阿托伐他汀对高胆固醇血症小鼠海马中tau蛋白磷酸化水平的影响

Objective To investigate the phosphorylation of tau protein and the effect of atorvastatin on tau protein phosphorylation in hypercholesteremic mouse hippocampus. Methods Male Kunming mice were randomly divided into normal control group, hypercholesteremia group, and low-dose atorvastatin treatment group (8mg·kg-1·d-1), middle-dose group (15mg·kg-1·d-1),and high-dose group (20mg·kg-1·d-1) with five mice in each group. The hypercholesteremia mouse model was induced by cholesterol-enriched diets. The expression level of tau protein phosphorylation in mouse hippocampus was detected by Western blot and immunohistochemistry methods. The activities of mitogen-activated protein kinase (MAPK) and cyelin dependent kinase 5 (Cdk-5) were measured by liquid scintillation counting of the hippocampus incorporated radioactivity and immunoprecipetation activity assay respectively. Results In hypercholesteremic group, the expression level of tau protein phosphorylation in mouse hippocampus was significantly increased(F=14.761,P＜0.01)as compared with control group, and so were MAPK activity and Cdk-5 activity(all P＜0.01). Atorvastatin treatment group showed the decreased expression level of tau protein phosphorylation at ser396/404 site in low-dose group (F=6.349,P＜0.05),middle-dose group (F=10.283,P＜0.01) and high-dose group (F=10.511,P＜0.01) as compared with hypercholesteremia mouse group. The activities of MAPK and Cdk-5 were decreased along with the increasing atorvastatin doses. Conclusions Hypercholesteremia induces tau protein hyperphosphorylation in mouse hippocampus. Abnormal cholesterol metabolism may play an important role in the pathology process of neurodegeneration in brain. Atorvastatin might inhibit tau protein hyperphosphorylation by inhibiting the activations of MAPK and Cdk-5 in brain, atorvastatin may have the protect effect for tau protein.     

阿托伐他汀对高胆固醇血症小鼠海马中tau蛋白磷酸化水平的影响

Objective To investigate the phosphorylation of tau protein and the effect of atorvastatin on tau protein phosphorylation in hypercholesteremic mouse hippocampus. Methods Male Kunming mice were randomly divided into normal control group, hypercholesteremia group, and low-dose atorvastatin treatment group (8mg·kg-1·d-1), middle-dose group (15mg·kg-1·d-1),and high-dose group (20mg·kg-1·d-1) with five mice in each group. The hypercholesteremia mouse model was induced by cholesterol-enriched diets. The expression level of tau protein phosphorylation in mouse hippocampus was detected by Western blot and immunohistochemistry methods. The activities of mitogen-activated protein kinase (MAPK) and cyelin dependent kinase 5 (Cdk-5) were measured by liquid scintillation counting of the hippocampus incorporated radioactivity and immunoprecipetation activity assay respectively. Results In hypercholesteremic group, the expression level of tau protein phosphorylation in mouse hippocampus was significantly increased(F=14.761,P＜0.01)as compared with control group, and so were MAPK activity and Cdk-5 activity(all P＜0.01). Atorvastatin treatment group showed the decreased expression level of tau protein phosphorylation at ser396/404 site in low-dose group (F=6.349,P＜0.05),middle-dose group (F=10.283,P＜0.01) and high-dose group (F=10.511,P＜0.01) as compared with hypercholesteremia mouse group. The activities of MAPK and Cdk-5 were decreased along with the increasing atorvastatin doses. Conclusions Hypercholesteremia induces tau protein hyperphosphorylation in mouse hippocampus. Abnormal cholesterol metabolism may play an important role in the pathology process of neurodegeneration in brain. Atorvastatin might inhibit tau protein hyperphosphorylation by inhibiting the activations of MAPK and Cdk-5 in brain, atorvastatin may have the protect effect for tau protein.     

阿托伐他汀对高胆固醇兔心肌线粒体能量代谢的影响

目的 探讨阿托伐他汀对高胆固醇血症兔心肌能量代谢的干预作用.方法 24只健康雄性新西兰兔随机分成正常对照组、高胆固醇组和阿托伐他汀组(予高胆固醇饮食并给与阿托伐他汀处理).喂养6周后,经兔耳缘静脉取空腹血标本测血清总胆固醇的浓度;取心肌组织,电镜观察心肌及线粒体超微结构改变;用高效液相色谱法测心肌线粒体ATP和辅酶Q10含量;用紫外分光光度法测线粒体呼吸链复合物Ⅱ、Ⅳ的活性.结果 高胆固醇组心肌纤维排列紊乱,部分断裂、溶解,线粒体肿胀,嵴紊乱、模糊,与正常对照组比较,线粒体呼吸链复合物Ⅱ、Ⅳ活性下降,线粒体ATP、辅酶Q10含量减少(P＜0.01);阿托伐他汀组与高胆固醇组比较,呼吸链复合物Ⅱ、Ⅳ活性升高(P＜0.01),线粒体ATP、辅酶Q10含量差异无统计学意义(P＞0.05).结论 阿托伐他汀可减轻高胆固醇血症导致的心肌及线粒体结构损伤,升高线粒体内膜呼吸链复合物Ⅱ、Ⅳ活性,进而改善线粒体氧化磷酸化能力.     

阿托伐他汀对大鼠胰岛功能影响的量效和时效关系

目的 观察阿托伐他汀对Wistar大鼠胰岛功能及糖耐量的影响,研究其效应与剂量、时间的相关性.方法 将60只8周龄正常Wistar大鼠采用随机数字表法分为正常对照组(生理盐水2 ml/d,n=10)、低剂量阿托伐他汀组(阿托伐他汀5 mg· kg-1·d-1,n=1O)、中剂量阿托伐他汀组(阿托伐他汀25 mg·kg-1·d-1,n=10)和高剂量阿托伐他汀组(阿托伐他汀50 mg·kg-1·d-1,n=30).于干预第0、4、8周分别行口服葡萄糖耐量试验(OGTr),测定血糖、血清胰岛素,计算稳态模型评估-β细胞功能指数(HOMA-β)、第一时相胰岛素分泌指数(△I30/△G30)、稳态模型评估-胰岛素抵抗指数(HOMA-IR)、胰岛素曲线下面积(AUCi)、葡萄糖曲线下面积(AUCg)和处置指数.然后将高剂量阿托伐他汀组部分大鼠采用随机数字表法分为两组,继续给药组仍给予高剂量阿托伐他汀灌胃,洗脱组改为生理盐水灌胃,4周后再次行OGTT检测.并取血行甘油三酯、总胆固醇检测.结果 干预8周后高剂量阿托伐他汀组OGTT 0、15、30、60、120 min的胰岛素水平及HOMA-β、△I30/△G30、AUCi、AUCg、HOMA-IR均低于正常对照组(F=4.168 ～ 306.493,P均＜0.05);干预4周时各组及干预8周时中、低剂量阿托伐他汀组均未见相似效应(P均＞0.05).经4周药物洗脱期后,洗脱组的OGTT0、15、30、60、120 min胰岛素水平(F=4.64 ～ 15.58,P均＜0.05)及上述指标均高于继续给药组(t=29.044、4.433、4.429、2.964,P均＜0.05).但各剂量阿托伐他汀组间血糖和处置指数均未见明显影响(P均＞0.05).HOMA-β、△I30/△G30、AUCi随阿托伐他汀剂量的增加和时间的延长,均逐渐降低,具有剂量及时间依赖关系(F=213.970、63.839、18.222,P均＜0.01).HOMA-IR、AUCg随阿托伐他汀剂量的增加逐渐降低,随着时间的延长逐渐升高,也呈剂量及时间依赖关系(F=214.437,P ＜O.01;F=9.33,P ＜O.05).结论 阿托伐他汀可抑制大鼠胰岛β细胞胰岛素分泌,改善胰岛素敏感性,并与给药剂量和时间有关,但对血糖影响不明显.     

普罗布考与阿托伐他汀联合用药对冠心病合并高胆固醇血症患者血脂与心绞痛发作的影响

目的比较普罗布考与阿托伐他汀单独及联合应用对冠心病合并高胆固醇血症患者血脂及心绞痛发作的影响。方法将119例冠心病合并高胆固醇血症患者随机分成普罗布考组、阿托伐他汀组及普罗布考与阿托伐他汀联合应用组,普罗布考剂量为0.5g,bid;阿托伐他汀剂量为10mg,qd。比较用药前和12周后三组患者平板运动心电图试验、血脂、氧化型低密度脂蛋白、超氧化物歧化酶和丙二醛等指标变化。结果三组血清总胆固醇水平(P<0.001)和低密度脂蛋白胆固醇水平(P<0.01)均明显降低;阿托伐他汀组高密度脂蛋白胆固醇增高(P<0.01),而氧化型低密度脂蛋白、超氧化物歧化酶和丙二醛变化不明显;普罗布考组氧化型低密度脂蛋白和丙二醛显著降低(P<0.001),超氧化物歧化酶升高(P<0.001),但高密度脂蛋白胆固醇降低(P<0.01);联合用药组氧化型低密度脂蛋白和丙二醛显著降低(P<0.001),超氧化物歧化酶升高(P<0.001),高密度脂蛋白胆固醇变化不明显。三组治疗后平板运动心电图试验阳性率和研究结束前2周内心绞痛发作次数均减少,普罗布考组较阿托伐他汀组更明显(P<0.05),联合用药组更为显著(P<0.01)。结论普罗布考为一安全有效的降血脂及减少心绞痛发作的药物,与阿托伐他汀联合应用安全,疗效更显著。     

阿托伐他汀对脂肪细胞分泌白细胞介素-6的影响

我们通过建立高胆固醇血症兔模型来观察阿托伐他汀对脂肪细胞分泌白细胞介素 6 (IL 6 )的影响、并进一步探讨其可能机制。一、材料与方法1.动物模型 :14只 3月龄的健康雄性新西兰兔 ,单笼饲养 1周后记录体重并进行基线血脂分析 ,然后随机给 10只兔喂食 1%的高胆固醇饲料 ,4只兔进食普通饲料。第 8周再次测血脂和体重 ,第 9周开始在高胆固醇饮食组随机给予阿托伐他汀 1 5mg·kg-1·d-1(n =5 )或淀粉 1 5mg·kg-1·d-1(n =5 )。 2周后复测血脂及体重 ,取腹股沟处皮下脂肪组织进行脂肪细胞培养。采用Agatha等的方法并作适当修改进行脂肪细胞…     

阿托伐他汀对高胆固醇血症患者血小板血管紧张素Ⅱ受体表达的影响

目的 通过观察高胆固醇血症患者血小板血管紧张素Ⅱ1型受体(AT1R)、血管紧张素Ⅱ2型受体(AT2R)表达的变化及阿托伐他汀对其表达变化的影响,探讨肾素血管紧张素系统(RAS)在高血压及动脉粥样硬化(AS)发生中的作用及他汀多效性作用的机制.方法 在我院健康查体中心随机选取健康对照60例和高胆固醇血症患者80例,分别为对照组和高脂组;高脂组予以阿托伐他汀20 mg/d,睡前口服,共12周.于试验开始前及高脂组服药12周时,肘静脉取血,分离血清、血浆并提取血小板.放射免疫法检测血浆的血管紧张素Ⅱ(AngⅡ)水平,RT-PCR和Western blot方法分别检测血小板AT1R、AT2R的mRNA和蛋白质表达水平.结果 阿托伐他汀组的胆圊醇相较高脂组明显降低(他汀组:5.57±1.27比高脂组:7.08±1.23 mmol/L,P＜0.05):①高脂组的血浆AngⅡ水平较对照组显著升高(P＜0.01),他汀治疗后较治疗前明显降低(P＜0.05).②阿托伐他汀治疗明显下降高脂组血小板的AT1R mRNA(治疗前:0.93±0.22比治疗后:0.52±0.13,P＜0.01)和蛋白质表达(治疗前:1.35±0.32比治疗后:0.72±0.16,P＜0.01).③阿托伐他汀治疗明显升高高脂组血小板的AT2R mRNA(治疗前:0.85±0.16比治疗后:1.24±0.28,P＜0.01)和蛋白质表达(治疗前:0.81±0.17比治疗后:1.23±0.25,P＜0.01).④高脂组血小板AT1R、AT2R的表达均与血浆的AngⅡ水平呈显著正相关(r=0.389,P＜0.01;r=0.356,P＜0.01).结论 阿托伐他汀下调高胆固醇血症患者血小板AT1R表达的增高,但进一步上调AT2R表达的增高.     

阿托伐他汀联合辅酶Q10对心肌梗死后心力衰竭大鼠丙二醛、超氧化物歧化酶及心肌纤维化的影响

目的 观察联合应用阿托伐他汀及辅酶Q10对心肌梗死后心衰大鼠丙二醛(MDA)、超氧化物歧化酶(SOD)以及心肌纤维化的影响,探讨阿托伐他汀联合辅酶Q10在治疗心衰中的作用.方法 Wistar大鼠氟烷麻醉后,结扎左冠状动脉前降支,术后6 w成功建立心衰模型.将大鼠随机分为4组(每组6只):假手术组、模型组、模型+阿托伐他汀组、模型+阿托伐他汀+辅酶Q10组,给药组均于术后第7周开始给药,其中阿托伐他汀给药浓度为10 mg·kg-1·d-1,辅酶Q10给药浓度为30 mg·kg-1·d-1,连续给药5 w,1次/d.5 w后硫代巴比妥酸法测定血清中MDA含量,黄嘌呤氧化酶法测定血清中SOD活性,光镜观察心肌纤维化的程度.结果 模型+阿托伐他汀组较模型组血清中MDA含量显著减少(P＜0.01),SOD活性显著增强(P＜0.01),心肌纤维化程度减轻;模型+阿托伐他汀+辅酶Q10组较模型+阿托伐他汀组MDA含量减少(P＜0.05),SOD活性增强(P＜0.05),心肌纤维化程度减轻.结论 阿托伐他汀联合辅酶Q10较单独应用阿托伐他汀能进一步保护心肌,减少心肌梗死后心衰大鼠血清中MDA含量,增加SOD活性,减轻心肌纤维化程度.     

阿托伐他汀对Aβ_1-42诱导AD模型抗凋亡作用的研究

目的 探讨阿托伐他汀对Aβ1-42诱导阿尔茨海默病(AD)大鼠模型学习记忆功能及神经细胞凋亡的影响.方法 采用侧脑室注射Aβ1-42的方法制备大鼠痴呆模型,阿托伐他汀5 mg·kg-1·d-1灌胃为治疗组,并设假手术组作为对照组.水迷宫实验观测大鼠的行为学变化,免疫组织化学方法测定海马区caspase-3的表达,尼氏染色观察海马区神经元凋亡情况,透射电镜观察海马区神经元超微结构的变化.结果 模型组大鼠的学习记忆成绩下降,半胱氨酸蛋白酶-3(caspase-3)生成增多(P＜0.01),凋亡神经元增多;阿托伐他汀治疗组与模型组大鼠相比较,学习和记忆成绩有所改善,海马区caspase-3生成减少(P＜0.01),凋亡神经元减少.细胞形态学观察显示,与模型组相比,阿托伐他汀治疗组模型海马区神经细胞损伤减轻.结论 阿托伐他汀可以减少AD大鼠模型海马区caspase-3的生成,减少神经元的凋亡,减轻神经细胞损伤,改善其学习和记忆能力.     

不同起始剂量阿托伐他汀治疗高胆固醇血症的疗效与安全性

目的　观察不同起始剂量阿托伐他汀治疗高胆固醇血症的达标率与安全性。方法　入选2012年2月至7月在我院门诊就诊的高胆固醇血症患者122例作为实验组，患者按心血管病危险因素分为4组：低危组（29例）、中危组（33例）、高危组（32例）及极高危组（28例），根据心血管病危险分层及低密度脂蛋白胆固醇水平确定个体化阿托伐他汀起始剂量；另选同期39例高胆固醇血症患者作为对照组，常规给予阿托伐他汀治疗；6周后所有入选患者低密度脂蛋白胆固醇不达标者每天加阿托伐他汀10　mg；均观察12周，同时记录不良事件。结果　实验组的低危组、中危组、高危组、极高危组患者在6周时低密度脂蛋白胆固醇达标率分别为75.9%、72.7%、71.9%、57.1%，12周时各组的达标率增至89.7%、81.8%、78.1%、71.4%；实验组患者低密度脂蛋白胆固醇总的达标率在6周及12周分别为69.7%及81.1%。对照组患者6周及12周达标率分别为48.7%及66.7%。实验组6周及12周达标率均显著高于对照组（分别为P<0.01，P<0.05）。所有患者均耐受治疗剂量。结论　根据心血管病危险分层及低密度脂蛋白胆固醇水平个体化确定阿托伐他汀治疗起始剂量，患者的达标率显著高于常规治疗的对照组，安全有效，值得推广。     

抗结核药致肝细胞线粒体的氧化损伤

目的 探讨抗结核药对小鼠肝细胞线粒体功能的影响,为减少抗结核药致肝损伤发生提供实验依据.方法 150只昆明种小鼠分成5组,分别为对照组(C组)、利福平(RFP)组、异烟肼(INH)组、吡嗪酰胺(PZA)组以及三种药物的混合组(MIX),分别予0.9％氯化钠溶液0.3 mL/d,RFP 135 mg·kg-1·d-1,INH 90 mg·kg-1·d-1,PZA 315 mg·kg-1·d-1和RFP+ INH+PZA(135+90+315) mg·kg-1·d-1,每天灌胃给药一次,在用药3、7和15 d分批处死小鼠取标本.动态观察各组肝细胞线粒体丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性、谷胱甘肽过氧化物酶(GSH-PX)活性和线粒体DNA(mtDNA)中8羟基脱氧鸟苷(8-OH-dG)含量.采用单因素方差分析或秩和检验.结果 随着用药时间的延长,RFP组(Z=6.020,P=0.049)、INH组(Z=10.220,P=0.006)和MIX组(Z=7.460,P=0.024) MDA含量逐步增高,RFP组(F=6.751,P=0.011)和MIX组(F=4.891,P=0.041)的SOD活性低于对照组和PZA组,RFP组GSH-PX活性明显减低(F=32.445,P＜0.01),其余各组无明显变化规律.各组8-OH-dG含量随用药时间延长均有升高趋势,其中RFP组(F=6.602,P＜0.01)、PZA组(F=5.927,P＜0.01)和MIX组(F=7.974,P＜0.01)升高明显.结论 抗结核药可导致小鼠肝细胞线粒体内MDA和mtDNA中8-OH-dG含量升高,SOD和GSH-PX活性降低.随着用药时间的延长损伤呈加重趋势,三种药物联合用药,可加重对小鼠肝细胞线粒体的损伤程度.     

叶酸对去卵巢大鼠骨质疏松的保护作用

目的 探讨叶酸对去卵巢大鼠骨质疏松的保护作用.方法 40只3月龄雌性SD大鼠随机分为5组:假手术组、去卵巢组、乙烯雌酚组(乙烯雌酚0.03 mg·kg-1·d-1)、低剂量叶酸组(叶酸5 mg·kg-1·d-1)、高剂量叶酸组(叶酸20 mg·kg-1·d-1).各组大鼠于术后1周开始灌胃给药,治疗10周,假手术组和去卵巢组给予溶媒灌胃.测定大鼠血浆总同型半胱氨酸(tHcy)浓度,骨匀浆中碱性磷酸酶(ALP)和抗酒石酸酸性磷酸酶(TRACP)的水平;取右股骨和腰5椎体进行骨密度和骨生物力学测定,取腰6椎体和左股骨制备HE切片,观察骨组织的形态学变化.结果 与假手术组比较,去卵巢大鼠血浆tHcy浓度明显升高,腰椎和股骨骨密度显著减低(均P＜0.01),血浆tHcy浓度与腰椎骨密度呈负相关(r=-0.359,P=0.040).叶酸显著降低去卵巢大鼠血浆tHcy浓度(均P＜0.01).大剂量叶酸显著增加去卵巢大鼠骨匀浆ALP水平,降低TRACP水平,增加腰椎和股骨骨密度(均P＜0.01),改善腰椎和股骨的生物力学性能.结论 去卵巢大鼠存在高同型半胱氨酸血症,高同型半胱氨酸参与了去卵巢大鼠骨质疏松的发生.叶酸对去卵巢大鼠骨质疏松具有保护作用,其机制可能与改善同型半胱氨酸的代谢作用有关.

Abstract：

Objective To investigate the protective effect of folic acid(FA) on osteoporosis in ovariectomized(OVX) rats.Methods Forty three-month-old female SD Rats were divided into 5 groups, sham operation group, OVX group, diethylstilbestrol group(0.03mg·kg-1·d-1),low dose FA Group (5 mg·kg-1·d-1),and high dose FA group (20 mg·kg-1·d-1).Gastric gavage in each group was started from one week after being ovariectomized and lasted 10 weeks. Sham operation group and OVX group were treated with solvent. The rats were sacrificed at the end of 10th week after treatment. The total homocysteine(tHcy) in plasma, alkaline phosphatase(ALP), and tartrate-resistant acid phosphatase(TRACP) activity of bone homogenates were measured. The bone mineral density(BMD) and bone biomechanics were determined using L5 vertebrae and right femur. The bone tissue slices were made with L6 vertebrae and left femur and HE stained, and then the histomorphology was observed. Results Compared with sham operation group, plasma tHcy level was significantly increased(P＜0.01), BMD of lumbar vertebrae and femur was remarkedly decreased in OVX group(all P＜0.01). Plasma tHcy concentration was negatively correlated with lumbar BMD(r=-0.359, P=0.040). Plasma tHcy level in both groups treated with folic acid was significantly reduced(all P＜0.01). The ALP concentration in bone homogenates was higher, the TRACP concentration in bone homogenates was lower, and BMD and bone biomechanics of lumbar vertebrae and femur were increased in high dose FA group than those in OVX group(all P ＜0.01). Conclusions In OVX rats hyperhomocysteinemia existed and was involved in the development of osteoporosis. Folic acid could protect OVX rats from osteoporosis, due probably to improved homocysteine metabolism.     

阿托伐他汀对慢性脑低灌注大鼠海马ADAM10的影响

目的 探讨慢性脑低灌注老龄大鼠学习记忆功能、海马解聚素和金属蛋白酶10(adisingtergrin and metalloprotease 10,ADAM 10) mRNA表达变化以及阿托伐他汀对其的影响.方法72只健康雄性Wistar老年大鼠随机分为假手术组、脑低灌注组和阿托伐他汀处理组.制作永久性双侧颈总动脉闭塞...     

缬沙坦与U0126对大鼠心房纤维化和缝隙连接蛋白40重构的影响

目的 探讨缬沙坦与U0126对血管紧张素Ⅱ(angiotensin Ⅱ,Ang Ⅱ)诱导的大鼠心房纤维化和缝隙连接蛋白40( connexin 40,Cx40)重构的影响.方法 将32只雄性SD大鼠随机分为空白对照组(A组)、盐酸异丙基肾上腺素( isopreterenol,ISO)+二甲基亚砜(DMSO)组(B组)、ISO+U0126组(C组,U0126溶于DMSO中)、ISO+缬沙坦+DMSO组(D组).给药28 d后处死大鼠取心肌组织,放射免疫法测Ang Ⅱ含量;HE和Masson染色法观察纤维化程度即胶原容积分数(CVF);免疫组化法测定磷酸化丝裂原活化蛋白激酶激酶1/2(P-MEK1/2)、磷酸化细胞外信号调节激酶1/2( P-ERK1/2)以及Cx40的表达.结果 B、C、D组中Ang Ⅱ含量较A组明显升高[分别为(368.243±6.283)ng/L、(357.175±5.944) ng/L、(359.908±2.496) ng/L比(250.380±4.261) ng/L,P＜0.01];A组CVF(9.025 ±0.456)％,显示无心房纤维化;C组和D组较B组心房纤维化程度明显减弱[CVF分别为(10.260±0.525)％、(10.238 ±0.524)％比(78.710±1.587)％,P＜0.01],C组和D组之间差异无统计学意义(P＞0.05);B组较A组中P-MEK1/2(0.311±0.007比0.203±0.009,P＜0.01)和P-ERK1/2含量明显增加(0.259±0.003比0.173±0.006,P＜0.01),而C组和D组中含量较B组明显减少(P-MEK1/2分别为0.212±0.004、0.213±0.005比0.311±0.007,P＜0.01;P-ERK1/2分别为0.178±0.004、0.175 ±0.007比0.259±0.003,P＜0.01),C组和D组之间差异无统计学意义(P＞0.05);B组较A组Cx40含量明显减少(0.199±0.007比0.241±0.004,P＜0.01)且分布紊乱,C组和D组中含量较B组减少程度明显减轻(分别为0.239±0.037、0.235±0.006比0.199±0.007,P＜0.01)且部分呈线性分布于闰盘,C组和D组之间差异无统计学意义(P＞0.05).结论 心肌组织中Ang Ⅱ含量长期升高可能参与心房纤维化的形成和Cx40重构,缬沙坦与U0126通过抑制ERK通路的不同位点,在改善心房纤维化程度和Cx40重构方面发挥相似的作用.     

益气养阴润肠方对小鼠肠道动力的影响

[目的]研究益气养阴润肠方对小鼠肠道动力的影响.[方法]小鼠40只,随机分为益气养阴润肠方高剂量(47.84 g·kg-1·d-1)组、中剂量(23.92 g·kg-1·d-1)组、低剂量(11.96 g·kg-1·d-1)组、正常组、新斯的明组(阳性组).实验7d后处死所有小鼠,测碳末推进率.[结果]阳性组、益气养阴润肠方各剂量组的碳末推进率均明显提高,与正常组比较,差异有统计学意义(P＜0.01).[结论]中医益气养阴润肠法汤剂对小鼠肠道动力有明显的促进作用.     

依达拉奉对大鼠脑缺血模型MAPK表达的影响

目的探讨自由基清除剂依达拉奉对大鼠脑缺血后丝裂原激活的蛋白激酶(MAPK)表达的影响。方法大脑中动脉阻断法制备大鼠脑缺血再灌注模型,缺血60min后再灌注23h,术前30min及再灌注2h时尾静脉注射依达拉奉1.0mg.kg-1或0.9%氯化钠注射液2ml.kg-1。观察大鼠脑缺血后神经功能缺损症状,TTC染色法检测梗死体积,Fluoro-Jade C法检测细胞死亡,采用免疫印迹法检测MAPK家族三个主要成员:蛋白激酶P38(P38 MAPK),细胞外信号调节激酶(ERK1/2)和c-jun氨基末端激酶(JNK)的表达。结果依达拉奉改善大鼠脑缺血再灌注23h后神经功能缺损症状,减少梗死体积和细胞死亡(P<0.05);大鼠脑缺血后MAPK家族被激活(P<0.01),依达拉奉能显著降低P38MAPK和JNK的激活,但对ERK1/2的表达无明显影响。结论依达拉奉可能能够通过抑制脑缺血后细胞内P38MAPK和JNK信号传导通路,减轻大鼠脑缺血损伤。     

瑞舒伐他汀干预野百合碱诱导大鼠肺动脉高压的实验研究

目的 探讨他汀类药物改善内皮细胞功能、抗增殖等降脂外作用在防治肺动脉高压中的作用及可能机制.方法 雄性SD大鼠,体重(255.7±12.5)g,皮下注射野百合碱诱导大鼠形成肺动脉高压,肺动脉高压形成前后分别接受瑞舒伐他汀预防和治疗.预防实验:32只SD大鼠随机分为4组,分别为瑞舒伐他汀低剂量(2 mg·kg-1·d-1)预防组(n=8)、瑞舒伐他汀高剂量(10 mg·kg-1·d-1)预防组(n=8)、肺动脉高压4周组(n=8)和正常对照4周组(n=8),野百合碱注射当日起预防组每日予瑞舒伐他汀灌胃至第4周末,正常对照组、肺动脉高压4周组仅予生理盐水灌胃.治疗实验:52只SD大鼠随机分为4组,分别为瑞舒伐他汀低剂量(2 mg·kg-1·d-1)治疗组(n=12)、瑞舒伐他汀高剂量(10 mg·kg-1·d-1)治疗组(n=12)、肺动脉高压8周组(n=20)和正常对照8周组(n=8),野百合碱注射4周后治疗组每日予瑞舒伐他汀灌胃至第8周末,正常对照组、肺动脉高压8周组仅予生理盐水灌胃.比较各组生存率、平均肺动脉压(mPAP)、肺小动脉管壁厚度、右心室肥厚程度,比较肺小动脉增殖细胞核抗原(PCNA)、内皮型一氧化氮合酶(eNOS)蛋白表达水平,比较肺组织Rho激酶1(ROCK-1)、eNOS mRNA表达水平.结果 预防实验大鼠均存活,肺动脉高压形成之后瑞舒伐他汀治疗能改善生存率(瑞舒伐他汀低剂量治疗组、瑞舒伐他汀高剂量治疗组与肺动脉高压8周组比较为58%、75%比30%,P均＜0.05);肺动脉高压形成之前和之后瑞舒伐他汀预防和治疗均能降低mPAP[预防实验:瑞舒伐他汀低剂量预防组、瑞舒伐他汀高剂量预防组与肺动脉高压4周组比较为(27.53±3.43)mm Hg(1 mm Hg=0.133 kPa)、(25.72±1.76)mm Hg比(36.05±2.45)mm Hg,P均＜0.01;治疗实验:瑞舒伐他汀低剂量治疗组、瑞舒伐他汀高剂量治疗组与肺动脉高压8周组比较为(30.39±3.17)mm Hg、(27.59±1.99)mmHg比(40.68±1.39)mm Hg,P均＜0.01],减轻肺小动脉管壁增厚、右心室肥厚程度(P均＜0.01),下调肺小动脉平滑肌细胞PCNA表达(P均＜0.01),上调内皮细胞eNOS表达(P均＜0.05),抑制ROCK-1基因表达(P均＜0.05),有一定的剂量依赖性(P均＜0.05).结论 瑞舒伐他汀防治肺动脉高压可能是通过抑制ROCK-1基因表达,抑制肺动脉平滑肌增殖和恢复内皮细胞功能等机制来实现的.

Abstract：

Objective To investigate the effects of rosuvastatin on monocrotaline (MCT)-induced pulmonary artery hypertension in rats. Methods Pulmonary arterial hypertension was induced by a single subcutaneous injection of monocrotaline (50 mg/kg) in rats. In the prevention protocol, 32 male SpragueDawley rats were randomly divided into four groups ( n = 8 each): low-dose rosuvastatin prevention group (2 mg · kg-1 · d-1 ), high-dose rosuvastatin prevention group ( 10 mg· kg-1 · d-1 ), pulmonary arterial hypertension group, normal control group. Beginning on the MCT injection day, rats were treated with rosuvastatin by daily gavage for 4 weeks. Normal control group and pulmonary arterial hypertension group received vehicle by garage. In the treatment protocol, 52 male Sprague-Dawley rats were randomly dividedinto four groups (n = 13 each): low-dose rosuvastatin treatment group (2 mg · kg-1 · d-1), high-dose rosuvastatin treatment group( 10 mg · kg-1 · d-1), pulmonary arterial hypertension group, normal control group. Four weeks after MCT injection, rats were treated with rnsuvastatin by daily gavage for 4 weeks.Normal control group and pulmonary arterial hypertension group received vehicle by gavage. At the end of study, survival rates, mean pulmonary arterial pressure (mPAP), wall thickness of small pulmonary artery and right ventricular hypertrophy among groups were compared. The expression levels of proliferating cell nuclear antigen (P CNA) and endothelial nitricoxide synthase (eNOS) protein in small pulmonary artery,the expression levels of Rho kinase 1 ( ROCK-1 ) and eNOS mRNA in lung tissue were also detected. Results All rats in the prevention protocol survived. Rosuvastatin treatment improved survival in the treatment protocol (58%, 75% vs. 30%, P ＜0. 05 ). Rosuvastatin therapy in both preventment or treatment protocols significantly lowered mPAP [prevention protocol: ( 27.53 ± 3.43 ), ( 25.72 ± 1.76 ) vs. ( 36. 05 ± 2. 45 )mm Hg(1 mm Hg =0. 133 kPa), P ＜0.01; treatment protocol: (30. 39 ±3. 17), (27.59 ±1.99) vs.(40. 68 ± 1.39) mm Hg, P ＜0. 01], reduced thickening of small pulmonary artery wall (P ＜0. 01 ) and right ventricular hypertrophy ( P ＜ 0. 01 ). Rosuvastatin also inhibited PCNA expression of SMC ( P ＜0. 01 ), restored eNOS expression of EC ( P ＜ 0. 05) and inhibited ROCK-1 mRNA expressions in lung tissue (P ＜ 0. 05 ). Conclusions Rosuvastatin therapy reduced mPAP in monocrotaline-induced pulmonary arterial hypertension rat model and this effect is linked with inhibition of ROCK-I expression, inhibition of smooth muscle cell proliferation and restoration of endothelial cell functions.     

白藜芦醇对去卵巢骨质疏松大鼠血同型半胱氨酸和氧化应激指标的影响

目的 观察白藜芦醇对去卵巢骨质疏松大鼠血同型半胱氨酸(Hcy)和氧化应激指标的影响.方法 32只3月龄雌性Sprague-Dawley (SD)大鼠,按随机数字表法分为4组:去卵巢组、乙烯雌酚组、白藜芦醇组和假手术组,每组8只.去卵巢组、乙烯雌酚组和白藜芦醇组大鼠行双侧卵巢切除术复制骨质疏松模型.术后1周开始灌胃给药,假手术组和去卵巢组大鼠给予蒸馏水(每日一次),其余两组大鼠分别予乙烯雌酚0.03 mg·kg-1·d-1和白藜芦醇20 mg·kg-1·d-1.治疗10周后,测定大鼠血浆总Hcy (tHcy)、总抗氧化能力(TAC)、谷胱甘肽过氧化物酶(GSH-Px)和丙二醛水平,取L5椎体和右股骨进行骨密度测定.结果 与假手术组相比,去卵巢组血浆tHcy和丙二醛水平升高,TAC和GSH-Px水平下降;与去卵巢组相比,乙烯雌酚组和白藜芦醇组血浆tHcy和丙二醛浓度均明显降低,TAC和GSH-Px水平显著升高(F=19.709,117.219,7.020,20.544,P均＜0.01);白藜芦醇组血浆丙二醛浓度较乙烯雌酚组升高(F=117.219,P＜0.01).与假手术组相比,去卵巢组腰椎和股骨骨密度均明显降低;与去卵巢组相比,乙烯雌酚组腰椎和股骨骨密度明显升高,接近假手术组水平(P＞0.05);白藜芦醇组腰椎和股骨骨密度升高,但仍低于乙烯雌酚组和假手术组(F=48.518,43.263,P均＜0.01).血浆tHcy与腰椎和股骨骨密度呈负相关(r=-0.663,P＜0.001;r=-0.520,P =0.002),TAC与股骨骨密度呈正相关(r=0.539,P=0.001).结论 高Hcy血症和氧化应激与去卵巢大鼠骨质疏松关系密切.白藜芦醇可能通过降低血浆tHcy水平和改善氧化应激,对去卵巢大鼠骨质疏松发挥保护作用.     

环孢素A对链脲佐菌素诱导的糖尿病大鼠肾脏基质金属蛋白酶-2和基质金属蛋白酶-9表达的影响

目的 观察免疫抑制剂环孢素A(CsA)对糖尿病大鼠肾脏基质金属蛋白酶(MMP)表达的影响.方法 健康雄性SD大鼠74只,平均体重250 g,采用数字表法随机分为正常对照组(n=10)、单纯糖尿病组(n=8)、胰岛素治疗组(n=9)、造模前低剂量CsA治疗组(n=9;造模前1周皮下注射1μg·g-1·d-1 CsA)、造模前中剂量CsA治疗组(n=8;造模前1周皮下注射4μg·g-1·d-1CsA)、造模前高剂量CsA治疗组(n=8;造模前1周皮下注射8μg·g-1·d-1CsA)、造模后低剂量CsA治疗组(n=8;造模后1周皮下注射1μg·g-1·d-1CsA)、造模后中剂量CsA治疗组(n=7;造模后1周皮下注射4μg·g-1·d-1 CsA)和造模后高剂量CsA治疗组(n=7;造模后1周皮下注射8μg·g-1·d-1 CsA).8周后处死动物,采用免疫组织化学法、逆转录-聚合酶链反应和Western blot检测肾脏MMP-2、MMP-9 mRNA和蛋白表达水平.采用单因素方差分析和直线相关分析进行统计学分析.结果 8周时,单纯糖尿病组24 h尿微量蛋白显著高于正常对照组[分别为(5.80±3.23)、(1.24±0.21)mg/24 h,F=4.229,P＜0.01];各CsA治疗组24 h尿微量蛋白不同程度降低,与正常对照组比较差异无统计学意义.单纯糖尿病组肾小管上皮细胞和肾小球系膜基质MMP-2、MMP-9mRNA(分别为2.22±0.08、2.55±1.10)和蛋白表达(分别为3.1±1.5、2.8±1.0)显著高于正常对照组(MMP-2 mRNA:0.70±0.26,F=6.031;MMP-9 mRNA:0.37±0.24,F=5.193;MMP-2蛋白:1.0±0.0,F=7.532;MMP-9蛋白:1.0±0.0,F=6.100;均P＜0.01).胰岛素治疗对其表达无影响,但CsA干预可下调MMP-2、MMP-9 mRNA和蛋白的异常表达.MMP-2 mRNA与蛋白表达呈显著正相关(r=0.618,P＜0.01),而MMP-9 mRNA与蛋白表达未见相关性(r=0.420,P＞0.05).结论 CsA可减少糖尿病大鼠肾脏MMP-2和MMP-9基因转录和蛋白表达,改善细胞外基质代谢紊乱,可能具有延缓糖尿病肾病发生的作用.