Objective:Anshen Dingzhi prescription(ADP)is an effective remedy for treating post-traumatic stress disorder(PTSD);however,the mechanism underlying its beneficial effects is unclear.This study explores the roles of th...Objective:Anshen Dingzhi prescription(ADP)is an effective remedy for treating post-traumatic stress disorder(PTSD);however,the mechanism underlying its beneficial effects is unclear.This study explores the roles of the neuroinflammation regulated by the FKBP prolyl isomerase 5(FKBP5)-IκB kinase alpha(IKKα)-nuclear factor kappa-B(NF-κB)-NOD-like receptor thermal protein domain-associated protein 3(NLRP3)signaling pathway in PTSD.Methods:The primary components of ADP,including ginsenosides Rg1 and Rb1,were quantified using ultra-performance liquid chromatography.Twelve C57BL/6 mice were allocated to control(D0)and experimental groups on days one,seven,and 14 of single prolonged stress(SPS).Eighteen C57BL/6 mice were allocated to control,SPS,and MCC950,an NLRP3 inhibitor(5 mg/kg)groups.Finally,24 C57BL/6 mice were allocated to control,SPS,paroxetine hydrochloride(PRX),or ADP(18.4 and 36.8 mg/kg)groups.Mice were administered MCC950,PRX,or ADP for 14 days.The open field test and elevated plus maze were used to evaluate anxiety-like behaviors,whereas fear memory extinction was evaluated using the fear memory test.Western blotting was employed to evaluate the expression levels of the FKBP5-IKKα-NF-κB-NLRP3 signaling pathway,tumor necrosis factor-α(TNF-α),interleukin(IL)-6,and IL-1β.The expression of FKBP5 and NLRP3 was further confirmed by immunofluorescence staining.Results:The amounts of ginsenosides Rg1 and Rb1 in ADP were(96.85±1.14)and(9.04±0.22)μg/g,respectively.Compared with the D0 group,the levels of the inflammatory cytokine proteins,TNF-α,IL-6,and IL-1β were elevated 1.33-to 1.51-fold and those of FKBP5-IKKα-NF-κB-NLRP3 signaling pathway were increased 1.16-to 1.41-fold in the hippocampus of the D14 group(P<0.05);the fluorescence intensity of FKBP5 and NLRP3 was also markedly increased(1.33-1.79-fold)in the hippocampus of the D14 group(P<0.5).Notably,injection of MCC950(5 mg/kg)reduced the levels of FKBP5-IKKα-NF-κB-NLRP3(0.80-0.88-fold)and inflammatory cytokines(0.74-0.83-fold),thereby improving the PTSD-like behaviors induced by SPS(P<0.05).In addition,ADP(36.8 g/kg)significantly improved PTSD-like behaviors and reduced levels of hippocampal inflammatory cytokines(0.70-0.79-fold)and FKBP5-IKKα-NF-κB-NLRP3(0.50-0.79-fold)(P<0.05)in SPS mice.Conclusion:The results suggest a potential therapeutic benefit of ADP in PTSD due to the inhibition of the FKBP5-IKKα-NF-κBNLRP3 signaling pathway.展开更多
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
目的探讨FK506结合蛋白5(FK506-binding protein 5,FKBP5)基因多态性与小儿支气管哮喘易感性及糖皮质激素(glucocorticoid,GC)疗效的关系。方法选取2021-04/2023-04月作者医院收治的120例支气管哮喘患儿作为研究对象(哮喘组)。另外将同...目的探讨FK506结合蛋白5(FK506-binding protein 5,FKBP5)基因多态性与小儿支气管哮喘易感性及糖皮质激素(glucocorticoid,GC)疗效的关系。方法选取2021-04/2023-04月作者医院收治的120例支气管哮喘患儿作为研究对象(哮喘组)。另外将同时期来作者医院进行体检的150例健康儿童作为健康组。根据GC疗效不同将支气管哮喘患儿分为良好组(n=92)和不良组(n=28)。采用限制性片段长度多态性聚合酶链反应(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)技术鉴定FKBP5基因rs4713916位点基因分型。采用Hardy-Weinberg遗传平衡度检验对样本代表性进行评估。结果健康组和哮喘组FKBP5基因rs4713916位点基因型符合Hardy-Weinberg遗传平衡定律,样本具有代表性(P>0.05)。健康组FKBP5基因rs4713916位点TT(7.33%vs.18.33%)、TC(34.67%vs.37.50%)、CC(58.00%vs.44.17%)基因型频率和T(24.67%vs.37.08%)、C(75.33%vs.62.92%)等位基因频率与哮喘组比较差异有统计学意义(P均<0.05)。良好组FKBP5基因rs4713916位点TT(7.61%vs.53.57%)、TC(40.22%vs.28.57%)、CC(52.17%vs.17.86%)基因型频率和T(27.72%vs.67.86%)、C(72.28%vs.32.14%)等位基因频率与不良组比较差异有统计学意义(P均<0.05)。FKBP5基因rs4713916位点TT基因型患儿治疗前后第1秒用力呼气容积(forced expiratory volume in one second,FEV1)、用力肺活量(forced vital capacity,FVC)、FEV1/FVC的差值低于TC、CC基因型患儿,且TC基因型低于CC基因型(P均<0.05)。结论FKBP5基因rs4713916位点多态性与小儿支气管哮喘易感风险和GC疗效有关,且携带TT基因型患儿对GC治疗的敏感性更差。展开更多
Adolescent depression is increasingly recognized as a serious mental health disorder with distinct clinical and molecular features.Using single-nucleus RNA sequencing,we identified cell-specific transcriptomic changes...Adolescent depression is increasingly recognized as a serious mental health disorder with distinct clinical and molecular features.Using single-nucleus RNA sequencing,we identified cell-specific transcriptomic changes in the nucleus accumbens(NAc),particularly in astrocytes,of adolescent macaques exhibiting depressive-like behaviors.The level of diacylglycerol kinase beta was significantly reduced in neurons and glial cells of depressed macaques,while FKBP5 levels increased in glial cells.Disruption of GABAergic synapses and disruption of D-glutamine and D-glutamate metabolism were linked to depressive phenotypes in medium spiny neurons(MSNs)and subtypes of astrocytes.Communication pathways between astrocytes and D1/D2-MSNs were also disrupted,involving factors like bone morphogenetic protein-6 and Erb-B2 receptor tyrosine kinase-4.Bulk transcriptomic and proteomic analyses corroborated these findings,and FKBP5 upregulation was confirmed by qRT-PCR,western blotting,and immunofluorescence in the NAc of rats and macaques with chronic unpredictable mild stress.Our results highlight the specific roles of different cell types in adolescent depression in the NAc,offering potential targets for new antidepressant therapies.展开更多
抑郁症是一种常见的精神疾病,其病因和发病机制尚未清楚,可能涉及遗传和环境因素的共同作用。既往研究发现童年虐待、他克莫司结合蛋白5(FK506 binding protein 5,FKBP5)基因多态性与抑郁症患者大脑结构改变存在潜在的关联。本文旨在探...抑郁症是一种常见的精神疾病,其病因和发病机制尚未清楚,可能涉及遗传和环境因素的共同作用。既往研究发现童年虐待、他克莫司结合蛋白5(FK506 binding protein 5,FKBP5)基因多态性与抑郁症患者大脑结构改变存在潜在的关联。本文旨在探讨这两方面因素对抑郁症患者大脑结构的影响,以期实现对抑郁症风险群体的精准识别,从而为抑郁症的早期预防提供参考依据。展开更多
基金supported by the National Natural Science Foundation of China(82404995,82404890)Research Funds of Center for Xin’an Medicine and Modernization of Traditional Chinese Medicine of IHM(2023CXMMTCM013)+3 种基金Scientific Research Program of Anhui Provincial Department of Education(2024AH051036,2024AH040137,2024AH051044)Excellent Funding for Academic and Scientific Research Activities for Academic and Technological Leaders in Anhui Province(2022D317)Key Research and Development Plan of Anhui Province(202104j07020004)Anhui University of Chinese Medicine Talent Support Program(DT2300000173).
文摘Objective:Anshen Dingzhi prescription(ADP)is an effective remedy for treating post-traumatic stress disorder(PTSD);however,the mechanism underlying its beneficial effects is unclear.This study explores the roles of the neuroinflammation regulated by the FKBP prolyl isomerase 5(FKBP5)-IκB kinase alpha(IKKα)-nuclear factor kappa-B(NF-κB)-NOD-like receptor thermal protein domain-associated protein 3(NLRP3)signaling pathway in PTSD.Methods:The primary components of ADP,including ginsenosides Rg1 and Rb1,were quantified using ultra-performance liquid chromatography.Twelve C57BL/6 mice were allocated to control(D0)and experimental groups on days one,seven,and 14 of single prolonged stress(SPS).Eighteen C57BL/6 mice were allocated to control,SPS,and MCC950,an NLRP3 inhibitor(5 mg/kg)groups.Finally,24 C57BL/6 mice were allocated to control,SPS,paroxetine hydrochloride(PRX),or ADP(18.4 and 36.8 mg/kg)groups.Mice were administered MCC950,PRX,or ADP for 14 days.The open field test and elevated plus maze were used to evaluate anxiety-like behaviors,whereas fear memory extinction was evaluated using the fear memory test.Western blotting was employed to evaluate the expression levels of the FKBP5-IKKα-NF-κB-NLRP3 signaling pathway,tumor necrosis factor-α(TNF-α),interleukin(IL)-6,and IL-1β.The expression of FKBP5 and NLRP3 was further confirmed by immunofluorescence staining.Results:The amounts of ginsenosides Rg1 and Rb1 in ADP were(96.85±1.14)and(9.04±0.22)μg/g,respectively.Compared with the D0 group,the levels of the inflammatory cytokine proteins,TNF-α,IL-6,and IL-1β were elevated 1.33-to 1.51-fold and those of FKBP5-IKKα-NF-κB-NLRP3 signaling pathway were increased 1.16-to 1.41-fold in the hippocampus of the D14 group(P<0.05);the fluorescence intensity of FKBP5 and NLRP3 was also markedly increased(1.33-1.79-fold)in the hippocampus of the D14 group(P<0.5).Notably,injection of MCC950(5 mg/kg)reduced the levels of FKBP5-IKKα-NF-κB-NLRP3(0.80-0.88-fold)and inflammatory cytokines(0.74-0.83-fold),thereby improving the PTSD-like behaviors induced by SPS(P<0.05).In addition,ADP(36.8 g/kg)significantly improved PTSD-like behaviors and reduced levels of hippocampal inflammatory cytokines(0.70-0.79-fold)and FKBP5-IKKα-NF-κB-NLRP3(0.50-0.79-fold)(P<0.05)in SPS mice.Conclusion:The results suggest a potential therapeutic benefit of ADP in PTSD due to the inhibition of the FKBP5-IKKα-NF-κBNLRP3 signaling pathway.
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。
文摘目的探讨FK506结合蛋白5(FK506-binding protein 5,FKBP5)基因多态性与小儿支气管哮喘易感性及糖皮质激素(glucocorticoid,GC)疗效的关系。方法选取2021-04/2023-04月作者医院收治的120例支气管哮喘患儿作为研究对象(哮喘组)。另外将同时期来作者医院进行体检的150例健康儿童作为健康组。根据GC疗效不同将支气管哮喘患儿分为良好组(n=92)和不良组(n=28)。采用限制性片段长度多态性聚合酶链反应(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)技术鉴定FKBP5基因rs4713916位点基因分型。采用Hardy-Weinberg遗传平衡度检验对样本代表性进行评估。结果健康组和哮喘组FKBP5基因rs4713916位点基因型符合Hardy-Weinberg遗传平衡定律,样本具有代表性(P>0.05)。健康组FKBP5基因rs4713916位点TT(7.33%vs.18.33%)、TC(34.67%vs.37.50%)、CC(58.00%vs.44.17%)基因型频率和T(24.67%vs.37.08%)、C(75.33%vs.62.92%)等位基因频率与哮喘组比较差异有统计学意义(P均<0.05)。良好组FKBP5基因rs4713916位点TT(7.61%vs.53.57%)、TC(40.22%vs.28.57%)、CC(52.17%vs.17.86%)基因型频率和T(27.72%vs.67.86%)、C(72.28%vs.32.14%)等位基因频率与不良组比较差异有统计学意义(P均<0.05)。FKBP5基因rs4713916位点TT基因型患儿治疗前后第1秒用力呼气容积(forced expiratory volume in one second,FEV1)、用力肺活量(forced vital capacity,FVC)、FEV1/FVC的差值低于TC、CC基因型患儿,且TC基因型低于CC基因型(P均<0.05)。结论FKBP5基因rs4713916位点多态性与小儿支气管哮喘易感风险和GC疗效有关,且携带TT基因型患儿对GC治疗的敏感性更差。
基金supported by STI2030-Major Projects(2022ZD0212900)the Joint Project of Chongqing Municipal Science and Technology Bureau and Chongqing Health Commission(2023CCXM003)+4 种基金the National Key Research and Development Program of China(2017YFA0505700)the National Natural Science Foundation of China(82271565 and 82301714)the China Postdoctoral Science Foundation(2023TQ0398,GZB20230916,2023MD734124)the Natural Science Foundation of Chongqing,China(CSTB2023NSCQ-BHX0106)the Postdoctoral Innovation Talents Support Program of Chongqing,China(2208013341918508).
文摘Adolescent depression is increasingly recognized as a serious mental health disorder with distinct clinical and molecular features.Using single-nucleus RNA sequencing,we identified cell-specific transcriptomic changes in the nucleus accumbens(NAc),particularly in astrocytes,of adolescent macaques exhibiting depressive-like behaviors.The level of diacylglycerol kinase beta was significantly reduced in neurons and glial cells of depressed macaques,while FKBP5 levels increased in glial cells.Disruption of GABAergic synapses and disruption of D-glutamine and D-glutamate metabolism were linked to depressive phenotypes in medium spiny neurons(MSNs)and subtypes of astrocytes.Communication pathways between astrocytes and D1/D2-MSNs were also disrupted,involving factors like bone morphogenetic protein-6 and Erb-B2 receptor tyrosine kinase-4.Bulk transcriptomic and proteomic analyses corroborated these findings,and FKBP5 upregulation was confirmed by qRT-PCR,western blotting,and immunofluorescence in the NAc of rats and macaques with chronic unpredictable mild stress.Our results highlight the specific roles of different cell types in adolescent depression in the NAc,offering potential targets for new antidepressant therapies.
文摘抑郁症是一种常见的精神疾病,其病因和发病机制尚未清楚,可能涉及遗传和环境因素的共同作用。既往研究发现童年虐待、他克莫司结合蛋白5(FK506 binding protein 5,FKBP5)基因多态性与抑郁症患者大脑结构改变存在潜在的关联。本文旨在探讨这两方面因素对抑郁症患者大脑结构的影响,以期实现对抑郁症风险群体的精准识别,从而为抑郁症的早期预防提供参考依据。
