The role of co-agonists of glucagon-like peptide-1 receptor(GLP-1R)and glucagon receptor(GCGR)in chronic kidney disease(CKD)remains unclear.Herein we found that GLP-1R and GCGR expression levels were lower in the kidn...The role of co-agonists of glucagon-like peptide-1 receptor(GLP-1R)and glucagon receptor(GCGR)in chronic kidney disease(CKD)remains unclear.Herein we found that GLP-1R and GCGR expression levels were lower in the kidneys of mice with CKD compared to healthy mice and were correlated with disease severity.Interestingly,GLP-1R or GCGR knockdown aggravated the progression of kidney injury in both diabetic db/db mice and non-diabetic mice undergoing unilateral ureteral obstruction(UUO).Based on the importance of GLP-1R and GCGR in CKD,we reported a novel monomeric peptide,1907-B,with dual-agonism on both GLP-1R and GCGR.The data confirmed that 1907-B had a longer half-life than long-acting semaglutide in rats or cynomolgus monkeys(~2-3 fold)and exhibited better therapeutic contribution to CKD than best-in-class monoagonists,semaglutide,or glucagon,in db/db mice and UUO mice.Various lock-of-function models,including selective pharmacological activation and genetic knockdown,confirmed that 1907-B’s effects on ameliorating diabetic nephropathy in db/db mice,as well as inhibiting kidney fibrosis in UUO mice,were mediated through GLP-1 and glucagon signaling.These findings highlight that 1907-B,a novel GLP-1R and GCGR co-agonist,exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment.展开更多
The antimicrobial peptide APKGVQGPNG(named YD),a natural peptide originating from Bacillus amyloliquefaciens CBSYD1,exhibited excellent antibacterial and antioxidant properties in vitro.These characteristics are close...The antimicrobial peptide APKGVQGPNG(named YD),a natural peptide originating from Bacillus amyloliquefaciens CBSYD1,exhibited excellent antibacterial and antioxidant properties in vitro.These characteristics are closely related to inflammatory responses which is the central trigger for liverfibrosis.However,the therapeutic effects of YD against hepatic fibrosis and the underlying mechanisms are rarely studied.In this study,we show that YD improved liver function and inhibited the progression of liver fibrosis by measuring the serum transaminase activity and the expression of a-smooth muscle actin and collagen I in carbon tetrachloride-induced mice.Then we found that YD inhibited the level of miR-155,which plays an important role in inflammation and liver fibrosis.Bioinformatics analysis and luciferase reporter assay indicate that Casp12 is a new target of miR-155.We demonstrate that YD signifi-cantly decreases the contents of inflammatory cytokines and suppresses the NF-k B signaling pathway.Further studies show that transfection of the miR-155 mimic in RAW264.7 cells partially reversed the YD-mediated CASP12 upregulation,the downregulated levels of inflammatory cytokines,and the inactivation of the NF-k B pathways.Collectively,our study indicates that YD reduces inflammation throughthe mi R-155 e Casp12 e NF-k B axis during liver fibrosis and provides a promising therapeutic candidate for hepatic fibrosis.展开更多
Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor(GLP-1 R/GCGR)...Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor(GLP-1 R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl_(4), a-naphthyl-isothiocyanate(ANIT), bile duct ligation(BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix(ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl_(4)-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of proinflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha(NFκB/IKBa) pathways as well as cJun N-terminal kinase(JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1 R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl_(4)-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.展开更多
Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Ac...Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Accumulating evidence suggests that the generation of elastin-derived peptides(EDPs)and the inhibition of adiponectin receptors(Adipo R)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis.We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix(ECM)and ameliorated liver fibrosis.However,the degradation of the ECM lead to the generation of EDPs,which could further alter liver homeostasis negatively.Thus,in this study,we successfully combined AdipoR1/2 agonist JT003 with V14,which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation.We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other.These effects are induced by the enhancement of the mitochondrial antioxidant capacity,mitophagy,and mitochondrial biogenesis via AMPK pathway.Furthermore,specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress,increased mitophagy and mitochondrial biogenesis.These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.展开更多
Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases,but no effective anti-fibrotic therapy is currently available.Glucagon receptor(GCGR)and glucagon-like peptide 1 receptor(GLP1R)ar...Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases,but no effective anti-fibrotic therapy is currently available.Glucagon receptor(GCGR)and glucagon-like peptide 1 receptor(GLP1R)are both peptide hormone receptors involved in energy metabolism of epithelial cells.However,their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored.Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn’s disease as well as in the fibrotic colon of mice with chronic colitis.The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate,resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition(EMT).Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo.We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation.Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.展开更多
基金financial support from the National Natural Science Foundation of China(No.82273761 and No.81871257)the Medical Innovation and Development Project of Lanzhou University(lzuyxcx-2022-156,China)+1 种基金the Undergraduate Teaching Quality Engineering Project of Sun Yat-sen University[2021]93the Guangdong Provincial Key Laboratory of Construction Foundation(2023B1212060022,China)。
文摘The role of co-agonists of glucagon-like peptide-1 receptor(GLP-1R)and glucagon receptor(GCGR)in chronic kidney disease(CKD)remains unclear.Herein we found that GLP-1R and GCGR expression levels were lower in the kidneys of mice with CKD compared to healthy mice and were correlated with disease severity.Interestingly,GLP-1R or GCGR knockdown aggravated the progression of kidney injury in both diabetic db/db mice and non-diabetic mice undergoing unilateral ureteral obstruction(UUO).Based on the importance of GLP-1R and GCGR in CKD,we reported a novel monomeric peptide,1907-B,with dual-agonism on both GLP-1R and GCGR.The data confirmed that 1907-B had a longer half-life than long-acting semaglutide in rats or cynomolgus monkeys(~2-3 fold)and exhibited better therapeutic contribution to CKD than best-in-class monoagonists,semaglutide,or glucagon,in db/db mice and UUO mice.Various lock-of-function models,including selective pharmacological activation and genetic knockdown,confirmed that 1907-B’s effects on ameliorating diabetic nephropathy in db/db mice,as well as inhibiting kidney fibrosis in UUO mice,were mediated through GLP-1 and glucagon signaling.These findings highlight that 1907-B,a novel GLP-1R and GCGR co-agonist,exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment.
基金the National Natural Science Foundation of China(No.81602945,81673283,and 81874315)the CAMS Innovation Fund for Medical Sciences(CIFMS,No.2019-I2M-5-074,China)the Program for the Ministry of Education“Peptide Drugs”Innovation Team(No.IRT_15R27,China).
文摘The antimicrobial peptide APKGVQGPNG(named YD),a natural peptide originating from Bacillus amyloliquefaciens CBSYD1,exhibited excellent antibacterial and antioxidant properties in vitro.These characteristics are closely related to inflammatory responses which is the central trigger for liverfibrosis.However,the therapeutic effects of YD against hepatic fibrosis and the underlying mechanisms are rarely studied.In this study,we show that YD improved liver function and inhibited the progression of liver fibrosis by measuring the serum transaminase activity and the expression of a-smooth muscle actin and collagen I in carbon tetrachloride-induced mice.Then we found that YD inhibited the level of miR-155,which plays an important role in inflammation and liver fibrosis.Bioinformatics analysis and luciferase reporter assay indicate that Casp12 is a new target of miR-155.We demonstrate that YD signifi-cantly decreases the contents of inflammatory cytokines and suppresses the NF-k B signaling pathway.Further studies show that transfection of the miR-155 mimic in RAW264.7 cells partially reversed the YD-mediated CASP12 upregulation,the downregulated levels of inflammatory cytokines,and the inactivation of the NF-k B pathways.Collectively,our study indicates that YD reduces inflammation throughthe mi R-155 e Casp12 e NF-k B axis during liver fibrosis and provides a promising therapeutic candidate for hepatic fibrosis.
基金the financial support from the National Natural Science Foundation of China (No.91853106)the Program for Guangdong Introducing Innovative and Enterpre-neurial Teams (No.2016ZT06Y337,China)+3 种基金Guangdong Provincial Key Laboratory of Construction Foundation (No.2019B030301005,China)Shenzhen Science and Technology Program (JSGG20200225153121723,China)the Fundamental Research Funds for the Central Universities (No.19ykzd25,China)CAMS Innovation Fund for Medical Sciences (CIFMS,2019-I2M-5-074,China)。
文摘Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor(GLP-1 R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl_(4), a-naphthyl-isothiocyanate(ANIT), bile duct ligation(BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix(ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl_(4)-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of proinflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha(NFκB/IKBa) pathways as well as cJun N-terminal kinase(JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1 R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl_(4)-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.
基金the financial support from the National Natural Science Foundation of China(Nos.91853106,81870420 and 82070590)the Program for Guangdong Introducing Innovative and Enterpre-neurial Teams(No.2016ZT06Y337,China)+3 种基金The Fundamental Research Funds for the Central Universities(No.19ykzd25,China)National Key Research and Development Program(No.2017YFE0109900,China)Special Topics of General Projects of Guangzhou Science and Technology Plan of China(201904010075)CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-074,China)。
文摘Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Accumulating evidence suggests that the generation of elastin-derived peptides(EDPs)and the inhibition of adiponectin receptors(Adipo R)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis.We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix(ECM)and ameliorated liver fibrosis.However,the degradation of the ECM lead to the generation of EDPs,which could further alter liver homeostasis negatively.Thus,in this study,we successfully combined AdipoR1/2 agonist JT003 with V14,which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation.We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other.These effects are induced by the enhancement of the mitochondrial antioxidant capacity,mitophagy,and mitochondrial biogenesis via AMPK pathway.Furthermore,specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress,increased mitophagy and mitochondrial biogenesis.These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.
基金supported by the National Key R&D Program of China(2023YFC2507300)the National Natural Science Foundation of China(82273761,81970483,82170537 and 82222010)the Medical Innovation and Development Project of Lanzhou University(lzuyxcx-2022-156,China).
文摘Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases,but no effective anti-fibrotic therapy is currently available.Glucagon receptor(GCGR)and glucagon-like peptide 1 receptor(GLP1R)are both peptide hormone receptors involved in energy metabolism of epithelial cells.However,their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored.Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn’s disease as well as in the fibrotic colon of mice with chronic colitis.The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate,resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition(EMT).Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo.We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation.Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.
