BACKGROUND AMPD2 is a critical enzyme catalyzing smooth muscle energy supply and metabolism;however,its cellular biological function and clinical implication in colorectal cancer(CRC)are largely unknown.AIM To clarify...BACKGROUND AMPD2 is a critical enzyme catalyzing smooth muscle energy supply and metabolism;however,its cellular biological function and clinical implication in colorectal cancer(CRC)are largely unknown.AIM To clarify the role of AMPD2 in CRC and study the pathway and prognostic value of its role.METHODS AMPD2 expression was analyzed by integrated bioinformatics analysis based on TCGA data sets and immunohistochemistry in tissue microarrays,and the correlation between AMPD2 expression and clinicopathological parameters,Notch3 expression,and prognostic features was assessed.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were then performed to investigate the regulatory pathway involved.The effects of AMPD2 expression on CRC cells and Notch3 protein expression were investigated by downregulation and overexpression of AMPD2.RESULTS AMPD2 mRNA was significantly overexpressed in tumor tissue when compared with normal tissue in a cohort of the TCGA-COAD data set.Biological function enrichment analysis indicated that the Notch pathway strongly correlated with AMPD2 expression,and that the expression of Notch3 and JAG2 mRNA was positively associated with AMPD2 in CRC tissues.In vitro,AMPD2 overexpression markedly reduced Notch3 protein expression in CRC cells,while knockdown of AMPD2 showed the opposite findings.In addition,protein expression was significantly up-regulated in our CRC cohort as indicated by tissue microarray analysis.High expression of AMPD2 protein correlated with advanced depth of tumor and poor differentiation.Furthermore,high AMPD2 expression in CRC tissues was an indicator of poor outcome for CRC patients.CONCLUSION AMPD2 is commonly overexpressed in CRC,and acts as a metabolism oncogene to induce CRC progression through the Notch signaling pathway.Thus,AMPD2 may be a novel prognostic biomarker for CRC.展开更多
In recent decades,the prevalence of hyperuricemia and gout has increased dramatically due to lifestyle changes.The drugs currently recommended for hyperuricemia are associated with adverse reactions that limit their c...In recent decades,the prevalence of hyperuricemia and gout has increased dramatically due to lifestyle changes.The drugs currently recommended for hyperuricemia are associated with adverse reactions that limit their clinical use.In this study,we report that berberine(BBR)is an effective drug candidate for the treatment of hyperuricemia,with its mechanism potentially involving the modulation of gut microbiota and its metabolite,succinic acid.BBR has demonstrated good therapeutic effects in both acute and chronic animal models of hyperuricemia.In a clinical trial,oral administration of BBR for 6 months reduced blood uric acid levels in 22 participants by modulating the gut microbiota,which led to an increase in the abundance of Bacteroides and a decrease in Clostridium sensu stricto_1.Furthermore,Bacteroides fragilis was transplanted into ICR mice,and the results showed that Bacteroides fragilis exerted a therapeutic effect on uric acid similar to that of BBR.Notably,succinic acid,a metabolite of Bacteroides,significantly reduced uric acid levels.Subsequent cell and animal experiments revealed that the intestinal metabolite,succinic acid,regulated the upstream uric acid synthesis pathway in the liver by inhibiting adenosine monophosphate deaminase 2(AMPD2),an enzyme responsible for converting adenosine monophosphate(AMP)to inosine monophosphate(IMP).This inhibition resulted in a decrease in IMP levels and an increase in phosphate levels.The reduction in IMP led to a decreased downstream production of hypoxanthine,xanthine,and uric acid.BBR also demonstrated excellent renoprotective effects,improving nephropathy associated with hyperuricemia.In summary,BBR has the potential to be an effective treatment for hyperuricemia through the gut-liver axis.展开更多
基金Supported by the Wuxi Young Medical Talents,Jiangsu Province,China,No.QNRC063.
文摘BACKGROUND AMPD2 is a critical enzyme catalyzing smooth muscle energy supply and metabolism;however,its cellular biological function and clinical implication in colorectal cancer(CRC)are largely unknown.AIM To clarify the role of AMPD2 in CRC and study the pathway and prognostic value of its role.METHODS AMPD2 expression was analyzed by integrated bioinformatics analysis based on TCGA data sets and immunohistochemistry in tissue microarrays,and the correlation between AMPD2 expression and clinicopathological parameters,Notch3 expression,and prognostic features was assessed.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were then performed to investigate the regulatory pathway involved.The effects of AMPD2 expression on CRC cells and Notch3 protein expression were investigated by downregulation and overexpression of AMPD2.RESULTS AMPD2 mRNA was significantly overexpressed in tumor tissue when compared with normal tissue in a cohort of the TCGA-COAD data set.Biological function enrichment analysis indicated that the Notch pathway strongly correlated with AMPD2 expression,and that the expression of Notch3 and JAG2 mRNA was positively associated with AMPD2 in CRC tissues.In vitro,AMPD2 overexpression markedly reduced Notch3 protein expression in CRC cells,while knockdown of AMPD2 showed the opposite findings.In addition,protein expression was significantly up-regulated in our CRC cohort as indicated by tissue microarray analysis.High expression of AMPD2 protein correlated with advanced depth of tumor and poor differentiation.Furthermore,high AMPD2 expression in CRC tissues was an indicator of poor outcome for CRC patients.CONCLUSION AMPD2 is commonly overexpressed in CRC,and acts as a metabolism oncogene to induce CRC progression through the Notch signaling pathway.Thus,AMPD2 may be a novel prognostic biomarker for CRC.
基金Jiandong Jiang,Yan Wang,and Linbin Pan have a patent related to this work(CN201810788495.7).
文摘In recent decades,the prevalence of hyperuricemia and gout has increased dramatically due to lifestyle changes.The drugs currently recommended for hyperuricemia are associated with adverse reactions that limit their clinical use.In this study,we report that berberine(BBR)is an effective drug candidate for the treatment of hyperuricemia,with its mechanism potentially involving the modulation of gut microbiota and its metabolite,succinic acid.BBR has demonstrated good therapeutic effects in both acute and chronic animal models of hyperuricemia.In a clinical trial,oral administration of BBR for 6 months reduced blood uric acid levels in 22 participants by modulating the gut microbiota,which led to an increase in the abundance of Bacteroides and a decrease in Clostridium sensu stricto_1.Furthermore,Bacteroides fragilis was transplanted into ICR mice,and the results showed that Bacteroides fragilis exerted a therapeutic effect on uric acid similar to that of BBR.Notably,succinic acid,a metabolite of Bacteroides,significantly reduced uric acid levels.Subsequent cell and animal experiments revealed that the intestinal metabolite,succinic acid,regulated the upstream uric acid synthesis pathway in the liver by inhibiting adenosine monophosphate deaminase 2(AMPD2),an enzyme responsible for converting adenosine monophosphate(AMP)to inosine monophosphate(IMP).This inhibition resulted in a decrease in IMP levels and an increase in phosphate levels.The reduction in IMP led to a decreased downstream production of hypoxanthine,xanthine,and uric acid.BBR also demonstrated excellent renoprotective effects,improving nephropathy associated with hyperuricemia.In summary,BBR has the potential to be an effective treatment for hyperuricemia through the gut-liver axis.
