GABA_(A) receptors containingα5-subunits(GABA_(A)R-α5)cluster at both extrasynaptic and synaptic locations,interacting with the scaffold proteins radixin and gephyrin,respectively,and the re-localization of GABA_(A...GABA_(A) receptors containingα5-subunits(GABA_(A)R-α5)cluster at both extrasynaptic and synaptic locations,interacting with the scaffold proteins radixin and gephyrin,respectively,and the re-localization of GABA_(A)R-α5 influences GABAergic transmission.Here,we found that when early spatial memory deficits occurred in aged mice at 24 h after sevoflurane anesthesia,there was a re-localization of GABA_(A)R-α5 that enhanced tonic inhibition and reduced the decay kinetics of miniature inhibitory postsynaptic currents in the hippocampal CA1 region.Mechanistically,increased phosphorylation of radixin at threonine 564(Thr564)mediates the re-localization of GABA_(A)R-α5.Acute treatment with the selective extrasynaptic GABA_(A)R-α5 antagonist S44819 restored the GABA_(A)R-α5-mediated inhibitory currents by reversing radixin phosphorylation-dependent GABA_(A)R-α5 re-localization,then improved the sevoflurane-induced spatial memory impairment in aged mice.Our results suggest that the localization of GABA_(A)R-α5 altered by sevoflurane is linked to unbalanced GABAergic transmission,which induces early memory impairment in aged mice.Modulating the GABA_(A)R-α5 localization might be a novel strategy to improve memory after sevoflurane exposure.展开更多
Many studies have shown that(5R)-5-hydroxytriptolide is the optimal modified analogue of triptolide, possessing comparable immunosuppressive activity but much lower cytotoxicity than triptolide. Whether(5R)-5-hydroxyt...Many studies have shown that(5R)-5-hydroxytriptolide is the optimal modified analogue of triptolide, possessing comparable immunosuppressive activity but much lower cytotoxicity than triptolide. Whether(5R)-5-hydroxytriptolide has preventive effects on neuroinflammation is unclear. This study was designed to pretreat primary astrocytes from the brains of neonatal Sprague-Dawley rats with 20, 100 and 500 nM(5R)-5-hydroxytriptolide for 1 hour before establishing an in vitro neuroinflammation model with 1.0 μg/mL lipopolysaccharide for 24 hours. The generation of nitric oxide was detected by Griess reagents. Astrocyte marker glial fibrillary acidic protein was measured by immunohistochemical staining. The levels of tumor necrosis factor-α and interleukin-1β in the culture supernatant were assayed by enzyme linked immunosorbent assay. Nuclear factor-κB/p65 expression was examined by immunofluorescence staining. The phosphorylation of inhibitor of nuclear factor IκB-α and the location of nuclear factor-κB/P65 were determined using western blot assay. Our data revealed that(5R)-5-hydroxytriptolide inhibited the generation of nitric oxide, tumor necrosis factor-α and interleukin-1β from primary astrocytes activated by lipopolysaccharide, decreased the positive reaction intensity of glial fibrillary acidic protein, reduced the expression of tumor necrosis factor alpha and interleukin-1β in culture supernatant, inhibited the phosphorylation of IκB-α and the translocation of nuclear factor-κB/P65 to the nucleus. These results have confirmed that(5R)-5-hydroxytriptolide inhibits lipopolysaccharide-induced glial inflammatory response and provides cytological experimental data for(5R)-5-hydroxytriptolide in the treatment of neurodegenerative diseases.展开更多
目的研究肺腺癌(lung adenocarcinoma,LA)患者血清中微核糖核酸(miRNA)在肺腺癌患者及正常人群组血清中的表达水平,分析其在肺腺癌诊断中的临床价值。方法收集60例肺腺癌及40例正常人群血清,通过实时荧光定量聚合酶链反应(quantitative ...目的研究肺腺癌(lung adenocarcinoma,LA)患者血清中微核糖核酸(miRNA)在肺腺癌患者及正常人群组血清中的表达水平,分析其在肺腺癌诊断中的临床价值。方法收集60例肺腺癌及40例正常人群血清,通过实时荧光定量聚合酶链反应(quantitative real time PCR,qRT PCR)检测各组血清miR-498,miR-339-5p和miR-210-3p的表达情况。统计分析各组miRNA的表达差异以及单个miRNA在肺腺癌诊断中的价值,进一步用统计学方法分析三者联合检测的诊断价值。结果相比正常人群,肺腺癌患者血清中miR-210-3p表达增加(6.41±1.85 vs 4.52±1.45),miR-498(2.09±0.88vs 3.01±0.69)和miR-339-5p(0.8±0.53 vs 1.24±0.58)表达下降,差异有统计学意义(t=4.72,1.34,2.75,均P<0.05)。受试者工作特征曲线下面积(AUC)分析结果显示,miR-498,miR-339-5p和miR-210-3p的AUC分别为0.788(95%CI0.695~0.864),0.715(95%CI 0.616~0.801)和0.799(95%CI 0.707~0.872);三者联合检测在肺腺癌诊断中AUC值为0.902(95%CI 0.826~0.952),三者联合检测优于单个miRNA的检测,差异有统计学意义(t=14.09~18.65,均P<0.05)。结论miR-498,miR-339-5p和miR-210-3p在肺腺癌患者血清中的表达情况改变,对肺腺癌具有一定的临床诊断价值。展开更多
基金supported by the Tianjin Scientific Research Start-up Foundation for Talent Introduction(2021-1-10)the 14th Five-Year Plan Peak Discipline Support Plan of Tianjin Medical University Cancer Institute and Hospital(7-2-13)+3 种基金National Natural Science Foundation of China(82171221),Beijing Bethune Charitable Foundation(YXJL-2024-0778-0030)Beijing Science and Technology Innovation Medical Development Foundation(KC2024-JF-0069)Tianjin Medical University Postgraduate Education Reform Research Program(TMUYY02)Tianjin Key Medical Discipline(Specialty)Construction(TJYXZDXK-009A).
文摘GABA_(A) receptors containingα5-subunits(GABA_(A)R-α5)cluster at both extrasynaptic and synaptic locations,interacting with the scaffold proteins radixin and gephyrin,respectively,and the re-localization of GABA_(A)R-α5 influences GABAergic transmission.Here,we found that when early spatial memory deficits occurred in aged mice at 24 h after sevoflurane anesthesia,there was a re-localization of GABA_(A)R-α5 that enhanced tonic inhibition and reduced the decay kinetics of miniature inhibitory postsynaptic currents in the hippocampal CA1 region.Mechanistically,increased phosphorylation of radixin at threonine 564(Thr564)mediates the re-localization of GABA_(A)R-α5.Acute treatment with the selective extrasynaptic GABA_(A)R-α5 antagonist S44819 restored the GABA_(A)R-α5-mediated inhibitory currents by reversing radixin phosphorylation-dependent GABA_(A)R-α5 re-localization,then improved the sevoflurane-induced spatial memory impairment in aged mice.Our results suggest that the localization of GABA_(A)R-α5 altered by sevoflurane is linked to unbalanced GABAergic transmission,which induces early memory impairment in aged mice.Modulating the GABA_(A)R-α5 localization might be a novel strategy to improve memory after sevoflurane exposure.
基金supported by the National Natural Science Foundation of China,No.81402932(to YQC)
文摘Many studies have shown that(5R)-5-hydroxytriptolide is the optimal modified analogue of triptolide, possessing comparable immunosuppressive activity but much lower cytotoxicity than triptolide. Whether(5R)-5-hydroxytriptolide has preventive effects on neuroinflammation is unclear. This study was designed to pretreat primary astrocytes from the brains of neonatal Sprague-Dawley rats with 20, 100 and 500 nM(5R)-5-hydroxytriptolide for 1 hour before establishing an in vitro neuroinflammation model with 1.0 μg/mL lipopolysaccharide for 24 hours. The generation of nitric oxide was detected by Griess reagents. Astrocyte marker glial fibrillary acidic protein was measured by immunohistochemical staining. The levels of tumor necrosis factor-α and interleukin-1β in the culture supernatant were assayed by enzyme linked immunosorbent assay. Nuclear factor-κB/p65 expression was examined by immunofluorescence staining. The phosphorylation of inhibitor of nuclear factor IκB-α and the location of nuclear factor-κB/P65 were determined using western blot assay. Our data revealed that(5R)-5-hydroxytriptolide inhibited the generation of nitric oxide, tumor necrosis factor-α and interleukin-1β from primary astrocytes activated by lipopolysaccharide, decreased the positive reaction intensity of glial fibrillary acidic protein, reduced the expression of tumor necrosis factor alpha and interleukin-1β in culture supernatant, inhibited the phosphorylation of IκB-α and the translocation of nuclear factor-κB/P65 to the nucleus. These results have confirmed that(5R)-5-hydroxytriptolide inhibits lipopolysaccharide-induced glial inflammatory response and provides cytological experimental data for(5R)-5-hydroxytriptolide in the treatment of neurodegenerative diseases.
文摘目的研究肺腺癌(lung adenocarcinoma,LA)患者血清中微核糖核酸(miRNA)在肺腺癌患者及正常人群组血清中的表达水平,分析其在肺腺癌诊断中的临床价值。方法收集60例肺腺癌及40例正常人群血清,通过实时荧光定量聚合酶链反应(quantitative real time PCR,qRT PCR)检测各组血清miR-498,miR-339-5p和miR-210-3p的表达情况。统计分析各组miRNA的表达差异以及单个miRNA在肺腺癌诊断中的价值,进一步用统计学方法分析三者联合检测的诊断价值。结果相比正常人群,肺腺癌患者血清中miR-210-3p表达增加(6.41±1.85 vs 4.52±1.45),miR-498(2.09±0.88vs 3.01±0.69)和miR-339-5p(0.8±0.53 vs 1.24±0.58)表达下降,差异有统计学意义(t=4.72,1.34,2.75,均P<0.05)。受试者工作特征曲线下面积(AUC)分析结果显示,miR-498,miR-339-5p和miR-210-3p的AUC分别为0.788(95%CI0.695~0.864),0.715(95%CI 0.616~0.801)和0.799(95%CI 0.707~0.872);三者联合检测在肺腺癌诊断中AUC值为0.902(95%CI 0.826~0.952),三者联合检测优于单个miRNA的检测,差异有统计学意义(t=14.09~18.65,均P<0.05)。结论miR-498,miR-339-5p和miR-210-3p在肺腺癌患者血清中的表达情况改变,对肺腺癌具有一定的临床诊断价值。
