BACKGROUND UDP-glucose 6-dehydrogenase(UGDH)is a key enzyme in glucuronic acid metabolism and acts as a key mediator in several cancer developmental signaling pathways.AIM To offer a more systematic and comprehensive ...BACKGROUND UDP-glucose 6-dehydrogenase(UGDH)is a key enzyme in glucuronic acid metabolism and acts as a key mediator in several cancer developmental signaling pathways.AIM To offer a more systematic and comprehensive elucidation of the involvement of UGDH in the onset and progression of various malignancies.METHODS The role of UGDH in cancer was investigated via public databases.The data were analyzed via various R packages and websites,including TISIDB,cBioPortal,STRING,Cytoscape,GSCALite,and CancerSEA.A rat hepatocellular carcinoma(HCC)model was established via the intraperitoneal injection of diethylnitrosamine.Hematoxylin-eosin staining,Masson staining,Ki67 and UGDH immunohistochemical staining,and ARG1 immunofluorescence staining of liver tissues were performed.Real-time quantitative PCR and Western blotting were used to detect UGDH expression.The UGDH gene was knocked down in Huh7 cells,and CCK8 and nude mouse tumor xenograft assays were performed.RESULTS High UGDH expression is associated with poor clinical outcomes in HCC,lung adenocarcinoma,lung squamous cell carcinoma,and sarcoma patients and is differentially expressed across molecular and immune subtypes.UGDH is primarily involved in the pentose and glucuronate interconversion pathway.Its expression is positively correlated with T helper,Tcm,and Th2 cells in most cancers.Moreover,experimental results demonstrated that UGDH expression is elevated in HCC tissues and that its downregulation inhibits HCC cell proliferation.CONCLUSION Our study revealed that UGDH could be a valuable prognostic biomarker and potential therapeutic target in many cancers,especially liver and lung cancer.UGDH could promote HCC cell proliferation,potentially by modulating the pentose and glucuronate interconversion pathways.展开更多
Edaravone glucuronate and edaravone sulfate,two metabolites of edaravone,were synthesized in improved yields. Edaravone glucuronate was synthesized by conjugation of edaravone with glucuronolactone through a series of...Edaravone glucuronate and edaravone sulfate,two metabolites of edaravone,were synthesized in improved yields. Edaravone glucuronate was synthesized by conjugation of edaravone with glucuronolactone through a series of reactions.Edaravone sulfate was synthesized through sulfonation of edaravone.Compared with the reported methods in the literature,the yields of both metabolites with the improved methods were much higher.展开更多
The objective of this study was to determine the concentrations of the metabolites of four selected phthalates, widely used industrial chemicals which possess endocrine-disrupting properties, in samples of amniotic fl...The objective of this study was to determine the concentrations of the metabolites of four selected phthalates, widely used industrial chemicals which possess endocrine-disrupting properties, in samples of amniotic fluid and maternal urine collected in the same day, in order to verify if the latter can be considered a measure of the fetal exposure. The quantitative determination of the metabolites was carried out by HPLC-MS/MS with isotopic dilution from 70 pregnant volunteers. Detectable concentrations of phthalates metabolites were found in amniotic fluids. As phthalate monoesters are excreted in the urine conjugated with glucuronic acid, an enzymatic hydrolysis is carried out before analysis. Amniotic fluids were tested with and without hydrolysis and only the free phthalate metabolites, not conjugated with glucuronic acid, were found. The concentration of metabolites after enzymatic hydrolysis in maternal urine is not correlated to those of amniotic fluids, but the free form concentrations are. These results suggest that only the free forms can cross the placenta. A significant number of mothers showed urine phthalate monoesters concentrations higher than non-pregnant women.展开更多
Objective:Phenolic acids widely exist in the human diet and exert beneficial effects such as improving glucose metabolism.It is not clear whether phenolic acids or their metabolites play a major role in vivo.In this s...Objective:Phenolic acids widely exist in the human diet and exert beneficial effects such as improving glucose metabolism.It is not clear whether phenolic acids or their metabolites play a major role in vivo.In this study,caffeic acid(CA)and ferulic acid(FA),the two most ingested phenolic acids,and their glucuronic acid metabolites,caffeic-4’-O-glucuronide(CA4G)and ferulic-4’-O-glucuronide(FA4G),were investigated.Methods:Three insulin resistance models in vitro were established by using TNF-a,insulin and palmitic acid(PA)in HepG2 cells,respectively.We compared the effects of FA,FA4G,CA and CA4G on glucose metabolism in these models by measuring the glucose consumption levels.The potential targets and related pathways were predicted by network pharmacology.Fluorescence quenching measurement was used to analyze the binding between the compounds and the predicted target.To investigate the binding mode,molecular docking was performed.Then,we performed membrane recruitment assays of the AKT pleckstrin homology(PH)domain with the help of the PH-GFP plasmid.AKT enzymatic activity was determined to compare the effects between the metabolites with their parent compounds.Finally,the downstream signaling pathway of AKT was investigated by Western blot analysis.Results:The results showed that CA4G and FA4G were more potent than their parent compounds in increasing glucose consumption.AKT was predicted to be the key target of CA4G and FA4G by network pharmacology analysis.The fluorescence quenching test confirmed the more potent binding to AKT of the two metabolites compared to their parent compounds.The molecular docking results indicated that the carbonyl group in the glucuronic acid structure of CA4G and FA4G might bind to the PH domain of AKT at the key Arg-25 site.CA4G and FA4G inhibited the translocation of the AKT PH domain to the membrane,while increasing the activity of AKT.Western blot analysis demonstrated that the metabolites could increase the phosphorylation of AKT and downstream glycogen synthase kinase 3βin the AKT signaling pathway to increase glucose consumption.Conclusion:In conclusion,our results suggested that the metabolites of phenolic acids,which contain glucuronic acid,are the key active substances and that they activate AKT by targeting the PH domain,thus improving glucose metabolism.展开更多
基金Supported by National Natural Science Foundation of China,No.82405314Horizontal Project of Dongzhimen Hospital,No.HX-DZM-202405+1 种基金Project of Beijing University of Chinese Medicine,No.DZMG-QNZX-24015Traditional Chinese Medicine Foundation of Xiamen,No.XWZY-2023-0616.
文摘BACKGROUND UDP-glucose 6-dehydrogenase(UGDH)is a key enzyme in glucuronic acid metabolism and acts as a key mediator in several cancer developmental signaling pathways.AIM To offer a more systematic and comprehensive elucidation of the involvement of UGDH in the onset and progression of various malignancies.METHODS The role of UGDH in cancer was investigated via public databases.The data were analyzed via various R packages and websites,including TISIDB,cBioPortal,STRING,Cytoscape,GSCALite,and CancerSEA.A rat hepatocellular carcinoma(HCC)model was established via the intraperitoneal injection of diethylnitrosamine.Hematoxylin-eosin staining,Masson staining,Ki67 and UGDH immunohistochemical staining,and ARG1 immunofluorescence staining of liver tissues were performed.Real-time quantitative PCR and Western blotting were used to detect UGDH expression.The UGDH gene was knocked down in Huh7 cells,and CCK8 and nude mouse tumor xenograft assays were performed.RESULTS High UGDH expression is associated with poor clinical outcomes in HCC,lung adenocarcinoma,lung squamous cell carcinoma,and sarcoma patients and is differentially expressed across molecular and immune subtypes.UGDH is primarily involved in the pentose and glucuronate interconversion pathway.Its expression is positively correlated with T helper,Tcm,and Th2 cells in most cancers.Moreover,experimental results demonstrated that UGDH expression is elevated in HCC tissues and that its downregulation inhibits HCC cell proliferation.CONCLUSION Our study revealed that UGDH could be a valuable prognostic biomarker and potential therapeutic target in many cancers,especially liver and lung cancer.UGDH could promote HCC cell proliferation,potentially by modulating the pentose and glucuronate interconversion pathways.
基金Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research Foundation(Grant No.BM2008201)
文摘Edaravone glucuronate and edaravone sulfate,two metabolites of edaravone,were synthesized in improved yields. Edaravone glucuronate was synthesized by conjugation of edaravone with glucuronolactone through a series of reactions.Edaravone sulfate was synthesized through sulfonation of edaravone.Compared with the reported methods in the literature,the yields of both metabolites with the improved methods were much higher.
文摘The objective of this study was to determine the concentrations of the metabolites of four selected phthalates, widely used industrial chemicals which possess endocrine-disrupting properties, in samples of amniotic fluid and maternal urine collected in the same day, in order to verify if the latter can be considered a measure of the fetal exposure. The quantitative determination of the metabolites was carried out by HPLC-MS/MS with isotopic dilution from 70 pregnant volunteers. Detectable concentrations of phthalates metabolites were found in amniotic fluids. As phthalate monoesters are excreted in the urine conjugated with glucuronic acid, an enzymatic hydrolysis is carried out before analysis. Amniotic fluids were tested with and without hydrolysis and only the free phthalate metabolites, not conjugated with glucuronic acid, were found. The concentration of metabolites after enzymatic hydrolysis in maternal urine is not correlated to those of amniotic fluids, but the free form concentrations are. These results suggest that only the free forms can cross the placenta. A significant number of mothers showed urine phthalate monoesters concentrations higher than non-pregnant women.
基金funded by Guangxi Innovation-driven Development 20 Special Foundation Project(No.AA18118049)Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica(19245-1)“the Fundamental Research Funds for the Central Universities”of Nankai University(No.63191723)。
文摘Objective:Phenolic acids widely exist in the human diet and exert beneficial effects such as improving glucose metabolism.It is not clear whether phenolic acids or their metabolites play a major role in vivo.In this study,caffeic acid(CA)and ferulic acid(FA),the two most ingested phenolic acids,and their glucuronic acid metabolites,caffeic-4’-O-glucuronide(CA4G)and ferulic-4’-O-glucuronide(FA4G),were investigated.Methods:Three insulin resistance models in vitro were established by using TNF-a,insulin and palmitic acid(PA)in HepG2 cells,respectively.We compared the effects of FA,FA4G,CA and CA4G on glucose metabolism in these models by measuring the glucose consumption levels.The potential targets and related pathways were predicted by network pharmacology.Fluorescence quenching measurement was used to analyze the binding between the compounds and the predicted target.To investigate the binding mode,molecular docking was performed.Then,we performed membrane recruitment assays of the AKT pleckstrin homology(PH)domain with the help of the PH-GFP plasmid.AKT enzymatic activity was determined to compare the effects between the metabolites with their parent compounds.Finally,the downstream signaling pathway of AKT was investigated by Western blot analysis.Results:The results showed that CA4G and FA4G were more potent than their parent compounds in increasing glucose consumption.AKT was predicted to be the key target of CA4G and FA4G by network pharmacology analysis.The fluorescence quenching test confirmed the more potent binding to AKT of the two metabolites compared to their parent compounds.The molecular docking results indicated that the carbonyl group in the glucuronic acid structure of CA4G and FA4G might bind to the PH domain of AKT at the key Arg-25 site.CA4G and FA4G inhibited the translocation of the AKT PH domain to the membrane,while increasing the activity of AKT.Western blot analysis demonstrated that the metabolites could increase the phosphorylation of AKT and downstream glycogen synthase kinase 3βin the AKT signaling pathway to increase glucose consumption.Conclusion:In conclusion,our results suggested that the metabolites of phenolic acids,which contain glucuronic acid,are the key active substances and that they activate AKT by targeting the PH domain,thus improving glucose metabolism.
