Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that gene...Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that genetics also shape the gut microbiota.It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to CIA.Here,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched B.fragilis than DBA/1J mice and RA patients.Transplantation of B.fragilis prevents CIA in DBA/1J mice.We identify that B.fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate.Fibroblast-like synoviocytes(FLSs)in RA are activated to undergo tumor-like transformation.Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of RA-FLSs.We treat CIA mice with propionate and show that propionate attenuates CIA.Moreover,a combination of propionate with anti-TNF etanercept synergistically relieves CIA.These results suggest that B.fragilis or propionate could be an alternative or complementary approach to the current therapies.展开更多
Objective:Pancreatic ductal adenocarcinoma(PDAC)is a disease with high mortality.Many so-called"junk"noncoding RNAs need to be discovered in PDAC.The purpose of this study was therefore to investigate the fu...Objective:Pancreatic ductal adenocarcinoma(PDAC)is a disease with high mortality.Many so-called"junk"noncoding RNAs need to be discovered in PDAC.The purpose of this study was therefore to investigate the function and regulatory mechanism of the long noncoding RNA MEG3 in PDAC.Methods:The Gene Expression Omnibus database(GEO database)was used to determine the differential expression of long noncoding RNAs in PDAC,and MEG3 was selected for subsequent verification.Tissue and cell samples were used to verify MEG3 expression,followed by functional detection in vitro and in vivo.Microarrays were used to characterize long noncoding RNA and mRNA expression profiles.Competing endogenous RNA analyses were used to detect differential MEG3 and relational miRNA expression in PDAC.Finally,promoter analyses were conducted to explain the downregulation of MEG3 PDAC.Results:We generated a catalogue of PDAC-associated long noncoding RNAs in the GEO database.The ectopic expression of MEG3 inhibited PDAC growth and metastasis in vitro and in vivo,which was statistically significant(P<0.05).Microarray analysis showed that multiple microRNAs interacted with MEG3.We also showed that MEG3,as a competing endogenous RNA,directly sponged miR-374a-5p to regulate PTEN expression.The transcription factor,Sp1,recruited EZH2 and HDAC3 to the promoter and transcriptionally repressed MEG3 expression.Finally,clinical data showed that MEG3 and miR-374a-5p expressions were correlated with clinicopathological features.Statistically,Sp1,EZH2,HDAC3,and miR-374 a-5p were negatively correlated with MEG3(P<0.05).Conclusions:Reduced MEG3 levels played a crucial role in the PDAC malignant phenotype,which provided insight into novel and effective molecular targets of MEG3 for pancreatic cancer treatment.展开更多
基金supported by the National Natural Science Foundation Council of China(82172386 and 81922081 to C.L.,82100943 to X.F.,82104216 to J.L.,and 82230081,82250710175 and 8226116039 to G.X.)the Department of Education of Guangdong Province(2021KTSCX104 to C.L.)+5 种基金the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong Kong-Macao Joint Lab)(2020B1212030006 to A.L.)the Guangdong Provincial Science and Technology Innovation Council Grant(2017B030301018 to G.X.)the Guangdong Basic and Applied Basic Research Foundation(2022A1515012164 to C.L.,and 2023A1515012000 to X.F.)the Science,Technology and Innovation Commission of Shenzhen(JCYJ20210324104201005 to C.L.,JCYJ20220530115006014 to X.F.,JCYJ20230807095118035 to J.L.,and JCYJ20220818100617036 to G.X.)the Hong Kong General Research Fund(12102722 to A.L.)the Hong Kong RGC Themebased Research Scheme(T12-201/20-R to A.L.).
文摘Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that genetics also shape the gut microbiota.It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to CIA.Here,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched B.fragilis than DBA/1J mice and RA patients.Transplantation of B.fragilis prevents CIA in DBA/1J mice.We identify that B.fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate.Fibroblast-like synoviocytes(FLSs)in RA are activated to undergo tumor-like transformation.Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of RA-FLSs.We treat CIA mice with propionate and show that propionate attenuates CIA.Moreover,a combination of propionate with anti-TNF etanercept synergistically relieves CIA.These results suggest that B.fragilis or propionate could be an alternative or complementary approach to the current therapies.
基金supported in part by the National Natural Science Foundation of China(Grant No.81902372 for Ting Han,81502017 for Feng Jiao,81903062 for Meng Zhuo and 81572315 and 81874048 for Liwei Wang)the Innovation Group Project of Shanghai Municipal Health Commission(Grant No.2019CXJQ03 for Liwei Wang)+2 种基金the State Key Laboratory of Oncogenes and Related Genes(Grant No.90-17-06 for Liwei Wang)the Shanghai Leading Talents Project(Grant No.075 for Liwei Wang)the Shanghai Key Clinical Specialty(Grant No.2018 Oncology for Liwei Wang)。
文摘Objective:Pancreatic ductal adenocarcinoma(PDAC)is a disease with high mortality.Many so-called"junk"noncoding RNAs need to be discovered in PDAC.The purpose of this study was therefore to investigate the function and regulatory mechanism of the long noncoding RNA MEG3 in PDAC.Methods:The Gene Expression Omnibus database(GEO database)was used to determine the differential expression of long noncoding RNAs in PDAC,and MEG3 was selected for subsequent verification.Tissue and cell samples were used to verify MEG3 expression,followed by functional detection in vitro and in vivo.Microarrays were used to characterize long noncoding RNA and mRNA expression profiles.Competing endogenous RNA analyses were used to detect differential MEG3 and relational miRNA expression in PDAC.Finally,promoter analyses were conducted to explain the downregulation of MEG3 PDAC.Results:We generated a catalogue of PDAC-associated long noncoding RNAs in the GEO database.The ectopic expression of MEG3 inhibited PDAC growth and metastasis in vitro and in vivo,which was statistically significant(P<0.05).Microarray analysis showed that multiple microRNAs interacted with MEG3.We also showed that MEG3,as a competing endogenous RNA,directly sponged miR-374a-5p to regulate PTEN expression.The transcription factor,Sp1,recruited EZH2 and HDAC3 to the promoter and transcriptionally repressed MEG3 expression.Finally,clinical data showed that MEG3 and miR-374a-5p expressions were correlated with clinicopathological features.Statistically,Sp1,EZH2,HDAC3,and miR-374 a-5p were negatively correlated with MEG3(P<0.05).Conclusions:Reduced MEG3 levels played a crucial role in the PDAC malignant phenotype,which provided insight into novel and effective molecular targets of MEG3 for pancreatic cancer treatment.
