Protective effect of recombinant human IL-1Ra on CCl4-induced acute liver injury in mice

AIM: To evaluate the effects of positive regulation of recombinant human interleukin 1 receptor antagonist (rhIL-1Ra) on hepatic tissue recovery in acute liver injury in mice induced by carbon tetrachloride (CCl 4 ). METHODS: Acute liver damage was induced by injecting 8-wk-old mice with CCl 4 1 mL/kg (1:3 dilution in corn oil) intraperitoneally (ip). Survival after liver failure was assessed by injecting 8-wk-old mice with a lethal dose of CCl 4 2.6 mL/kg (1:1 dilution in corn oil) ip. Mice were subcutaneo...     

Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein

Amyloid-beta peptide (Abeta) is central to the pathogenesis of Alzheimer's disease, and the low-density lipoprotein receptor-related protein (LRP) has been shown to alter Abeta metabolism in vitro. Here, we show that overexpression of a functional LRP minireceptor in the brain of PDAPP mice results in age-dependent increase of soluble brain Abeta, with no changes in Abeta plaque burden. Importantly, soluble brain Abeta was found to be primarily in the form of monomers/dimers and to be highly correlated with deficits in spatial learning and memory. These results provide in vivo evidence that LRP may contribute to memory deficits typical of Alzheimer's disease by modulating the pool of small soluble forms of Abeta.     

芡实提取物对D-半乳糖衰老小鼠学习记忆障碍的改善作用

目的 观察芡实不同提取物对D-半乳糖致衰老小鼠学习记忆能力的影响及其作用机制.方法 将昆明种小鼠随机分为8组,即对照组、模型组、芡实乙醇提取物高低剂量组、芡实乙酸乙酯提取物高低剂量组、芡实正丁醇提取物高低剂量组.分别采用旷场装置和Morris水迷宫装置测试各组小鼠的自主活动状况及学习记忆能力,同时测定各组小鼠脑组织一氧化氮合成酶(NOS)、谷胱甘肽过氧化物酶(GSH-Px)、乙酰胆碱酯酶(AChE)的活性.结果 芡实乙醇提取物、乙酸乙酯提取物、正丁醇提取物均能浓度依赖性地改善亚急性衰老小鼠的学习记忆能力,提高脑组织NOS、GSH-Px活力,降低AChE活力.结论 芡实乙醇、乙酸乙酯、正丁醇提取物具有改善小鼠衰老状态的作用,其机制可能与其能促进机体清除脂类过氧化物,增强脑组织抗氧化能力,改善胆碱能系统在学习和记忆中的作用有关.芡实正丁醇提取物的作用优于乙醇提取物,乙醇提取物的作用优于乙酸乙酯提取物.     

丹参注射液对D-半乳糖致衰老小鼠学习记忆能力的影响

目的探讨丹参对D-半乳糖致衰老模型小鼠学习记忆能力的影响及其作用途径。方法 120 mg·kg-1·d-1D-半乳糖注射6 w建立衰老小鼠模型,第15天随机分组后,丹参组注射丹参注射液0.1 ml/d连续28 d,空白对照和模型对照组注射等量的生理盐水。水迷宫实验检测小鼠的学习记忆能力;试剂盒测定血清和脑海马组织超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、单胺氧化酶(MAO)活力及丙二醛(MDA)含量。结果与对照组比较,模型组小鼠学习记忆能力降低,血清和海马组织SOD、GSH-Px活性下降,MDA含量增加MAO活性升高(P<0.05);腹腔注射丹参后小鼠认知记忆能力较模型组明显改善,血清和海马组织SOD、GSH-Px活性明显升高而MDA含量减少(P<0.05),海马中MAO活性降低(P<0.05)。结论丹参注射液可改善D-半乳糖致衰老模型小鼠的学习记忆能力,其作用机制可能与改善血液和脑组织中SOD、GSH-Px活力,降低血液和脑组织中MAO活性、MDA含量有关。     

Investigation of thymol effect on learning and memory impairment induced by intrahippocampal injection of amyloid beta peptide in high fat diet- fed rats

Metabolic Brain Disease - Obesity and consumption of a high fat diet (HFD) are known to increase the risk of Alzheimer’s disease (AD). In the present study, we have examined the protective...     

Protective effect of recombinant alpha interferon on coxsackievirus B3 myocarditis in mice

The effects of recombinant human leukocyte interferon alpha-A/D on experimental myocarditis caused by coxsackievirus B3 were investigated. Four-week-old male C3H/He mice were inoculated intraperitoneally with 10(5.5) 50% tissue culture infective dose (TCD50) in 0.1 ml of coxsackievirus B3 (Nancy strain). Interferon alpha-A/D, 10(4) U/gm/day, was administered subcutaneously daily, starting 1 day before (group 1) or on the day of (group 2) infection. Animals were killed on day 7. The infectivity of myocardial virus was significantly lower in group 1 (0.7 +/- 0.1 log10TCD50/mg, p less than 0.005) and in group 2 (2.5 +/- 1.2 log10TCD50/mg, p less than 0.005) than in control mice (4.4 +/- 0.9 log10TCD50/mg). Results of histologic examination showed extensive myocardial necrosis and cellular infiltration in all mice in the untreated group, but significantly less severe necrosis and infiltration in the treated groups. Thus, interferon alpha-A/D, when given before and simultaneously with virus, effectively inhibited replication of myocardial virus and reduced the inflammatory response and myocardial damage in an experimental model of viral myocarditis.     

重组人硫氧还蛋白对小鼠病毒性心肌炎的保护作用

目的 观察重组人硫氧还蛋白(TRX)对病毒性心肌炎小鼠心肌损伤的保护作用.方法 给予Balb/c小鼠腹腔注射0.1 ml 100TCID50(50%细胞感染率)的柯萨奇B3m病毒(CVB3m),建立病毒性心肌炎模型,同时给予尾静脉注射2 mg/kg的重组人TRX加以保护,对照组给予等量的生理盐水,7 d后处死动物,检测血清乳酸脱氢酶(LDH) 活性,采用光镜观察心肌组织损伤情况.结果 病毒感染组小鼠血清LDH活性[(313030±390.57)U/L)]明显高于对照组[(1617.86±155.42)U/L]和TRX保护组[(1959.43±540.75)U/L],两两比较差异有统计学意义(P<0.05);TBX保护组与对照组比较,差异无统计学意义(P0.05).光镜结果显示,病毒感染组8只小鼠有5只检出心肌病变,小鼠心脏病理切片可见局灶性心肌坏死和炎细胞浸润;而TRX保护组小鼠未出现心肌损伤.结论 重组人TBX可以减轻CVB3m病毒感染导致的心肌损伤,起到心肌保护作用.     

丹参酮对海马内注射β-淀粉样肽后大鼠学习记忆障碍的影响

目的 观察丹参田对β—淀粉样肽1—40片段(Aβ1—40)诱导大鼠学习记忆功能障碍的改善作用。方法 应用凝聚态Aβ1—40在大鼠海马内注射以建立动物模型；采用明暗箱被动回避法、穿梭法测试学习记忆功能；采用HE染色、结晶紫染色和Nissel染色观察病理组织。结果 大鼠双侧海马内注射Aβ1—40(20μg)后，经行为学测试，其学习记忆功能明显障碍；HE染色、Nissel染色发现海马受损区内神经细胞数量明显减少，胶质细胞呈反应性增多；结晶紫染色显示海马内大量淀粉样蛋白沉积。丹参酮(100、50、25mg/kg)连续灌胃14d，处理后分别对上述改变有不同程度的抑制作用，其中尤以50mg／kg剂量组效果最好。结论 丹参酮对Aβ1—40诱导大鼠的学习记忆功能障碍具有显著改善作用。     

甘氨酸对高脂饮食诱导小鼠高脂血症的保护作用

目的研究甘氨酸(Gly)降低高脂血症小鼠血脂的作用。方法将40只小鼠随机分为对照组、高脂组、小剂量和大剂量甘氨酸处理组,在不同处理2周后,取血测定小鼠血酯水平、肝组织丙二醛(MDA)和超氧化物歧化酶(SOD)活性,及观察肝组织病理形态学表现。结果与对照组比,高脂饮食小鼠TC、LDL、HDL-C、MDA含量明显增高(P0.05),SOD活性下降(P0.05);与高脂血症动物比,甘氨酸处理小鼠血TC、LDL明显降低(P0.01),MDA含量下降(P0.05),SOD活性升高(P0.05);高脂血症小鼠肝组织可见弥漫性脂肪变性,而甘氨酸处理动物肝细胞内脂滴小且少。结论甘氨酸可通过调节血脂代谢增强抗氧化能力,从而能防治高脂血症所致的肝脂肪变性。     

海藻糖对异氟烷诱导转APP基因小鼠学习记忆功能的影响

目的探讨吸入麻醉药异氟烷对转APP基因小鼠学习记忆功能的影响及海藻糖的干预保护作用。方法 60只12月龄转APP小鼠随机分为空白对照组(Control组)、异氟烷组(Iso组)、海藻糖组(Iso+Tre组),每组20只。Iso+Tre组和Iso组分别于麻醉前30 min腹腔注射海藻糖400μg/kg或等量生理盐水,然后给予1.4%异氟烷吸入麻醉2 h,麻醉后24 h应用Morris水迷宫测试小鼠学习记忆能力,麻醉后6、24 h杀鼠取脑,采用TUNEL染色观察各组小鼠海马区神经元凋亡,应用ELISA法检测Aβ含量,Western印迹法检测Bcl-2、Bax、Caspase-3的表达变化。结果与Control组相比,Iso组小鼠总体的平均逃避潜伏期明显延长,空间探索时间明显缩短(P0.01),海马神经元凋亡指数、Aβ含量、Bax/Bcl-2比值及Caspase-3表达均明显增加(P0.01);Iso+Tre组与Iso组相比,逃避潜伏期缩短,空间探索时间延长(P0.05),Aβ含量、Bax/Bcl-2比值及Caspase-3表达均明显减少(P0.01)。结论海藻糖能够改善异氟烷诱导转APP基因小鼠学习记忆能力的损害,减少海马神经元的凋亡及Aβ的生成。     

促血小板生成素对小鼠药物性心肌损伤的保护作用

目的研究促血小板生成素（thrombopoietin,TPO）的心肌保护作用。方法小鼠分为对照组、多柔比星组、TPO组。多柔比星组及TPO组小鼠第1天予多柔比星20 mg/kg经腹腔注射;TPO组小鼠予TPO 15μg/kg,共3次经腹腔注射。第1天（多柔比星注射前）和第5天予小鼠做超声心动图检查;第5天取小鼠心肌组织行苏木素伊红染色,显微镜下评价心肌组织损伤程度。比较第1～8天内多柔比星组和TPO组存活率。结果与第0天相比,第5天多柔比星组的心率、每分钟心输出量、左心室短轴缩短率明显下降,差异有统计学意义（P〈0.05）;镜下见小鼠心肌组织明显损伤,说明药物性心肌损伤的模型能成功建立。相对多柔比星组,TPO组心率、每分钟心输出量、左心室短轴缩短率明显改善,差异有统计学意义（P〈0.05）。TPO组镜下评分示心肌损伤显著降低,8 d内的生存率明显高于多柔比星组,差异有统计学意义（P〈0.05）。结论 TPO对损伤心肌有保护作用。     

Dissociation of learning and performance deficits in aged mice

The present study was undertaken to determine whether an age-related learning deficit would occur in a complex visual discrimination task and whether the learning impairment could be separated from performance deficits. The study also sought to determine whether treatment with an inhibitor of protein synthesis, anisomycin, would impair learning in this task. Two age groups (7-10 mo; 27-30 mo) of C56BL/6j mice were given training in a five-choice, simultaneous, visual discrimination task. Errors, freezing, avoidances, and response latencies were recorded. Results revealed that the difference in errors between the two groups disappeared during the middle part of training whereas the difference in the performance measures persisted until the end of training. Anisomycin caused increased errors in the adult but not the old mice. These results indicate that old mice can learn a discrimination task as well as adults but the rate of learning is slower, whereas their physical performance on the task is persistently inferior to adult mice.     

Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits

According to the prevailing "amyloid cascade hypothesis," genetic dementias such as Alzheimer's disease and familial Danish dementia (FDD) are caused by amyloid deposits that trigger tauopathy, neurodegeneration, and behavioral/cognitive alterations. To efficiently reproduce amyloid lesions, murine models of human dementias invariably use transgenic expression systems. However, recent FDD transgenic models showed that Danish amyloidosis does not cause memory defects, suggesting that other mechanisms cause Danish dementia. We studied an animal knock-in model of FDD (FDD(KI/+)) genetically congruous with human cases. FDD(KI/+) mice present reduced Bri2 levels, impaired synaptic plasticity and severe hippocampal memory deficits. These animals show no cerebral lesions that are reputed characteristics of human dementia, such as tangles or amyloid plaques. Bri2(+/-) mice exhibit synaptic and memory deficits similar to FDD(KI/+) mice, and memory loss of FDD(KI/+) mice is prevented by expression of WT BRI2, indicating that Danish dementia is caused by loss of BRI2 function. Together, the data suggest that clinical dementia in Danish patients occurs via a loss of function mechanism and not as a result of amyloidosis and tauopathy.     

Antithrombotic effect of recombinant human thrombomodulin on thrombin-induced thromboembolism in mice

Antithrombotic effect of recombinant human thrombomodulin in mice, both in vitro and in vivo, was studied. The soluble recombinant human thrombomodulin was expressed in Chinese hamster ovary cells and purified from the conditioned medium by a modification of the conventional method. Recombinant thrombomodulin prolonged thrombin clotting time for mouse plasma in a dose-dependent manner. Thrombin was injected into the lateral tail vein of mice and caused acute thromboembolism. All mice injected with thrombin died of thromboembolism; however, preinjection with recombinant human thrombomodulin neutralized the lethal effect of thrombin in a concentration-dependent manner. Histologic examination showed that fibrin deposits were found in all large and small arteries in the lung from mice injected with thrombin; however, fibrin deposits were not detected in any large arteries from the mouse preinjected with thrombomodulin.     

The effect of apolipoprotein E deficiency on islet amyloid deposition in human islet amyloid polypeptide transgenic mice

AIMS/HYPOTHESIS: Islet amyloid deposits are present in over 85% of Type 2 diabetic patients and have been suggested to be pathogenic. The mechanism that converts islet amyloid polypeptide (IAPP), the unique component of these deposits, into amyloid fibrils in vivo is not known. The amino acid sequence of IAPP is critical but insufficient for beta-pleated sheet formation. As apolipoprotein E (apoE), another component of islet amyloid deposits, plays a critical role in amyloid formation in Alzheimer's disease, we hypothesised that apoE could play an important role in islet amyloid formation. METHODS: Transgenic mice expressing the human form of IAPP ( hIAPP (+/0)) were crossbred with apoE deficient ( apoE (-/-)) mice and followed for 12 months, at which time the prevalence and severity of islet amyloid, as well as plasma glucose, hIAPP, immunoreactive insulin (IRI) and lipid concentrations were measured. RESULTS: The prevalence and severity of islet amyloid after one year of follow up were comparable among hIAPP (+/0) mice that were apoE (+/+), apoE (+/-) or apoE (-/-). Differences in glucose tolerance, lipid abnormalities or changes in pancreatic content or plasma concentrations of hIAPP and/or IRI did not account for these findings. CONCLUSION/INTERPRETATION: Our data shows that, unlike in the localized amyloidosis in the brain characteristic of Alzheimer's disease, apoE is not critical for islet amyloid formation in a transgenic mouse model of Type 2 diabetes mellitus. These results indicate that the mechanisms of localised amyloid formation probably vary among different amyloid-associated disorders. Therefore, therapeutic strategies targeting apoE might not apply equally to patients with different amyloid associated diseases.     

刺五加提取液对小鼠学习记忆障碍和淀粉样前体蛋白酶解通路影响及作用机制

目的研究刺五加提取液对衰老模型小鼠学习记忆障碍和淀粉样前体蛋白(APP)酶解通路的影响及作用机制。方法 70只2月龄雄性昆明种小鼠随机分为正常对照、衰老模型、衰老+刺五加低剂量、衰老+刺五加中剂量、衰老+刺五加高剂量、刺五加高剂量、衰老+维生素E组,共7组。连续55 d颈后皮下注射D-半乳糖(200 mg/kg)建立衰老模型,运用Morris水迷宫及行为学测量方法,观察小鼠学习记忆能力。采用酶联免疫吸附实验(ELISA)检测脑组织中α、β、γ-分泌酶、β淀粉样蛋白(Aβ)_(1～42)及可溶性APP(sAPP)α含量;Western印迹法检测脑组织中去整合素-金属蛋白酶(ADAM)10、β-分泌酶(BACE)1、衰老蛋白(PS)1、糖原合成酶激酶(GSK)-3β、磷酸化(Phospho)-GSK-3β(Ser9)表达水平。结果行为学显示,随着刺五加提取液浓度的提高,小鼠的学习记忆能力得到一定的巩固和强化,衰老小鼠的记忆障碍得到了一定改善。生化学显示,与衰老组比较,刺五加提取液可以增强α-分泌酶活性,抑制β、γ-分泌酶的活性,增加组织内的sAPPα含量及有效抑制Aβ_(1～42)产生。Western印迹法检测显示,与正常对照组比较,衰老模型组GSK-3β、BACE1蛋白表达水平上调;ADAM10、Phospho-GSK-3β(Ser9)蛋白表达水平下降;与衰老模型组比较,刺五加组ADAM10、Phospho-GSK-3β(Ser9)蛋白表达水平明显升高,GSK-3β、BACE1、PS1蛋白表达水平明显降低(均P0.05)。结论刺五加通过增加α-分泌酶活性,抑制β、γ-分泌酶活性,增加sAPPα生成,减少Aβ_(1～42)产生,降低BACE1蛋白表达水平,可能对APP酶解通路起到一定作用,改善小鼠学习记忆障碍,对阿尔茨海默病的发病及进展有一定预防保护作用。     

Immune hyporesponsiveness to amyloid beta-peptide in amyloid precursor protein transgenic mice: implications for the pathogenesis and treatment of Alzheimer's disease

Alzheimer's disease is a dementia that involves progressive deposition of amyloid beta-protein (Abeta) in brain regions important for memory and cognition, followed by secondary inflammation that contributes to the neuropathologic process. Immunization with Abeta can reduce cerebral Abeta burden and consequent neuropathologic changes in the brains of mice transgenic for the beta-amyloid precursor protein (APP). We found that transgenic expression of human APP in B6SJL mice, under the prion promoter, results in immune hyporesponsiveness to human Abeta, in terms of both antibody and cellular immune responses. The decreased antibody responses were related not to B cell tolerance but rather to the inability of Abeta-specific T cells to provide help for antibody production. The immune hyporesponsiveness could be overcome if T cell help was provided by coupling an Abeta B cell epitope to BSA. Our results suggest that expression of APP in transgenic mice is associated with an Abeta-specific impaired adaptive immune response that may contribute to the neuropathology. Moreover, humans with life-long elevation of brain and peripheral Abeta (e.g., patients with presenilin mutations or Down syndrome) could have reduced immune responses to Abeta vaccination.     

杜仲粕对D-半乳糖致衰老小鼠学习记忆能力的影响

目的 研究杜仲粕对D-半乳糖致衰老小鼠学习记忆能力的影响及其作用机制.方法 小鼠随机分为三组:空白对照组,衰老模型组(350 mg· kg-1·d-1),杜仲粕实验组(300mg·kg-1 ·d-1).除空白对照组外,其余各组小鼠每天按照350 mg/kg剂量颈部皮下注射D-半乳糖,空白对照组注射同等容量生理盐水,1次/d,连续6w.检测衰老小鼠学习记忆能力,测定小鼠肝组织、脑组织中单胺氧化酶(MAO)活性和谷胱苷肽过氧化物酶(GSH-Px)活力.结果 杜仲粕实验组潜伏期明显缩短,穿越原平台的次数明显增加;杜仲粕实验组肝组织、脑组织中MAO活性降低,GSH-Px活力增强.结论 杜仲粕能明显改善D-半乳糖致衰老小鼠学习记忆能力,其机制可能与降低MAO活性,增强GSH-Px活力有关.     

硒酸精氨酸对D-半乳糖诱导的衰老小鼠肝损伤的保护作用

目的 探讨硒酸精氨酸对D-半乳糖(D-gal)衰老小鼠肝功能的影响.方法 40只昆明种小鼠随机分成4组:正常对照组、衰老模型组、低硒组和高硒组.通过后颈背部皮下注射D-gal建立亚急性衰老模型,以灌胃方式加入硒酸精氨酸,连续处理6 w后检测各组小鼠血清中谷丙转氨酶(ALT),谷草转氨酶(AST)活性和碱性磷酸酶(AKP)活性,并对肝脏切片做HE染色,光镜下观察肝组织病理学变化.结果 硒酸精氨酸能显著降低AST、ALT和AKP活性(P＜0.01),明显减轻D-gal对小鼠肝细胞的毒性.结论 硒酸精氨酸对D-gal所致衰老小鼠的肝功能具有明显的保护作用,这种保护效应可能与硒酸精氨酸提高抗氧化酶活性,增强抗氧化防御机制有关.