黄芪多糖对2型糖尿病大鼠HPA轴及海马糖皮质激素受体水平的调节作用

目的：观察黄芪多糖（APS）对2型糖尿病大鼠HPA轴及海马组织中糖皮质激素受体水平的调节作用。方法：30只SD大鼠随机分为正常对照组、DM模型组、APS干预组组,采用小剂量链脲佐茵素加高脂饮食饲养的方法建立2型糖尿病肥胖大鼠模型。成模4周后,断头处死所有大鼠,检测各组大鼠血CRH、ACTH、CorT的含量,以及海马组织中糖皮质激素受体（GR）mRNA的表达。结果：DM模型组血ACTH、CorT含量较正常组显著升高,与模型组大鼠相比,APS干预组大鼠血ACTH、CorT含量显著降低（P〈0．05）;DM模型组海马GRmRNA含量较正常组极显著降低,与模型组大鼠相比,APS干预组大鼠海马GRmRNA含量明显上调（P〈0．01）。结论：APS保护高糖环境下的海马组织,改善HPA轴功能。对糖尿病以及合并症起到治疗作用。     

Inhibition of immunological function mediated DNA damage of alveolar macrophages caused by cigarette smoke in mice

Exposure to cigarette smoke impairs the pulmonary immune system, including alveolar macrophage function, although the mechanisms by which this occurs are not fully elucidated. This study investigates the effect of cigarette smoke exposure on the antigen-presenting activity of alveolar macrophages, which is required for antigen-specific response to T cells. C57BL/6 mice were exposed to cigarette smoke for 10 days using a Hamburg II smoking machine, and alveolar macrophages were obtained by bronchoalveolar lavage. The antigen-presenting activity of alveolar macrophages was significantly inhibited in mice exposed to cigarette smoke compared with mice not exposed to cigarette smoke. Major histocompatibility complex class II cell surface molecule–positive cells, B7-1 molecule–positive cells, and interleukin-1β messenger RNA gene expression in alveolar macrophages were significantly decreased in mice exposed to cigarette smoke compared with mice not exposed to cigarette smoke. In contrast, DNA damage and generation of superoxide and hydrogen peroxide in alveolar macrophages were significantly increased by cigarette smoke exposure. These results suggest that inhibition of the antigen-presenting activity of alveolar macrophages may result from decreased expression of major histocompatibility complex class II and B7-1 molecules and interleukin-1β messenger RNA gene expression following cigarette smoke exposure. Furthermore, inhibition of antigen presentation in alveolar macrophage may result from DNA damage induced by excessive amounts of reactive oxygen species being generated by alveolar macrophages following cigarette smoke exposure. These findings suggest that cigarette smoke impairs the immunological function of alveolar macrophages and, as a result, increases the risk for pulmonary infection.     

Use of mTOR inhibitors in the treatment of malignancies

Introduction: mTOR and its effectors are central regulators of cellular metabolism in malignant cells and control mRNA translation that ultimately leads to generation of mitogenic proteins. Efforts to target this pathway have been ongoing for over a decade and have had a substantial impact in the management of certain patients with solid tumors. Although activity of mTOR inhibitors has been established in several trials, inability to predict responses remains a limiting factor for the successful incorporation of these agents in the treatment of a variety of malignancies.

Areas covered: Recent clinical findings are discussed and studies focused on advanced phase development of mTOR inhibitors are summarized. The emergence of precision medicine approaches and the effects that such approaches may have on prospective selection of patients for treatment with mTOR inhibitors are discussed. Also, potential approaches and future prospects to improve responses to mTOR inhibitors by modulating other parallel mitogenic pathways essential for malignant cell proliferation are discussed.

Expert opinion: Selective targeting of the mTOR pathway offers significant clinical advantage in subsets of patients with diverse malignancies. Approaches to enhance responses by concomitant targeting of resistance pathways and/or predict responses via identification of molecular markers should substantially impact this area in the near and distant future.     

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

The use of small interfering RNAs (siRNAs) has been under investigation for the treatment of several unmet medical needs, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS) wherein siRNA may be implemented to modify the expression of pro-inflammatory cytokines and chemokines at the mRNA level. The properties such as clear anatomy, accessibility, and relatively low enzyme activity make the lung a good target for local siRNA therapy. However, the translation of siRNA is restricted by the inefficient delivery of siRNA therapeutics to the target cells due to the properties of naked siRNA. Thus, this review will focus on the various delivery systems that can be used and the different barriers that need to be surmounted for the development of stable inhalable siRNA formulations for human use before siRNA therapeutics for ALI/ARDS become available in the clinic.     

Nucleic acid vaccines: prospects for non-viral delivery of mRNA vaccines

Introduction: Nucleic acid-based vaccines are being developed as a means to combine the positive attributes of both live-attenuated and subunit vaccines. Viral vectors and plasmid DNA vaccines have been extensively evaluated in human clinical trials and have been shown to be safe and immunogenic, although none have been licensed for human use. More recently, mRNA-based vaccine alternatives have emerged and might offer certain advantages over their DNA-based counterparts.

Areas covered: This review describes the two main categories of mRNA vaccines: conventional non-amplifying and self-amplifying mRNA. It summarizes the initial clinical proof-of-concept studies and outlines the preclinical testing of the next wave of innovations for the technology. Finally, this review highlights the versatile functionality of the mRNA molecule and introduces opportunities for future improvements in vaccine design.

Expert opinion: The prospects for mRNA vaccines are very promising. Like other types of nucleic acid vaccines, mRNA vaccines have the potential to combine the positive attributes of live attenuated vaccines while obviating many potential safety limitations. Although data from initial clinical trials appear encouraging, mRNA vaccines are far from a commercial product. These initial approaches have spurred innovations in vector design, non-viral delivery, large-scale production and purification of mRNA to quickly move the technology forward. Some improvements have already been tested in preclinical models for both prophylactic and therapeutic vaccine targets and have demonstrated their ability to elicit potent and broad immune responses, including functional antibodies, type 1 T helper cells-type T cell responses and cytotoxic T cells. Though the initial barriers for this nucleic acid vaccine approach seem to be overcome, in our opinion, the future and continued success of this approach lies in a more extensive evaluation of the many non-viral delivery systems described in the literature and gaining a better understanding of the mechanism of action to allow rational design of next generation technologies.     

绞股蓝总皂苷对高糖培养条件下小鼠足细胞nephrin、VEGF mRNA表达的影响

目的:观察绞股蓝总皂苷对高糖培养条件下小鼠永生足细胞nephrin、VEGF(vascular endothelial growth factor,血管内皮生长因子)mRNA表达的影响。方法:利用体外培养条件性永生小鼠足细胞,高糖干预24小时,模拟糖尿病肾病足细胞损伤,分为正常组、高糖模型组、高渗对照组、绞股蓝治疗组(绞股蓝总皂苷高、中、低剂量组)及缬沙坦对照组,Real Time PCR法检测足细胞nephrin、VEGF mRNA的表达。结果:绞股蓝总皂苷干预组nephrin mRNA含量显著升高,VEGF mRNA表达有一定程度提高,与模型对照组比较,差异有显著统计学意义(P0.05或P0.01)。结论:绞股蓝总皂苷可有效调节肾脏足细胞nephrin、VEGF mRNA表达。     

酸枣仁汤对抑郁模型大鼠皮质、海马中NMDAR1、NMDAR2A、NMDAR2B基因表达的影响

目的观察酸枣仁汤对抑郁模型大鼠大脑皮质、海马中NMDAR1、NMDAR2A、NMDAR2B基因表达的影响,并探讨其作用机制。方法将大鼠随机分为空白组、模型组、西药组和酸枣仁汤高、中、低剂量组,除空白组外,其余各组大鼠均以慢性应激法复制抑郁症模型,各给药组给予相应药物灌胃。采用RT-PCR检测大鼠皮质、海马中NMDAR1、NMDAR2A和NMDAR2B基因的表达。结果与模型组比较,酸枣仁汤高、中剂量组大鼠皮质和海马中NMDAR1阳性表达均降低(P0.01);酸枣仁汤高、中剂量组和西药组皮质和海马中NMDAR2A阳性表达均降低(P0.05,P0.01),酸枣仁汤低剂量组海马中NMDAR2A表达增高(P0.05);酸枣仁汤高、中、低剂量组和西药组皮质中NMDAR2B阳性表达均降低(P0.01),酸枣仁汤中、低剂量组海马中NMDAR2B表达增高(P0.01)。结论酸枣仁汤可能通过降低大鼠皮质、海马中NMDAR1、NMDAR2A、NMDAR2B基因表达达到治疗抑郁症的作用。     

电针对大鼠穴区血管内皮细胞间黏附因子1表达及肥大细胞分布的影响

目的:观察电针后大鼠皮下组织血管内皮细胞间黏附因子1(intercellular adhesion molecule-1,ICAM-1)表达及肥大细胞(mast cell,MC)分布,探讨电针刺激后穴区血管ICAM-1mRNA表达的变化,及其与MC活性的关系。方法:将20只大鼠随机均分为正常组和电针组,电针组给予双侧"足三里"穴电针刺激25min。用原位杂交技术观察两组大鼠"足三里"穴区皮下组织ICAM-1mRNA的表达;同时用乙酰胆碱酯酶组化染色并甲苯胺蓝复染法观察"足三里"穴区皮下组织MC的分布。结果:电针组"足三里"穴区组织ICAM-1mRNA阳性表达明显高于正常组(P0.01);电针组穴区组织MC数和MC脱颗粒率均升高,与正常组比较均具有统计学意义(P0.01)。结论:电针可增强正常大鼠穴区组织血管内皮ICAM-1mRNA的表达,ICAM-1对电针促进肥大细胞向穴区迁移、聚集具有一定趋化作用。     

灭幽汤对 Hp 相关性胃炎“脾胃湿热证”模型小鼠 HSP70 表达的影响

目的观察灭幽汤对Hp相关性胃炎“脾胃湿热证”模型小鼠热休克蛋白70（HSP70）蛋白及其mRNA的影响。方法采用复合因素（肥甘食物＋湿热环境＋幽门螺杆菌）建立BALB／c小鼠Hp相关性胃炎“脾胃湿热证”模型．造模成功后将小鼠随机分为5组：高浓度灭幽汤组、低浓度灭幽汤组、胃三联组（替硝唑＋克拉霉素＋枸橼酸铋钾颗粒）、模型组、对照组。连续给药14d后,分别采用Western Blot和qPCR检测HSP70蛋白、HSP70mRNA的表达情况。结果HSP70蛋白及其mRNA的表达：BALB／c小鼠模型组与对照组比较,HSP70蛋白、HSP70mRNA表达均增加（P〈0．01）;与模型组比较,高、低浓度灭幽汤组,胃三联组小鼠HSP70蛋白、HSP70mRNA表达均增加（P〈0．01）;胃三联组与高、低浓度灭幽汤组中HSPT0蛋白HSPT0mRNA表达均增加（P〈0．05）。结论灭幽汤可能通过上调HSP70蛋白及其mRNA表达而发挥治疗Hp相关性胃炎的作用。