选择性5-HT1A受体拮抗剂WAY-100635抑制帕金森病模型大鼠腹内侧前额叶皮质的神经活动

目的腹内侧前额叶皮质在随意运动的起始和控制、情感以及认知中具有重要作用。然而,黑质-纹状体通路变性后腹内侧前额叶皮质的神经活动和5-HT_(1A)受体的作用仍不清楚。本研究观察了6-羟基多巴胺(6- hydroxydopamine,6-OHDA)损毁黑质致密部(substantia nigra pars compacta,SNc)后大鼠腹内侧前额叶皮质神经活动的变化和体循环给予选择性5-HT_(1A)受体拮抗剂WAY-100635后神经元活动的改变。方法采用在体玻璃微电极细胞外记录方法,记录正常大鼠和SNc单侧损毁大鼠的腹内侧前额叶皮质神经元的活动。结果6-OHDA损毁SNc大鼠的腹内侧前额叶皮质神经元放电频率显著增加,放电形式没有明显改变。体循环给予WAY-100635 (0.1 mg/kg,i.v.)不改变正常大鼠腹内侧前额叶皮质神经元的平均放电频率和放电形式,而显著降低了SNc损毁大鼠前额叶皮质神经元的平均放电频率。结论黑质-纹状体通路的变性可导致腹内侧前额叶皮质神经活动增强,5-HT_(1A)受体拮抗剂WAY-100635可以抑制这种活动增强,提示可能存在腹内侧前额叶皮质5-HT_(1A)受体功能失调。     

KiSS-1和E钙黏蛋白在贲门癌组织中的表达及临床意义

目的检测KiSS-1及上皮细胞E钙黏蛋白（E—cadherin）在贲门癌组织中的表达，探讨其临床意义及两者的相关性。方法采用免疫组织化学方法检测80例贲门癌、20例正常贲门组织中KiSS-1及E钙黏蛋白的表达情况。分析其与相关临床病理参数的关系以及两者表达的相关性。结果KiSS-1的表达与贲门癌的临床分期、淋巴结转移呈负相关（均P〈0．05），与分化程度无相关性（均P〉0．05）；E钙黏蛋白的表达与贲门癌的临床分期、淋巴结转移、分化程度均呈负相关（均P〈0．05）。Spearman等级相关分析显示，KiSS-1与E钙黏蛋白在贲门癌中的表达呈正相关（rs=0．722，P〈0．05）。结论KiSS-1与E钙黏蛋白可能在抑制贲门癌的侵袭和转移过程中起重要作用。     

Attenuation of colitis injury in rats using Garcinia cambogia extract

Inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis are chronic enteropathies that probably result from a dysregulated mucosal immune response. These pathologies are characterized by oxidative and nitrosative stress, leukocyte infiltration and up-regulation of pro-inflammatory substances. Current IBD treatment presents limitations in both efficacy and safety that stimulated the search for new active compounds. Garcinia cambogia extract has attracted interest due to its pharmacological properties, including gastroprotective effects. In this study, the antiinflammatory activity of a garcinia extract was assessed in TNBS-induced colitis rats. The results obtained revealed that garcinia administration to colitic rats significantly improved the macroscopic damage and caused substantial reductions in increases in MPO activity, COX-2 and iNOS expression. In addition, garcinia extract treatment was able to reduce PGE(2) and IL-1beta colonic levels. These antiinflammatory actions could be related to a reduction in DNA damage in isolated colonocytes, observed with the comet assay. Finally, garcinia extract caused neither mortality nor toxicity signals after oral administration. As such, the antiinflammatory effects provided by the Garcinia cambogia extract result in an improvement of several parameters analysed in experimental colitis and could provide a source for the search for new antiinflammatory compounds useful in IBD treatment.     

肝细胞癌中Ephrin-A1及其受体的表达与血管生成的关系

目的:探讨Ephrin-A1 及其受体与肝细胞癌血管生成之间的关系。方法:采用免疫组织化学SP法和逆转录聚合酶链反应(RT-PCR)检测52例肝细胞癌（肝癌组）和癌旁组织（癌旁组）标本中Ephrin-A1及其受体EphA1和EphA2蛋白及mRNA的表达情况，并分析其与肝细胞癌的临床病理因素及微血管密度(microvessel density, MVD)之间的关系。结果:在52例肝癌组中 Ephrin-A1及其受体EphA1，EphA2的蛋白阳性表达率分别为59.6%(31/52)，53.8%(28/52)和17.3%(9/52),而癌旁组织中的蛋白阳性表达率分别为23.1%(12/52)，28.9% (15/52)以及21.2%(11/52)。Ephrin-A1及其受体EphA1在两组中的差异有统计学意义(P<0.05)，而EphA2在两组间的差异无显著性（P>0.05）。Ephrin-A1及其受体EphA1mRNA在肝癌组的阳性表达率为67.3%(35/52)和73.7%(38/52)，明显高于癌旁组中的阳性表达42.3%(22/52)和48.1% (25/52) (P<0.05)，而EphA2mRNA在两组间的差异无显著性（P>0.05）。Ephrin-A1蛋白的高表达与患者的甲胎蛋白(AFP)水平及有无门静脉癌栓有关(P<0.05)。Spearman等级相关分析显示，在肝癌组中Ephrin-A1的表达与EphA1的表达呈正相关(r=0.671,P<0.01);而Ephrin-A1与EphA2的表达无相关性;肝癌组中Ephrin-A1的表达与MVD呈正相关(r=0.826,P<0.01)。结论:Ephrin-A1通过与其受体EphA1相结合，促进肝细胞癌的血管生成，从而促进肝细胞癌的生长、浸润和转移; Ephrin-A1及其受体EphA1有望成为肝癌抗血管生成治疗新的靶点。     

藏药佐太对西红花苷-1大鼠体内药动学的影响

目的 探讨藏药佐太对西红花苷-1在大鼠体内药动学特征的影响.方法 对照组(连续ig生理盐水7 d)和实验组(连续ig佐太混悬液7 d或21 d)大鼠按5 mg/kg剂量im西红花苷-1后,采用反相高效液相色谱法测定给药后大鼠血浆中西红花苷-1的质量浓度,DAS 2.0软件计算各组大鼠西红花苷-1的药动学参数.结果 实验组大鼠分别按10 mg/(kg·d)连续ig佐太7 d和21 d后,西红花苷-1的药动学特征发生明显变化,AUC、C_(max)和MRT显著大于对照组,而CL和Vd显著小于对照组,并且随着佐太用药时间的延长,西红花苷-1的AUC增大.结论 给予佐太后西红花苷-1在大鼠体内的吸收显著增多、消除显著减慢.     

Effect of berberine on the pharmacokinetics of substrates of CYP3A and P‐gp

The in vivo effects of berberine (BBR), the widely used bioactive herbal ingredient from many traditional Chinese medicinal herbs, on the pharmacokinetics of carbamazepine (CBZ, a substrate of CYP3A) and its metabolite carbamazepine 10,11‐epoxide (ECBZ), digoxin (DIG, a substrate of P‐gp) and cyclosporine A (CsA, a dual substrate of CYP3A and P‐gp) were evaluated in rats. After a 2‐week pretreatment with BBR, the pharmacokinetic parameters of i.g. administered CBZ and ECBZ were not significantly altered. The pharmacokinetics of i.v. administered DIG was not modified by single and 2‐week pretreatments with BBR, but a dose‐dependent increase in AUC and C_max was observed in the i.g. administered DIG parameters in rats. The AUCs of DIG with BBR (30 mg/kg, 100 mg/kg) were 133%, 170% (single) and 123%, 169% (2‐week) of control, respectively. The AUC and C_max of i.g. administered CsA with a 2‐week pretreatment with BBR increased by 62% and 43% (BBR 30 mg/kg, p < 0.05), 96% and 60% (BBR 100 mg/kg, p < 0.01), compared with the control. In conclusion, berberine produced a dose‐dependent increased bioavailability of digoxin and cyclosporine A by inhibition of intestinal P‐gp. No significant changes in CYP3A activity by berberine were observed. Copyright © 2009 John Wiley & Sons, Ltd.     

Intrahippocampal Injection of Endothelin-1: A New Model of Ischemia-induced Seizures in Immature Rats

Summary:  The goal of this study was to develop a new model of ischemia-induced seizures in immature rats using injection of vasoconstrictor Endothelin-1 (ET-1) into the brain. ET-1 (10, 20, or 40 pmol) was infused into the left dorsal hippocampus of freely moving Wistar rats 12 (P12) and 25 (P25) days old. Animals were then video/EEG-monitored for 100 min and monitoring was repeated 22 h later. Parameters of electrographic seizures (frequency and mean duration) as well as pattern of their behavioral correlates were evaluated. The pattern of behavioral seizures was used to develop model-specific scoring system. Cresyl violet and Fluoro Jade-B-staining were used to evaluate brain damage. Extension of the lesion was correlated with seizure severity. After ET-1-injection, seizures occurred in 83–100% animals of all age-and-dose groups and persisted for 24 h except P12 rats with 10 pmol. There were no differences in average seizure duration (18–40 s) or seizure frequency (3–7 seizures/100 min) among individual dose-groups. Between the 1st and 2nd observation period, total seizure duration decreased in 71% of P12 and 47% of P25 rats. Electrographic seizure activity was most frequently accompanied by clonus, incidence of more severe convulsions (barrel rolling or generalized clonic seizures) increased with dose of ET-1. Morphologic examination did not reveal any dose-related difference in damage severity, hippocampal damage was however more extensive in P12 compared to P25 animals. Seizure severity correlated positively with severity of the damage in both age groups. Our study presents focal injection of ET-1 into the brain as a new and practical model of ischemia-induced seizures in immature rats.     

P38MAPK信号转导通路在大蒜素诱导THP-1细胞凋亡中的作用

目的:探讨大蒜素诱导THP-1细胞凋亡中P38MAPK及Fas基因表达的变化.方法:采用四甲基偶氮唑蓝(MTT)法测定不同浓度大蒜素对THP-1细胞增殖抑制率;Annexin V-FITC/PI双染法流式细胞术(FCM)检测凋亡率的变化;免疫细胞化学法观察大蒜素处理后细胞内磷酸化P38MAPK(P-p38MAPK)表达及分布变化;Western blot检测大蒜素处理前后细胞内P-p38MAPK和Fas蛋白表达量的变化.结果:MTT显示大蒜素能抑制THP-1细胞增殖,并呈时间-剂量依赖性.其72h中效浓度(IC_(50))为12.8 mg·L~(-1).Annexin V-FITC/PI检测凋亡率随大蒜素浓度增加而增加.免疫细胞化学法检测药物处理后P-p38MAPK表达增加,主要分布于细胞核与细胞浆,而阴性对照组仅弱表达.Western blot结果分析P-p38MAPK,Fas蛋白表达量随大蒜素浓度的增加而增加,呈剂量依赖性.其阴性组、72 h的1/2 IC_(50)组、IC_(50)组P-p38MAPK蛋白表达水平(相对灰度值)分别为0.259 8±0.013 2,0.361 2±0.008 3,0.505 6±0.005 5;Fas蛋白表达水平分别为0.287 4±0.008 9,0.426 8±0.007 9和0.597 1±0.010 9,差别均有显著性意义(P<0.01).结论:大蒜素可诱导THP-1细胞凋亡,其诱导凋亡机制可能是通过激活P-p38MAPK/Fas途径实现.     

Infection dynamics and virus-induced apoptosis in cell culture-based influenza vaccine production—Flow cytometry and mathematical modeling

Cell culture-based influenza vaccine manufacturing is of growing importance. Depending on virus strains, differences in infection dynamics, virus-induced apoptosis, cell lysis and virus yields are observed. Comparatively little is known concerning details of virus–host cell interaction on a cellular level and virus spreading in a population of cells in bioreactors. In this study, the infection of MDCK cells with different influenza A virus strains in lab-scale microcarrier culture was investigated by flow cytometry. Together with the infection status of cells, virus-induced apoptosis was monitored. A mathematical model has been formulated to describe changes in the concentration of uninfected and infected adherent cells, dynamics of virus particle release (infectious virions, hemagglutinin content), and the time course of the percentage composition of the cell population.     

前列腺素E1抑制血吸虫病家兔肝脏Ⅰ，Ⅲ型胶原生成的研究

目的:探讨前列腺素E1对血吸虫病家兔肝脏Ⅰ，Ⅲ型胶原的生成及分子伴侣Grp78/BiP基因表达的影响。 方法:用血吸虫尾蚴皮肤敷贴法感染14只家兔，构建血吸虫病肝纤维化动物模型。其中7只兔于感染后60d开始静脉注射PGE1［2.5μg/（kg.d）］至120d。用RT-PCR检测肝组织Ⅰ，Ⅲ型胶原和Grp78/BiP基因mRNA的表达水平。 结果:血吸虫病家兔肝纤维化形成过程中Ⅰ，Ⅲ型胶原基因表达水平明显增加，分别为(14.81±3.57)%和(12.9±3.25) %;Grp78/BiP mRNA表达显著上调(P<0.05)。外源性PGE1与模型组比较显著降低胶原Ⅰ，ⅢmRNA，分别为(5.79±1.26)%和(5.34±1.08) % （P<0.01)。分子伴侣Grp78/BiP mRNA水平显著下调，分别为(0.43±0.07)%和(0.29±0.02) % （P<0.05)。结论:PGE1可通过抑制基因表达和阻遏胶原成熟而有效地降低血吸虫病家兔肝脏胶原纤维的生成。