目的:通过外源性注射趋化因子(C-X3-C基序)配体1(Fractalkine,CX3CL1)探索其对阿尔茨海默病(Alzheimer’sdisease,AD)小鼠神经元功能的影响及机制。方法:采用APP/PS1双转基因小鼠建立AD模型。将小鼠随机分为4组:对照组、AD模型组、AD+PB...目的:通过外源性注射趋化因子(C-X3-C基序)配体1(Fractalkine,CX3CL1)探索其对阿尔茨海默病(Alzheimer’sdisease,AD)小鼠神经元功能的影响及机制。方法:采用APP/PS1双转基因小鼠建立AD模型。将小鼠随机分为4组:对照组、AD模型组、AD+PBS溶剂组、AD+CX3CL1组。AD+CX3CL1组颅内给予CX3CL1。AD+PBS溶剂组注射等容积的PBS溶剂。采用旷场实验和Morris水迷宫测试小鼠认知行为,免疫荧光染色、TUNEL染色、尼氏染色、蛋白质印迹和RT-PCR技术对小鼠海马组织进行分析。结果:①AD小鼠接受CX3CL1注射后增加了移动距离,但没有显著差异(P=0.189);在水迷宫测试中,AD+CX3CL1组寻找水下平台的移动距离显著缩短(P=0.001);②AD模型组中GSDMD(Gasdermin D)蛋白和炎症相关蛋白表达显著升高(P<0.05),而CX3CL1注射能显著降低这些蛋白的表达水平(P<0.05);③AD模型组的尼氏体数量、突触相关蛋白25 kDa(synaptosomal-associated protein of 25 kDa,SNAP25)、突触后致密区蛋白95(post synaptic density protein 95,PSD95)和囊泡相关膜蛋白1(vesicle-associated membrane protein 1,VAMP1)表达水平显著降低,而CX3CL1组尼氏体数量(P=0.001)和SNAP25、PSD95、VAMP1蛋白的表达增加(P=0.043,P=0.026,P=0.003)。结论:外源性CX3CL1注射能够通过调节炎症因子和减少细胞焦亡来改善AD小鼠的神经元功能,保护神经元免受损伤。展开更多
Objective The ATP responsive P2 purinergic receptors can be subdivided into metabotropic P2X family and ionotropic P2Y family.Among these,P2X3 is a type of P2X receptor which is specifically expressed on nerves,especi...Objective The ATP responsive P2 purinergic receptors can be subdivided into metabotropic P2X family and ionotropic P2Y family.Among these,P2X3 is a type of P2X receptor which is specifically expressed on nerves,especially on pre-ganglionic sensory fibers.This study investigates whether gefapixant possesses the potential of inhibiting cardiac sympathetic hypersensitivity to protect against cardiac remodeling in the context of myocardial infarction.Methods The Sprague-Dawley rats were divided randomly into three groups:sham group-myocardial infarction group,and myocardial infarction with gefapixant treatment group.Myocardial infarction was induced by left anterior descending branch ligation.The gefapixant solution was intraperitoneally injected each time per day for 7 days and the appropriate dosage of gefapixant was determined according to the results of hematoxylin-eosin(HE)staining and myocardial injury biomarkers.Conditions of cardiac function were assessed by echocardiograph and cardiac fibrosis was evaluated by Western blotting and immunofluorescence staining of collagen I and collagen III.The sympathetic innervation was detected by norepinephrine concentration(pg/mL),in-vivo electrophysiology,and typical sympathetic biomarkers.Inflammatory cell infiltration was shown from immunofluorescence staining and pro-inflammatory signaling pathway activation was checked by immunohistology,quantitative realtime PCR(qPCR)and Western blotting.Results It was found that gefapixant injection of 10 mg/kg per day had the highest dosage-efficacy ratio.Furthermore,gefapixant treatment improved cardiac pump function as shown by increased LVEF and LVFS,and decreased LVIDd and LVIDs.The expression levels of collagen I and collagen III,and TNF-αwere all decreased by P2X3 inhibition.Mechanistically,the decreased activation of nucleotide-binding and oligomerization domain-like receptors family pyrin-domain-containing 3(NLRP3)inflammasome and subsequent cleavage of caspase-1 which modulated interleukin-1β(IL-1β)and IL-18 level in heart after gefapixant treatment were associated with the suppressed cardiac inflammation.Conclusion It is suggested that P2X3 inhibition by gefapixant ameliorates post-infarct autonomic nervous imbalance,cardiac dysfunction,and remodeling possibly via inactivating NLRP3 inflammasome.展开更多
如果要问去年哪一款桌面处理器卖得最火,当然非A M D(超威)锐龙75800X3D莫属。借助3 D堆叠缓存,三级缓存容量比其他处理器大得多的锐龙75800X3D在游戏性能上可以战胜竞争对手的不少第12代酷睿、第13代酷睿产品,而且售价也非常给力。不...如果要问去年哪一款桌面处理器卖得最火,当然非A M D(超威)锐龙75800X3D莫属。借助3 D堆叠缓存,三级缓存容量比其他处理器大得多的锐龙75800X3D在游戏性能上可以战胜竞争对手的不少第12代酷睿、第13代酷睿产品,而且售价也非常给力。不过锐龙75800X3D使用的并非最新的Zen 4架构,其所用的Zen 3架构从现在的眼光来看也稍显落伍,更关键的是锐龙75800X3D的处理器核心数量仅有8颗,对那些需要更高处理器性能的用户而言,这样的规格显然不是那么尽如人意,想要战胜竞争对手的24核心32线程旗舰:酷睿i9-13900K,也是力不从心。展开更多
文摘目的:通过外源性注射趋化因子(C-X3-C基序)配体1(Fractalkine,CX3CL1)探索其对阿尔茨海默病(Alzheimer’sdisease,AD)小鼠神经元功能的影响及机制。方法:采用APP/PS1双转基因小鼠建立AD模型。将小鼠随机分为4组:对照组、AD模型组、AD+PBS溶剂组、AD+CX3CL1组。AD+CX3CL1组颅内给予CX3CL1。AD+PBS溶剂组注射等容积的PBS溶剂。采用旷场实验和Morris水迷宫测试小鼠认知行为,免疫荧光染色、TUNEL染色、尼氏染色、蛋白质印迹和RT-PCR技术对小鼠海马组织进行分析。结果:①AD小鼠接受CX3CL1注射后增加了移动距离,但没有显著差异(P=0.189);在水迷宫测试中,AD+CX3CL1组寻找水下平台的移动距离显著缩短(P=0.001);②AD模型组中GSDMD(Gasdermin D)蛋白和炎症相关蛋白表达显著升高(P<0.05),而CX3CL1注射能显著降低这些蛋白的表达水平(P<0.05);③AD模型组的尼氏体数量、突触相关蛋白25 kDa(synaptosomal-associated protein of 25 kDa,SNAP25)、突触后致密区蛋白95(post synaptic density protein 95,PSD95)和囊泡相关膜蛋白1(vesicle-associated membrane protein 1,VAMP1)表达水平显著降低,而CX3CL1组尼氏体数量(P=0.001)和SNAP25、PSD95、VAMP1蛋白的表达增加(P=0.043,P=0.026,P=0.003)。结论:外源性CX3CL1注射能够通过调节炎症因子和减少细胞焦亡来改善AD小鼠的神经元功能,保护神经元免受损伤。
基金supported by the National Natural Science Foundation of China(No.81370282).
文摘Objective The ATP responsive P2 purinergic receptors can be subdivided into metabotropic P2X family and ionotropic P2Y family.Among these,P2X3 is a type of P2X receptor which is specifically expressed on nerves,especially on pre-ganglionic sensory fibers.This study investigates whether gefapixant possesses the potential of inhibiting cardiac sympathetic hypersensitivity to protect against cardiac remodeling in the context of myocardial infarction.Methods The Sprague-Dawley rats were divided randomly into three groups:sham group-myocardial infarction group,and myocardial infarction with gefapixant treatment group.Myocardial infarction was induced by left anterior descending branch ligation.The gefapixant solution was intraperitoneally injected each time per day for 7 days and the appropriate dosage of gefapixant was determined according to the results of hematoxylin-eosin(HE)staining and myocardial injury biomarkers.Conditions of cardiac function were assessed by echocardiograph and cardiac fibrosis was evaluated by Western blotting and immunofluorescence staining of collagen I and collagen III.The sympathetic innervation was detected by norepinephrine concentration(pg/mL),in-vivo electrophysiology,and typical sympathetic biomarkers.Inflammatory cell infiltration was shown from immunofluorescence staining and pro-inflammatory signaling pathway activation was checked by immunohistology,quantitative realtime PCR(qPCR)and Western blotting.Results It was found that gefapixant injection of 10 mg/kg per day had the highest dosage-efficacy ratio.Furthermore,gefapixant treatment improved cardiac pump function as shown by increased LVEF and LVFS,and decreased LVIDd and LVIDs.The expression levels of collagen I and collagen III,and TNF-αwere all decreased by P2X3 inhibition.Mechanistically,the decreased activation of nucleotide-binding and oligomerization domain-like receptors family pyrin-domain-containing 3(NLRP3)inflammasome and subsequent cleavage of caspase-1 which modulated interleukin-1β(IL-1β)and IL-18 level in heart after gefapixant treatment were associated with the suppressed cardiac inflammation.Conclusion It is suggested that P2X3 inhibition by gefapixant ameliorates post-infarct autonomic nervous imbalance,cardiac dysfunction,and remodeling possibly via inactivating NLRP3 inflammasome.
