目的探讨脑小血管病(CSVD)患者外周血G蛋白耦联雌激素受体30(GPER30)、神经元PAS结构域蛋白4(NPAS4)、FK506结合蛋白5(FKBP5)表达与认知功能障碍(CD)的相关性。方法前瞻性选取2022年1月至2023年12月郑州大学第二附属医院收治的227例CSV...目的探讨脑小血管病(CSVD)患者外周血G蛋白耦联雌激素受体30(GPER30)、神经元PAS结构域蛋白4(NPAS4)、FK506结合蛋白5(FKBP5)表达与认知功能障碍(CD)的相关性。方法前瞻性选取2022年1月至2023年12月郑州大学第二附属医院收治的227例CSVD患者,根据有无CD分为障碍组(n=66)与无障碍组(n=161)。比较两组患者的一般资料及外周血GPER30、NPAS4、FKBP5 m RNA表达水平,Logistic回归分析CSVD患者CD的影响因素,比较不同程度CD患者外周血GPER30、NPAS4、FKBP5 m RNA表达水平,采用Pearson法分析外周血GPER30、NPAS4、FKBP5 m RNA表达与蒙特利尔认知评估量表(Mo CA)评分的相关性。结果障碍组患者的年龄、病程分别为(72.49±5.68)岁、(2.69±0.78)年,明显高(长)于无障碍组的(67.51±7.04)岁、(2.31±0.62)年,差异均有统计学意义(P<0.05);障碍组患者的外周血GPER30 m RNA表达水平为1.02±0.17,明显低于无障碍组的1.66±0.31,NPAS4m RNA、FKBP5 m RNA表达水平分别为2.79±0.60、3.88±1.12,明显高于无障碍组的1.55±0.51、2.10±0.59,差异均有统计学意义(P<0.05);Logistic回归分析结果显示,年龄、病程、GPER30 m RNA、NPAS4 m RNA及FKBP5 m RNA均为CSVD患者CD的独立影响因素(P<0.05)。轻度组患者的外周血GPER30 m RNA表达水平为1.27±0.25,明显高于中重度组的0.70±0.12,NPAS4 m RNA、FKBP5 m RNA表达水平分别为2.31±0.58、3.19±1.07,明显低于中重度组的3.40±0.72、4.76±1.39,差异均有统计学意义(P<0.05);Pearson法分析结果显示,外周血GPER30 m RNA表达与CSVD患者Mo CA评分呈正相关(r=0.704,P<0.05),NPAS4 m RNA、FKBP5 m RNA与Mo CA评分呈负相关(r=-0.572、-0.542,P<0.05)。结论外周血GPER30、NPAS4、FKBP5是CSVD患者CD的独立相关因素,各指标表达水平与CD病情严重程度均具有一定相关性,可为临床判断CD、评估CD病情严重程度提供参考,以指导后续临床工作。展开更多
FK506(Tacrolimus)is a systemic immunosuppressant approved by the U.S.Food and Drug Administration.FK506 has been shown to promote peripheral nerve regeneration,however,its precise mechanism of action and its pathways ...FK506(Tacrolimus)is a systemic immunosuppressant approved by the U.S.Food and Drug Administration.FK506 has been shown to promote peripheral nerve regeneration,however,its precise mechanism of action and its pathways remain unclear.In this study,we established a rat model of sciatic nerve injury and found that FK506 improved the morphology of the injured sciatic nerve,increased the numbers of motor and sensory neurons,reduced inflammatory responses,markedly improved the conduction function of the injured nerve,and promoted motor function recovery.These findings suggest that FK506 promotes peripheral nerve structure recovery and functional regeneration by reducing the intensity of inflammation after neuronal injury and increasing the number of surviving neurons.展开更多
Inflammatory bowel disease(IBD)is commonly treated via enteral administration,which suffers from limited drug stability,low bioavailability,and short retention time.Parenteral administration—particularly intraperiton...Inflammatory bowel disease(IBD)is commonly treated via enteral administration,which suffers from limited drug stability,low bioavailability,and short retention time.Parenteral administration—particularly intraperitoneal injection-offers a promising alternative by bypassing the gastrointestinal tract and enhancing drug delivery to the intestines.However,intraperitoneally administered drugs primarily localize on the serosal rather than the mucosal side,where inflammation occurs.It remains unclear whether drug nanoparticles can penetrate the intestinal wall or modulate inflammation indirectly via lymphoid organs.Here,we employed tacrolimus(FK506)-loaded core–shell nanoparticles(FK506-Core/Shell)to investigate the feasibility and mode of action of parenteral administration for IBD treatment,with comparison to uncoated FK506-Core nanoparticles.Among three parenteral routes—intravenous,subcutaneous,and intraperitoneal injection—we found that intraperitoneal administration led to stronger accumulation of nanoparticles,especially FK506-Core/Shell,in the colon,with detectable signals also observed in mesenteric lymph nodes(mLNs)and the spleen.Following intraperitoneal injection,these nanoparticles were effectively internalized by antigen-presenting cells in the peritoneal fluid,accompanied by changes in cell populations,suggesting cell-mediated trafficking in vivo.Furthermore,nanoparticle signals were detected on the mucosal side of the intestine,as well as within mLNs and the spleen,supporting localized and systemic antiinflammatory effects.Treatment with FK506-Core/Shell significantly ameliorated dextran sulfate sodium(DSS)-induced colitis in mice,correlating with suppressed immune activation and induction of tolerance.These findings support the potential of intraperitoneally delivered nanotherapeutics as an effective strategy for IBD treatment.展开更多
Idiopathic pulmonary fibrosis(IPF)is a complex interstitial lung disease in which myofibroblasts are the primary effector cells.FK506-binding protein(FKBP10),a procollagen chaperone,is upregulated in IPF and primarily...Idiopathic pulmonary fibrosis(IPF)is a complex interstitial lung disease in which myofibroblasts are the primary effector cells.FK506-binding protein(FKBP10),a procollagen chaperone,is upregulated in IPF and primarily localizes to myofibroblasts.Exosomes have garnered significant attention as novel drug delivery vehicles,particularly when engineered.However,myofibroblasts remain underexplored in terms of engineered exosome-based therapies and associated drug targets.In this study,RDYH58,a peptide that targets myofibroblasts,was conjugated to the exosomal membrane protein Lamp2b to produce RDYH58-linked exosomes(RDYH58-exo).In vitro and in vivo experiments demonstrated that compared to unmodified exosomes(unm-exo),RDYH58-exo preferentially localized to myofibroblasts.A small interfering RNA targeting FKBP10(siFKBP10)was loaded into exosomes using ultrasonic microfluidics method,and the antifibrotic effects of RDYH58-exo carrying siFKBP10(RDYH58-siFKBP10)were assessed both in vitro and in vivo.The results demonstrated that RDYH58-siFKBP10 effectively silenced FKBP10 gene expression,significantly inhibiting fibroblast activation and extracellular matrix deposition,with superior antifibrotic efficacy compared to unmodified exosome vectors(unm-siFKBP10).RNA-seq analysis confirmed the pivotal regulatory role of FKBP10,providing critical evidence for the development of targeted therapeutic strategies.The RDYH58-siFKBP10 delivery system developed in this study demonstrates remarkable clinical translation potential.展开更多
文摘目的探讨脑小血管病(CSVD)患者外周血G蛋白耦联雌激素受体30(GPER30)、神经元PAS结构域蛋白4(NPAS4)、FK506结合蛋白5(FKBP5)表达与认知功能障碍(CD)的相关性。方法前瞻性选取2022年1月至2023年12月郑州大学第二附属医院收治的227例CSVD患者,根据有无CD分为障碍组(n=66)与无障碍组(n=161)。比较两组患者的一般资料及外周血GPER30、NPAS4、FKBP5 m RNA表达水平,Logistic回归分析CSVD患者CD的影响因素,比较不同程度CD患者外周血GPER30、NPAS4、FKBP5 m RNA表达水平,采用Pearson法分析外周血GPER30、NPAS4、FKBP5 m RNA表达与蒙特利尔认知评估量表(Mo CA)评分的相关性。结果障碍组患者的年龄、病程分别为(72.49±5.68)岁、(2.69±0.78)年,明显高(长)于无障碍组的(67.51±7.04)岁、(2.31±0.62)年,差异均有统计学意义(P<0.05);障碍组患者的外周血GPER30 m RNA表达水平为1.02±0.17,明显低于无障碍组的1.66±0.31,NPAS4m RNA、FKBP5 m RNA表达水平分别为2.79±0.60、3.88±1.12,明显高于无障碍组的1.55±0.51、2.10±0.59,差异均有统计学意义(P<0.05);Logistic回归分析结果显示,年龄、病程、GPER30 m RNA、NPAS4 m RNA及FKBP5 m RNA均为CSVD患者CD的独立影响因素(P<0.05)。轻度组患者的外周血GPER30 m RNA表达水平为1.27±0.25,明显高于中重度组的0.70±0.12,NPAS4 m RNA、FKBP5 m RNA表达水平分别为2.31±0.58、3.19±1.07,明显低于中重度组的3.40±0.72、4.76±1.39,差异均有统计学意义(P<0.05);Pearson法分析结果显示,外周血GPER30 m RNA表达与CSVD患者Mo CA评分呈正相关(r=0.704,P<0.05),NPAS4 m RNA、FKBP5 m RNA与Mo CA评分呈负相关(r=-0.572、-0.542,P<0.05)。结论外周血GPER30、NPAS4、FKBP5是CSVD患者CD的独立相关因素,各指标表达水平与CD病情严重程度均具有一定相关性,可为临床判断CD、评估CD病情严重程度提供参考,以指导后续临床工作。
基金supported by the National Natural Science Foundation of China,No.81971177(to YK)the Natural Science Foundation of Beijing,No.7222198(to NH)the Peking University People's Hospital Research and Development Fund,No.RDX2021-01(to YK)。
文摘FK506(Tacrolimus)is a systemic immunosuppressant approved by the U.S.Food and Drug Administration.FK506 has been shown to promote peripheral nerve regeneration,however,its precise mechanism of action and its pathways remain unclear.In this study,we established a rat model of sciatic nerve injury and found that FK506 improved the morphology of the injured sciatic nerve,increased the numbers of motor and sensory neurons,reduced inflammatory responses,markedly improved the conduction function of the injured nerve,and promoted motor function recovery.These findings suggest that FK506 promotes peripheral nerve structure recovery and functional regeneration by reducing the intensity of inflammation after neuronal injury and increasing the number of surviving neurons.
基金National Natural Science Foundation of China(Nos.82404520,and 824B2106)Construction Fund of Key Medical Disciplines of Hangzhou(No.2025HZZD06)+2 种基金the Medical and Health Technology Project of Hangzhou(No.Z20240018)China Postdoctoral Science Foundation(No.2024M752834)China National Postdoctoral Program for Innovative Talents(No.BX20230321)。
文摘Inflammatory bowel disease(IBD)is commonly treated via enteral administration,which suffers from limited drug stability,low bioavailability,and short retention time.Parenteral administration—particularly intraperitoneal injection-offers a promising alternative by bypassing the gastrointestinal tract and enhancing drug delivery to the intestines.However,intraperitoneally administered drugs primarily localize on the serosal rather than the mucosal side,where inflammation occurs.It remains unclear whether drug nanoparticles can penetrate the intestinal wall or modulate inflammation indirectly via lymphoid organs.Here,we employed tacrolimus(FK506)-loaded core–shell nanoparticles(FK506-Core/Shell)to investigate the feasibility and mode of action of parenteral administration for IBD treatment,with comparison to uncoated FK506-Core nanoparticles.Among three parenteral routes—intravenous,subcutaneous,and intraperitoneal injection—we found that intraperitoneal administration led to stronger accumulation of nanoparticles,especially FK506-Core/Shell,in the colon,with detectable signals also observed in mesenteric lymph nodes(mLNs)and the spleen.Following intraperitoneal injection,these nanoparticles were effectively internalized by antigen-presenting cells in the peritoneal fluid,accompanied by changes in cell populations,suggesting cell-mediated trafficking in vivo.Furthermore,nanoparticle signals were detected on the mucosal side of the intestine,as well as within mLNs and the spleen,supporting localized and systemic antiinflammatory effects.Treatment with FK506-Core/Shell significantly ameliorated dextran sulfate sodium(DSS)-induced colitis in mice,correlating with suppressed immune activation and induction of tolerance.These findings support the potential of intraperitoneally delivered nanotherapeutics as an effective strategy for IBD treatment.
基金funded by National Natural Science Foundation of China(Nos.82404552,82273969,and 82473967)Natural Science Foundation of Shandong Province(No.ZR2021MH395,China)+5 种基金Yantai University Doctoral Program(No.SM20B35,China)Development of engineered exosomes for nucleic acid drug delivery in the treatment of pulmonary fibrosis(No.SK22KH114,China)Research on the development of multiple methods to increase exosome production(No.SK22KH304,China)Science Fund of Shandong Laboratory of Advanced Materials and Green Manufacturing at Yantai(No.AMGM2024A07,China)Taishan Scholar Project of Shandong Province(No.tsqn202211112,China)Shandong Laboratory Program(No.SYS202205,China).
文摘Idiopathic pulmonary fibrosis(IPF)is a complex interstitial lung disease in which myofibroblasts are the primary effector cells.FK506-binding protein(FKBP10),a procollagen chaperone,is upregulated in IPF and primarily localizes to myofibroblasts.Exosomes have garnered significant attention as novel drug delivery vehicles,particularly when engineered.However,myofibroblasts remain underexplored in terms of engineered exosome-based therapies and associated drug targets.In this study,RDYH58,a peptide that targets myofibroblasts,was conjugated to the exosomal membrane protein Lamp2b to produce RDYH58-linked exosomes(RDYH58-exo).In vitro and in vivo experiments demonstrated that compared to unmodified exosomes(unm-exo),RDYH58-exo preferentially localized to myofibroblasts.A small interfering RNA targeting FKBP10(siFKBP10)was loaded into exosomes using ultrasonic microfluidics method,and the antifibrotic effects of RDYH58-exo carrying siFKBP10(RDYH58-siFKBP10)were assessed both in vitro and in vivo.The results demonstrated that RDYH58-siFKBP10 effectively silenced FKBP10 gene expression,significantly inhibiting fibroblast activation and extracellular matrix deposition,with superior antifibrotic efficacy compared to unmodified exosome vectors(unm-siFKBP10).RNA-seq analysis confirmed the pivotal regulatory role of FKBP10,providing critical evidence for the development of targeted therapeutic strategies.The RDYH58-siFKBP10 delivery system developed in this study demonstrates remarkable clinical translation potential.
