目的 探究大鼠原代星形胶质细胞体外牵张损伤后微小核糖核酸(microRNA)表达谱差异,并通过生物信息学分析预测差异表达microRNA在星形胶质细胞被损伤诱导活化后的作用.方法 使用细胞损伤控制仪Ⅱ型构建大鼠原代星形胶质细胞体外牵张损伤模型,阀门压力设置为40 PSI,模拟重型颅脑损伤.损伤后24 h收集对照组及损伤组星形胶质细胞总RNA,使用Agilent microRNA芯片检测差异表达microRNA,通过R语言软件构建火山图及聚类分析热图;利用DIANA TOOLS和miRDB数据库预测microRNA的靶基因,并对靶基因集进行基因本体论(GO)和京都基因和基因组百科全书(KEGG)富集分析;使用STRING数据库构建蛋白互作(PPI)网络,应用Cytoscape软件筛选关键基因.结果 大鼠原代星形胶质细胞体外牵张损伤24 h后共有9个microRNA差异表达[| Log2 Fold Change(FC)|≥0.26,P＜0.05],其中5个表达上调,分别是rno-miR-34a-5p、rno-miR-34b-5p、rno-miR-129-5p、rno-miR-140-3p 和 rno-miR-7a-5p;4 个表达下调,分别是 rno-miR-199a-3p、rno-miR-199a-5p、rno-miR-221-3p 和 rno-miR-1306-3p.rno-miR-34b-5p 差异表达倍数最为显著,对其进行靶基因预测共获得154个基因,进一步的GO和KEGG富集分析发现,rno-miR-34b-5p靶基因参与蛋白磷酸酶2A结合及磷脂酶C活性正向调节,并调控磷脂酶D信号通路、MAPK信号通路及PI3K-AKT信号通路,与颅脑创伤(TBI)后神经修复及再生密切相关.同时使用靶基因集构建PPI网络,筛选5个关键基因,分别为Tp53、Notch 1、Ki tlg、Pdgfrb和Pdgfra.结论 大鼠原代星形胶质细胞体外牵张损伤后rno-miR-34b-5p显著升高,生物信息学预测rno-miR-34b-5p靶向抑制Notch1及PDGFRA基因的表达,降低PI3K-AKT信号通路活性,可能使损伤星形胶质细胞向A1型转化,阻碍TBI后神经修复及再生.本研究为TBI后康复治疗提供了潜在的作用新靶点及新的研究方向.

Cocaine use disorder (CUD) is a major public health challenge with a high relapse rate and lack of effective pharmacotherapies; therefore, there is a substantial need to identify novel medications to treat this epidemic. Since the advent of glucagon-like peptide-1 (GLP-1) receptors (GLP-1Rs) agonists (GLP-1RAs), their potential has been extensively explored and expanded. In this review, we first summarized the biological effects of GLP-1, GLP-1Rs, and GLP-1RAs. Subsequently, the recent literature examining the behavioral effects and the possible pharmacological mechanisms of GLP-1RAs on CUD was reviewed. Increasing preclinical evidence suggests that GLP-1RAs are promising in regulating dopamine release, dopamine transporter (DAT) surface expression and function, mesolimbic reward system and GABAergic neurons, and maladaptive behaviors in animal models of self-administration and conditioned place preference. In addition, the emerging role of GLP-1RAs in inhibiting inflammatory cytokines was reported. These findings indicate that GLP-1RAs perform essential functions in the modulation of cocaine-seeking and cocaine-taking behaviors likely through multifaceted mechanisms. Although the current preclinical evidence provides convincing evidence to support GLP-1RA as a promising pharmacotherapy for CUD, other questions concerning clinical availability, impact and specific mechanisms remain to be addressed in further studies.