焦虑症是高发的心理疾病,研究表明肥胖是导致焦虑症的重要危险因素。该研究探讨竹节参总皂苷(saponins from Panax japonicus,SPJ)对高脂饮食小鼠焦虑症的改善作用及机制。将50只C57BL/6J小鼠随机分为正常组、高脂饮食组、SPJ低剂量组、...焦虑症是高发的心理疾病,研究表明肥胖是导致焦虑症的重要危险因素。该研究探讨竹节参总皂苷(saponins from Panax japonicus,SPJ)对高脂饮食小鼠焦虑症的改善作用及机制。将50只C57BL/6J小鼠随机分为正常组、高脂饮食组、SPJ低剂量组、SPJ高剂量组。第12周从高脂饮食组取6只小鼠,分为对照组、外源性给予成纤维细胞生长因子21(FGF21)组。旷场和高架十字迷宫实验评价小鼠焦虑样行为;苏木素-伊红(HE)染色和油红O染色观察肝脏、脂肪的病理变化;葡萄糖耐量实验和胰岛素耐量实验评估小鼠糖代谢水平;蛋白免疫印迹法检测肝脏和皮层中FGF21及下游相关蛋白和大脑皮层中脑源性神经营养因子(BDNF)、突触后膜蛋白4(DLG4)和突触素(SYP)表达;实时荧光定量PCR(qPCR)检测肝脏和皮层中FGF21及相关受体基因表达;免疫荧光检测大脑皮层神经元激活物(c-Fos)、FGF21、FGF21辅助受体β-klotho的表达。结果显示,SPJ可显著改善高脂饮食小鼠在高架十字迷宫的开臂区及旷场中心区的活动频率,并上调BDNF、DLG4和SYP表达,有效改善高脂饮食小鼠的焦虑样行为。与正常组相比,高脂饮食组小鼠的肝脏及大脑皮层中FGF21的表达上调,成纤维细胞生长因子受体1(FGFR1)与β-klotho的表达显著下降,提示高脂饮食小鼠呈FGF21抵抗状态;SPJ可显著上调高脂饮食小鼠β-klotho水平,逆转FGF21抵抗。进一步与外源性给予FGF21进行对比,显示SPJ激活大脑皮层区域与其一致,同时SPJ能促进大脑皮层中c-Fos与β-klotho阳性细胞数量及共定位。综上所述,SPJ可有效改善高脂饮食小鼠的焦虑样行为,其机制与上调大脑β-klotho表达,逆转FGF21抵抗,进而激活大脑皮层、杏仁核神经元有关。展开更多
Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory.Kinesin-4 KIF21A helps organize the microtubule-actin network at th...Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory.Kinesin-4 KIF21A helps organize the microtubule-actin network at the cell cortex by interacting with KANK1;however,whether KIF21A modulates dendritic structure and function in neurons remains unknown.In this study,we found that KIF21A was distributed in a subset of dendritic spines,and that these KIF21A-positive spines were larger and more structurally plastic than KIF21A-negative spines.Furthermore,the interaction between KIF21A and KANK1 was found to be critical for dendritic spine morphogenesis and synaptic plasticity.Knockdown of either KIF21A or KANK1 inhibited dendritic spine morphogenesis and dendritic branching,and these deficits were fully rescued by coexpressing full-length KIF21A or KANK1,but not by proteins with mutations disrupting direct binding between KIF21A and KANK1 or binding between KANK1 and talin1.Knocking down KIF21A in the hippocampus of rats inhibited the amplitudes of long-term potentiation induced by high-frequency stimulation and negatively impacted the animals’cognitive abilities.Taken together,our findings demonstrate the function of KIF21A in modulating spine morphology and provide insight into its role in synaptic function.展开更多
Background:The prognostic significance of the chemokine receptor CCR7 in diffuse large B-cell lymphoma(DLBCL)has been reported previously.However,the detailed mechanisms of CCR7 in DLBCL,particularly regarding its int...Background:The prognostic significance of the chemokine receptor CCR7 in diffuse large B-cell lymphoma(DLBCL)has been reported previously.However,the detailed mechanisms of CCR7 in DLBCL,particularly regarding its interaction with lenalidomide treatment,are not fully understood.Methods:Our study utilized bioinformatics approaches to identify hub genes in SU-DHL-2 cell lines treated with lenalidomide compared to control groups.Immunohistochemical data and clinical information from 122 patients with DLBCL were analyzed to assess the correlation of CCR7 and p-ERK1/2 expression with the prognosis of DLBCL.Furthermore,in vitro and in vivo experiments were conducted to clarify the role of CCR7 in the response of DLBCL to lenalidomide treatment.Results:Our bioinformatics analysis pinpointed CCR7 as a hub gene in the context of lenalidomide treatment in DLBCL.Notably,31.14%and 36.0%(44/122)of DLBCL cases showed positive expression for CCR7 and ERK1/2 respectively,establishing them as independent prognostic factors for adverse outcomes in DLBCL via multivariate Cox regression analysis.Additionally,our studies demonstrated that the external application of the protein CCL21 promoted proliferation,migration,invasion,and activation of the ERK1/2 pathway in SU-DHL-2 and OCI-LY3 cell lines with high levels of CCR7 expression.This effect was mitigated by CCR7 silencing through siRNA,application of ERK inhibitors,or lenalidomide treatment.In vivo experiments reinforced the efficacy of lenalidomide,significantly reducing tumor growth rate,tumor mass,serum total LDH levels,and expression of CCR7 and p-ERK1/2 in a SUDHL-2 xenograft model in nude mice(p<0.05).Conclusion:Our study clarifies the potential role of the CCL21/CCR7/ERK1/2 axis in the therapeutic effects of lenalidomide in DLBCL treatment.展开更多
文摘焦虑症是高发的心理疾病,研究表明肥胖是导致焦虑症的重要危险因素。该研究探讨竹节参总皂苷(saponins from Panax japonicus,SPJ)对高脂饮食小鼠焦虑症的改善作用及机制。将50只C57BL/6J小鼠随机分为正常组、高脂饮食组、SPJ低剂量组、SPJ高剂量组。第12周从高脂饮食组取6只小鼠,分为对照组、外源性给予成纤维细胞生长因子21(FGF21)组。旷场和高架十字迷宫实验评价小鼠焦虑样行为;苏木素-伊红(HE)染色和油红O染色观察肝脏、脂肪的病理变化;葡萄糖耐量实验和胰岛素耐量实验评估小鼠糖代谢水平;蛋白免疫印迹法检测肝脏和皮层中FGF21及下游相关蛋白和大脑皮层中脑源性神经营养因子(BDNF)、突触后膜蛋白4(DLG4)和突触素(SYP)表达;实时荧光定量PCR(qPCR)检测肝脏和皮层中FGF21及相关受体基因表达;免疫荧光检测大脑皮层神经元激活物(c-Fos)、FGF21、FGF21辅助受体β-klotho的表达。结果显示,SPJ可显著改善高脂饮食小鼠在高架十字迷宫的开臂区及旷场中心区的活动频率,并上调BDNF、DLG4和SYP表达,有效改善高脂饮食小鼠的焦虑样行为。与正常组相比,高脂饮食组小鼠的肝脏及大脑皮层中FGF21的表达上调,成纤维细胞生长因子受体1(FGFR1)与β-klotho的表达显著下降,提示高脂饮食小鼠呈FGF21抵抗状态;SPJ可显著上调高脂饮食小鼠β-klotho水平,逆转FGF21抵抗。进一步与外源性给予FGF21进行对比,显示SPJ激活大脑皮层区域与其一致,同时SPJ能促进大脑皮层中c-Fos与β-klotho阳性细胞数量及共定位。综上所述,SPJ可有效改善高脂饮食小鼠的焦虑样行为,其机制与上调大脑β-klotho表达,逆转FGF21抵抗,进而激活大脑皮层、杏仁核神经元有关。
基金supported by the National Key Research and Development Program of China,No.2021ZD0202503(to AHT)the National Natural Science Foundation of China,Nos.31872759(to AHT)and 32070707(to CF)+1 种基金Shenzhen Science and Technology Program,No.RCJC20210609104333007(to ZW)Shenzhen-Hong Kong Institute of Brain Science,Shenzhen Fundamental Research Institutions,No.2021SHIBS0002(to ZW).
文摘Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory.Kinesin-4 KIF21A helps organize the microtubule-actin network at the cell cortex by interacting with KANK1;however,whether KIF21A modulates dendritic structure and function in neurons remains unknown.In this study,we found that KIF21A was distributed in a subset of dendritic spines,and that these KIF21A-positive spines were larger and more structurally plastic than KIF21A-negative spines.Furthermore,the interaction between KIF21A and KANK1 was found to be critical for dendritic spine morphogenesis and synaptic plasticity.Knockdown of either KIF21A or KANK1 inhibited dendritic spine morphogenesis and dendritic branching,and these deficits were fully rescued by coexpressing full-length KIF21A or KANK1,but not by proteins with mutations disrupting direct binding between KIF21A and KANK1 or binding between KANK1 and talin1.Knocking down KIF21A in the hippocampus of rats inhibited the amplitudes of long-term potentiation induced by high-frequency stimulation and negatively impacted the animals’cognitive abilities.Taken together,our findings demonstrate the function of KIF21A in modulating spine morphology and provide insight into its role in synaptic function.
基金supported by the Key Research and Development Program of Science and Technology Department of Guizhou Province(No.20204Y147).
文摘Background:The prognostic significance of the chemokine receptor CCR7 in diffuse large B-cell lymphoma(DLBCL)has been reported previously.However,the detailed mechanisms of CCR7 in DLBCL,particularly regarding its interaction with lenalidomide treatment,are not fully understood.Methods:Our study utilized bioinformatics approaches to identify hub genes in SU-DHL-2 cell lines treated with lenalidomide compared to control groups.Immunohistochemical data and clinical information from 122 patients with DLBCL were analyzed to assess the correlation of CCR7 and p-ERK1/2 expression with the prognosis of DLBCL.Furthermore,in vitro and in vivo experiments were conducted to clarify the role of CCR7 in the response of DLBCL to lenalidomide treatment.Results:Our bioinformatics analysis pinpointed CCR7 as a hub gene in the context of lenalidomide treatment in DLBCL.Notably,31.14%and 36.0%(44/122)of DLBCL cases showed positive expression for CCR7 and ERK1/2 respectively,establishing them as independent prognostic factors for adverse outcomes in DLBCL via multivariate Cox regression analysis.Additionally,our studies demonstrated that the external application of the protein CCL21 promoted proliferation,migration,invasion,and activation of the ERK1/2 pathway in SU-DHL-2 and OCI-LY3 cell lines with high levels of CCR7 expression.This effect was mitigated by CCR7 silencing through siRNA,application of ERK inhibitors,or lenalidomide treatment.In vivo experiments reinforced the efficacy of lenalidomide,significantly reducing tumor growth rate,tumor mass,serum total LDH levels,and expression of CCR7 and p-ERK1/2 in a SUDHL-2 xenograft model in nude mice(p<0.05).Conclusion:Our study clarifies the potential role of the CCL21/CCR7/ERK1/2 axis in the therapeutic effects of lenalidomide in DLBCL treatment.
