BACKGROUND Diabetic kidney disease(DKD),characterized by increased urinary microalbumin levels and decreased renal function,is the primary cause of end-stage renal di-sease.Its pathological mechanisms are complicated ...BACKGROUND Diabetic kidney disease(DKD),characterized by increased urinary microalbumin levels and decreased renal function,is the primary cause of end-stage renal di-sease.Its pathological mechanisms are complicated and multifactorial;Therefore,sensitive and specific biomarkers are needed.Urinary exosome originate from diverse renal cells in nephron segments and partially mirror the pathological changes in the kidney.The microRNAs(miRNAs)in urinary exosome are remark-ably stable and highly tissue-specific for the kidney.METHODS Type 2 diabetic mellitus(T2DM)patients were recruited from the Second Hospital of Hebei Medical University and were divided into two groups:DM,diabetic pa-tients without albuminuria[urinary albumin to creatinine ratio(UACR)<30 mg/g]and DKD,diabetic patients with albuminuria(UACR≥30 mg/g).Healthy subjects were the normal control(NC)group.Urinary exosomal miR-145-5p,miR-27a-3p,and miR-29c-3p,were detected using real-time quantitative polymerase chain reaction.The correlation between exosomal miRNAs and the clinical in-dexes was evaluated.The diagnostic values of exosomal miR-145-5p and miR-27a-3p in DKD were determined using receiver operating characteristic(ROC)analysis.Biological functions of miR-145-5p were investigated by performing RESULTS Urinary exosomal expression of miR-145-5p and miR-27a-3p was more upregulated in the DKD group than in the DM group(miR-145-5p:4.54±1.45 vs 1.95±0.93,P<0.001;miR-27a-3p:2.33±0.79 vs 1.71±0.76,P<0.05)and the NC group(miR-145-5p:4.54±1.45 vs 1.55±0.83,P<0.001;miR-27a-3p:2.33±0.79 vs 1.10±0.51,P<0.001).The exosomal miR-145-5p and miR-27a-3p positively correlated with albuminuria and serum creatinine and negatively correlated with the estimated glomerular filtration rate.miR-27a-3p was also closely related to blood glucose,gly-cosylated hemoglobin A1c,and low-density lipoprotein cholesterol.ROC analysis revealed that miR-145-5p had a better area under the curve of 0.88[95%confidence interval(CI):0.784-0.985,P<0.0001]in diagnosing DKD than miR-27a-3p with 0.71(95%CI:0.547-0.871,P=0.0239).Bioinformatics analysis revealed that the target genes of miR-145-5p were located in the actin filament,cytoskeleton,and extracellular exosome and were involved in the pathological processes of DKD,including apoptosis,inflammation,and fibrosis.CONCLUSION Urinary exosomal miR-145-5p and miR-27a-3p may serve as novel noninvasive diagnostic biomarkers or promising therapeutic targets for DKD.展开更多
Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were establi...Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were established and used to conduct integrative targetingactive enhancer histone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency.Notably,LBP^(-/-)reduced the inflammatory response but markedly aggravated high-fat diet(HFD)-induced NAFLD in rats,with pronounced alterations in the histone acetylome and regulatory transcriptome.In total,1128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type(WT)and LBP^(-/-)NAFLD rats.Based on integrative analysis,CCAAT/enhancer-binding proteinβ(C/EBPβ)was identified as a pivotal transcription factor(TF)and contributor to dysregulated histone acetylome H3K27ac,and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD.This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβand functional gene SCD as potential regulators and therapeutic targets.展开更多
目的:探讨免疫细胞表型对HSP27的因果作用。方法:采用两样本孟德尔随机化(MR)综合分析来确定免疫细胞表型与HSP27表达水平之间的因果关系。基于公开的遗传数据,我们探索了731个免疫细胞表型与HSP27表达的因果关系,总共包括四种类型的免...目的:探讨免疫细胞表型对HSP27的因果作用。方法:采用两样本孟德尔随机化(MR)综合分析来确定免疫细胞表型与HSP27表达水平之间的因果关系。基于公开的遗传数据,我们探索了731个免疫细胞表型与HSP27表达的因果关系,总共包括四种类型的免疫特征(中位数荧光强度(MFI)、相对细胞(RC)、绝对细胞(AC)和形态参数(MP))。综合敏感性分析用于验证结果的稳健性、异质性和水平多效性。结果:我们进行了双向FDR校正,HSP27的表达在统计学上对细胞免疫表型没有显著影响(P>0.05)。然而,在研究细胞免疫表型对HSP27的因果影响时,我们发现在三种细胞免疫性状类别(MFI、RC、AC)中,21种免疫表型与HSP27表达存在因果联系(P<0.05)。其中,12种免疫表型可促进HSP27的表达(IVW:P<0.05,OR<1),包括:IgD-CD24-AC;IgD-CD24-%lymphocyte;Myeloid DC AC;CD62L-myeloid DC AC;Activated Treg%CD4 Treg;CD38 on IgD+CD38dim;CCR2 on granulocyte;CD80 on CD62L+myeloid DC;CD80 on monocyte;CD8 on TD CD8br;CD4 on activated&secreting Treg;CD11c on granulocyte。另外9种免疫表型可抑制HSP27的表达(IVW:P<0.05,OR>1),即:CD62L-plas-macytoid DC AC;Naive CD4+AC;CD14+CD16+monocyte AC;CD3 on T cell;CD3 on CD8br;HVEM on CM CD4+;HVEM on naive CD4+;CX3CR1 on CD14-CD16-;CD45 on Mo MDSC。结论:本研究揭示了免疫细胞表型与HSP27之间存在显著的遗传相关性,这对了解HSP27的病理机制具有重要意义。它不仅为未来临床疾病的诊断和治疗提供了新思路,而且有助于开发更准确的生物标志物和治疗方法。此外,我们的研究结果扩展了免疫学的研究成果,并为进一步研究免疫细胞与热休克蛋白在免疫应答和疾病中的相互作用提供了新的证据。展开更多
基金Supported by the Nature Science Foundation of Hebei Province,No.H2023104011.
文摘BACKGROUND Diabetic kidney disease(DKD),characterized by increased urinary microalbumin levels and decreased renal function,is the primary cause of end-stage renal di-sease.Its pathological mechanisms are complicated and multifactorial;Therefore,sensitive and specific biomarkers are needed.Urinary exosome originate from diverse renal cells in nephron segments and partially mirror the pathological changes in the kidney.The microRNAs(miRNAs)in urinary exosome are remark-ably stable and highly tissue-specific for the kidney.METHODS Type 2 diabetic mellitus(T2DM)patients were recruited from the Second Hospital of Hebei Medical University and were divided into two groups:DM,diabetic pa-tients without albuminuria[urinary albumin to creatinine ratio(UACR)<30 mg/g]and DKD,diabetic patients with albuminuria(UACR≥30 mg/g).Healthy subjects were the normal control(NC)group.Urinary exosomal miR-145-5p,miR-27a-3p,and miR-29c-3p,were detected using real-time quantitative polymerase chain reaction.The correlation between exosomal miRNAs and the clinical in-dexes was evaluated.The diagnostic values of exosomal miR-145-5p and miR-27a-3p in DKD were determined using receiver operating characteristic(ROC)analysis.Biological functions of miR-145-5p were investigated by performing RESULTS Urinary exosomal expression of miR-145-5p and miR-27a-3p was more upregulated in the DKD group than in the DM group(miR-145-5p:4.54±1.45 vs 1.95±0.93,P<0.001;miR-27a-3p:2.33±0.79 vs 1.71±0.76,P<0.05)and the NC group(miR-145-5p:4.54±1.45 vs 1.55±0.83,P<0.001;miR-27a-3p:2.33±0.79 vs 1.10±0.51,P<0.001).The exosomal miR-145-5p and miR-27a-3p positively correlated with albuminuria and serum creatinine and negatively correlated with the estimated glomerular filtration rate.miR-27a-3p was also closely related to blood glucose,gly-cosylated hemoglobin A1c,and low-density lipoprotein cholesterol.ROC analysis revealed that miR-145-5p had a better area under the curve of 0.88[95%confidence interval(CI):0.784-0.985,P<0.0001]in diagnosing DKD than miR-27a-3p with 0.71(95%CI:0.547-0.871,P=0.0239).Bioinformatics analysis revealed that the target genes of miR-145-5p were located in the actin filament,cytoskeleton,and extracellular exosome and were involved in the pathological processes of DKD,including apoptosis,inflammation,and fibrosis.CONCLUSION Urinary exosomal miR-145-5p and miR-27a-3p may serve as novel noninvasive diagnostic biomarkers or promising therapeutic targets for DKD.
基金supported by the National Natural Science Foundation of China(81971875,82300661)Natural Science Foundation of Anhui province(2308085QH246)+3 种基金Natural Science Foundation of the Anhui Higher Education Institutions(KJ2021A0205)Basic and Clinical Cooperative Research Program of Anhui Medical University(2019xkjT002,2019xkjT022,2022xkjT013)Talent Training Program,School of Basic Medical Sciences,Anhui Medical University(2022YPJH102)National College Students Innovation and Entrepreneurship Training Program of China(202210366024)。
文摘Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were established and used to conduct integrative targetingactive enhancer histone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency.Notably,LBP^(-/-)reduced the inflammatory response but markedly aggravated high-fat diet(HFD)-induced NAFLD in rats,with pronounced alterations in the histone acetylome and regulatory transcriptome.In total,1128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type(WT)and LBP^(-/-)NAFLD rats.Based on integrative analysis,CCAAT/enhancer-binding proteinβ(C/EBPβ)was identified as a pivotal transcription factor(TF)and contributor to dysregulated histone acetylome H3K27ac,and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD.This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβand functional gene SCD as potential regulators and therapeutic targets.
文摘目的:探讨免疫细胞表型对HSP27的因果作用。方法:采用两样本孟德尔随机化(MR)综合分析来确定免疫细胞表型与HSP27表达水平之间的因果关系。基于公开的遗传数据,我们探索了731个免疫细胞表型与HSP27表达的因果关系,总共包括四种类型的免疫特征(中位数荧光强度(MFI)、相对细胞(RC)、绝对细胞(AC)和形态参数(MP))。综合敏感性分析用于验证结果的稳健性、异质性和水平多效性。结果:我们进行了双向FDR校正,HSP27的表达在统计学上对细胞免疫表型没有显著影响(P>0.05)。然而,在研究细胞免疫表型对HSP27的因果影响时,我们发现在三种细胞免疫性状类别(MFI、RC、AC)中,21种免疫表型与HSP27表达存在因果联系(P<0.05)。其中,12种免疫表型可促进HSP27的表达(IVW:P<0.05,OR<1),包括:IgD-CD24-AC;IgD-CD24-%lymphocyte;Myeloid DC AC;CD62L-myeloid DC AC;Activated Treg%CD4 Treg;CD38 on IgD+CD38dim;CCR2 on granulocyte;CD80 on CD62L+myeloid DC;CD80 on monocyte;CD8 on TD CD8br;CD4 on activated&secreting Treg;CD11c on granulocyte。另外9种免疫表型可抑制HSP27的表达(IVW:P<0.05,OR>1),即:CD62L-plas-macytoid DC AC;Naive CD4+AC;CD14+CD16+monocyte AC;CD3 on T cell;CD3 on CD8br;HVEM on CM CD4+;HVEM on naive CD4+;CX3CR1 on CD14-CD16-;CD45 on Mo MDSC。结论:本研究揭示了免疫细胞表型与HSP27之间存在显著的遗传相关性,这对了解HSP27的病理机制具有重要意义。它不仅为未来临床疾病的诊断和治疗提供了新思路,而且有助于开发更准确的生物标志物和治疗方法。此外,我们的研究结果扩展了免疫学的研究成果,并为进一步研究免疫细胞与热休克蛋白在免疫应答和疾病中的相互作用提供了新的证据。
