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发育早期铅暴露所致仔鼠海马中突触相关蛋白表达的改变
铅暴露可导致儿童的认知功能障碍,因此在中国乃至世界范围内仍是重要的公共健康问题。目前,对于铅损害学习记忆方面的研究虽然取得了一些进展,但其具体机制仍不清楚,有待进一步研究。突触后致密蛋白-95(postsynaptic density protein 95, PSD-95)是突触后致密区的主要组成部分,研究表明PSD-95先于其他突触后蛋白锚定于突触后膜上,在突触后致密区内发挥初始作用。研究发现PSD-95可以结合突触后膜上的N-甲基-D-天门冬氨酸受体(N-methyl-D-aspartate receptor, NMDAR)和下游信号转导蛋白-神经元型一氧化氮合成酶(neuronal nitric oxide synthase, nNOS)组成三联体结构,在学习记忆等生理功能上发挥重要作用。研究人员自母鼠孕期开始,通过饮水铅暴露,给予0、0.5、1.0和2.0 g/L的醋酸铅染毒,分别于仔鼠出生后10、20和40 d,采用透射电镜观察仔鼠的突触超微结构,并在蛋白和基因水平检测位于突触后膜上的PSD-95和nNOS以及位于突触前膜上的突触素(Synaptophysin, SYP)的表达。研究结果显示,发育早期铅暴露可以引起海马组织内突触后致密区变薄,导致PSD-95,nNOS以及SYP蛋白水平的下调,另一方面,在仔鼠出生后40 d,PSD-95和SYP的mRNA表达也明显受到抑制。提示,发育早期铅暴露所致的突触相关蛋白表达的改变可能是铅所致学习记忆功能障碍中的重要原因。
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糖尿病大鼠动脉血管内皮型一氧化氮合酶丝氨酸磷酸化水平降低
由内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)催化产生的一氧化氮(nitric oxide,NO)在维持血管内皮功能稳态上起着重要作用.糖尿病时血管内皮功能障碍是其血管并发症发生的病理生理学基础,但其机制尚未完全阐明.本研究观察了糖尿病早期动脉血管eNOS蛋白表达及其磷酸化以及NO含量的变化,为进一步探讨糖尿病血管并发症的发生机制提供实验依据.
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氨基胍缓解糖尿病大鼠主动脉内皮损伤
糖尿病大血管病变是糖尿病严重慢性并发症之一,其病理基础是动脉粥样硬化(atherosclerosis,AS).血管内皮损伤被认为是AS的始动和关键环节.氨基胍(aminoguanidine,AG)对糖尿病主动脉内皮的保护作用,是否通过抑制诱导性一氧化氮合酶(inducible nitric oxide synthase,iNOS),进而降低过氧亚硝基(ONOO-)的过量生成而发挥作用?尚未见报道.本研究探讨AG对糖尿病大鼠主动脉内皮保护作用的机制.
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大鼠门静脉高压形成过程中血浆内毒素水平与肠道iNOS的表达
在肝硬化形成过程中常伴随着f J静脉高压(portal hypertension,PHT)的形成,其血流动力变化过程中肠道高动力循环的形成是PHT维持和发展的重要条件.各种因素如内毒素,内皮素-1(endothelin-1,ET-1)等通过刺激血管舒张剂如NO等可引起肠道血管扩张而使门脉血流增加.近年来,肠源性内毒素血症(intestinal endotoxemia,IETM)与PHT的关系日益受到重视,前者可通过增加肠道iNOS(inducible nitric oxide synthase,NOS)的表达,促进肠道高动力循环的形成.而在PHT形成的早期及后期内毒素是否均参与了PHT的形成,未见报道.本实验重点研究血浆内毒素与肠道iNOS的动态关系,尤其在PHT形成早期及后期有何异同.
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一氧化氮/一氧化氮合酶在寄生虫学研究中的应用
自20世纪80年代内源性一氧化氮(Nitric oxide,NO)被发现以来,其在生物学中广泛而重要的生理及病理作用越来越受到人们的重视,其限速酶一氧化氮合酶(Nitric oxide synthase,NOS)的研究也取得较大进展,本文就近年来NO/NOS在寄生虫学研究中的应用作一综述.
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慢性应激大鼠结肠黏膜NO含量变化的意义
目的:观察慢性应激大鼠结肠黏膜一氧化氮(nitric oxide,NO)的含量变化,探讨NO在慢性应激肠黏膜损伤中的作用及意义.方法:采用慢性束缚应激模型.Wistar大鼠30只,随机分为对照组、应激组、应激+氨基胍组.应激组和应激+氨基胍组大鼠每天置于束缚笼内2 h.氨基胍组腹腔注射氨基胍150 me/kg,持续14 d处死动物.化学比色法测定肠黏膜组织NO、诱导型NO合成酶(inducible nitric oxide synthase,iNOS)的含量,组织切片观察肠黏膜炎性细胞浸润情况,电镜观察结肠上皮细胞超微结构的变化.结果:应激组结肠黏膜中NO、iNOS含量高于对照组(N0:47.5±7.9 vs32.3±4.7 μmol/g,P<0.0l;iNOS 6.7±1.0vs 4.0±0.6 nkat/g,P<0.01),中性粒细胞、单核细胞数目增加(N:70±12 vs 30±6/mm2P<0.0l;M:52±9 vs26±8/mm2,P<0.01),并出现上皮细胞线粒体肿胀、细胞间紧密连接间隙加大等超微结构的变化氨基呱组结肠黏膜NO、iNOS含量低于应激组(N0:27.7±12.4vs47.8±7.9 μmol/g,P<0.05;iNOS3.8±0.8vs6.7±1.0 nkat/g,P<0.01),炎性细胞浸润及超微结构的变化较轻.结论:慢性应激大鼠结肠黏膜NO含量增加,可能参与了应激诱导的肠黏膜损伤.氨基胍对应激诱导的肠黏膜损伤起保护作用.
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一氧化氮和一氧化氮合酶与肿瘤放疗敏感性的关系
一氧化氮(nitric oxide,NO)的生物学作用具有复杂性和多样性,在基础条件下诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)活性很低,当机体遭受微生物内外毒素、炎症介质等刺激时iNOS可诱导合成大量的NO.肿瘤生物学上一般认为高水平的NO对肿瘤细胞具有直接的细胞毒作用,而较低水平的NO具有生长刺激作用.多种试验显示NO的供体能增加肿瘤的放疗敏感性.研究认为,NO的生物学作用可能是通过p53依赖途径介导的.调节NO杀灭肿瘤或促进肿瘤生长,p53起到关键性的作用.已有多种药品作为放射敏化剂,NO供体药物在体内给药可能导致系统低血压,增加肿瘤血液灌注和氧合作用,具有潜在的促进肿瘤生长的作用,限制了其临床使用,直接将iNOS基因转染入肿瘤细胞内,肿瘤内的乏氧环境,可降低iNOS的活性而影响NO的产量.携带iNOS基因的腺病毒(adenoviral vector carrying the iNOS cDNA,AdiNOS)转染靶细胞导致iNOS过表达,产生大量NO,有望成为一种增加肿瘤放疗敏感性有效可行的方法.
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AIM To study the relationship between nitric oxide (NO), nitric oxide synthase (NOS) and humanhepatocellular carcinoma (HCC).METHODS Plsama NO2-/NO3- was measured by Griess reaction in 122 patients with chronic hepatitis(CH) and compensated liver cirrhosis (LC), among which 62 patients were complicated with HCC(CH = 28, LC = 34), and the rest 60 patients were not (CH = 29, LC = 31). Thirty healthy persons served asnormal controls (NC). There were no prominent differences among the groups in sex, age and the ratio ofCH to LC. The expression of inducible nitric oxide synthase (iNOS) in HCC (n = 40), CH (n = 30) and LC(n = 30) samples obtained from liver biopsy or operation was compared with that in normal liver tissues byusing immunohistochemistry. Ten normal liver tissue samples obtained from liver operation served as normalcontrols. The samples were fixed in formalin and embeded in paraffin. Anti-iNOS antibody (Santacruzcompany) was served as antibody-Ⅰ in immunohistochemical assay of iNOS in tissue.RESULTS Plasma NO2-/NO3- level in normal was 11.5 μmol/L±4.2μmol/L. The plasma level ofNO2 /NO3- in CH (58.6±17.4 μmol/L) and LC (38.7±10.6μmol/L) accompanied with HCC wasnotably higher than in those patients without HCC (CH: 24.8±9.4 μmol/L; LC: 22.3±8.7μmol/L,t=2.901, 2.756, P<0.01). Plasma NO2-/NO3- level in HCC accompanied with CH was significantlyhigher than in those accompanied with LC ( t = 2.216, P<0.05). Positive rate of iNOS in HCC, CH and LCwas 95%, 93% and 57% respectively. iNOS was not expressed in normal liver tissues. The expression level ofiNOS in HCC (χ2=17.4, P<0.001) and CH (χ2=11.64, P<0.025) was much higher than in LC.CONCLUSION Plasma NO2 / NO3- level significantly increased in patients with HCC and theimmunohistochemical staining of iNOS was positive. This suggests that the liver secrets NO in the higherlevel may participate in the carcinogenesis and progression of HCC.
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AIM To investigate the expression of endothelial NO synthase (eNOS), inducible NO synthase (iNOS)protein and eNOS mRNA gene in the splanchnic organs of liver cirrhosis and portal hypertensive rats.METHODS In control and CCl4-induced liver cirrhotic rats, the expression of eNOS and iNOS proteins wasdetected by immunohistochemical method, and eNOS mRNA was detected by in situ hybridization.RESULTS The expression of eNOS protein and eNOS mRNA increased in most organs of the cirrhotic rats,including bronchial and alveolar epithelial cells, renal tubular epithelial cells and mesenchyma, endothelialand adventitial cells of aorta and superior mesenteric artery, whereas no significant increase of iNOS proteinwas found. In the hepatic tissue, NOS protein and eNOS mRNA were present in mesenchymal cells and vesseladventitial cells, no difference was observed in the expression between control and cirrhotic rats.CONCLUSION The expression of NOS varied in region. In splanchnic organs and vasculars there was anincreased expression of eNOS which induced aplanchnic vasodilation and increased the inflow of portal vein,while in the liver tissue and blood vessel showed no increased expression, which may be associated withincreased intrahepatic vascular resistance.
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AIM To investigate the effects of low dosage of nitric oxide synthesis (NOS) inhibitor NG-nitro-L-argininemethyl ester (L-NAME) in long-term treatment on hyperdynamic circulatory state in rats with cirrhosis.METHODS Cirrhosis model was induced in male SD rats by injection of 60% CC14 oily solutionsubcutaneously. Cirrhotic rats were treated with L-NAME (0.5 mg·kg-1·d-1) by gavage for two weeks. Meanarterial pressure (MAP), cardiac output (CO), cardiac index (CI), splanchnic vascular resistance (SVR),splanchnic blood flow (SBF) and serum NO levels were determinded in L-NAME-treated, L-NAME-untreated cirrhotic rats and controls by using 57Co-Labled microsphere technique and a fluorometric assay,respectively.RESULTS Untreated cirrhotic rats had significantly lower MAP, SVR and higher PP, CO, CI, SBF andNO concentration than controls ( 14.42±0,47 kPa vs 17.05±0.34 kPa, 2.974±0.186 kPa·mL-1·min-1 vs4.234±0.118 kPa·mL-1·min-1, 1.665±0.067 kPa vs 1.123±0.096 kPa, 189.99±9.26 mL/min vs 135.5±3.55 mL/min, 55.89±1.82 mL-1·min-1·100g-1 BW vs 39.68±1.64 mL-1·min-1·100g-1 BW, 4.60±1.25μmol/L vs 0.53±0.26 μmol/L, P<0.01, respectively). In treated cirrhotic rats, L-NAME significantlyattenuated the increase of CO, CI, SBF, NO concentration and the decrease of MAP and SVR. In treatedcirrhotic rats, L-NAME induced a marked decrement of NO concentration than untreated cirrhotic rats(1.471 ±0.907 μmol/L vs 4.204±1.253 μmol/L, P<0.01).CONCLUSION The endogenous NO may play an important role in the changes of hemodynamics pattern incirrhosis,and hyperdynamic circulatory state in rats with cirrhosis can be ameliorated by long-term low doseL-NAME treatment.
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蛋白激酶C对内毒素休克大鼠肝损伤iNOS表达的调控
一氧化氮(NO)具有较强的血管扩张和细胞毒作用,NO在内毒素诱导下主要是由诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)催化底物左旋精氨酸(L-Arg)而生成[1].
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诱导型一氧化氮合酶的表达对移植静脉内膜增生的影响
我们通过对20只建立肌肉注射γ-干扰素刺激诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS),表达观察其对移植静脉内膜增生(intimal hyperplasia,IH)的影响.
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caveolin-1与内皮型一氧化氮合成酶在人肝硬化组织中表达的相关性研究
小凹(caveolae)为一新近发现的定位于细胞质膜上的膜结构,可从细胞质膜上脱落下来形成囊泡,通过其主要结构蛋白小凹蛋白(caveolin-1)与多种信号分子相结合形成复合物,调节信号分子的"激活"与"失活"状态,进而调控细胞跨膜信号转导.我们通过比较caveolin-1和内皮型一氧化氮合成酶(endothelial nitric oxide synthase,eNOS)在肝硬化组织和正常肝组织的蛋白表达水平变化,探讨在肝硬化门静脉高压症发病中caveolin-1表达对eNOS的影响.
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辛伐他汀对新生大鼠缺氧缺血后脑皮质区诱导型一氧化氮合酶活性的影响
新生儿缺氧缺血性脑损伤(hypoxic-ischemic brain damage, HIBD)病理过程的发生、发展与多种因素有关,不同亚型的一氧化氮合酶(nitric oxide synthase, NOS)在其中的作用不同,内皮型一氧化氮合酶 (endothelial nitric oxide synthase, eNOS)产生的一氧化氮(nitric oxide,NO)有神经保护作用,而神经元型一氧化氮合酶 (neuronal nitric oxide synthase, nNOS)与诱导型一氧化氮合酶 (inducible nitric oxide synthase, iNOS)产生的NO与神经损伤有关[1].本研究通过观察新生大鼠缺氧缺血损伤后脑皮质区iNOS活性的变化以及辛伐他汀对其的影响,探讨辛伐他汀对缺氧缺血新生鼠脑的保护作用及可能机制.
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子癎前期患者胎盘内源性一氧化氮合酶抑制物水解酶的表达
子癎前期(pre-eclampsia)是妊娠期特有的疾病,严重威胁母婴安全和健康.但其病因及发病机理还有许多值得探讨之处,近年关注到内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)的抑制物及抑制物水解酶在子癎前期发病中的作用.
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Objective: To analyze the expression of inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) in hepatocellular carcinoma (HCC) and its relation to angiogenesis. Methods: Tissue sections from 71 HCC patients were examined immunohistochemically for protein expression of iNOS, eNOS, and VEGF. Microvessal density (MVD) was counted by endothelial cells immunostained by anti-CD34 antibody. Results: Positive immunostaining for iNOS, eNOS was detected in 83.1% and 85.9% of HCC respectively. INOS and eNOS were not detected in normal hepatic tissue. MVD was 34.3±1.5/HP and 38.6±1.6/HP in HCC with positive staining for iNOS and VEGF while it was 31.2± 2.8/HP, and 22.4± 2.0/HP in HCC with negative staining for iNOS and VEGF (P<0.01). A correlation between NOS expression and VEGF in HCC was not observed. Conclusion: iNOS and eNOS may play a role in malignant transformation f post-hepatic cirrhosis. The expression of iNOS and VEGF favors angiogenesis of HCC.
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诱导型一氧化氮合酶与环氧合酶-2在鼻咽癌中表达的初步研究
诱导型-氧化氮合酶(inducible nitric oxide synthase,iNOS)与环氧合酶-2(cyclooxygenase-2,COX-2)的表达在许多肿瘤中一致上调,两者间呈正相关[1,2].
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大鼠创伤性脑损伤后iNOS表达与神经元凋亡
一、材料与方法健康SD大鼠共52只.随机分为(1)假手术组,仅去除骨瓣开骨窗而不打击;(2)创伤性脑损伤(traumatic braininjury,TBI)组;(3)生理盐水组;(4)氨基胍(aminoguanide,AG)组.生理盐水组、AG组于伤后6h分别腹腔注射生理盐水、AG(100mg/kg),每隔24h注射,连续注射3次;(5)空白对照组.TBI采用改进的Feeney法大鼠脑损伤模型,致伤力度为550g/cm.预设伤后24h、72h、168h 3个时相点,在各预设时点灌注取脑作相应检测:尼氏染色病理学观察;诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)免疫组化检测;凋亡细胞原位缺口末端标记法(TdT mediateddUDP nick endlabeling,TUNEL)观察细胞凋亡情况.
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一氧化氮合酶在鼻息肉中的表达
一氧化氮合酶(nitric oxide synthase,NOS)有3种亚型[1],分别为神经元型一氧化氮合酶 (neuronic nitric oxide synthase,nNOS)、内皮型一氧化氮合酶 (endothelial nitric oxide synthase,eNOS) 和诱导型一氧化氮合酶 (inducible nitric oxide synthase, iNOS).NOS可能在鼻炎和鼻息肉形成中起着重要作用.为了解NOS在鼻息肉组织中分布情况,我们再次通过免疫组化方法,分别检测NOS的3种同功酶在38例鼻息肉组织和17例鼻中隔偏曲患者鼻黏膜组织中的定位及表达情况.
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诱导型一氧化氮合酶在鼻息肉中的表达
鼻息肉的形成与多种因素相关.一氧化氮合酶(nitric oxide synthase,NOS)具有广泛的生物活性功能,参与许多疾病的病理过程.我们观察了诱导型一氧化氮合酶(inducible nitric oxide synthase, iNOS)在鼻息肉中的定位表达.