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nr4a1激动剂胞孢子酮B挽救小鼠噪声性听力损失

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神经损伤与功能重建 2024年第5期19卷 249-255页

作者：苏波赖彦冰王晓迪褚汉启冰丹华中科技大学同济医学院附属同济医院耳鼻咽喉-头颈外科武汉430030

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... 详细信息

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。

关键词： nr4a1 Csn-B 噪声性耳聋氧化应激

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nr4a1 agonist cytosporone B attenuates neuroinflammation in a mouse model of multiple sclerosis

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Neural Regeneration Research 2022年第12期17卷 2765-2770页

作者： Hai-Zhen Yu Bing-Qing Zhu Lin Zhu Shuo Li Li-Mei Wang Department of Neurology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina

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.

关键词： cytosporone B(Csn-B) experimental autoimmune encephalomyelitis macrophages microglia multiple sclerosis nr4a1 agonist nr4a1 Th1 Th17 treatment

nr4a1 enhances glycolysis in hypoxia-exposed pulmonary artery smooth muscle cells by upregulating HIF-1αexpression

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BIOCELL 2023年第11期47卷 2423-2433页

作者： CHENYANG CHEN JUAN WEN WEI HUANG JIANG LI Cardiovascular Department The Third Xiangya Hospital of Central South UniversityChangsha410013China Department of Cardiovascular Medicine The Second Xiangya HospitalCentral South UniversityChangsha410011China

Background:Pulmonary arterial hypertension(PAH)is a chronic and progressive disease that is strongly associated with dysregulation of glucose metabolism.Alterations in nuclear receptor subfamily 4 group A member 1(nr4a1)activity alter the outcome of PAH.This study aimed to investigate the effects of nr4a1 on glycolysis in PAH and its underlying mechanisms.Methods:This study included twenty healthy volunteers and twenty-three PAH patients,and plasma samples were collected from the participants.To mimic the conditions of PAH in vitro,a hypoxia-induced model of pulmonary artery smooth muscle cell(PASMC)model was established.The proliferation of PASMCs was assessed using CCK8 assays.Results:Levels of nr4a1,hypoxia-inducible factor-1α(HIF-1α),and various glycolysis-related enzymes were measured.In addition,extracellular glucose and lactate production were assessed.The interaction between nr4a1 and HIF-1αwas evaluated by co-immunoprecipitation assays.Levels of nr4a1 and HIF-1αwas increased in PAH patients,and exposure to hypoxia resulted in increased levels of nr4a1 and HIF-1αin PASMCs.nr4a1 interacted with HIF-1α.nr4a1 overexpression enhanced hypoxia-induced expression of HIF-1α,GLUT1,PKM2,HK2,and CD36,decreased glucose levels,increased lactate levels and promoted hypoxic PASMC viability.Conversely,silencing nr4a1 decreased hypoxia-induced expression of HIF-1α,GLUT1,PKM2,HK2,and CD36,promoted glucose production,reduced lactate levels and inhibited hypoxic PASMC viability.Furthermore,overexpression of HIF-1αreversed the regulation of glycolysis caused by nr4a1 knockdown.Conclusion:nr4a1 enhances glycolysis in hypoxia-induced PASMCs by upregulating HIF-1α.Our findings indicate that the management of nr4a1 activity may be a promising strategy for PAH therapy.

关键词： Pulmonary arterial hypertension nr4a1 HIF-1α Glycolysis Hypoxia Pulmonary arterial smooth muscle cells

SPDEF suppresses head and neck squamous cell carcinoma progression by transcriptionally activating nr4a1

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International Journal of Oral Science 2021年第4期13卷 370-380页

作者： Yanting Wang Xianyue Ren Weiyu Li Ruoyan Cao Suyang Liu Laibo Jiang Bin Cheng Juan Xia Hospital of Stomatology Sun Yat-sen UniversityGuangzhouChina Guangdong Provincial Key Laboratory of Stomatology GuangzhouChina Guanghua School of Stomatology Sun Yat-sen UniversityGuangzhouChina

SAM pointed domain containing E26 transformation-specific transcription factor(SPDEF)plays dual roles in the initiation and development of human malignancies.However,the biological role of SPDEF in head and neck squamous cell carcinoma(HNSCC)remains unclear.In this study,the expression level of SPDEF and its correlation with the clinical parameters of patients with HNSCC were determined using TCGA-HNSC,GSE65858,and our own clinical cohorts.CCK8,colony formation,cell cycle analysis,and a xenograft tumor growth model were used to determine the molecular functions of SPDEF in HNSCC.ChIP-qPCR,dual luciferase reporter assay,and rescue experiments were conducted to explore the potential molecular mechanism of SPDEF in HNSCC.Compared with normal epithelial tissues,SPDEF was significantly downregulated in HNSCC tissues.Patients with HNSCC with low SPDEF mRNA levels exhibited poor clinical outcomes.Restoring SPDEF inhibited HNSCC cell viability and colony formation and induced G0/G1 cell cycle arrest,while silencing SPDEF promoted cell proliferation in vitro.The xenograft tumor growth model showed that tumors with SPDEF overexpression had slower growth rates,smaller volumes,and lower weights.SPDEF could directly bind to the promoter region of nr4a1 and promoted its transcription,inducing the suppression of AKT,MAPK,and NF-κB signaling pathways.Moreover,silencing nr4a1 blocked the suppressive effect of SPDEF in HNSCC cells.Here,we demonstrate that SPDEF acts as a tumor suppressor by transcriptionally activating nr4a1 in HNSCC.Our findings provide novel insights into the molecular mechanism of SPDEF in tumorigenesis and a novel potential therapeutic target for HNSCC.

关键词： inhibited SPD nr4a1

Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent m6A demethylation of nr4a1 mRNA

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Cellular & Molecular Immunology 2021年第6期18卷 1412-1424页

作者： Benyu Liu Nian Liu Xiaoxiao Zhu Liuliu Yang Buqing Ye Huimu Li Pingping Zhu Tiankun Lu Yong Tian Zusen Fan Key Laboratory of Infection and Immunity of CAS CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina Research Center of Basic Medicine Academy of Medical SciencesZhengzhou UniversityZhengzhouChina University of Chinese Academy of Sciences BeijingChina Key Laboratory of RNA Biology Institute of BiophysicsChinese Academy of SciencesBeijingChina

Group 3 innate lymphoid cells(ILC3s)play critical roles in innate immunity and gut homeostasis.However,how ILC3 homeostasis is regulated remains elusive.Here,we identified a novel circular RNA,circZbtb20,that is highly expressed in ILC3s and required for their maintenance and function.CircZbtb20 deletion causes reduced ILC3 numbers,increasing susceptibility to C.rodentium infection.Mechanistically,circZbtb20 enhances the interaction of Alkbh5 with nr4a1 mRNA,leading to ablation of the m6A modification of nr4a1 mRNA to promote its stability.nr4a1 initiates Notch2 signaling activation,which contributes to the maintenance of ILC3 homeostasis.Deletion of Alkbh5 or nr4a1 also impairs ILC3 homeostasis and increases susceptibilities to bacterial infection.Thus,our findings reveal an important role of circular RNA in the regulation of innate lymphoid cell homeostasis.

关键词： circZbtb20 ILC3 Alkbh5 nr4a1 Homeostasis

The effect of nr4a1 on APP metabolism and tau phosphorylation

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Genes & Diseases 2018年第4期5卷 342-348页

作者： Li-Ge Zhao Ying Tang Jia-Ze Tan Jing-Wen Wang Guo-Jun Chen Bing-Lin Zhu Department of Neurology The First Affiliated Hospital of Chongqing Medical UniversityChongqing Key Laboratory of Neurology1 Youyi RoadChongqing400016China

Alzheimer’s disease(AD)is characterized by senile plaques(SP)composed of b-amyloid protein(Ab)and neurofibrillary tangles(NFTs)composed of intracellular hyperphosphorylated tau.Recently,nuclear receptor subfamily 4 group A member 1(nr4a1)was implicated in synaptic plasticity,long-term memory formation,suggesting that it may play a role in the pathophysiology of AD.Here,we showed that the expression of nr4a1 was significantly increased in the hippocampus of APP/PS1 transgenic mice.In addition,nr4a1 overexpression in HT22 cells up-regulated APP and BACE1 levels,down-regulated ADAM10 expression,and promoted amyloidogenesis as indicated by decreased a-CTF levels and elevated b-CTF levels.Furthermore,a raised level of phospho-tau(p-tau,S396)was accompanied by p-GSK3b(S9)expression reducing,but total tau,p-tau(S262 and T231),CDK5 and ERK remained unchanged in nr4a1-overexpressing cells.Collectively,our results suggest that nr4a1 promotes the amyloidogenic processing of APP by regulating ADAM10 and BACE1 expression in HT22 cells;as well as nr4a1 accelerates tau hyperphosphorylation by GSK3b signal.Therefore,nr4a1 may play an important role in the pathogenesis of AD.

关键词： Alzheimer’s disease(AD) ADAM10 BACE1 GSK3b nr4a1 tau

nr4a1对毒胡萝卜素诱导C2C12肌管细胞糖代谢功能障碍的影响

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山东大学学报（医学版） 2023年第11期61卷 38-47页

作者：芦兴晨强晔刘昕宇左丹姜子晗张玉超刘元涛马小莉青岛大学附属青岛临床医学院青岛市市立医院山东青岛266011 康复大学青岛医院(青岛市市立医院)内分泌中心山东青岛266011 烟台毓璜顶医院莱山分院临床营养科山东烟台264000 康复大学青岛医院(青岛市市立医院)医学杂志编辑部山东青岛266011 山东大学齐鲁医院内分泌科(青岛) 山东青岛266011

目的探讨nr4a1对毒胡萝卜素(TG)诱导小鼠C2C12肌管细胞糖代谢功能障碍的影响及机制。方法体外诱导C2C12细胞分化为成熟肌管细胞,将加入20 nmol/L胰岛素刺激10 min的细胞标记为胰岛素组,未做特殊处理的细胞标记为对照组,采用Western blot... 详细信息

目的探讨nr4a1对毒胡萝卜素(TG)诱导小鼠C2C12肌管细胞糖代谢功能障碍的影响及机制。方法体外诱导C2C12细胞分化为成熟肌管细胞,将加入20 nmol/L胰岛素刺激10 min的细胞标记为胰岛素组,未做特殊处理的细胞标记为对照组,采用Western blotting法检测磷酯酰肌醇⁃3⁃激酶/蛋白激酶B(PI3K/AKT)信号通路、nr4a1蛋白水平。采用CCK8法检测TG浓度梯度处理的C2C12肌管细胞活力,建立糖代谢损伤细胞模型。将C2C12肌管细胞分为对照组、无水乙醇(EtOH)组、TG组,分别处理后加入胰岛素刺激,采用葡萄糖试剂盒检测葡萄糖消耗水平,采用Western blotting法检测nr4a1、p⁃PI3K、p⁃AKT蛋白表达。采用慢病毒感染并筛选,获得对照与稳定过表达nr4a1的C2C12肌管细胞,并进行TG处理,分为Ad⁃NC组、Ad⁃NC+EtOH组、Ad⁃NC+TG组和Ad⁃nr4a1+TG组。分化成熟后加入胰岛素刺激,检测葡萄糖消耗水平,检测nr4a1、p⁃PI3K、p⁃AKT的表达。结果与对照组相比,胰岛素组C2C12肌管细胞PI3K/AKT通路磷酸化水平及nr4a1表达水平显著升高(P1)。CCK⁃8结果显示,TG浓度大于1μmol/L时,细胞活力显著下降(P1)。与EtOH组相比,TG组葡萄糖消耗减少,nr4a1表达水平下降,PI3K/AKT蛋白磷酸化水平受到抑制(P均1)。胰岛素刺激C2C12肌管细胞,与Ad⁃NC+TG组相比,Ad⁃nr4a1+TG组葡萄糖消耗增加(P12肌管细胞糖代谢功能障碍。nr4a1对TG诱导的C2C12肌管细胞糖代谢障碍具有改善作用,其机制可能通过PI3K/AKT信号途径发挥作用。

关键词： nr4a1 C2C12肌管细胞磷酯酰肌醇⁃3⁃激酶/蛋白激酶B信号通路毒胡萝卜素糖代谢

益气活血通络方调控nr4a1/NF-κB减轻UUO大鼠炎性损伤的机制研究

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世界科学技术-中医药现代化 2023年第1期25卷 243-250页

作者：徐贺朋何珍王洪双张孟娟周文平许畅刘佳志王筝王香婷河北中医学院基础医学院石家庄050200 河北省中西医结合肝肾病证研究重点实验室石家庄050091 河北中医学院中西医结合研究所石家庄050091

目的观察益气活血通络方通过调控孤核受体4A1(Nuclear receptor subfamily 4 group A member 1,nr4a1)对单侧输尿管结扎(Unilateral uretera obstruction,UUO)大鼠炎性损伤的影响。方法健康雄性Wistar大鼠随机分为假手术组(Sham)、UUO组(UUO)、氯沙坦组(LOS)、益气活血通络方组(TCM),每组12只。UUO组、LOS组、TCM组采用单侧输尿管结扎建立肾纤维化模型。TCM组给予益气活血通络方1.92 g·kg^(-1)·d^(-1)灌胃,LOS组给予氯沙坦溶液20 mg·kg^(-1)·d^(-1)灌胃,其余两组给予生理盐水灌胃,每日1次。术后第14天,处死大鼠,收集梗阻侧肾脏,检测各组大鼠肾功能,免疫组化、蛋白印迹法(Western BLOT)检测nr4a1、核因子κB(Nuclear factor-kappa B,NF-κB)及炎症因子白介素-6(Interleukin-6,Il-6),单核细胞趋化蛋白-1(Monocyte chemoattractant protein-1,MCP-1)的表达,实时荧光定量PCR(qRT-PCR)检测nr4a1、NF-κB mRNA的表达。结果与Sham组比较,UUO组大鼠血清肌酐(Scr)、尿素氮(BUN)水平显著升高(P1表达显著升高(Pnr4a1表达显著降低(P1表达显著降低(Pnr4a1表达明显升高(P1蛋白表达显著升高(Pnr4a1蛋白表达显著降低(P1表达显著降低(Pnr4a1表达显著升高(Pnr4a1 mRNA显著降低(Pnr4a1 mRNA水平显著升高(Pnr4a1,下调NF-κB、MCP-1与IL-6的表达,减轻UUO大鼠肾脏炎性损伤。

关键词：益气活血通络方慢性肾脏病 nr4a1 炎性损伤

nr4a1通过保护IRS1以拮抗胰岛素抵抗的机制研究

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NR4A1通过保护IRS1以拮抗胰岛素抵抗的机制研究

作者：余天富山东大学

学位级别：硕士

胰岛素抵抗是大多数2型糖尿病形成时的起始阶段。弄清胰岛素抵抗的机制是2型糖尿病防治的关键。胰岛素抵抗的形成受到多种因素影响,因此机制非常复杂,如今探究胰岛素抵抗的形成过程已经成为糖尿病研究领域的一个瓶颈。在之前的研究中,... 详细信息

胰岛素抵抗是大多数2型糖尿病形成时的起始阶段。弄清胰岛素抵抗的机制是2型糖尿病防治的关键。胰岛素抵抗的形成受到多种因素影响,因此机制非常复杂,如今探究胰岛素抵抗的形成过程已经成为糖尿病研究领域的一个瓶颈。在之前的研究中,我们曾发现在胰岛β细胞中nr4a1可以通过降低MKK4（JNK的激酶）表达和增强MKP7（p-JNK的磷酸酶）的表达来减少由于细胞应激（内质网应激和氧化应激）所产生的JNK的活化。有文献报道,JNK在胰岛素抵抗过程发挥重要作用,且胰岛素受体底物1（IRS1）是JNK的靶向分子。而在脂肪和肌肉细胞中nr4a1能否通过减少JNK的活化减轻胰岛素抵抗的现象尚未得以证实。我们的实验结果表明,相较野生型小鼠,nr4a1敲除的小鼠表现出了一系列的代谢异常和胰岛素抵抗的表型,例如体重增加,体脂增加和胰岛素敏感性的降低。为了探寻其中的机制,我们在3T3L1脂肪前体细胞和C2C12成肌细胞中建立了过表达nr4a1的细胞系,经诱导可分化为相应的成熟脂肪细胞或肌肉细胞。体外实验结果显示:在过表达nr4a1的脂肪或肌肉细胞中,JNK活化的水平和IRS1在Ser307位点磷酸化水平明显降低;经胰岛素刺激后,nr4a1过表达的细胞中AKT活化的水平显著提高;提示nr4a1具有减轻胰岛素抵抗或提高胰岛素敏感性的功能。后来我们又证实了 IRS1（Ser307）的磷酸化与JNK的酶活性相关联。后续的结果说明,在脂肪细胞和肌肉细胞中nr4a1的过表达会导致cblb的表达上升和MKK4的表达下降。我们因此推断,在肌肉和脂肪细胞中,nr4a1通过cblb-MKK4-JNK通路来减少IRS1在Ser307位点的磷酸化水平以保护可利用的IRS1从而提高胰岛素敏感性。我们的动物实验也验证了这一结论。我们发现,野生型小鼠肌肉和脂肪组织中的nr4a1和cblb都有较高水平的表达,而nr4a1 KO小鼠因nr4a1表达的缺失导致其肌肉和脂肪中cblb表达的显著下调。后续的实验结果表明可诱导表达的nr4a1在肌肉和脂肪组织中可以通过下调JNK的活化水平以减少IRS1（Ser307）的磷酸化;相反,当缺乏nr4a1表达时,JNK的活化水平就会升高,导致IRS1（Ser307）磷酸化水平上升以至于减少了胰岛素信号通路中可以利用的IRS1,最终导致了胰岛素抵抗。我们研究的结论为胰岛素抵抗的发生提供了新的解释。

关键词： nr4a1 胰岛素抵抗 2型糖尿病