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
Peptides can be potentmolecules with high efficacy and selectivity in the development of biotherapeutics.However,the poor pharmacokinetic properties of peptides pose major challenges for their broader medicinal applic...Peptides can be potentmolecules with high efficacy and selectivity in the development of biotherapeutics.However,the poor pharmacokinetic properties of peptides pose major challenges for their broader medicinal applications.Inspired by the proteinstabilizing role of natural N-glycosylation,we design and synthesize a series of parathyroid hormone(PTH)peptides(1-34),bearing either N-GlcNAc or biantennary complex-type N-glycan modification,and evaluate their serum stability and biological activities.The results indicate that an N-Asn-linked complex-type sialylundecasaccharide can increase the serum half-life and in vivo bioactivity of PTH peptides with a broad tolerance of modification sites.Further,hydrogen/deuterium exchange mass spectroscopy indicates that the larger-sized Nglycan can induce enhanced hydration dynamics in its surroundings,which may facilitate an improved resistance for the peptide against enzymatic proteolysis.This sialylundecasaccharide-based peptideengineering strategy has also been applied to glucagon-like peptide-1(7-37),leading to glycopeptides with enhanced hypoglycemic activity and acting time in vivo.Together,these results demonstrate the potential of using sialylated complextype N-glycan as a general engineering strategy for developing long-acting peptide therapeutics.展开更多
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.
基金This research was made possible as a result of a generous grant from the Beijing National Science Foundation(grant no.JQ18024)the National Key R&D Program of China(grant no.2018YFA0507602)the National Natural Science Foundation of China(grant nos.91953111 and 91853113).
文摘Peptides can be potentmolecules with high efficacy and selectivity in the development of biotherapeutics.However,the poor pharmacokinetic properties of peptides pose major challenges for their broader medicinal applications.Inspired by the proteinstabilizing role of natural N-glycosylation,we design and synthesize a series of parathyroid hormone(PTH)peptides(1-34),bearing either N-GlcNAc or biantennary complex-type N-glycan modification,and evaluate their serum stability and biological activities.The results indicate that an N-Asn-linked complex-type sialylundecasaccharide can increase the serum half-life and in vivo bioactivity of PTH peptides with a broad tolerance of modification sites.Further,hydrogen/deuterium exchange mass spectroscopy indicates that the larger-sized Nglycan can induce enhanced hydration dynamics in its surroundings,which may facilitate an improved resistance for the peptide against enzymatic proteolysis.This sialylundecasaccharide-based peptideengineering strategy has also been applied to glucagon-like peptide-1(7-37),leading to glycopeptides with enhanced hypoglycemic activity and acting time in vivo.Together,these results demonstrate the potential of using sialylated complextype N-glycan as a general engineering strategy for developing long-acting peptide therapeutics.
