest CLint value,5.05 mL/min/mg.The CLint values of microsomes derived from monkeys and minipigs were 1.99 mL/min/mg and 2.12 mL/min/mg,respectively,exhibiting similar intrinsic metabolic clearance activity to that observed in humans.Conclusion:Monkey may represent a suitable model for experimental studies of acacetin pharmacokinetics owing to a high sequence homology of UGT1A1 and similar UGT1A1 glucuronidation activity to humans.
基金National Natural Science Foundation of China(No.81273876).
文摘Objective:To uncover and identify the hot topic and frontier of Chinese medicines treatment of type 2 diabetes mellitus(T2DM).Methods:Web of Science TM was searched for published articles for Chinese medicines treatment of T2DM ranging from January 1st,2002 to July 6th,2016.Knowledge maps of the international Chinese medicines treatment of T2DM are visualized by using document cooccurrence analysis and word frequency analysis(Institution and Journal),co-citation clustering analysis(Co-reference),keyword co-occurrence clustering analysis with CiteSpac III,a tool of scientometrics.Results:Universidad Nacional Autonoma de Mexico is the institution with the highest number of published papers that had been cited in this field,while China has four institutions among the top 10.The journal of the highest frequency of co-cited journal was Diabetes Care,a core one in the field.Keywords co-occurrence network was composed of 185 nodes,541 lines,and divided into 10 clusters.Co-citation network of co-reference was composed of 407 nodes,1199 lines,and divided into 20 clusters.Using Chinese medicine to improve insulin resistance and Chinese medicine research on blood glucose control are the hot topics.The frontier contains two aspects:new drugs development and application of intestinal insulin treatment and development and use of traditional Chinese medicine antidiabetic plants.Conclusion:Institutions from China still plays a major role in TCM-focused T2DM studies.The effect of TCM herbs on insulin resistance is the hot topic of the domain.Developing new TCM herbal medicine that regulates incretin effect is the domain frontier.Research on the Chinese medicines treatment of T2DM needs more high-quality evidence to support,and its mechanism requires further exploration.
