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1.
目的探讨吡格列酮是否可抑制胶原诱导性关节炎(CIA)大鼠的炎症性骨吸收。方法分别用肿瘤坏死因子(TNFα)拮抗剂(注射用重组人Ⅱ型肿瘤坏死因子受体抗体融合蛋白,TNFR Ⅱ-Fc)腹腔注射,低、中、高剂量(3、10、30mg.kg-1.d-1)吡格列酮灌胃治疗CIA大鼠3周。比较各治疗组与正常对照组、模型对照组的病理差异、骨代谢指标——骨保护素(OPG)、核因子κB受体活化因子配体(RANKL)及TNFα的蛋白水平差别。用酶联免疫吸附法(ELISA)、免疫组织化学、蛋白印迹法等方法检测OPG、RANKL及TNFα的蛋白表达。结果模型对照组后踝关节炎性细胞浸润、滑膜组织增生及软骨不同程度破坏;各治疗组关节炎症和滑膜增生不同程度改善,无软骨及骨破坏。相比模型对照组,各治疗组血清及软骨中OPG水平明显增高,而血清中TNFα及软骨中RANKL水平明显降低(P<0.05)。相比低剂量吡格列酮治疗组,高剂量吡格列酮治疗组OPG水平较高,而TNFα及RANKL水平较低(P<0.05)。相比TNFα拮抗剂治疗组,高剂量吡格列酮治疗组软骨中OPG水平较高,而RANKL水平较低(P<0.05)。结论吡格列酮可通过下调CIA大鼠血清中的TNFα及关节软骨中的RANKL,上调关节软骨、滑膜及血清中OPG的蛋白表达,起到抑制CIA大鼠的炎症性骨吸收的作用;并且有随剂量增大而增强的趋势,高剂量吡格列酮治疗时此作用可能稍强于TNFRⅡFc。 相似文献
2.
目的:探讨非诺贝特与吡格列酮对佐剂性关节炎大鼠的抗炎效果。方法24只雄性Lewis大鼠随机分成4组,空白组、模型对照组:给予等量的羧甲基纤维素;非诺贝特组:100 mg · kg-1· d-1、吡格列酮组:30 mg· kg-1· d-1,于造模后开始给药,共给药21 d。大鼠尾静脉皮内注射完全弗氏佐剂每只0 k.1 ml,制备 AA 大鼠模型。关节炎的严重程度是由临床观察(体重,关节炎指数评分,足跟肿胀度)进行评估。骨密度( BMD),骨矿物质含量( BMC)于给药20 d由双能X线骨密度仪测定。应用real-time PCR法检测IL-1β,IL-6和IL-10 mRNA的表达水平。结果与模型对照组相比,非诺贝特组和吡格列酮组关节炎指数评分和足跟肿胀度明显降低( P <0.05),骨密度和骨矿物质含量明显增加( P <0.05),IL-1β和IL-6 mRNA的表达水平明显增加( P <0.05),IL-10 mRNA的表达水平降低( P <0.05)。结论非诺贝特和吡格列酮对大鼠佐剂性关节炎具有一定的治疗作用。 相似文献
3.
目的探讨吡格列酮对2型糖尿病大鼠炎症因子及其糖耐量水平的影响。方法8周龄健康Wistar大鼠,用链脲菌素(STZ)加高脂肪高热卡饮食诱导2型糖尿病大鼠模型,将糖尿病大鼠随机分为2组:糖尿病组(n=10)、吡格列酮组(n=10,10mg·kg-1.d-1,灌胃),健康Wistar大鼠作为对照组(n=10),糖尿病组和对照组给予同体积生理盐水灌胃,8周后分别测定空腹血糖(FBG)和胰岛素水平(FINS),进行口服葡萄糖耐量试验(OGTT),计算胰岛素抵抗指数(HOMA。IR),测定大鼠血清中白介素1B(IL-1B)、白介素6(IL.6)、肿瘤坏死因子α(TNF-α)、急相反应蛋白C(CRP)水平。结果FBG、FINS和HOMA-R水平,糖尿病组比对照组显著升高(P〈0.05),而吡格列酮可以明显降低糖尿病大鼠的水平,差异有统计学意义(P〈0.05);OGTF实验结果显示:糖尿病大鼠餐后血糖水平明显升高(P〈0.05),吡咯列酮明显减低糖尿病大鼠餐后血糖水平差异有统计学意义(P〈0.05);IL-1β、IL-6、TNF-α、CRP水平与正常对照组比较糖尿病组显著升高(P〈0.05),而吡格列酮可以明显降低糖尿病大鼠的水平,差异有统计学意义(P〈0.05)。结论吡格列酮可下调血清炎症因子的表达,改善胰岛素抵抗。 相似文献
4.
摘要:目的:通过佐剂型大鼠关节炎模型探讨豨莶草对类风湿关节炎的治疗作用及机制研究。方法:豨莶草药材粉碎后乙醇加热回流制成干浸膏。60只雄性大鼠随机分为6组:正常对照组、模型组、美洛昔康组(40.0 mg·kg-1)、豨莶草高、中、低剂量组(1.6,0.8,0.4 g·kg-1),每组10只。通过注射完全弗氏佐剂进行刺激,构建佐剂型关节炎模型,造模成功后美洛昔康和豨莶草组灌胃给药,模型组和正常对照组给予等体积生理盐水,1次/d,持续28 d。测量大鼠足跖肿胀度、脾脏脏器系数,HE染色观察关节滑膜组织病理变化,Western blot检测关节滑膜NLRP3炎性小体的表达,ELISA检测血浆白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、C反应蛋白(CRP)、干扰素-γ(IFN-γ)、白细胞介素18(IL-18)的表达。结果:与正常对照组比较,模型组大鼠足跖肿胀度和脾脏系数明显增大,关节滑膜内NLRP3蛋白表达及血浆IL-1β、IL-6、TNF-α、CRP、IFN-γ、IL-18明显升高(P<0.05)。与模型组比较,豨莶草各剂量组大鼠足跖肿胀度和脾脏系数明显减少,关节滑膜内NLRP3蛋白表达及血浆IL-1β、IL-6、TNF-α、CRP、IFN-γ、IL-18明显降低(P<0.05)。结论:豨莶草高、中剂量组均可能通过抑制NLRP3炎性小体的表达,从而抑制滑膜细胞增殖,调节炎性因子生成,进而抑制类风湿关节炎的炎性反应,以达到减轻关节损伤的作用。 相似文献
5.
摘要 目的:观察噻唑烷二酮类药物对糖尿病大鼠肝脏chemerin、cmklr1及肿瘤坏死因子(TNF)-α mRNA表达的影响。方法:雄性SD大鼠随机分为正常对照组、糖尿病组与吡格列酮组,尾静脉注射链脲佐菌素制作糖尿病大鼠模型,造模成功后吡格列酮组每天按15 mg/kg经胃灌药,连续给药8周。第8周末处死大鼠留取肝脏组织。采用实时定量PCR法检测大鼠肝脏chemerin、cmklr1及TNF-α mRNA的表达水平。结果:糖尿病组肝脏chemerin表达低于正常组及吡格列酮组,差异均有统计学意义(均P <0.017)。3组间肝脏cmklr1表达差异无统计学意义。糖尿病组肝脏TNF-α表达较正常组升高(P <0.017),吡格列酮组较糖尿病组有所降低,但差异无统计学意义。结论:糖尿病大鼠肝脏TNF-α表达增高,吡格列酮可能通过上调chemerin的表达而改善肝脏的胰岛素敏感性。 相似文献
6.
川芎嗪对实验性肝纤维化大鼠TNF-α、IL-4和IFN-γ表达的影响 总被引:1,自引:0,他引:1
目的观察川芎嗪对大鼠肝Ⅱ肿瘤坏死因子(TNF—α)、白介素-4(IL-4)和γ干扰素(IFN-γ)表达的影响,进一步阐明川芎嗪抗肝纤维化的可能作用机理。方法80只大鼠随机分为正常对照组(N组)、模型对照组(M组)、川芎嗪治疗组(T组)和空白对照组(R组),采用四氯化碳造模。8周后,T组予以川芎嗪腹腔注射(一日1次80mg/kg),R组予以相同容最生理盐水腹腔注射,共8周。实验结束后所有大鼠处死,分别行苏木素-伊红(HE)染色,采用半定量计分系统(SSS)评估肝纤维化程度,荧光定量聚合酶链式反应(PCR)技术检测TNF—α、IL-4和IFN—Y在肝内的表达。结果T组大鼠肝纤维化程度明显低于R组,且差异有统计学意义(P〈0.05);M组TNF—α、IL-4的表达明显高于N组,IFN-γ的表达明显低丁N组;T组TNF-α、IL-4的表达明显低于M组,IFN—γ的表达则明显高于M组;R组TNF-α、IL-4及IFN—γ的表达介于M组和T组之间。结论川芎嗪用于大鼠肝纤维化有显著疗效,其机制可能与其能影响TNF—α、IL-4及IFN-γ等细胞因子存肝组织的表达有关。 相似文献
7.
目的 观察吡格列酮对2型糖尿病(T2DM)模型大鼠心肌纤维化的影响。方法 清洁级雄性SD大鼠随机分为对照组和模型组,对照组喂饲正常食物,模型组喂饲高脂饲料,2周后模型组大鼠一次性尾iv链脲佐菌素(STZ)50 mg/kg。造模成功大鼠又随机分为模型组和吡格列酮低、高剂量(5、10 mg/kg)组,除对照组,其余大鼠继续给予高脂饲料,每天ig给药1次至12周。心室彩色超声检测心输出量(CO)、左心室舒张末期(LVIDd)和收缩末期内径(LVIDs);眼眶采血,应用葡萄糖氧化酶法检测试剂盒测血糖;天狼猩红染色计算胶原容积分数;ELISA法检测外周血肿瘤坏死因子α(TNF-α)和白介素-6(IL-6)水平;Western blotting检测心肌组织转化生长因子β1(TGF-β1)和Smad3蛋白表达。结果 与模型组比较,吡格列酮组血糖、LVIDd和LVIDs显著降低(P<0.05、0.01),CO显著升高(P<0.05、0.01);吡格列酮低、高剂量组心肌间质胶原纤维显著减少,胶原容积分数显著降低(P<0.01);吡格列酮组TNF-α和IL-6表达水平显著降低(P<0.01);吡格列酮组TGF-β1和Smad3蛋白相对表达量显著降低(P<0.01);作用均呈剂量相关性。结论 吡格列酮通过抑制炎症反应以及TGF-β1/Smad3信号通路,发挥抗糖尿病大鼠心肌纤维化的作用。 相似文献
8.
吡格列酮对脂多糖诱导的星形胶质细胞炎性细胞因子释放的影响 总被引:1,自引:7,他引:1
目的研究吡格列酮对脂多糖(LPS)诱导的星形胶质细胞炎症介质释放的抑制作用及其信号传导通路。方法神经胶质酸性蛋白(glial fibrillary acid protein,GFAP)免疫荧光染色法鉴定星形胶质细胞纯度。ELISA方法检测IL-1β、IL-6和TNF-α蛋白表达量的变化。Griess法测定培养细胞上清液中一氧化氮(NO)含量。结果星形胶质细胞经GFAP免疫荧光鉴定,其阳性率可达95%以上。LPS组能明显增加星形胶质细胞分泌IL-1β、IL-6、TNF-α及NO。吡格列酮能明显抑制LPS引起的这些作用,并呈一定浓度依赖性。过氧化物酶体增殖物激活受体γ(PPARγ)的特异性阻断剂GW9662能明显对抗吡格列酮对LPS引起的IL-1β、IL-6、TNF-α及NO增加的抑制作用。与LPS组相比,JNK特异性阻断剂SP600125(5μmol·L-1)亦能有效对抗LPS诱导星形胶质细胞IL-1β、IL-6、TNF-α及NO分泌的增加;特异性iNOS抑制剂SMT可明显抑制LPS引起的NO分泌增加。结论吡格列酮能明显改善LPS诱导的大鼠皮层星形胶质细胞的损伤,这种作用可能与激活PPARγ、抑制JNK信号传导通路有关。 相似文献
9.
地塞米松与吡格列酮对哮喘T_H1/T_H2细胞因子作用机制的比较 总被引:1,自引:2,他引:1
目的初步探讨地塞米松(DXM)和过氧化物酶增殖活化受体γ(PPARγ)激动剂吡格列酮对哮喘模型TH1/TH2细胞因子表达的影响及其机制,并比较二者的异同。方法24只Balb/c小鼠随机分为正常对照组、哮喘组、地塞米松组和吡格列酮组,每组各6只。采用W estern b lot方法检测各组小鼠肺组织T-bet和GATA3的表达,同时运用流式细胞仪检测小鼠脾细胞胞内白介素4(IL-4)和干扰素γ(IFNγ)的表达。结果哮喘模型鼠脾细胞内IL-4/IFNγ比值与正常组相比明显升高(P<0.01),经DXM治疗后,IL-4/IFNγ比值明显降低,肺组织GATA 3和T-bet的表达均减低(P<0.01),但GATA 3比T-bet减低更明显;而经吡格列酮治疗后,不仅IL-4/IFNγ比值明显降低(P<0.01),同时肺组织T-bet的表达也明显增高(P<0.01),但GATA3无变化(P>0.05)。结论地塞米松与吡格列酮对哮喘TH1/TH2细胞因子的调节及机制有所不同,地塞米松同时抑制GATA3和T-bet的表达,从而扭转了IL-4和IFNγ的比值;而吡格列酮可能通过参与调控TH1细胞转化过程中重要转录因子T-bet的表达,改变IL-4/IFNγ比值,从而改善相应的炎性症状。 相似文献
10.
雷公藤多甙片对胶原诱导关节炎大鼠细胞因子的调节作用 总被引:4,自引:0,他引:4
目的观察雷公藤多甙片对Ⅱ型胶原诱导的关节炎(CIA)大鼠外周血清和关节腔中TNF-α、IL-1β以及滑膜中VEGF的影响,探讨雷公藤多甙片治疗CIA的可能机制。方法建立CIA大鼠模型,常规HE染色,测量关节体积,计算关节炎指数及病理积分,用雷公藤多甙片灌胃治疗,治疗一月后用ELISA检测血清和关节液中TNFα-、IL-1β含量;用免疫组织化学染色检测滑膜中VEGF的蛋白表达。结果模型组大鼠血清和关节液中TNFα、IL-1β及滑膜中VEGF明显高于正常组(P〈0.01)。经过TP治疗后,血清和关节液中TNFα、IL-1β及滑膜中VEGF表达均明显下降。结论细胞因子的表达可能在关节炎的形成及发展过程中起重要作用,TP能够通过调整细胞因子变化而发挥治疗作用。 相似文献
11.
M. ASHTON 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(2):195-204
1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species. 相似文献
12.
Ashton M Johansson L Thornqvist AS Svensson US 《Xenobiotica; the fate of foreign compounds in biological systems》1999,29(2):195-204
1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg x kg(-1)) or i.p. (50 mg x kg(-1)) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) 1 x h(-1) x kg(-1) in the male rat and 10.6 (95% CI: 7.5, 15.0) 1 x h(-1) x kg(-1) in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was approximately 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p < 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p < 0.001) in plasma obtained from the male (8.8 +/- 2.0%) compared with the female rat (11.7 +/- 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species. 相似文献
13.
本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。 相似文献
14.
J P KNOWLES 《British medical journal》1961,2(5264):1396-1399
15.
Boobis AR 《Environmental toxicology and pharmacology》1996,2(2-3):161-163
In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process. 相似文献
16.
Markus Müller Bettina v.Osten Rainer Schmid Evelyne Piegler Ingeborg Gerngroß 《Naunyn-Schmiedeberg's archives of pharmacology》1995,352(4):438-441
Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (cmax, tmax, AUC) were calculated for plasma and tissue time courses. The mean AUCtissue /AUCplasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA
Fluorescence polarisation immuno assay
- AUC
Area under the curve
- tmax
Time to peak concentration
- cmax
Peak concentration 相似文献
17.
AIM: To study the potential pathological role of endogenous angiopoietins in daunorubicin-induced progressive glomerulosclerosis in rats. METHODS: Seventy male Wistar rats were allocated randomly into a daunorubicin group (DRB; n=40) or a control group (n=30). The rats in the DRB group were injected with DRB (15 mg/kg), in their tails. Subsequently, at intervals of 1, 2, 4, 6, 8, and 12 weeks, 5 male Wistar rats in each group were chosen randomly for 24 h urinary protein quantitative measurements (24 h UPQM), and determination of plasma tumor necrosis factor alpha (TNF-alpha), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) levels. Kidney sections were examined by electron microscopy, Periodic Acid Schiff (PAS) staining, immunohistochemical staining and in situ hybridization histochemistry. RESULTS: As glomerulosclerosis progressed in the DRB group, expression of Ang1 mRNA and protein in glomeruli decreased and expression of TNF-alpha protein, Ang2 mRNA and protein in glomeruli increased. Expression of Ang1 mRNA and protein in glomeruli were negatively correlated with 24 h UPQM, Fn protein expression, and mean area of extracellular matrix (MAECM). In comparison, expression of Ang2 mRNA and protein in glomeruli were positively correlated with 24 h UPQM, Fn protein expression and MAECM; furthermore, there was a positive correlation between plasma Ang2 and 24 h UPQM. Plasma TNF-alpha and expression of TNF-alpha in glomeruli were positively correlated with expression of Ang2 mRNA and protein in glomeruli. There was a negative correlation between Ang1 protein expression and Ang2 protein expression in glomeruli. CONCLUSION: During DRB-induced glomerulosclerosis, podocyte injury led to a shift in the balance of Ang1 and Ang2 in glomeruli. Increased TNF-alpha in plasma and glomeruli may upregulate Ang2 expression in glomeruli. Elevated Ang2 in both plasma and glomeruli may mediate protein permeability through the glomerular filtration barrier. Moreover, local expression of Ang2 may facilitate the progress of glomerulosclerosis by upregulating a component expression of extracellular matrix. 相似文献
18.
19.
G Mellsop 《The New Zealand medical journal》1983,96(745):1010-1013
20.
LEATHER HM 《British medical journal》1960,1(5190):1930-1938