灯盏乙素介入IP3R-Ca2+途径抑制β淀粉样蛋白诱导的神经细胞凋亡

目的：观察灯盏乙素（Scu）对β淀粉样蛋白（Aβ）诱导的细胞模型中1，4，5-三磷酸肌醇受体（IP₃R）-Ca²⁺途径的影响，探讨其在阿尔茨海默病（AD）病程中可能发挥的积极作用。方法：选用神经母细胞瘤细胞分为对照组、Scu处理组、Aβ处理组、Aβ+Scu （高、中、低）处理组及Aβ+IP₃R拮抗剂组，用CCK-8法筛选药物浓度并检测各组细胞生存率；用酶联免疫吸附法检测各组细胞中1，4，5-三磷酸肌醇（IP₃）的含量；用蛋白印迹和实时荧光定量聚合酶链反应方法检测各组细胞IP₃R和凋亡相关因子Caspase-3、Bcl-2、Bax的蛋白及mRNA的表达水平；用激光共聚焦显微镜观察各组细胞内Ca²⁺浓度的变化；用AnnexinV/PI双染法测定各组细胞的凋亡率。结果：与对照组和Scu处理组相比，Aβ处理组细胞存活率下降，IP₃含量升高，IP₃R、Bax和Caspase-3的蛋白及mRNA表达上调，Bcl-2蛋白及mRNA的表达下调，细胞胞浆内Ca²⁺浓度及细胞凋亡率升高；Aβ+Scu处理组细胞中各检测指标的变化与Aβ处理组的结果正好相反，IP₃R通道下游指标的变化与Aβ+IP₃R拮抗剂组基本一致。结论：Scu能够下调通路蛋白IP₃、IP₃R的表达，抑制Aβ介导的Ca²⁺内流所致的细胞凋亡，可能通过对IP₃R-Ca²⁺途径的调控来影响AD病程。     

Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney

The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with K_i values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with K_m values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CL_R) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CL_R (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CL_R of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates.     

Synthesis,in vivo and in silico evaluation of novel 2,3-dihydroquinazolin-4(1H)-one derivatives as potential anticonvulsant agents

In light of the pharmacophoric structural requirements for achieving anticonvulsant activity, a series of N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)benzamide (4a-g) and N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)-2-phenylacetamide (4h-n) derivatives were synthesized in two steps starting from the reaction of N-methyl isatoic anhydride with the appropriate hydrazide and followed by condensation with the appropriate aldehyde. The anticonvulsant activities of the synthesized compounds were evaluated according to the anticonvulsant drug development (ADD) programme protocol. Among the synthesized compounds, 4n showed promising activity in both the maximal electroshock (MES) and pentylenetetrazole (PTZ) tests with median effective dose (ED₅₀) values of 40.7 and 6 mg/kg, respectively. The six most promising derivatives, 4b , 4a , 4c , 4f , 4j , and 4i , showed very low ED₅₀ values in the PTZ test (3.1, 4.96, 8.68, 9.89, 12, and 13.53 mg/kg, respectively). All the tested compounds showed no to low neurotoxicity in the rotarod test with a wide therapeutic index. Docking studies of compound 4n suggested that GABA_A binding could be the mechanism of action of these derivatives. The in silico drug likeliness parameters indicated that none of the designed compounds violate Lipinski's rule of five and that they are able to cross the blood–brain barrier.

儿童外科教学方法实践及探讨

目的探讨儿童外科的教学特点及教学方法,提高儿外科医生的总体执业水平,促进儿童外科学的发展。方法通过分析四川大学华西医院多年儿童外科疾病的临床教学实践经验,总结出适合医学生、初级儿童外科专科医生的实用的教学方法及经验。结果结合儿童外科特有的疾病特点所总结出的故事式讲述教学、典型病例教学、漫画形式学习、比较学习法及多媒体素材教学五种方式是非常适合儿童外科教学的方法。能够加深记忆,提高兴趣,轻松快捷,事半功倍的掌握相关医学专业知识。结论独特有趣的儿童外科教学方法可提高医学生及儿童外科初级从业者的学习兴趣、专业知识和执业水平。     

PBL教学法在临床心肺复苏术教学中的应用分析

目的 分析重症医学科PBL教学法在临床心肺复苏术教学中的应用效果.方法 本次实验的开展基础数据选择2016年9月—2018年7月进入医院重症医学科实习学生64例,按照学生自身意愿以及学校安排将参与实验学生分为均数相同的两个小组(对照组、观察组),每组实验人数均为32例,其中对照组(n=32)采用传统教学方法 ,观察组(n=32)则应用PBL教学法教学,对比两组学生在学期结束后整体的学习质量情况和教学满意率.结果 观察组学生经过测试后理论知识和专业技能得分均对比对照组更高,教学效果更加理想,观察组学生对于教学的满意率评价更高,P<0.05.结论 重症医学科临床心肺复苏术教学中应用PBL教学法,将理论与实践进行结合,对教学方法 进行改进,全面提升学生的思维理解能力,培养良好的动手能力,促进理论教学与实践的结合,为学生以后的职业生涯提供更加理想的条件.     

PBL与CBL教学法在留学生实验诊断教学的应用探讨

目的探讨PBL与CBL教学法在留学生实验诊断教学的应用效果。方法将PBL联合案例教学法(CBL)应用于临床医学本科留学生实验诊断教学,与大班传统讲授教学方法(对照组)相比较,通过问卷调查和成绩分析学习效果。结果试验组在激发学习兴趣和培养临床思维能力方面均高于对照组,理论知识的成绩和实习的成绩也是试验组优于对照组,P<0.05。结论PBL与CBL教学联合应用于实验诊断教学中能够有效提高教学质量,并受到学生的认可和喜爱。     

负载IL-4及BMP-2的氧化石墨烯-羧甲基壳聚糖凝胶对骨免疫和骨修复的早期影响研究

目的探讨负载 IL-4 和 BMP-2 的氧化石墨烯（graphene oxide，GO）-羧甲基壳聚糖（carboxymethyl chitosan，CMC）凝胶诱导巨噬细胞 M2 型分化及对 BMSCs 成骨分化的影响。方法取 CMC、GO 制备混合溶液后，分别添加 PBS、IL-4、BMP-2 或 IL-4+BMP-2，在交联剂作用下制备单纯或负载不同因子的 GO-CMC 凝胶支架；取单纯 GO-CMC 凝胶表征观测，包括大体、扫描电镜及傅里叶变换红外吸收光谱仪（Fourier transform infrared spectroscopy，FTIR）检测，以单纯 CMC 凝胶作为对照；取负载不同因子的 GO-CMC 凝胶行体外缓释实验。取 4～5 周龄 SPF 级 SD 雌性大鼠分离培养巨噬细胞，分别与单纯以及负载不同因子的 GO-CMC 凝胶培养，24 h 后行 CD206 免疫荧光检测巨噬细胞分化情况；取第 3 代大鼠 BMSCs 分别与单纯以及负载不同因子的 GO-CMC 凝胶成骨诱导培养，10 d 后行 ALP 染色观测早期成骨，21 d 行茜素红染色观测晚期成骨。结果大体观察 GO-CMC 凝胶呈棕色、半透明状；扫描电镜观察示，GO-CMC 凝胶孔径及孔壁厚度与单纯 CMC 凝胶相似，但内壁粗糙度增加；FTIR 检测显示 CMC 发生聚合形成凝胶。体外缓释实验示 3 种负载不同因子的 GO-CMC 凝胶缓释性能相似，均呈线性缓慢释放因子。CD206 免疫荧光检测示 GO-CMC 凝胶可诱导巨噬细胞 M2 型分化，ALP 及茜素红染色示 GO-CMC 凝胶可诱导 BMSCs 成骨分化；其中负载 IL-4+BMP-2 的 GO-CMC 凝胶作用最显著（P<0.05）。 结论负载 IL-4 和 BMP-2 的 GO-CMC 凝胶可诱导巨噬细胞 M2 型分化，增强 BMSCs 成骨分化能力，为后期骨缺损修复及骨免疫调节研究提供了新的策略。     

临床医学专业“5+3”一体化本科全程导师制创新人才培养的实践与探索

以培养创新型人才为目标，大连医科大学制定实施了“5+3”创新人才培养改革方案，以导师制培养为载体，在医学本科教育全过程中，制定分阶段创新能力培养体系，涵盖课程、讲座、实验设计、论文等基本科研能力训练，强化本科生科研能力培养。通过对首届“5+3”学生阶段性培养成果的统计学分析发现，“5+3”学生发表中文期刊、SCI，主持国家级创新项目、省级创新项目的比例均显著高于普通5年制学生，差异具有统计学意义（P<0.05）。虽然实施过程中存在一些问题和不足，但以导师制为核心的科研基础训练对提高学生科研思维和创新能力效果显著，对培养医学创新型人才具有可实施性。     

MOB1A regulates glucose deprivation-induced autophagy via IL6-STAT3 pathway in gallbladder carcinoma

MOB kinase activator 1A (MOB1A) plays an important role in many diseases and cancers. Here, we observed that MOB1A was substantially overexpressed in gallbladder carcinoma (GBC) tissues compared with nontumor tissues. The high expression of MOB1A was closely associated with poor survival in patients with GBC at advanced TNM stages. Furthermore, our study indicated that MOB1A promoted autophagy by activating the IL6/STAT3 signaling pathway and regulating the chemosensitivity to gemcitabine under glucose deprivation conditions both in vitro and in vivo. In conclusion, these findings suggested that MOB1A is critical for the development of GBC via the MOB1A-IL6/STAT3-autophagy axis.