近年来,糖尿病患病率持续攀升,其中2型糖尿病(diabetes mellitus type 2,T2DM)最为常见,其主要特征为慢性低度炎症与胰岛素代谢紊乱。Toll样受体4(TLR4)是重要的模式识别受体,其活化后可通过核因子κB(NF-κB)通路引起促炎细胞因子的上...近年来,糖尿病患病率持续攀升,其中2型糖尿病(diabetes mellitus type 2,T2DM)最为常见,其主要特征为慢性低度炎症与胰岛素代谢紊乱。Toll样受体4(TLR4)是重要的模式识别受体,其活化后可通过核因子κB(NF-κB)通路引起促炎细胞因子的上调,介导T2DM的发生。外周5-羟色胺(5-HT)主要由肠道内定居的肠嗜铬(EC)细胞产生,其与胰岛素作用的重要靶组织肝脏、脂肪和骨骼肌细胞的5-HT受体(5-HTR)结合后,可影响糖异生、脂肪动员和白色脂肪组织褐变等过程,当外周5-HT水平升高时,可导致机体糖脂代谢紊乱,驱动T2DM发生发展。线粒体中5-HT在单胺氧化酶A(MAO-A)的作用下被降解失活并产生活性氧类(ROS),ROS过量聚积导致氧化应激反应发生,这可能也是T2DM进展的原因。血小板是血液中5-HT的主要储存场所,血小板表面TLR4信号的激活、细胞表面5-HT转运蛋白表达下降,会引起血清中5-HT增加,加速T2DM进程。因此,抑制TLR4并降低外周5-HT水平或可成为治疗T2DM的有效策略。本文聚焦外周5-HT的合成、运输和代谢,以及其在TLR4介导的T2DM中的作用机制,旨在为T2DM的临床诊断、治疗及评估提供新思路。展开更多
Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HN...Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HNF4A pathogenic mutations exhibit decreased responses to arginine and reduced plasma triglyceride levels,but the mechanisms remain unclear.This study aims to investigate the potential target genes transcriptionally regulated by HNF4A and explore its role in these metabolic pathways.Methods A stable 293T cell line expressing the HNF1A reporter was overexpressed with HNF4A.RNA sequencing(RNA-seq)was performed to analyze transcriptional differences.Transcription factor binding site prediction was then conducted to identify HNF4A binding motifs in the promoter regions of relevant target genes.Results RNA-seq results revealed a significant upregulation of transmembrane 4 L six family member 5(TM4SF5)mRNA in HNF4A-overexpressing cells.Transcription factor binding predictions suggested the presence of five potential HNF4A binding motifs in the TM4SF5 promoter.Finally,we confirmed that the DR1 site in the-57 to-48 region of the TM4SF5 promoter is the key binding motif for HNF4A.Conclusion This study identified TM4SF5 as a target gene of HNF4A and determined the key binding motif involved in its regulation.Given the role of TM4SF5 as an arginine sensor in mTOR signaling activation and triglyceride secretion,which closely aligns with phenotypes observed in MODY1 patients,our findings provide novel insights into the possible mechanisms by which HNF4A regulates triglyceride secretion in the liver and arginine-stimulated insulin secretion in the pancreas.展开更多
ZnAl_(2)O_(4) and ZnAl_(2)O_(4)-based ceramics have attracted much attention from researchers due to their good microwave dielectric,thermal and mechanical properties.In this work,the influence of 5%(in mass)CuO-TiO_(...ZnAl_(2)O_(4) and ZnAl_(2)O_(4)-based ceramics have attracted much attention from researchers due to their good microwave dielectric,thermal and mechanical properties.In this work,the influence of 5%(in mass)CuO-TiO_(2)-Nb_(2)O_(5)(CTN)ternary composite oxide additives with different composition ratios on sintering behavior and properties of ZnAl_(2)O_(4) microwave dielectric ceramics was investigated.When the molar fraction ranges of Cu,Ti and Nb elements in 5%CTN additives are 0.625-0.875,0-0.250 and 0.125-0.625,respectively,sintering temperature of ZnAl_(2)O_(4) ceramics can be reduced from above 1400℃to below 1000℃.The sintering additives CN(Cu:Nb=1:1,molar ratio)and CTN(Cu:Ti:Nb=4:1:3,molar ratio)can reduce sintering temperature of ZnAl_(2)O_(4) ceramics to 975 and 1000℃,respectively,while maintaining good dielectric properties(dielectric constantε_(r)=11.36,quality factor Q׃=8245 GHz andε_(r)=9.52,Q׃=22249 GHz)and flexural strengths(200 and 161 MPa),which are expected to be applied in preparation of low temperature co-fired ceramic(LTCC)materials with copper electrodes.Low-temperature sintering of the ZnAl_(2)O_(4)+CTN system is characterized as activated sintering.Nanometer-level amorphous interfacial films containing Cu,Ti,and Nb elements are observed at the grain boundaries,which may provide fast diffusion pathways for mass transportation during the sintering process.Valence changes of Ti and Cu ions,along with changes of oxygen vacancies,are confirmed,which provides a potential mechanism for reduced sintering temperature of ZnAl_(2)O_(4) ceramics.In addition,a series of reactions occurring at the grain boundaries can activate these boundaries and further promote the sintering densification process.These results suggest a promising way to design a novel LTCC material with excellent properties based on the low temperature sintering of ceramics with the sintering aid of CuO-TiO_(2)-Nb_(2)O_(5) composite oxide.展开更多
文摘近年来,糖尿病患病率持续攀升,其中2型糖尿病(diabetes mellitus type 2,T2DM)最为常见,其主要特征为慢性低度炎症与胰岛素代谢紊乱。Toll样受体4(TLR4)是重要的模式识别受体,其活化后可通过核因子κB(NF-κB)通路引起促炎细胞因子的上调,介导T2DM的发生。外周5-羟色胺(5-HT)主要由肠道内定居的肠嗜铬(EC)细胞产生,其与胰岛素作用的重要靶组织肝脏、脂肪和骨骼肌细胞的5-HT受体(5-HTR)结合后,可影响糖异生、脂肪动员和白色脂肪组织褐变等过程,当外周5-HT水平升高时,可导致机体糖脂代谢紊乱,驱动T2DM发生发展。线粒体中5-HT在单胺氧化酶A(MAO-A)的作用下被降解失活并产生活性氧类(ROS),ROS过量聚积导致氧化应激反应发生,这可能也是T2DM进展的原因。血小板是血液中5-HT的主要储存场所,血小板表面TLR4信号的激活、细胞表面5-HT转运蛋白表达下降,会引起血清中5-HT增加,加速T2DM进程。因此,抑制TLR4并降低外周5-HT水平或可成为治疗T2DM的有效策略。本文聚焦外周5-HT的合成、运输和代谢,以及其在TLR4介导的T2DM中的作用机制,旨在为T2DM的临床诊断、治疗及评估提供新思路。
文摘Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HNF4A pathogenic mutations exhibit decreased responses to arginine and reduced plasma triglyceride levels,but the mechanisms remain unclear.This study aims to investigate the potential target genes transcriptionally regulated by HNF4A and explore its role in these metabolic pathways.Methods A stable 293T cell line expressing the HNF1A reporter was overexpressed with HNF4A.RNA sequencing(RNA-seq)was performed to analyze transcriptional differences.Transcription factor binding site prediction was then conducted to identify HNF4A binding motifs in the promoter regions of relevant target genes.Results RNA-seq results revealed a significant upregulation of transmembrane 4 L six family member 5(TM4SF5)mRNA in HNF4A-overexpressing cells.Transcription factor binding predictions suggested the presence of five potential HNF4A binding motifs in the TM4SF5 promoter.Finally,we confirmed that the DR1 site in the-57 to-48 region of the TM4SF5 promoter is the key binding motif for HNF4A.Conclusion This study identified TM4SF5 as a target gene of HNF4A and determined the key binding motif involved in its regulation.Given the role of TM4SF5 as an arginine sensor in mTOR signaling activation and triglyceride secretion,which closely aligns with phenotypes observed in MODY1 patients,our findings provide novel insights into the possible mechanisms by which HNF4A regulates triglyceride secretion in the liver and arginine-stimulated insulin secretion in the pancreas.
基金National Natural Science Foundation of China (U24A2052)Shanghai Eastern Talent Plan。
文摘ZnAl_(2)O_(4) and ZnAl_(2)O_(4)-based ceramics have attracted much attention from researchers due to their good microwave dielectric,thermal and mechanical properties.In this work,the influence of 5%(in mass)CuO-TiO_(2)-Nb_(2)O_(5)(CTN)ternary composite oxide additives with different composition ratios on sintering behavior and properties of ZnAl_(2)O_(4) microwave dielectric ceramics was investigated.When the molar fraction ranges of Cu,Ti and Nb elements in 5%CTN additives are 0.625-0.875,0-0.250 and 0.125-0.625,respectively,sintering temperature of ZnAl_(2)O_(4) ceramics can be reduced from above 1400℃to below 1000℃.The sintering additives CN(Cu:Nb=1:1,molar ratio)and CTN(Cu:Ti:Nb=4:1:3,molar ratio)can reduce sintering temperature of ZnAl_(2)O_(4) ceramics to 975 and 1000℃,respectively,while maintaining good dielectric properties(dielectric constantε_(r)=11.36,quality factor Q׃=8245 GHz andε_(r)=9.52,Q׃=22249 GHz)and flexural strengths(200 and 161 MPa),which are expected to be applied in preparation of low temperature co-fired ceramic(LTCC)materials with copper electrodes.Low-temperature sintering of the ZnAl_(2)O_(4)+CTN system is characterized as activated sintering.Nanometer-level amorphous interfacial films containing Cu,Ti,and Nb elements are observed at the grain boundaries,which may provide fast diffusion pathways for mass transportation during the sintering process.Valence changes of Ti and Cu ions,along with changes of oxygen vacancies,are confirmed,which provides a potential mechanism for reduced sintering temperature of ZnAl_(2)O_(4) ceramics.In addition,a series of reactions occurring at the grain boundaries can activate these boundaries and further promote the sintering densification process.These results suggest a promising way to design a novel LTCC material with excellent properties based on the low temperature sintering of ceramics with the sintering aid of CuO-TiO_(2)-Nb_(2)O_(5) composite oxide.
