微透析技术用于化疗药物——吉西他滨体内药动学的初步研究

目的：建立以微透析法（microdialysis,MD）为采样技术的肿瘤化疗药物在体检测方法,并进行药动学研究。方法：以吉西他滨（GEM）为研究对象,大鼠为实验动物,采用尾静脉注射为给药方式,通过微透析技术进行血管内取样,对血药浓度进行在线、实时、连续监测,求算相关药动学参数。结果：GEM在大鼠体内血液中的探针回收率为（11.9±2.0）%,经大鼠尾静脉给药后GEM体内过程为二室模型,其消除和分布为一级动力学过程。实验过程中大鼠未见明显副作用。结论：微透析技术可用于活体动物体内GEM浓度的连续监测,提示微透析技术可用于抗肿瘤药物的局部药动学研究。     

单眼剥夺性弱视小鼠图形视觉诱发电位时间频率调制变化的研究

目的 探讨单眼剥夺性弱视小鼠图形视觉诱发电位（PVEP）的时间频率调制的变化。方法 生后26 d健 康C57BL/6J小鼠18只，随机均分为正常对照组和单眼剥夺（MD）组。MD组小鼠右眼眼睑行褥式缝合，5 d造成单眼 形觉剥夺，建立弱视模型。对照组在相同环境下饲养至生后31 d。随后，2组小鼠均于视皮层硬脑膜表面埋置电极。 于生后32 d在麻醉状态下对小鼠的右眼行不同时间频率（2.50、1.25、1.00、0.75、0.50和0.25 Hz）的图形视觉刺激，记 录PVEP，比较2组在不同时间频率的视觉刺激下PVEP的P100波幅值的差异。结果 对照组小鼠对所有6种时间 频率的PVEP P100波反应幅值差异无统计学意义（F=2.214，P＞0.05）；MD组小鼠对6种时间频率的PVEP P100波反 应幅值差异有统计学意义（F=6.588，P＜0.01），其时间频率调制曲线表现为低通特性。与对照组相比，高时间频率 （2.50和1.25 Hz）视觉刺激条件下，MD组P100波幅值显著降低（t分别为2.362和2.425，P＜0.05）。在中低时间频率 （1.00、0.75、0.50和0.25 Hz）刺激条件下，与对照组相比，MD组的P100波反应幅值差异无统计学意义（均P＞0.05）。 结论 MD小鼠对高时间频率视觉刺激的PVEP反应降低，而中低时间频率下的PVEP反应未受到明显影响。     

姜黄素固体分散体对2型糖尿病大鼠氧化应激的影响

目的研究姜黄素固体分散体对2型糖尿病大鼠氧化应激的影响。方法以聚乙烯吡咯烷酮（PVP）为载体制备姜黄素固体分散体。大鼠腹腔注射小剂量链脲佐菌素（STZ）建立2型糖尿病模型,随机分成糖尿病模型（MD）组、聚乙烯吡咯烷酮（PVP）组、姜黄素（CU）组、姜黄素固体分散体低剂量（LSD）组、姜黄素固体分散体高剂量（HSD）组。大鼠给药6周后,测定血清及肾脏组织中超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）的活力,丙二醛（MDA）的含量。结果与正常对照组比较,MD组大鼠超氧化物歧化酶、谷胱甘肽过氧化物酶活力显著降低,氧化应激增强;与MD组比较,姜黄素固体分散体组SOD、GSH-Px活力显著提高,MDA含量显著降低。结论姜黄素固体分散体可显著提高糖尿病大鼠的抗氧化能力,抑制氧化应激。     

茶皂素抗炎镇痛作用的实验研究

目的探讨茶皂素的抗炎镇痛作用。方法采用二甲苯致小鼠耳廓肿胀、角叉菜胶致大鼠足跖肿胀、检测大鼠炎性组织中前列腺素E2（PGE2）含量、大鼠棉球肉芽肿实验观察茶皂素抗炎作用;通过小鼠热板致痛实验观察其镇痛作用。结果茶皂素能够明显抑制二甲苯致小鼠耳廓肿胀（P〈0.01）,减轻角叉菜胶致大鼠足跖肿胀（P〈0.01）,使其局部炎性组织中PGE2含量降低（P〈0.01）,抑制大鼠棉球肉芽肿的增重（P〈0.01）,延长小鼠热板痛反应时间（P〈0.05和P〈0.01）。结论茶皂素具有明显的抗炎镇痛作用。     

巴曲酶对糖尿病大鼠肾脏保护作用的实验研究

目的研究巴曲酶对糖尿病大鼠肾脏的保护作用。方法将Wistar大鼠分为正常组（C）、糖尿病组（M）、治疗1组（T1）、治疗2组（T2）和治疗3组（T3）。除正常组外，其余四组用链尿佐菌素诱导大鼠糖尿病模型，T1、T2和T3组分别于大鼠出现高血糖、尿微量白蛋白及肾脏早期病理改变时给予巴曲酶治疗O实验共进行8周，实验过程中观察大鼠体质量、饮食、饮水量、精神及尿量变化。每2周检测血糖1次，于实验第2周、6周、7周和8周分别用代谢笼收集各组大鼠尿液，测定24：h尿白蛋白排泄量。8周末时，在10％水合氯醛麻醉状态下，腹主动脉取抗凝血和血清，用于测定糖化血红蛋白（HbAlc）、血糖（BS）、血肌酐（ScrJ、l尿素氮（BUN）等指标，并计算血清肌酐清除率（Ccr）。留取单侧肾脏称重，计算肾脏肥大指数（肾重／45质量）。结果4周末发现糖尿病组大鼠肾脏基膜增生系膜区扩大，出现早期。肾脏病理改变。2、6、7、8周糖尿病组大鼠24h尿白蛋白排泄量明显高于健康对照组（P〈0．01），给予巴曲酶治疗后，白蛋白排泄较糖尿病组明显降低（P〈0．01或0．05）。8周末发现糖尿病大鼠Scr、BUN、HbAlc、肾脏指数均较健康对照组明显升高（P〈0．01或0．05），Ccr较健康对照组明显降低（P〈0．01），症状均有所缓解（P〈0．01或0．05）。结论巴曲酶可能具有改善糖尿病大鼠肾小球滤过率，降低糖化血红蛋白水平，有利于控制血糖，阻断糖尿病大鼠肾脏病变发展的作用。     

神经生长因子对单眼剥夺大鼠外侧膝状体nNOS表达的影响

目的观察单眼剥夺大鼠神经生长因子（nerve growth factor,NGF）治疗前后外侧膝状体背核（dorsal lateral geniculate nucleus,dLGN）神经型一氧化氮合酶（neuronal nitric oxide synthase,nNOS）阳性神经元表达的改变。方法健康雄性SD大鼠,随机分为正常组（N）、单眼剥夺组（MD）、单眼剥夺脑室内注射NGF组（MD＋NGF）和注射生理盐水组（MD＋NS）,每组随机分为2个亚组。剥夺自14d龄开始,分别于28、42d龄处死,脑室注射分别于14、28d龄开始。采用SABC免疫组织化学染色法观察dLGNnNOS阳性神经元的表达。结果nNOS阳性神经元在dLGN散在分布,单眼剥夺和年龄增长可致其阳性神经元数密度降低。N组及MD＋NGF组分别与MD组和MD＋NS组比较差异均有统计学意义（P〈0．05）。42d龄处死大鼠dLGN阳性神经元数密度N组与其他3组比较差异有统计学意义（P〈0．05）。4组42d龄与28d龄比较,dLGN阳性神经元数密度均有显著下降（P〈0．05）。结论视觉发育具有可塑性,弱视治疗具有时效性。在视觉发育敏感期内,外源性提供NGF,可以促进dLGNnNOS增多,从而拮抗剥夺效应。     

微透析法测定青藤碱大鼠体外血浆蛋白结合率

微透析法（microdialysis，MD）是新型药物动力学采样方法，可在活体动物身上进行实时（realtime）、动态（dynamic state）采样，所采集的样品不需前处理可直接进样分析。但此法对于高分子量、高蛋白结合率和高脂溶性的药物不适宜进行药物动力学研究。青藤碱是一种具有抗风湿活性的弱亲脂性生物碱，为了采用微透析法研究青藤碱的大鼠药物动力学行为，有必要测定大鼠的体外血浆蛋白结合率来评价体内微透析采样的可行性。     

枇杷糖清咽作用的研究

目的：研究枇杷糖的清咽功效。方法本次研究进行了大鼠棉球植入、大鼠足趾肿胀、小鼠耳肿胀实验。将动物按体重随机分为低、中、高剂量组和1个空白对照组,分别给予不同浓度样品和蒸馏水,每天1次,连续30d。实验结束当天再给一次样品,计算肉芽肿净量、足趾肿胀率和耳廓肿胀率。结果1h高剂量组足趾肿胀率,高剂量组小鼠耳肿胀率,与对照组比较差异有统计学意义（P＜0．01）。各剂量组大鼠肉芽肿净重与对照组比较,差异均无统计学意义（ P＞0．05）。结论枇杷糖具有一定的清咽功能。     

微透析技术在神经重症监护中的研究进展

微透析技术（microdialysis，MD）是1种活体细胞外液生化物质采样分析技术。因其独有的微创性和取样的连续性，现已被广泛应用于脑组织各种病理生理现象的探索性实验、神经生物化学的监测和药物代谢研究。近来，甚至被用于局部的治疗性给药。1966年，Bito等闭首次使用MD将1张灌有液体的半透膜置入犬体内进行实验。自1972年美国耶鲁大学首次报道了猴脑的微透析研究，微透析技术用于脑部研究已有30多年。     

细胞同工酶分析进行细胞鉴定

细胞同工酶电泳常用于细胞系鉴定，乳酸脱氢酶（LD）、嘌呤核苷磷酸化酶（NP）、葡萄糖-6-磷酸脱氢酶（G6PD）、苹果酸脱氢酶（MD）是比较常用的酶等。本文采用琼脂糖凝胶电泳技术，对工程细胞（CHO）中提取的LD、NP、G6PD及MD进行分析。用于工程细胞的鉴定。     

Alcohol-induced locomotor activation in C57BL/6J, A/J, and AXB/BXA recombinant inbred mice: strain distribution patterns and quantitative trait loci analysis

RATIONALE: Quantitative trait loci (QTLs) for initial sensitivity to alcohol have been identified in a number of mouse strains (e.g. BXD); however, confirmation is required. OBJECTIVES: The present paper aimed to characterize the C57BL/6J, A/J, and AXB/BXA recombinant inbred (RI) strains of mice for basal and ethanol-induced locomotor activation as measured in an open field and to provide provisional location of QTLs for these phenotypes. METHODS: A/J and C57BL/6J mice were habituated to handling and then randomly assigned to receive one of four alcohol doses (0, 0.5, 1.0, 2.0 g/kg). Subsequently, all available strains of the AXB/BXA RI were tested with the 2 g/kg dose of ethanol or vehicle control. RESULTS: Simple regression and interval mapping were used initially to identify significant gene markers associated with ethanol-induced activation (calculated as total activity on alcohol day-total activity on saline day). Subsequently, composite interval mapping (CIM) was used to increase the accuracy in mapping individual loci. Genetic markers on chromosomes 2, 3, 8, 13, 16, 18 and 19 were associated with ethanol-induced activation. CONCLUSIONS: Three significant markers identified through CIM accounted for 86% of the genetic variance in the ethanol-induced activation. QTLs on chromosome 16 (45.6 cM) and 19 (24 cM) previously associated with alcohol consumption in the AXB/BXA RI mice were found to overlap with QTLs for ethanol-induced activation identified in the present study.     

荷癌小鼠与正常小鼠组织中抑癌因子活性观察研究

目的观察癌鼠的实体瘤和肝脏、肌肉以及正常小鼠的肝脏、肌肉组织中抑癌因子的活性。方法(1)制作肝癌、S180肉瘤小鼠实体瘤模型。(2)分别将两癌鼠的实体瘤和肝脏、肌肉组织以及正常小鼠的肝脏、肌肉组织用生理盐水制成匀浆并提取纯化抑癌因子G50制品。用HepA细胞作为鉴定抑癌因子活性的指示细胞。用台酚兰染色法鉴定抑癌因子的活性。结果抑癌因子只存在癌鼠的实体瘤组织且活性高,而两种癌鼠和正常小鼠的肝脏、肌肉几乎未检出抑癌因子的活性。结论抑癌因子具有特异性强、敏感性高、只由肿瘤组织产生、不存在正常组织和非癌组织、能与正常组织相区别等特点。     

双苯氟嗪对小鼠记忆障碍的改善作用(英文)

用跳台法和电迷宫法,观察双苯氟嗪(dipfluzine)对亚硝酸钠和戊巴比妥钠造成的小鼠记忆障碍的改善作用,双苯氟嗪可明显改善亚硝酸钠引起的小鼠记忆障碍和戊巴比妥钠造成的小鼠方向辨别的获得障碍,且有剂量关系,20和40mg·kg~(-1)双苯氟嗪使小鼠跳台错误次数和出现跳台错误动物的百分率均显著低于溶剂对照组.20 mg·kg~(-1)双苯氟嗪使小鼠在训练的d1和d2受到电刺激后的正确逃避反应数均显著高于溶剂对照组(P<0.05).双苯氟嗪改善亚硝酸钠引起的小鼠记忆障碍的作用与桂利嗪(cinnarizine)相似,在改善记忆的有效剂量(20mg·kg~(-1))下,双苯氟嗪还有抗小鼠急性脑缺氧作用,使断头后小鼠张口呼吸动作持续时间(32±s7s)显著长于溶剂对照组(20±s4s,P<0.01).     

浅谈国内BALB／c小鼠及KM小鼠的基本生物学特性

小鼠是在生物医学研究中广泛使用的实验动物。BALB／c小鼠是我国常用的近交系小鼠,KM小鼠是我国常用的封闭群小鼠。本文对我国BALB／c小鼠及KM小鼠的生物学特性作一综述,以利于研究者在生物医学研究中选择适宜的小鼠。     

Studies on the Distribution and Metabolism of 14C-dimethylnitrosamine in Foetal and Young Mice

Abstract In pregnant mice injected with ¹⁴C-dimethylnitrosamine, whole-body autoradiography was performed with hemisections at -80° (to prevent evaporation of the volatile dimethylnitrosamine) and with dry tape sections (to localize the non-volatile metabolites). The results indicated that the non-metabolized substance passed to the foetal tissues with a uniform distribution and without formation or accumulation of non-volatile metabolites. Autoradiography in young (1-10 days old) and adult mice showed a high level of metabolites in the liver already 5 min. after the administration of ¹⁴C-dimethylnitrosamine. No metabolism of the substance could be detected at in vitro incubations of liver tissue obtained from foetuses on the last day of gestation (¹⁴CO²-production and incorporation of radioactivity in acid-insoluble macromolecules were used as metabolic indices). However, in vitro experiments with livers of 1-5 days old mice indicated a rapid increase in enzymatic activity after birth. Studies in vivo showed an increased incorporation of radioactivity in the acid-insoluble macromolecules of the liver and a decreased exhalation of ¹⁴CO₂ in 10 and 14 days old mice as compared with 21 and 60 days old mice. This indicates a difference in the fate of dimethylnitrosamine in vivo between the young and older mice.     

The toxic effects of titanium dioxide nanoparticles on plasma glucose metabolism are more severe in developing mice than in adult mice

Titanium dioxide nanoparticles (TiO₂ NPs) are authorized food additives, and children have the highest exposure. Therefore, children are likely more susceptible to the adverse effects of TiO₂ NPs than adults. Previous study showed that oral administration of 50 mg/kg body weight (bw) TiO₂ NPs increase plasma glucose in mice. However, few studies have directly compared the adverse effects of exposure to TiO₂ NPs on plasma glucose metabolism of different age groups. In this study, the developing (age 3 weeks) and adult mice (age 10 weeks) were orally administered with 50 mg/kg bw TiO₂ NPs per day. The TiO₂ NPs induced hyperglycemia earlier in the developing mice than in the adult mice. Then mechanisms were analyzed after mice were oral administration of TiO2 NPs for 8 weeks and 26 weeks, respectively. Results showed that the treatment with TiO₂ NPs activated xenobiotic biodegradation in livers of both developing and adult mice at the early stage. However, only in the developing mice, TiO₂ NPs induced endoplasmic reticulum (ER) stress in livers and increased reactive oxygen species in livers and sera in the early stage. The ER stress and ROS activated an inflammation response and mitogen‐activated protein kinase pathways, thereby inducing insulin resistance in the livers of developing mice at the early stage. The response of the adult mice was delayed, and these changes were observed in the late stage of the study. The results of this study all suggest that children are more susceptible than adults to the toxicity of orally administered TiO₂ NPs.     

Role of test activity in ethanol-induced disruption of place preference expression in mice

Rationale Reduced expression of a drug-induced conditioned place preference (CPP) may reflect a decrease in the drug’s conditioned rewarding effects. However, CPP is also open to disruption by processes unrelated to the underlying motivation. In unpublished studies, we previously observed that ethanol pretreatment before testing disrupted expression of ethanol-induced CPP in DBA/2J mice. We hypothesized that this interference effect was due to large ethanol-induced increases in activity. Objective The present studies were designed to examine the relationship between test activity and expression of ethanol-induced CPP both in the presence and absence of ethanol. To assess the generality of this relationship, we examined these effects both in DBA/2J (which are highly activated by ethanol) and in NZB/B1NJ mice (which show similar CPP, but less ethanol-induced activation). Materials and methods In separate experiments, inbred mice from each strain underwent ethanol (2 g/kg) place conditioning. Saline or ethanol was then administered immediately before the test. Results Ethanol, given immediately before the test, blocked the expression of ethanol CPP in DBA/2J, but not in NZB/B1NJ mice. Moreover, ethanol significantly increased test activity levels in DBA/2J and to a much lesser degree in NZB/B1NJ mice. Correlation analyses showed an inverse phenotypic relationship between preference and test activity, reflecting stronger preferences in less active mice. Conclusions Disruption of ethanol-CPP observed in DBA/2J mice may be a consequence of high ethanol-induced activity levels. More generally, these studies suggest that competing behaviors can affect expression of a drug-induced CPP independent of affecting the conditioned rewarding effects of the drug.     

Knockout mouse models are predictive of malformations or embryo-fetal death in drug safety evaluations

Traditionally, understanding potential developmental toxicity from pharmaceutical exposures has been based on the results of ICH guideline studies in two species. However, support is growing for the use of weight of evidence approaches when communicating the risk of developmental toxicity, where the intended pharmacologic mode of action affects fundamental pathways in developmental biology or phenotypic data from genetically modified animals may increasingly be included in the overall assessment. Since some concern surrounds the use of data from knockout (KO) mice to accurately predict the risk for pharmaceutical modulation of a target, a deeper understanding of the relevance and predictivity of adverse developmental effects in KO mice for pharmacological target modulation is needed. To this end, we compared the results of embryo-fetal development (EFD) studies for 86 drugs approved by the FDA from 2017 to 2019 that also had KO mouse data available in the public domain. These comparisons demonstrate that data from KO mouse models are overall highly predictive of malformations or embryo-fetal lethality (MEFL) from EFD studies, but less so of a negative outcome in EFD studies. This information supports the use of embryo-fetal toxicity data in KO models as part of weight of evidence approaches in the communication of developmental toxicity risk of pharmaceutical compounds.