微透析-液相色谱-化学发光法测定大鼠脑组织中丹参酚类化合物浓度及其药代动力学研究

目的基于丹参素(DSS)、原儿茶醛(PAL)和丹酚酸B(SalB)对HAuCl4-luminol-H2O2化学发光的增强作用,建立测定大鼠脑微透析液中3种水溶性酚类化合物浓度的液相色谱-化学发光法(HPLC-CL),探讨该分析法在大鼠脑组织药代动力学研究中的应用。方法采用微透析体内连续采样技术,6只SD大鼠腹腔注射水合氯醛麻醉后,将微透析脑探针植入左侧皮质,用林格液2.0μl·min-1的流速灌流。尾静脉注射丹参滴注液(DSS2.5mg·kg-1、PAL0.4mg·kg-1、SalB0.4mg·kg-1)并收集脑透析液样品,脑透析液收集时间间隔为15min。用HPLC-CL法测定给药后大鼠脑透析液中的药物浓度,利用DAS软件拟合并计算其药代动力学参数。结果丹参素、原儿茶醛和丹酚酸B的脑透析液浓度分别在1.64～430.40、5.30～528.00和8.00～800.00μg·L-1范围内线性关系良好,其检测限分别为0.33、0.22和2.56μg·L-1。以质控样品计算,在各浓度水平下,日间和日内精密度小于5.2%,符合生物样品分析要求。大鼠单剂量静注丹参滴注液后,丹参素在脑组织中的主要药代动力学参数T12、AUC0-∞、MRT0-∞和k分别为(0.64±0.20)h、(369.39±114.77)ng·h·ml-1、(0.64±0.18)h和1.36±0.27。结论建立的HPLC-CL法具有高选择性和高灵敏度等优点,结合微透析采样技术能够实现脑组织中游离丹参素浓度的动态监测,可用于丹参素的生物样品定量分析及药代动力学研究。其中丹参素的脑组织药代动力学参数为国内外首次报道。     

当归芍药散对小鼠免疫功能的影响

目的 研究当归芍药散(DSS)对小鼠免疫功能的作用,为临床用于老年性痴呆的防治提供一定依据。方法 采用亚急性衰老小鼠胸腺指数、2,4,6-三硝基氯苯诱导小鼠迟发性变态反应(PC—DTH)、炭粒廓清、溶血素生成及体外脾淋巴细胞增殖等实验,观察DSS对机体免疫功能的影响。结果 DSS明显升高D-半乳糖所致亚急性衰老小鼠降低的胸腺指数;显著增强醋酸泼尼松龙所致免疫抑制小鼠由2,4,6-三硝基氯苯诱导的迟发型变态反应(PC-DTH)反应能力;体外对小鼠脾淋巴细胞增殖有一定促进作用;而对正常及免疫功能抑制小鼠炭粒廓清及溶血素生成均无明显影响。结论 当归芍药散对免疫系统具有一定选择性作用,主要增强细胞免疫功能。     

Cost-effectiveness of pneumococcal conjugate vaccines of 7, 10, and 13 valences in Colombian children

Background

Currently there are three pneumococcal conjugate vaccines with different coverage of serotypes for use in children under one year. We evaluate the cost-effectiveness of the introduction of pneumococcal conjugate vaccines of 7, 10, and 13 valences in the Colombian EPI.

Methods

A Markov model, which followed a cohort of children under one year to life expectancy, was developed. Parameters of occurrence and care costs were based on data from National Health System and literature review. PCV-7 is a dominated strategy. PCV-10 and PCV-13 were each compared to no vaccination or PCV-10 vaccination, respectively. A 2 + 1 schedule and a vaccination price of US$ 14.00, US$ 14.85 and US$ 16.34 per dose were assumed in the base case for PCV-7, -10, and PCV-13 vaccines.

Results

Introduction of PCV-13 rather than PCV-10 increases the number of life years gained (LYG). From the societal perspective, in the ‘competing choice’ framework cost per LYG was US$ 1837 with PCV-10 and US$ 9514 with PCV-13, while PCV-7 is a dominated strategy. The ICER of PCV-13 is above the per capita Gross Domestic Product. Incremental cost-effectiveness ratios (ICERs) were influenced mainly by effectiveness against radiologically-confirmed pneumonia and AOM, vaccine price, and discount rate.

Conclusion

Routine vaccination against Streptococcus pneumoniae in Colombia would be cost-effective with PCV-10, with ICER below the per-capita GDP, but its inclusion requires evaluating the budget impact. PCV-13 would prevent more disease and deaths with a higher LYG, but PCV-10 would save more cost to the healthcare system due its higher impact in the prevention of AOM. There is limitation in the clinical evidence of both strategies.     

基于网络药理学分析龙血竭缓解实验性溃疡性结肠炎小鼠结肠黏膜损伤的作用机制

目的考察龙血竭(CDB)对葡聚糖硫酸钠(DSS)诱导的小鼠溃疡性结肠炎(UC)的作用,以及通过网络药理学预测CDB潜在的主要活性成分、作用靶点、信号通路。方法利用DSS诱导小鼠UC模型。Balb/c小鼠随机分为对照组,模型组,CDB组高、中、低剂量组及美沙拉嗪对照组,每组10只。除对照组外,各组小鼠自由饮用3.0%DSS溶液,连续7 d,CDB组、美沙拉嗪组在造模期间ig给予对应的药物,每天称量小鼠体质量,进行隐血实验,观察动物粪便性状,进行DAI评分,实验末处死小鼠,取结肠进行HE染色并评分。通过TCMSP、String、Cytoscape等在线数据库构建"化合物-化合物靶点-疾病靶点"网络,提取核心化合物靶点、化合物作用的疾病靶点,对相关靶点进行GO、KEGG富集分析,分析CDB治疗UC可能调控的生物过程及作用机制。结果与对照组比较,模型组小鼠炎症细胞浸润明显,大量杯细胞消失,病变程度波及肌层甚至全层;CDB组大鼠杯细胞重新长出,病变程度仅限于黏膜层,炎症减轻。通过网络药理学筛选出CDB的作用靶点112个,其中ABL1、F2、JAK2等14个核心化合物靶点可作用于ICAM1、IL-6、PTGS2、MTOR等11个疾病靶点。GO分析中包含415条富集通路,其中生物过程389条,分子功能9条,细胞组成17条。利用KEGG数据库对入选靶点进行相关通路富集,筛选出84条通路与UC有关。结论 CDB可以缓解DSS诱导的UC小鼠结肠黏膜损伤,可能通过剑叶龙血素C等黄酮类成分调控ABL1、F2、JAK2等靶点表达,然后间接调控IL-6、PTGS2等疾病蛋白表达,进而干预JAK2/STAT3、PI3K-Akt-m TOR通路,调节炎症因子的水平,抑制炎症反应,最终缓解UC小鼠结肠黏膜损伤。     

当归芍药散对脑缺血再灌注所致记忆损伤模型小鼠的影响

目的：观察当归芍药散（DSS）对脑缺血再灌注所致记忆损伤模型的影响。方法：建立小鼠脑缺血再灌注损伤模型,采用避暗实验小鼠记忆功能,并观察DSS对其影响,同时测定小鼠脑内Ca-ATP酶活性、NO含量,蛋白质含量及脑指数、胸腺指数、脾脏指数等。结果：DSS可明显延长脑缺血再灌注损伤模型小鼠避暗潜伏期,明显抑制模型小鼠脑内Ca-ATP酶活性、脑指数及蛋白质含量的降低,明显降低脑内升高的NO含量,对脑缺血再灌所致小鼠脾脏萎缩有显著恢复作用。结论：DSS可能通过升高蛋白质含量、抑制脑萎缩、减轻钙离子超载等环节改善脑缺血再灌注损伤所致小鼠记忆障碍。     

Survival outcome of weak estrogen/progesterone receptor expression in HER2 negative breast cancer is similar to triple negative breast cancer

Background

Recent publications have suggested that human epidermal growth factor receptor 2 (HER2)-negative breast cancers with “weak” estrogen receptor (ER)/progesterone receptor (PR) expression levels by immunohistochemical (IHC) analysis were considered as the triple-negative (TN) subtype. This study aimed to evaluate the overall survival (OS), disease-free survival rates (DFS), and disease-specific survival (DSS) based on ER and PR expression levels into one of three groups, ER and PR <1%, ER and PR 1%–20%, and ER or PR >20% by hormone therapy.

The MUTYH base excision repair gene protects against inflammation-associated colorectal carcinogenesis

MUTYH DNA glycosylase removes mismatched adenine opposite 7, 8-dihydro-8-oxoguanine (8-oxoG), which is the major mutagenic lesion induced by oxidative stress. Biallelic mutations in MUTYH are associated with MUTYH-Associated polyposis (MAP) and increased risk in colorectal cancer (CRC). We investigated cancer susceptibility associated with MUTYH inactivation in a mouse model of inflammation-dependent carcinogenesis induced by azoxymethane (AOM) and dextran sulphate (DSS). Mutyh^−/− mice were more sensitive than wild-type (WT) animals to AOM/DSS toxicity and accumulated DNA 8-oxoG in their gastrointestinal tract. AOM/DSS-induced colonic adenomas were significantly more numerous in Mutyh^−/− than in WT animals, and frequently showed a tubulo-villous feature along with high-grade dysplasia and larger size lesions. This condition resulted in a greater propensity to develop adenocarcinomas. The colon of untreated Mutyh^−/− mice expressed higher basal levels of pro-inflammatory cytokines GM-CSF and IFNγ, and treatment with AOM/DSS induced an early decrease in circulating CD4+ and CD8+ T lymphocytes and an increase in myeloid-derived suppressor cells (MDSCs). Adenomas from Mutyh^−/− mice had a greater infiltrate of Foxp3+ T regulatory cells, granulocytes, macrophages, MDSCs and strong expression of TGF-β-latency-associated peptide and IL6. Our findings indicate that MUTYH loss is associated with an increase in CRC risk, which involves immunosuppression and altered inflammatory response. We propose that the AOM/DSS initiation/promotion protocol in Mutyh^−/− mice provides a good model for MAP.     

Microstructure and Mechanical Properties of Friction Stir Welded 2205 Duplex Stainless Steel Butt Joints

Friction stir welding (FSW) as a solid-state process is an excellent candidate for high softening temperature materials welding; however, extending the tool life is required to make the process cost-effective. This work investigates the use of a high pin to shoulder ratio (65%) tungsten carbide (WC) tool for friction stir welding of 5 mm thick 2205 DSS to extend the tool life of this low-cost tool material. In addition, the effect of FSW parameters in terms of rotational rates, travel speeds, and downward forces on the microstructural features and mechanical properties of the welded joints were investigated. Characterization in terms of visual inspection, macro and microstructures, hardness, and tensile testing was conducted. The obtained results indicated that the combined rotational rate, travel speed, and downward force parameters govern the production of defect-free joints. The 2205 DSS friction stir welds show an enhancement in hardness compared to the base material. The stir zone showed a significantly refined grain structure of ferrite and austenite with the reduction in the average grain size from 8.8 µm and 13.3 µm for the base material to 2.71 µm and 2.24 µm, respectively. Moreover, this joint showed higher yield strength and ultimate tensile strength compared to the DSS as-received material.