格列齐特对2型糖尿病大鼠心肌缺血预适应保护作用的影响

目的 探讨格列齐特对2型糖尿病大鼠离体心脏缺血预适应保护作用的影响。方法 将造模成功的2型糖尿病大鼠随机分为糖尿病缺血预处理组、糖尿病再灌注损伤组、糖尿病缺血预处理+格列齐特组、糖尿病再灌注损伤+格列齐特组。将对照组大鼠随机分为缺血预处理组、再灌注损伤组。分别于平衡灌注后、缺血再灌注开始及再灌注60 min末3个时间点分别收集冠脉流出液,测定乳酸脱氢酶（LDH）、肌酸激酶（CK）、肌酸激酶同工酶（CK-MB）的释放量;在再灌注末,取左心室游离壁心肌组织,进行荧光定量PCR检测心肌ATP敏感性钾离子（KATP）通道组成亚基Kir6.2和SUR2A mRNA的表达;免疫组织化学技术检测其蛋白的表达水平。结果 对于糖尿病非药物治疗大鼠,糖尿病缺血预处理组与糖尿病再灌注损伤组比较,冠脉流出液中LDH、CK、CK-MB无明显差异;Kir6.2和SUR2A mRNA及蛋白表达也均无明显差异。而与糖尿病缺血预处理组、糖尿病再灌注损伤+格列齐特组比较,糖尿病缺血预处理+格列齐特组均降低了糖尿病大鼠心肌缺血预处理后缺血再灌注损伤冠脉流出液中LDH、CK、CK-MB释放量（P<0.05）;也使Kir6.2 mRNA及蛋白表达明显增加（P<0.05）;但SUR2A mRNA表达差异无统计学意义。与糖尿病再灌注损伤+格列齐特组比较,糖尿病缺血预处理+格列齐特组SUR2A蛋白表达水平也增加明显（P<0.05）。结论 格列齐特对心肌缺血预处理的保护作用无不利影响,反而能改善2型糖尿病大鼠心肌缺血预适应的保护作用。     

丹皮酚预处理对大鼠脑缺血再灌注损伤的保护作用

目的 探讨丹皮酚预处理对大鼠脑缺血再灌注损伤的保护作用。方法 60只健康雄性SD大鼠随机分为丹皮酚预处理组、模型组、假手术组,每组20只。采用颈外动脉线栓法制作脑缺血再灌注损伤模型,造模前12 h,药物预处理组给予丹皮酚（100 mg·L^-1）,模型组和假手术组给予等量生理盐水,均采用腹腔注射。造模成功后,采用Zealongal法对大鼠神经功能缺损评分;采用氯化三苯四氮唑（TTC）法判断梗死灶体积;采用原位细胞凋亡检测（TUNEL）法检测海马细胞凋亡;采用免疫组织化学法检测海马细胞Hsp-70、Bcl-2及Bax蛋白表达。结果 脑缺血再灌注损伤后,大鼠出现神经功能缺损、梗死灶和Hsp-70、Bcl-2、Bax蛋白表达变化等表现。与模型组比较,丹皮酚预处理组大鼠脑梗死灶缩小、神经功能缺损有所改善,TUNEL和Bax的阳性细胞数明显减少,Hsp-70和Bcl-2的阳性细胞数明显增加（P＜0.05）。结论 丹皮酚可能通过下调Bax蛋白表达,上调Hsp-70和Bcl-2蛋白表达,减轻脑缺血再灌注损伤后的神经细胞凋亡,对受损神经细胞起到一定的保护作用。     

栝楼桂枝颗粒抑制MCAO大鼠神经元凋亡的机制研究

目的 研究栝楼桂枝颗粒（Gualou Guizhi granule,GLGZG）是否通过调控PI3K/AKT通路抑制脑缺血再灌注损伤大鼠神经元凋亡而达到抗脑缺血再灌注损伤的作用。方法 SD大鼠36只,♂,分为假手术组、大脑中动脉栓塞（middle cerebral artery occlusion,MCAO）组、GLGZG组,每组12只。其中MCAO组、GLGZG组采用线栓法致MCAO建立大鼠脑缺血再灌注损伤模型,GLGZG灌胃给药,连续给药7 d。采用改良的神经功能缺损评分法对大鼠神经功能损伤进行评分,MRI观察大鼠脑梗死体积,Real-time PCR检测脑组织中PI3K、Akt mRNA的表达,Western blot法检测大鼠缺血侧脑组织PI3K（p85）、Akt、p-Akt、PDK1、Bcl-2、Bcl-xL、cleaved-caspase-3、Bad、Bax蛋白表达。结果 与MCAO组比较,GLGZG组神经行为学评分降低,第5、7天神经评分显著低于MCAO组（P<0.05）;与MCAO组比较,MRI观察发现GLGZG组大鼠脑梗死体积显著减小（P<0.05）;PI3K（p85）、p-Akt、PDK1、Bcl-2、Bcl-xL蛋白的表达上调（P<0.01）,cleaved-caspase-3、Bad、Bax蛋白的表达下调（P<0.01）,对Akt的表达没有影响。结论 GLGZG能够提高MCAO大鼠神经功能,抑制神经细胞凋亡,其作用机制可能是通过激活PI3K/AKT信号通路抑制MCAO大鼠神经元凋亡。     

番茄红素对大鼠心脏缺血再灌注的保护作用及其机制研究

目的 观察番茄红素对SD大鼠在体心脏缺血再灌注损伤的影响,并探求其作用机制。方法 SD大鼠随机分为假手术组,缺血再灌注损伤组,番茄红素5、15 mg/kg+缺血再灌注损伤组。番茄红素组术前15 d开始ig给药,其他组给予生理盐水,1次/d。制备大鼠缺血再灌注损伤模型后再灌3 h,收集血液,测定血清中心肌酶谱相关指标肌酸激酶（CK）和乳酸脱氢酶（LDH）、氧化应激相关指标超氧化物歧化酶（SOD）和丙二醛（MDA）,以及炎症相关指标肿瘤坏死因子α（TNF-α）和白介素1β（IL-1β）的水平,Western blotting法检测心肌中生存素的表达。再灌24 h后取心脏,依文思蓝–氯化三苯基四氮唑双染色测定心肌梗死面积。结果 与缺血再灌注损伤组比较,番茄红素可显著减小心肌缺血再灌注损伤后心肌梗死面积（P<0.05）,显著降低缺血再灌注损伤后血清中CK、LDH水平（P<0.05）,显著升高缺血再灌注损伤后血清中SOD水平而降低MDA水平（P<0.05）,显著降低缺血再灌注损伤后血清中TNF-α和IL-1β水平（P<0.05）,显著逆转缺血再灌注损伤下调的生存素表达（P<0.05）。结论 番茄红素对SD大鼠在体心肌缺血再灌注损伤具有保护作用,其机制与减轻缺血再灌注损伤后氧化应激损伤、抑制炎症反应和激活生存素通路有关。     

积雪草苷对大鼠心肌缺血再灌注损伤的保护作用研究

目的 研究积雪草苷(AC)对在体大鼠心肌缺血再灌注损伤的保护作用, 初步探讨其机制。方法 40只SPF级Wistar大鼠, 随机分为假手术组、心肌缺血再灌注模型组及积雪草苷低、中、高剂量组, 每组8只。积雪草苷低、中、高剂量组分别以2.5、5.0、10.0 mL/kg体质量的剂量连续ig药液14 d, 药液质量浓度1.5 mg/mL。其他各组同时点ig 0.5%羧甲基纤维素钠溶液。除假手术组外, 其他各组结扎左冠状动脉前降支, 使心肌缺血30 min, 再灌注60 min。用7020全自动生化分析仪检测血清中超氧化物歧化酶(SOD)、乳酸脱氢酶(LDH)、肌酸激酶同工酶(CK-MB)活性和丙二醛(MDA)水平;ELISA法测定血清中C反应蛋白(CRP);TUNEL法检测各组大鼠缺血心肌细胞凋亡;RT-PCR法检测B细胞白血病/淋巴瘤-2基因(Bcl-2)和与Bcl-2相关的x蛋白(Bax)的mRNA表达。结果 与模型组比较, 积雪草苷各剂量组均能降低血清中LDH、CK-MB活性及MDA的量(P<0.05), 升高血清中SOD活性(P<0.05);降低血清中CRP水平(P<0.05);降低心肌细胞凋亡指数(P<0.05);积雪草苷各组凋亡基因Bcl-2表达水平上升(P<0.05), Bax表达水平下降(P<0.05), Bcl-2/Bax比值升高(P<0.05)。结论 积雪草苷预处理能通过减少心肌细胞凋亡、抗脂质过氧化物产生及抗炎症反应等机制, 对心肌缺血再灌注损伤产生保护作用。     

灵仙新苷对大鼠心肌缺血再灌注损伤的保护作用及机制研究

目的 考察灵仙新苷对大鼠心肌缺血再灌注损伤（MIRI）的保护作用,并阐述可能的作用机制。方法 SD大鼠随机分为6组：假手术组、模型组、丹参酮Ⅱ_A（阳性药,16 mg/kg）组和灵仙新苷低、中、高（8、16、32 mg/kg）组,连续ig给药7 d;采用结扎冠状动脉左前降支法制备大鼠MIRI模型,缺血40 min再灌120 min;试剂盒法检测MIRI大鼠血清肿瘤坏死因子-α（TNF-α）、白介素-1β（IL-1β）、白介素-6（IL-6）水平;TTC染色法检测心肌梗死率,流式细胞术检测心肌细胞凋亡率;Western blotting法检测心肌组织中Bcl-2、Bax、TNF-α及Caspase-3的蛋白表达水平。结果 与模型组比较,灵仙新苷（8、16、32 mg/kg）显著降低MIRI模型大鼠血清中TNF-α、IL-1β、IL-6水平,心肌梗死率和心肌细胞凋亡率;明显上调Bcl-2蛋白表达水平,下调Bax、TNF-α、Caspase-3蛋白表达水平,且均具有显著性差异（P<0.05、0.01）。结论 灵仙新苷对MIRI大鼠心肌具有保护作用,其机制可能与抑制TNF-α,调节Bcl-2/Bax蛋白平衡,减少MIRI诱导的心肌细胞凋亡有关。     

金丝桃苷保护大鼠脑缺血再灌注损伤的机制研究

目的 探究金丝桃苷（hyperoside，Hyp）对脑缺血再灌注大鼠脑组织的保护作用及相关机制。方法 采用线栓法建立大脑中动脉闭塞/再灌注（middle cerebral artery occlusion/reperfusion，MCAO/R）大鼠模型，分成假手术组、模型组、Hyp低、中、高剂量组（30，60，120 mg·kg^-1）。持续给药14 d后，采用Zea Longa法对大鼠进行神经功能评分，并测定脑含水量。TTC染色法测定大鼠脑梗死体积，ELISA检测炎症相关因子，HE染色观察大脑海马CA1区神经元病理形态，TUNEL染色观察大鼠脑组织细胞凋亡程度，Western blotting检测TLR4和COX-2以及凋亡相关蛋白的表达。结果 Hyp干预能够显著改善MCAO/R大鼠Zea Longa评分（P<0.05），减少脑含水量和脑梗死体积，显著降低炎症因子（TNF-α、IL-1β、IL-6、ICAM-1以及VCAM-1）的表达（P<0.05或P<0.01），并且有效改善海马CA1区神经元的病理学改变和凋亡情况，显著抑制TLR4、COX-2、NF-kB、caspase-3、caspase-9以及Bax蛋白的表达（P<0.05或P<0.01），上调Bcl-2蛋白的表达（P<0.05）。结论 Hyp对脑缺血再灌注损伤的保护作用与抗炎、抗凋亡以及抑制TLR4/COX-2信号通路有关。     

参附注射液对大鼠脑缺血再灌注损伤脑组织磷酸果糖激酶表达的影响

目的 观察参附注射液对大鼠脑缺血再灌注后磷酸果糖激酶（PFK）表达的影响,探讨参附注射液对脑的保护机制。方法 清洁级雄性SD大鼠90只,随机分为假手术（Sham）组、脑缺血再灌注（IR）组、参附注射液预处理（SFI组）,每组30只。采用线栓法制备大鼠大脑中动脉闭塞（MCAO）后再灌注模型,TTC染色测脑梗死面积,并检测PFK活性及PFK mRNA和蛋白的表达。结果 参附注射液能明显减少脑缺血再灌注大鼠脑梗死灶的面积。IR组与Sham组比较,PFK活性明显降低（P＜0.05）,PFK mRNA及蛋白的表达明显增加（P＜0.05）;SFI组PFK mRNA及蛋白的表达水平及活性明显高于IR组（P＜0.05）。结论 参附注射液对脑缺血再灌注大鼠脑组织有保护作用,其机制可能与上调PFK表达及活性有关。     

白芍总苷调节RhoA/ROCK1信号通路对大鼠肝缺血再灌注损伤的影响

目的 探讨白芍总苷通过调节Ras同源基因家族成员A/Rho相关卷曲螺旋蛋白激酶1（RhoA/ROCK1）信号通路对大鼠肝缺血再灌注损伤的影响。方法 通过阻断肝动脉和门静脉1 h建立肝缺血再灌注损伤大鼠模型,设假手术组、模型组、白芍总苷（100 mg/kg）组、白芍总苷＋Rhosin（100 mg/kg＋40 mg/kg）组和白芍总苷＋LPA（100 mg/kg＋1 mg/kg）组,每组8只。连续治疗6周后,检测各组大鼠血清肝功能指标[丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、总胆红素（TBiL）];HE、TUNEL染色法观察肝组织病理改变和细胞凋亡,并计算肝损伤评分和凋亡指数（AI）;分光光度法检测肝组织中氧化应激指标[超氧化物歧化酶（SOD）、过氧化氢酶（CAT）活性和丙二醛（MDA）含量],ELISA检测炎症因子[白细胞介素（IL）-1β、IL-6、肿瘤坏死因子-α（TNF-α）]含量;通过反转录聚合酶链反应（RT-PCR）、蛋白免疫印迹（Western blotting）法检测肝组织中RhoA、ROCK1、核因子-κB p65（NF-κB p65）、B细胞淋巴瘤-2（Bcl-2）、Bcl-2相关X蛋白（Bax）、活化型半胱氨酸蛋白酶-3（C-Caspase-3）mRNA和蛋白表达。结果 与模型组比较,白芍总苷组和白芍总苷＋Rhosin组血清ALT、AST、TBiL水平显著降低（P＜0.05）;肝组织病理改变和细胞凋亡状况均明显改善,肝损伤评分和细胞AI均显著降低（P＜0.05）;SOD、CAT活性显著升高,MDA、IL-1β、IL-6、TNF-α含量显著降低（P＜0.05）;RhoA、ROCK1、NF-κB p65、Bax、C-Caspase-3 mRNA和蛋白表达均显著降低,Bcl-2 mRNA和蛋白表达均显著升高（P＜0.05）。与白芍总苷组相比,Rhosin可显著增强白芍总苷对模型大鼠肝功能、肝组织病变、细胞凋亡、氧化应激、炎症及RhoA/ROCK1信号通路相关mRNA和蛋白表达的作用;LPA则显著逆转了上述调控作用。结论 白芍总苷可能通过抑制RhoA/ROCK1信号通路,减轻氧化应激、炎症和细胞凋亡,从而对大鼠肝缺血再灌注损伤起到一定的保护作用。     

银杏内酯注射液对脑缺血再灌注损伤治疗时间窗及凋亡信号通路的影响

目的 研究银杏内酯注射液（Ginkgolide Injection,GI）作用于大鼠脑缺血再灌注损伤的治疗时间窗及对凋亡信号通路的影响。方法 采用Longa法制备大鼠大脑中动脉短暂阻塞再灌注（tMCAO）模型,（1）分别于再灌后1、3、6、9 h ip首次给予GI （2.5 mg/kg）,每天给药2次,连续给药3 d,通过神经功能评分、脑梗死体积及脑组织含水量评价动物缺血损伤程度。（2）于再灌注后1 h ip给予GI （2.5 mg/kg）,每天给药2次,连续给药3 d,分别于再灌注后24、72 h取脑检测缺血半影区p53、Bax、Bcl-2、Caspase 3蛋白表达水平。结果 与模型组比较,（1）再灌注后1、3 h给予GI能显著降低神经功能评分、减少脑梗死体积与脑组织含水量（P<0.05、0.01）,6、9 h给药大鼠脑损伤未见明显改善。（2）于再灌注后1 h给予GI显著抑制p53、Bax、Caspase 3蛋白表达,上调Bcl-2蛋白表达（P<0.05）。结论 GI对tMCAO模型大鼠的有效治疗时间在缺血再灌注后3 h内;其可能的作用机制涉及抑制凋亡信号通路的激活。     

Affective and Anxiety Disorders and Alcohol and Drug Dependence:

Depression and anxiety frequently coexist in patients with substance use disorders. This clinically-oriented article examiens the relationship between these conditions and emphasizes data showing that substances of abuse can cause signs and symptoms of both depression and anxiety. These substance-related syndromes appear to have a different course and prognosis than uncomplicated, independent anxiety and major depressive disorders, and clinicians should consider the role of alcohol and other drugs in all patients presenting with these complaints. The authors will also outline an approach for diagnosing and managing patients with the combination of a substance use and depressive or anxiety disorder.     

Synthesis and anti-nociceptive and anti-inflammatory effects of gaultherin and its analogs

The synthesis of gaultherin (1) and its analogs was carried out to provide 11 glycosides under phase-transfer catalytic conditions. The activities of all synthesized compounds were evaluated by nitric oxide production inhibitory assay in vitro. Methyl 2-O-(4-O-β-d-galactopyranosyl)-β-d-glucopyranosylbenzoate (5f) showed significantly anti-nociceptive and anti-inflammatory effects by the evaluation in vivo. Structure–activity relationships within these compounds were discussed.     

Modelling and simulation of variability and uncertainty in toxicokinetics and pharmacokinetics

Two important methodological issues within the framework of the variability and uncertainty analysis of toxicokinetic and pharmacokinetic systems are discussed: (i) modelling and simulation of the existing physiologic variability in a population; and (ii) modelling and simulation of variability and uncertainty when there is insufficient or not well defined (e.g. small sample, semiquantitative, qualitative and vague) information available. Physiologically based pharmacokinetic models are especially suited for separating and characterising the physiologic variability from the overall variability and uncertainty in the system. Monte Carlo sampling should draw from multivariate distributions, which reflect all levels of existing dependencies in the intact organism. The population characteristics should be taken into account. A fuzzy simulation approach is proposed to model variability and uncertainty when there is semiquantitative, qualitative and vague information about the model parameters and their statistical distributions cannot be defined reliably.     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

益生菌与肿瘤防治

益生菌广泛存在于自然界中,通过维持宿主体内菌群平衡、影响肠屏障功能和调节免疫应答等作用,提高宿主健康水平,被公认为"肠道健康卫士".一些益生菌可以增强机体的免疫功能,抑制致癌物质,影响肿瘤细胞的基因表达,对肿瘤具有拮抗作用.大量研究表明,益生菌在未来的肿瘤防治中有很好的应用和发展前景.     

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.     

Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats

Rationale  Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. Objectives  The present experiments utilized a “reinforcer blocking” approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats. Materials and methods  In “nondependent” experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For “dependent” experiments, rats were made dependent in vapor/inhalation chambers. Results  Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate’s effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats. Conclusions  The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The “nondependent” paradigm may model early stages of “problem drinking” in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.     

Antiinfective and encrustation-inhibiting materials--myth and facts

Catheters, urethral and ureteral stents and other urological implants are frequently affected by encrustration and infection due to their permanent contact with urine. Indwelling urinary catheters provide a haven for microorganisms and thus require extensive monitoring. Several surface modification techniques have been proposed to improve the performance of devices including the immobilization of biomolecules, the incorporation of hydrophilic grafts to reduce protein adsorption, the creation of hydrophobic surfaces, the creation of microdomains to regulate cellular and protein adhesion, new polymers and antimicrobial coatings. Physico-chemical explanation to elucidate the mechanism of such encrustation or infection inhibiting materials is still not available. Our series of experiments showed a marked decrease of silver-activity in biological fluids which corresponds with the controversial clinical results obtained with silver coated urinary catheters. Rifampicin/minocycline coated catheters had very low activity against Gram-negative rods, enterococci and Candida spp., the main causing organisms of urinary catheter infection. Surface engineered materials and antimicrobial drug delivery systems will be the next generation of sophisticated urinary catheters and stents, if both efficacy as well as efficiency has been proved clinically.     

Alprazolam and lorazepam single and multiple-dose effects on psychomotor skills and sleep

Summary The effects of alprazolam 0.5 mg and lorazepam 2 mg on cognitive and psychomotor skills were assessed in twelve normal volunteer subjects in a randomised, double-blind, crossover design. Single and multiple dose effects were monitored using a battery of tests comprising critical flicker fusion threshold (CFFT), choice reaction time (CRT), simulated car tracking, and subjective ratings of perceived sedation (LARS) and of sleep behaviour (LSEQ). Compared with placebo baseline scores, treatment with lorazepam 2 mg (both single and multiple doses) resulted in a widespread impairment of CRT, tracking accuracy, and CFFT. Single doses of alprazolam 0.5 mg reduced CFFT with respect to the placebo baseline. Single and multiple dose treatment with both drugs resulted in subjective reports of sedation, a reduction of sleep onset latency, and improved sleep quality. Only lorazepam 2 mg significantly disrupted the integrity of behaviour on waking from sleep. These results suggest important pharmacodynamic differences between the two drugs in the doses used.