Biocleavable comb-shaped gene carriers from dextran backbones with bioreducible ATRP initiation sites

It is of crucial importance to design reduction-sensitive polysaccharide-based copolymers for intracellular triggered gene and drug delivery. In this work, a simple two-step method involving the reaction of hydroxyl groups of dextran with cystamine was first developed to introduce reduction-sensitive disulfide linked initiation sites of atom transfer radical polymerization (ATRP) onto dextran. Well-defined biocleavable comb-shaped vectors consisting of nonionic dextran backbones and disulfide-linked cationic P(DMAEMA) side chains were subsequently prepared via ATRP for highly efficient gene delivery. The P(DMAEMA) side chains can be readily cleavable from the dextran backbones under reducible conditions. Moreover, the bioreducible P(DMAEMA) side chains can be functionalized by poly(poly(ethylene glycol)ethyl ether methacrylate) (P(PEGEEMA)) end blocks to reduce the cytotoxicity and further enhance the gene transfection efficiency. This present study demonstrated that properly grafting short bioreducible polycation side chains from a nonionic polysaccharide backbone with biocleavable ATRP initiation sites is an effective means to produce a class of polysaccharide-based gene delivery vectors.     

夏至草醇提物对急性微循环障碍大鼠器官损伤的干预作用

目的:观察夏至草醇提物对高分子右旋糖苷(Dextran500)致急性微循环障碍大鼠器官损伤的影响。方法:Wistar雄性大鼠20只,随机分为夏至草组(n=8)、模型组(n=6)和对照组(n=6)。前二组静注10%Dextran500(10ml/kg体重)复制急性微循环障碍模型(对照组以等量生理盐水代替)。6min后,夏至草组自颈静脉缓慢推注夏至草醇提物(5g/ml,6g/kg体重),其它两组以等量生理盐水代替,监测平均动脉血压(MAP)。40min后,制备血清,进行血液生化指标检测;制备病理切片,观察肺、肝、肾、心肌形态学变化。结果:与对照组相比,模型组血清天门冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、尿素氮(BUN)、肌酐(Cre)、乳酸脱氢酶-1(LDH-1)、肌酸激酶同工酶(CK-MB)水平显著升高,MAP下降;与模型组相比,夏至草组血清AST、ALT、BUN、Cre、LDH-1、CK-MB水平显著降低,MAP升高。组织形态学显示,对照组肝、肾、肺、心肌结构正常,模型组各器官病变较重,多见红细胞瘀滞、血栓形成及坏死,夏至草组病变较轻,未见坏死。结论:夏至草醇提物能明显减轻Dextran500致急性微循环障碍大鼠各器官功能障碍与组织学损伤。     

夏至草醇提物对急性微循环障碍大鼠器官血流量的影响

目的:观察夏至草醇提物对高分子右旋糖苷(Dextran500)致急性微循环障碍(AMD)大鼠小肠、胃、肝等器官血流量的影响。方法:Wistar雄性大鼠20只,随机分为夏至草组、模型组(均n=10)。静注10%Dextran500(10ml/kg)复制AMD模型。6min后,夏至草组自颈静脉缓慢推注夏至草醇提物(1g/ml,6g/kg),模型组以等量生理盐水代替。应用激光多普勒技术,分别于实验前、AMD期、治疗后观察大鼠小肠、胃、肝等器官微区血流量变化。结果:AMD期,两组大鼠小肠、胃、肝区血流的浓度、流速、流量均显著低于实验前;经输注生理盐水或夏至草醇提物实施治疗后,小肠、胃、肝区血流浓度、流速、流量均显著高于AMD期,但仍低于实验前水平;且输注夏至草醇提物对各器官血流的改善作用显著优于输注生理盐水。结论:夏至草醇提物能明显提高AMD大鼠的器官血流量。     

葡聚糖包裹超顺磁性氧化铁纳米材料用于关节软骨磁共振T2-Map成像研究

本研究制备了粒径(18±2)nm的葡聚糖包裹的超顺磁性氧化铁纳米颗粒,作为磁共振T2造影剂,对兔关节软骨进行增强磁共振T2-Map成像,并分析注射前后24 hT2弛豫时间的变化,发现T2弛豫时间均下降。行组织病理学普鲁士兰染色,发现软骨基质及细胞内均有氧化铁纳米颗粒的存在,说明葡聚糖包裹超顺磁性氧化铁纳米材料可应用于关节软骨磁共振增强成像。     

Leucocyte sequestration in endotoxemia and the effect of low-molecular-weight dextran

Leucocyte sequestration in various organs during endotoxin-induced shock in sheep was studied using leucocytes labelled with indium 111 oxine. A moderate dose ofEscherichia coli endotoxin (10 g/kg body weight) was slowly infused intravenously in 16 sheep, 9 of which subsequently received a continuous i.v. infusion of low-molecular-weight dextran (LMWD) given at an infusion rate of 15 ml/h over 4 h, starting 30 min after administration of the endotoxin. By that time, signs of acute lung injury had developed, thus mimicking a clinical situation. The remaining animals were untreated and served as controls. A marked increase in lung, liver and kidney leucocyte sequestration, together with a sharp, corresponding drop in splenic activity and leucocyte count in peripheral blood, occurred shortly after the endotoxin infusion in both groups. However, after 90 min there was a significantly lower leucocyte activity in the lungs, liver and kidneys of LMWD-treated animals as compared with controls. Less marked hemodynamic and respiratory alterations were also observed in animals treated with LMWD. The present study confirms previous reports that significant leucocyte sequestration in the lungs occurs early during endotoxemia. Furthermore, we found that leucocyte sequestration also occurs in the liver and kidneys, which could explain the development of multi-organ failure, frequently described in clinical sepsis. Even after injury to organs, LMWD infusion seems to be beneficial by significantly lowering leucocyte sequestration and could therefore be justified as an addition to the arsenal of interventions used in the treatment of endotoxemia.This study was supported by grants MS 008, MLN 018 and MLS 033, Kuwait University Research Council, Kuwait     

雷公藤多苷通过NOXs-ROS-NLRP3炎症小体信号通路抑制结肠炎症

目的:观察雷公藤多苷对右旋葡聚糖硫酸钠(dextran sulphate sodium,DSS)诱导的小鼠溃疡性结肠炎(ulcerative colitis,UC)的防治作用及对黏膜组织NADPH氧化酶(NADPH oxidases,NOXs)-活性氧簇(reactive oxygen species,ROS)-NOD样受体蛋白3(NOD-like receptor protein 3,NLRP3)炎症小体信号通路表达的影响,探讨其治疗溃疡性结肠炎的作用及机制。方法:BALB/c小鼠随机分为5组:模型组;低、中及高剂量雷公藤多苷灌胃组;正常组。采用DSS诱发UC动物模型,雷公藤多苷灌胃21 d后,取结肠组织,运用实时荧光定量PCR法检测结肠黏膜组织NLRP3、ASC及caspase-1的mRNA表达,免疫组化法检测结肠黏膜组织caspase-1的表达,ELISA法检测结肠组织匀浆上清IL-1α、TNF-α及IL-13的含量,鲁米诺化学发光法检测结肠黏膜组织ROS的生成和经DPI(NOXs抑制剂)抑制后的NADPH消耗率来分析NOXs活性;体外分离结肠组织中性粒细胞,检测分离的中性粒细胞中ROS的生成、NOXs活性以及NLRP3、ASC、caspase-1的mRNA表达。结果:雷公藤多苷灌胃各组小鼠结肠黏膜组织病理均存在不同程度异常,但组织病理学评分均低于模型组;雷公藤多苷灌胃各组结肠黏膜组织和分离的中性粒细胞中,除高剂量组结肠黏膜组织caspase-1的mRNA表达与正常组相比差异无统计学显著性外,其余各组ROS生成、NOXs活性及NLRP3、ASC、caspase-1的mRNA表达水平低于模型组(P0.05),高于正常组(P0.05);雷公藤多苷灌胃各组间两两比较发现,除中、高剂量组结肠黏膜组织及分离的中性粒细胞caspase-1的mRNA表达差异无统计学显著性外,其它指标相比均有统计学显著性(P0.05);雷公藤多苷灌胃各组小鼠结肠组织匀浆上清中促炎因子(IL1α和TNF-α)含量低于模型组(P0.05),高于正常组(P0.05),抑炎因子(IL-13)含量各组间比较差异无统计学显著性。结论:雷公藤多苷可能通过抑制NOXs-ROS-NLRP3炎症小体信号通路来降低IL-1α、TNF-α等促炎因子的表达从而对DSS诱导的UC小鼠起保护作用,中性粒细胞可能是参与其保护作用的主要炎性细胞。     

A repeated tests procedure to assess onset and duration of the cue properties of (−)Δ 9-THC, (−)Δ 8-THC-DMH and (+)Δ 8-THC

Rats were trained in a two-lever operant box in a drug discrimination procedure to respond differentially to the effects induced by 3 mg/kg of (-) ⁹-tetrahydrocannabinol and the drug vehicle. Tests with (-) ⁸-THC and the dimethyl-heptyl (DMH) homologue of (-) ⁸-THC indicated that (-) ⁸-THC-DMH was more potent but had a slower onset of action than (-) ⁸-THC. Two ways of testing the onset and duration of action were compared. In one procedure (separate tests) the time course of the drug action was established by testing each time interval on separate days with a new injection each test day, whereas in the other procedure (repeated tests) all intervals were evaluated after a single injection. The results were similar for both procedures. The median time intervals for the decay of the (-) ⁸-THC stimulus were 122 and 127 min for the separate and repeated tests procedures respectively. The median time intervals for the onset of action of the (-) ⁹-THC effects of (-) ⁸-THC were 65 and 62 min for the separate and repeated tests procedures respectively. The median time intervals for the decay of (-) ⁸-THC-DMH (0.30 and 0.56 mg/kg) was between 8 and 24 h after injection. Furthermore, a stereoselective action is indicated, as (+) ⁸-THC (5.6 and 10 mg/kg) did not substitute for (-) ⁹-THC.     

Chromosomal Aberrations Accumulate during Metastasis of Virus-Negative Merkel Cell Carcinoma

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Long-term Survival After Endoscopic Resection For Gastric Cancer: Real-world Evidence From a Multicenter Prospective Cohort

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