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1.
目的探讨1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的慢性帕金森病(PD)小鼠中脑黑质部α-突触核蛋白(α-synuclein,α-syn)表达与免疫炎性反应变化情况。方法采用MPTP小剂量长期注射诱导慢性PD小鼠模型,设置实验组和对照组,每组各10只小鼠,实验组给予MPTP/丙磺舒背部皮下注射,对照组给予生理盐水/丙磺舒背部皮下注射。注射完毕后3 w,观察小鼠行为学变化,在形态学上采用HE染色观察黑质细胞丢失情况,采用SP免疫组织化学法检测酪氨酸羟化酶(TH)和α-syn表达及中脑黑质CD11b和肿瘤坏死因子-α(TNF-α)表达变化。结果与对照组相比,实验组小鼠出现竖毛,动作减少等类PD样症状;实验组小鼠中脑黑质多巴胺能神经元数目较对照组明显减少(P<0.01);α-syn表达较对照组明显增加(P<0.01);小鼠中脑黑质CD11b和TNF-α表达较对照组显著增加(P<0.01),且α-syn表达与CD11b表达成线性正相关(r=0.67)。结论 MPTP慢性PD小鼠中脑黑质部α-syn表达显著增加同时伴有小胶质细胞激活增加,炎性细胞因子分泌增加。 相似文献
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《中国老年学杂志》2018,(24)
目的研究核苷酸寡聚结合域蛋白(NOD2)基因敲除对神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的帕金森病(PD)模型小鼠黑质细胞凋亡的影响及对黑质多巴胺(DA)神经元的保护作用。方法将健康雄性C57BL/6小鼠随机分为对照组(注射生理盐水)和PD模型组(注射MPTP),NOD2基因敲除小鼠随机分为NOD2对照组(注射生理盐水)和NOD2组(注射MPTP)。对注射14 d的各组小鼠进行旋转行为学检测鉴定建模效果,TUNEL法观察黑质细胞凋亡情况,Western印迹检测黑质组织中炎症因子肿瘤坏死因子(TNF)-α、细胞凋亡相关蛋白B细胞淋巴瘤/白血病(Bcl)-2和活化的含半胱氨酸天冬氨酸蛋白水解酶(酶切Caspase)-3的表达情况。免疫荧光染色法观察各组脑黑质脑酪氨酸羟化酶(TH)阳性神经元数目的变化,高效液相色谱荧光法检测DA和高香草酸(HVA)的含量变化。结果注射MPTP 14 d后,PD模型组和NOD2组均发生不同程度旋转(P0. 05),且模型组旋转次数显著高于NOD2组(P0. 05);TUNEL检测结果显示,与对照组和NOD2对照组相比,PD模型组和NOD2组凋亡阳性细胞数均明显增多(P0. 05),且NOD2组明显少于PD模型组(P0. 05)。Western印迹检测结果显示,与对照组和NOD2对照组相比,PD模型组和NOD2组TNF-α和酶切Caspase-3蛋白表达水平均明显升高(P0. 05),Bcl-2蛋白表达水平明显下降(P0. 05),且NOD2组TNF-α和酶切Caspase-3蛋白表达水平明显低于PD模型组(P0. 05),NOD2组Bcl-2蛋白表达量明显高于PD模型组(P0. 05)。PD模型组和NOD2组TH阳性神经元数量、DA和HVA含量较对照组和NOD2对照组均显著降低(P0. 05),且NOD2组均明显高于PD模型组(P0. 05)。结论 NOD2基因敲除对PD小鼠DA神经元具有保护作用,其作用机制可能与抑制注射MPTP引起的凋亡阳性细胞数、酶切Caspase-3和TNF-α蛋白表达的升高及减轻注射MPTP引起的Bcl-2蛋白表达、TH阳性细胞数、DA含量和HVA含量的下降有关。 相似文献
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目的观察炎症反应和细胞凋亡在帕金森病发病过程中的作用,探讨罗格列酮对PD多巴胺(DA)能神经元的保护作用。方法采用1-甲基-4-苯基-1,2,3,6四氢吡啶(MPTP)制备PD模型,观察各组小鼠行为学变化,免疫组织化学和免疫印迹观察小鼠中脑黑质酪氨酸羟化酶(TH)、环氧合酶(COX)-2、前列腺素E2(PGE2)和半胱氨酸蛋白酶(caspase)-3的表达变化,及给予罗格列酮后对上述变化的影响。结果模型组小鼠出现震颤、步态迟缓等PD样症状,黑质区TH阳性神经元缺失,COX-2、PGE2和caspase-3阳性细胞明显增多,蛋白水平亦升高;经罗格列酮治疗后,上述症状得到改善。结论罗格列酮对PD小鼠DA能神经元保护作用可能与抑制炎症反应和细胞凋亡有关。 相似文献
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目的 探究G蛋白耦联受体激酶(GRK)2在帕金森病(PD)小鼠纹状体中的作用机制。方法 选用C57BL/J雄性8周龄小鼠,随机分为对照组和模型组;对照组腹腔注射0.2 ml生理盐水,模型组腹腔注射30 mg/kg的1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP),2次/w,共5 w。35 d后对两组进行爬杆实验和旷场实验检测。行为学检测后,小鼠麻醉后眼球取血、取脑,运用酶联免疫吸附试验(ELISA)及免疫组化检测血清和中脑酪氨酸羟化酶(TH)表达,Western印迹和免疫组化检测纹状体GRK2和多巴胺2受体(D2R)表达。结果 在旷场实验中,MPTP干预后模型组自发活动总距离、穿越中心格次数和距离比对照组明显减少(均P<0.001)。在爬杆实验中,模型组爬杆时间比对照组明显延长(P<0.001)。ELISA及免疫组化显示,模型组血清和中脑TH值较对照组明显减少(P<0.001)。Western印迹和免疫组化提示,与对照组相比,纹状体D2R表达显著减少,而CRK2表达显著升高(P<0.05)。结论 GRK2可能通过D2R参与调控PD的症状,针对GRK2是潜... 相似文献
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中药平颤方加褪黑素对PD模型大鼠行为和前脑多巴胺及其代谢的影响 总被引:1,自引:0,他引:1
目的 观察中药平颤方加褪黑素(MT)对N-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)所致帕金森病(PD)模型大鼠行为学和前脑多巴胺(DA)及其代谢产物含量的影响,探讨中药与MT联合治疗PD的疗效及作用机制.方法 SD大鼠60只,分5个组:对照组、模型组、MT组、中药组、中药+MT组.模型组和各治疗组大鼠腹腔注射MPTP建立PD模型,用爬杆法和迷宫实验测量大鼠行为学改变和智力状况,用高压液相电化学法测定前脑DA、高香草酸(HVA)及二羟基苯乙酸(DOPAC)含量.结果 PD模型大鼠出现不同程度爬杆能力下降和智力减退,与模型组相比各治疗组大鼠行为学异常可部分改善(P<0.01);模型组DA、HVA、 DOPAC含量均较对照组显著降低(P<0.01),各治疗组DA、HVA、DOPAC含量较对照组低,但较模型组明显增高(P<0.05,P<0.01).结论 平颤方与MT联合通过调节大鼠前脑DA神经元活性从而改善PD症状. 相似文献
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目的观察1-甲基4-苯基1,2,3,6四氢吡啶(MPTP)致帕金森病(PD)模型小鼠黑质多巴胺能神经细胞过表达Calbindin D28k(CB)时,纹状体细胞抗损伤作用机制。方法选择C57BL/6小鼠连续5 d腹腔注射MPTP,构建成功PD模型小鼠30只,随机分为模型组,人类免疫缺陷病毒(HIV)Ⅰ组(注射HIV Ⅰ)和CB-HIV-Ⅰ组(注射CB-HIV-Ⅰ),每组10只,连续6周对各组小鼠行为学检测,Western blot法检测各组小鼠CB,Bcl 2和Bax的表达变化。结果与模型组和HIV-Ⅰ组比较,CB-HIV-Ⅰ组小鼠各时间点移动格子次数,第1、2、5和6周站立次数,第6周时游泳和悬挂时间,差异有统计学意义(P0.05,P0.01);CB-HIV Ⅰ组小鼠中脑黑质中CB的表达量显著升高(P0.05),纹状体细胞中Bcl-2的表达量亦明显升高(P0.01),而Bax的表达量明显降低(P0.01)。模型组和HIV-Ⅰ组上述指标差异无统计学意义(P0.05)。结论黑质多巴胺能神经细胞过表达CB时,纹状体细胞Bcl-2/Bax表达上调,提示其与纹状体细胞抗凋亡能力增强有关。 相似文献
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目的 观察中药(平颤方)联合褪黑激素(MT)对帕金森病(PD)模型大鼠行为学和前脑纹状体细胞凋亡的影响,探讨中药联合MT治疗PD的作用及其机制. 方法 SD大鼠60只,分5个组:空白对照组、模型对照组、MT组、中药组、中药+MT组.模型对照组和各治疗组大鼠腹腔注射N-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)建立PD模型,用爬杆法和迷宫试验测量大鼠行为学改变和智力状况,Bax/Bcl-2免疫组织化学染色和Tunel法检测前脑纹状体凋亡细胞. 结果 PD大鼠出现不同程度爬杆能力下降和智力减退;与病理对照组相比,用药实验组尤其是中药+MT组大鼠行为学异常可部分或全部改善(P<0.05),前脑纹状体神经元和胶质细胞Bcl-2蛋白表达明显增强(P<0.01),Bax基因表达受抑制(P<0.01),同时前脑黑质纹状体通路细胞凋亡减少(P<0.01).结论 中药平颤方联合MT通过抗氧化应激途径,激活Bax/Bcl-2系统,调节前脑黑质纹状体通路多巴胺(DA)神经活性,抑制细胞凋亡和改善PD症状. 相似文献
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《中国老年学杂志》2016,(21)
目的观察家族型帕金森病(PD)alpha-突触核蛋白(α-Syn)突变体A53T和A30P寡聚体导致小鼠PD模型的行为学变化,探讨α-Syn寡聚体在体内的神经毒性作用。方法制备野生型α-Syn、家族型突变体A53T和A30P的聚集体,对C57BL/6小鼠进行纹状体注射。培养至第30、60天,进行爬杆实验、悬吊实验、滚轴实验和平衡木实验评估行为学改变。免疫组织化学方法检测黑质多巴胺能神经元改变。结果实验鼠纹状体α-Syn寡聚体注射后30 d出现PD样运动障碍表现,纹状体注射30 d和60 d后,各组小鼠的爬杆实验结果均与对照组无差异(P0.05)。注射30 d后,野生型α-Syn寡聚体组小鼠平衡木实验、悬挂实验、滚轴实验与对照组无差异(P0.05);A53T和A30P组小鼠平衡木时间比对照组长(P0.05),滚轴上时间比对照组小鼠缩短(P0.05),悬挂评分比对照组明显降低(P0.01),与野生型α-Syn寡聚体组相比有统计学差异(P0.05)。注射60 d后,野生型α-Syn寡聚体组小鼠平衡木实验平均通过时间比对照组小鼠长(P0.05)、悬挂实验评分较对照组小鼠降低(P0.05);A53T和A30P组小鼠各项行为学评估与对照组小鼠差异显著(P0.01)、与野生型α-Syn寡聚体组相比有差异(P0.05)。A53T和A30P组小鼠黑质多巴胺能神经元数目下降(P0.05)。结论纹状体注射α-Syn突变体A53T和A30P寡聚体,模型小鼠出现PD样行为学改变和黑质多巴胺能神经元减少。 相似文献
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Klotho蛋白对帕金森病模型小鼠的神经保护作用 总被引:1,自引:1,他引:0
目的 观察Klotho蛋白对1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导所致C57BL/6小鼠黑质神经元损伤的保护作用,并探讨其可能的保护机制.方法 C57BL/6小鼠分4组:野生型(WT)生理盐水(NS)对照(WT+NS)组,野生型MPTP(WT+MPTP)组,Klotho蛋白高表达型(KO)生理盐水对照组(KO+NS),Klotho蛋白高表达型MPTP组(KO+MPTP).WT+MPTP组和KO+MPTP组小鼠皮下注射MPTP(20 mg/kg),连用2 d制备帕金森病(PD)模型;WT+NS和KO+NS皮下注射等体积生理盐水.用酪氨酸羟化酶(TH)免疫组织化学法观察黑质神经元的变化;应用高效液相电化学方法(HPLC)检测纹状体(Str)多巴胺(DA)及其代谢产物3,4-二羟基苯乙酸(DOPAC)和高香草酸(HVA)的含量变化.结果 KO+MPTP组黑质致密带(SNc)TH免疫阳性神经元数目较KO+NS组有所减少,但差异不显著;而WT+MPTP组SNc区TH免疫阳性神经元数目较WT+NS组明显减少(P<0.01).KO+MPTP组小鼠Str区DA及其代谢产物DOPAC含量较KO+NS减少,但差异不显著,HVA含量的改变差异显著(P<0.05);而WT+MPTP组DA及其代谢产物DOPAC、HVA含量较WT+NS明显减少(P<0.01).结论 Klotho蛋白可以拮抗MPTP对小鼠黑质多巴胺能神经元损伤,其机制可能因为Klotho蛋白是成纤维细胞生长因子23(FGF23)信号转导中其受体的基本辅助因子及抗氧化应激作用有关. 相似文献
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目的探讨川芎嗪对PD小鼠黑质多巴胺神经元的保护作用。方法将30只健康雄性C57BL/6小鼠随机分为正常组、模型组和治疗组。模型组与治疗组腹腔注射百草枯和代森锰建立PD模型,建模成功后,治疗组给予盐酸川芎嗪注射液腹腔注射10d。观察三组小鼠行为学的改变,并用免疫组织化学法检测黑质TH、GSK-3β的表达。结果模型组与治疗组比较,爬杆时间明显延长,黑质TH阳性神经元数量显著降低,GSK-3β的表达显著升高。结论川芎嗪可显著改善百草枯和代森锰引起的损伤,有明显的神经保护作用。 相似文献
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Kravetz RE 《The American journal of gastroenterology》2000,95(11):3282-3282
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This paper is based on a talk given at the Arterial Hemodynamics: Past, Present and Future symposium in June 2016. Like the talk it is divided into three different but related parts. Part 1 describes the calculation of reservoir and excess pressure from clinical pressure waveforms measured at 5 different aortic sites in 40 patients. The main results are that the reservoir pressure waveform propagates down the aorta and is effectively constant from the aortic root to the aortic bifurcation. Part 2 describes a low-frequency asymptotic analysis of the input impedance of an arterial tree. Neglecting terms of second order, the results show that the low-frequency component of the pressure waveform is uniform throughout the arterial tree and is delayed by an effective wave travel time that depends on the properties of the network. The low-frequency pressure waveform shares all of the properties of the reservoir pressure waveform, but it is premature to say that they are identical. Part 3 describes the analysis of arterial hemodynamicsusing wave fronts. It shows that every wave front introduced at the root of the aorta generates an exponentially increasing number of reflected and transmitted waves with exponentially decreasing amplitudes. The long-time response of the arterial tree can be described by a number of exponentially decaying eigen-modes, each with a different time constant. The analysis is applied to a 55-artery model of the human circulation and the modes and their time constants are shown. This theory provides an alternative method for studying arterial hemodynamics and helps in the interpretation of reservoir and excess pressure. 相似文献
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Stochastic model revisited 总被引:5,自引:0,他引:5
Ogawa M 《International journal of hematology》1999,69(1):2-5
Micromanipulation of murine and human hematopoietic progenitors has demonstrated various combinations of lineages in multilineage colonies, a finding consistent with the stochastic model of stem cell differentiation. Debate continued, however, on the mechanisms of stem cell differentiation, partly because some studies of cell lines suggested a deterministic model. Recently, transfection of primary hematopoietic progenitors with natural or chimeric cytokine receptors demonstrated that forced expression of cytokine receptors does not change the intrinsic differentiation potential of the primary progenitors. Studies also have demonstrated remarkable absence of specificity of signaling pathways in the primary progenitors. These studies are consistent with the stochastic model of stem cell differentiation in which cytokines play permissive and not instructive roles. This review summarizes some of the pertinent literature and discusses the cellular and molecular mechanisms of stem cell differentiation. 相似文献
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Summary. A number of experimental bleeding models have been applied to animal models of haemophilia in order to evaluate the acute haemostatic effect of procoagulant compounds. In contrast, in vivo thrombosis models (including the FeCl3 induced injury model) have mainly been used to study antithrombotic pharmacological intervention. However, as there are limitations to existing bleeding models and as new recombinant FVIII, FIX, and FVIIa variants with increased and prolonged activity are generated there is an increasing need for new and optimized in vivo animal models for testing the efficacy of these haemostatic drug candidates. This led us to look at existing thrombosis models in a new perspective. We have studied the effect of a FeCl3 induced arterial injury in both F8-KO and F9-KO mice using optimized conditions where exposure to FeCl3 induces occlusion within 4.2 ± 0.2 min in wild type mice with a normal coagulation system. In contrast, no occlusion was observed in haemophilic mice providing a therapeutic window in the model making it suitable for pharmacological testing of therapeutic intervention. We demonstrate that replacement therapy with a clinical relevant dose of rFVIII (Advate® 20–80 U kg−1 ) and rFIX [(0.75 mg kg−1 BeneFIX®) ∼50 IU kg−1 ] restored coagulation and normalized the time to occlusion following FeCl3 induced injury in F8-KO mice and restored coagulation and nearly normalized the time to occlusion in F9-KO mice. In conclusion, we have demonstrated that under optimized conditions the FeCl3 induced arterial injury model provides a therapeutic window that makes it an useful effect model for evaluation of the haemostatic potential of procoagulant drugs. 相似文献
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Pearson RG 《Proceedings of the National Academy of Sciences of the United States of America》1981,78(7):4002-4005
The energies of several two- and three-electron atoms, in both ground states and excited states, are calculated by a very simple semiclassical model. The only change from Bohr's original method is to replace definite orbits by probability distribution functions based on classical dynamics. The energies are better than Hartree-Fock values. There is still a need for an exchange-energy correction. 相似文献