G蛋白偶联受体35(G protein coupled receptor 35,GPR35)是一种孤儿受体,现有研究表明其参与多种疾病的发生和发展,同时作为潜在的治疗靶点引起了研究者广泛的兴趣。基因组学研究发现GPR35与炎症性肠病、2型糖尿病和冠状动脉疾病等密切...G蛋白偶联受体35(G protein coupled receptor 35,GPR35)是一种孤儿受体,现有研究表明其参与多种疾病的发生和发展,同时作为潜在的治疗靶点引起了研究者广泛的兴趣。基因组学研究发现GPR35与炎症性肠病、2型糖尿病和冠状动脉疾病等密切相关。最近的功能学研究发现GPR35介导缺氧和炎症等多种病理过程,并在高血压、冠心病和心力衰竭的发病机制中起重要作用。现总结GPR35在心血管相关疾病中的研究进展,并讨论其作为新兴治疗靶标的潜在应用价值。展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis(MASH),cirrhosis,and cancer.The zonal distribution of biomolec...Metabolic dysfunction-associated steatotic liver disease(MASLD)is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis(MASH),cirrhosis,and cancer.The zonal distribution of biomolecules in the liver is implicated in mediat-ing the disease progression.Recently,G-protein-coupled receptor 35(GPR35)has been highlighted to play a role in MASLD,but the precise mechanism is not fully understood,particularly,in a liver-zonal manner.Here,we aimed to identify spatially distributed specific genes and metabolites in different liver zonation that are regulated by GPR35 in MASLD,by combining lipid metabolomics,spatial transcriptomics(ST),and spatial metabolomics(SM).We found that GPR35 influenced lipid accumulation,inflammatory and metabolism-related factors in specific regions,notably affecting the anti-inflammation factor ELF4(E74 like E-twenty six(ETS)tran-scription factor 4),lipid homeostasis key factor CIDEA(cell death-inducing DNA fragmentation factor alpha(DFFA)-like effector A),and the injury response-related genes SAA1/2/3(serum amyloid A1/2/3),thereby impacting MASLD progression.Furthermore,SM elucidated specific metabolite distributions across different liver regions,such as C10H11N4O7P(3ʹ,5ʹ-cyclic inosine monophosphate(3ʹ,5ʹ-IMP))for the central vein,and this metabolite significantly decreased in the liver zones of GPR35-deficient mice during MASLD progression.Taken together,GPR35 regulates hepatocyte damage repair,controls inflammation,and prevents MASLD progression by influencing phospholipid homeostasis and gene expression in a zonal manner.展开更多
Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestin...Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan(Trp)àkynurenine(KYN)àkynurenic acid(KA) axis metabolism. Mechanistically,chemotherapy-induced intestinal damage triggered the formation of an interleukin-6(IL-6)àindoleamine2,3-dioxygenase 1(IDO1)àaryl hydrocarbon receptor(AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35(GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic.This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.展开更多
The phenotypic diversity resulting from artificial or natural selection of sheep has made a significant contribution to human civilization.Hu sheep are a local sheep breed unique to China with high reproductive rates ...The phenotypic diversity resulting from artificial or natural selection of sheep has made a significant contribution to human civilization.Hu sheep are a local sheep breed unique to China with high reproductive rates and rapid growth.Genomic selection signatures have been widely used to investigate the genetic mechanisms underlying phenotypic variation in livestock.Here,we conduct whole-genome sequencing of 207 Hu sheep and compare them with the wild ancestors of domestic sheep(Asiatic mouflon)to investigate the genetic characteristics and selection signatures of Hu sheep.Based on six signatures of selection approaches,we detect genomic regions containing genes related to reproduction(BMPR1B,BMP2,PGFS,CYP19,CAMK4,GGT5,and GNAQ),vision(ALDH1A2,SAG,and PDE6B),nervous system(NAV1),and immune response(GPR35,SH2B2,PIK3R3,and HRAS).Association analysis with a population of 1299 Hu sheep reveals that those missense mutations in the GPR35(GPR35 g.952651 A>G;GPR35 g.952496 C>T)and NAV1(NAV1 g.84216190 C>T;NAV1 g.84227412 G>A)genes are significantly associated(P<0.05)with immune and growth traits in Hu sheep,respectively.This research offers unique insights into the selection characteristics of Hu sheep and facilitates further genetic improvement and molecular investigations.展开更多
文摘G蛋白偶联受体35(G protein coupled receptor 35,GPR35)是一种孤儿受体,现有研究表明其参与多种疾病的发生和发展,同时作为潜在的治疗靶点引起了研究者广泛的兴趣。基因组学研究发现GPR35与炎症性肠病、2型糖尿病和冠状动脉疾病等密切相关。最近的功能学研究发现GPR35介导缺氧和炎症等多种病理过程,并在高血压、冠心病和心力衰竭的发病机制中起重要作用。现总结GPR35在心血管相关疾病中的研究进展,并讨论其作为新兴治疗靶标的潜在应用价值。
基金supported by the National Key Research and Development Program of China(2022YFA0806503)the National Natural Science Foundation of China(81972625 and 32201217)+3 种基金Liaoning Revitalization Talents Program(XLYC2002035)Liaoning Science and Technology Innovation Funding(20230101-JH2/1013)the Innovation Program of Science and Research from Dalian Institute of Chemical Physics,Chinese Academy of Sciences(DICP I202129 and DICP I202209)the Science and Technology Innovation Fund(Youth Science and Technology Star)of Dalian(2021RQ009 and 2023RQ040).
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis(MASH),cirrhosis,and cancer.The zonal distribution of biomolecules in the liver is implicated in mediat-ing the disease progression.Recently,G-protein-coupled receptor 35(GPR35)has been highlighted to play a role in MASLD,but the precise mechanism is not fully understood,particularly,in a liver-zonal manner.Here,we aimed to identify spatially distributed specific genes and metabolites in different liver zonation that are regulated by GPR35 in MASLD,by combining lipid metabolomics,spatial transcriptomics(ST),and spatial metabolomics(SM).We found that GPR35 influenced lipid accumulation,inflammatory and metabolism-related factors in specific regions,notably affecting the anti-inflammation factor ELF4(E74 like E-twenty six(ETS)tran-scription factor 4),lipid homeostasis key factor CIDEA(cell death-inducing DNA fragmentation factor alpha(DFFA)-like effector A),and the injury response-related genes SAA1/2/3(serum amyloid A1/2/3),thereby impacting MASLD progression.Furthermore,SM elucidated specific metabolite distributions across different liver regions,such as C10H11N4O7P(3ʹ,5ʹ-cyclic inosine monophosphate(3ʹ,5ʹ-IMP))for the central vein,and this metabolite significantly decreased in the liver zones of GPR35-deficient mice during MASLD progression.Taken together,GPR35 regulates hepatocyte damage repair,controls inflammation,and prevents MASLD progression by influencing phospholipid homeostasis and gene expression in a zonal manner.
基金supported by the National Nature Science Foundation of China (NSFC Nos.81773861 and 81773682)National Science and Technology Major Project (2017ZX09101001, China)+3 种基金Jiangsu Provincial National Science Foundation for Distinguished Young Scholars(No. BK20180027, China)Double First-Class University Projectthe Program for Jiangsu province Innovative Research Teamfunded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, China)。
文摘Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan(Trp)àkynurenine(KYN)àkynurenic acid(KA) axis metabolism. Mechanistically,chemotherapy-induced intestinal damage triggered the formation of an interleukin-6(IL-6)àindoleamine2,3-dioxygenase 1(IDO1)àaryl hydrocarbon receptor(AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35(GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic.This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.
基金supported by the National Key Research and Development Program of China(2021YFD1300901,2022YFD1302000)National Natural Science Foundation of China(32260818,31960653)。
文摘The phenotypic diversity resulting from artificial or natural selection of sheep has made a significant contribution to human civilization.Hu sheep are a local sheep breed unique to China with high reproductive rates and rapid growth.Genomic selection signatures have been widely used to investigate the genetic mechanisms underlying phenotypic variation in livestock.Here,we conduct whole-genome sequencing of 207 Hu sheep and compare them with the wild ancestors of domestic sheep(Asiatic mouflon)to investigate the genetic characteristics and selection signatures of Hu sheep.Based on six signatures of selection approaches,we detect genomic regions containing genes related to reproduction(BMPR1B,BMP2,PGFS,CYP19,CAMK4,GGT5,and GNAQ),vision(ALDH1A2,SAG,and PDE6B),nervous system(NAV1),and immune response(GPR35,SH2B2,PIK3R3,and HRAS).Association analysis with a population of 1299 Hu sheep reveals that those missense mutations in the GPR35(GPR35 g.952651 A>G;GPR35 g.952496 C>T)and NAV1(NAV1 g.84216190 C>T;NAV1 g.84227412 G>A)genes are significantly associated(P<0.05)with immune and growth traits in Hu sheep,respectively.This research offers unique insights into the selection characteristics of Hu sheep and facilitates further genetic improvement and molecular investigations.
