目的:探究核受体亚家族4A组成员1(nuclear receptor subfamily 4 group A member 1,Nr4a1)Nr4a1激动剂胞孢子酮B(cytosporone B,Csn-B)对小鼠噪声暴露后听力损失的治疗作用。方法:采用双氧水刺激HEI-OC1毛细胞系的方法构建氧化应激细胞...目的:探究核受体亚家族4A组成员1(nuclear receptor subfamily 4 group A member 1,Nr4a1)Nr4a1激动剂胞孢子酮B(cytosporone B,Csn-B)对小鼠噪声暴露后听力损失的治疗作用。方法:采用双氧水刺激HEI-OC1毛细胞系的方法构建氧化应激细胞模型;通过实时荧光定量PCR(quantitative real-time PCR,q PCR)检测细胞中Nr4a1的mRNA表达水平;分别通过细胞计数试剂盒(cell counting kit-8,CCK8)及流式细胞术的方法检测细胞活力和细胞凋亡水平以评估Csn-B预处理后经双氧水刺激的细胞状态。构建小鼠噪声性听力损失模型,运用qPCR和免疫荧光技术检测噪声暴露后Nr4a1在小鼠耳蜗中的表达;通过检测听性脑干反应(auditory brainstem response,ABR)评估噪声暴露后以及Csn-B连续治疗13 d后小鼠听力情况。结果:双氧水刺激后HEI-OC1毛细胞中Nr4a1表达上升,细胞活力显著下降,凋亡水平显著升高;Csn-B预处理HEI-OC1毛细胞经双氧水刺激,细胞活力显著高于对照组而凋亡水平则显著低于对照组。在体研究结果显示,噪声暴露后小鼠听力显著降低,Nr4a1在小鼠耳蜗中的表达水平显著升高。噪声暴露后经Csn-B治疗小鼠听力得到改善,主要表现为Click-ABR以及Tone Burst-ABR(4000、8000Hz处)阈值下降。结论:Nr4a1激动剂Csn-B增强内耳毛细胞对氧化应激损伤的抵御能力,部分改善噪声暴露后的小鼠听力。展开更多
Nuclear receptor subfamily 4 group A1(NR4A1)is an orphan nuclear receptor,which is expressed in the majority of cells.NR4A1 expression in peripheral blood mononuclear cells is low during the preclinical stage of multi...Nuclear receptor subfamily 4 group A1(NR4A1)is an orphan nuclear receptor,which is expressed in the majority of cells.NR4A1 expression in peripheral blood mononuclear cells is low during the preclinical stage of multiple sclerosis.Knockout of the Nr4a1 gene in mice can aggravate the symptoms of experimental autoimmune encephalomyelitis(EAE),which is an animal model of multiple sclerosis.In this study,we intragastrically administered the NR4A1 agonist cytosporone B(Csn-B)to mice after inducing EAE.After treatment with Csn-B,the clinical symptoms in the EAE mice were substantially attenuated compared with that in PBS-treated control mice.The percentages of CD4+T cells and F4/80+cells in the central nervous system were decreased.In addition,interferon-γand interleukin-17 production by proinflammatory Th1/Th17 cells in the central nervous system and interferon-γlevels in splenocytes were decreased after Csn-B treatment.These findings suggest that the NR4A1 agonist Csn-B can alleviate nerve injury after EAE induction,and,therefore,may be useful as a potential treatment for multiple sclerosis.展开更多
基金supported by the National Natural Science Foundation of China, Nos.U1804178(to LMW)and 31870334(to LZ)
文摘Nuclear receptor subfamily 4 group A1(NR4A1)is an orphan nuclear receptor,which is expressed in the majority of cells.NR4A1 expression in peripheral blood mononuclear cells is low during the preclinical stage of multiple sclerosis.Knockout of the Nr4a1 gene in mice can aggravate the symptoms of experimental autoimmune encephalomyelitis(EAE),which is an animal model of multiple sclerosis.In this study,we intragastrically administered the NR4A1 agonist cytosporone B(Csn-B)to mice after inducing EAE.After treatment with Csn-B,the clinical symptoms in the EAE mice were substantially attenuated compared with that in PBS-treated control mice.The percentages of CD4+T cells and F4/80+cells in the central nervous system were decreased.In addition,interferon-γand interleukin-17 production by proinflammatory Th1/Th17 cells in the central nervous system and interferon-γlevels in splenocytes were decreased after Csn-B treatment.These findings suggest that the NR4A1 agonist Csn-B can alleviate nerve injury after EAE induction,and,therefore,may be useful as a potential treatment for multiple sclerosis.
