Inhibitors of COX activity preserve muscle mass in mice bearing the Lewis lung carcinoma, but not the B16 melanoma

Tumor-induced skeletal muscle wasting (SMW) contributes to the fatigue and weakness experienced by persons with cancer cachexia. Tumor necrosis factor-alpha (TNFa) and cyclooxygenase (COX) activity have been implicated in SMW in some animal models of cancer cachexia. We report that indomethacin, a nonspecific inhibitor of COX, and NS398, a specific inhibitor of COX2, preserved muscle mass and reduced type 1 TNF receptors in muscles of mice bearing the Lewis lung carcinoma, but not in mice bearing the B16 melanoma. These data suggest that tumor-induced SMW can occur via a COX2-independent pathway. The COX2-dependent pathway may involve reducing the catabolic effects of TNFa in muscle. Further study is needed to understand the relationship between COX and SMW, and whether patients with cancer cachexia might benefit from COX inhibitors.     

高功率微波辐射对小鼠心肌氧化应激及ATPase的影响

目的观察高功率微波辐射(high power microwave radiation,HPM)对小鼠心肌氧化应激及ATPase活性的影响。方法雄性ICR小鼠32只,随机分为4组(n=8):假照组、微波辐射10 min组、微波辐射20 min组、微波辐射30 min组。采用S波段,平均表面功率为10 mW/cm2微波;照射时间分别为0,10,20,30 min/次,每周2次,共2周。末次辐射完毕,立即处死小鼠,取心脏、冰冷生理盐水冲洗后,加入匀浆液制作匀浆。采用试剂盒测定超氧化物歧化酶(SOD)活性、谷胱甘肽过氧化物酶(GSH-px)活性、总抗氧化能力(T-AOC)、谷胱甘肽(GSH)及丙二醛(MDA)的含量以及Na+K+-ATPase和Ca2+Mg2+-AT-Pase活性。结果微波辐射后,与假照组比,微波辐射20 min组和微波辐射30 min组SOD活性降低(P<0.05)、GSH-px活性增加(P<0.05);而微波辐射20 min组GSH含量明显增加(P<0.01);微波辐射30 min组Ca2+Mg2+-ATPase活性明显降低(P<0.01),其他指标变化无明显统计学差异。结论微波辐射可能引起小鼠心脏氧化应激平衡状态以及Ca2+转运的改变。     

热应激复合敌敌畏中毒对小鼠全血乙酰胆碱脂酶和组织抗氧化能力的影响

目的研究热应激复合有机磷敌敌畏（O,O-dimethyl-O-2,2-dichlorovinylphosphate,DDVP）中毒对小鼠全血乙酰胆碱酯酶活性及组织脂质过氧化的影响。方法将54只小鼠随机分为对照组、热应激组和热应激复合DDVP中毒组。实验舱相对湿度控制在（60±5）%,对照组小鼠置于24℃环境下1 h,热应激组小鼠置于38或40℃的热环境下1 h。有机磷中毒组小鼠经腹腔注射给予9或15 mg/kg DDVP,对照组给予等量生理盐水。30 min后,取全血测量乙酰胆碱酯酶（AChE）活性,取心、脑和肝组织匀浆,测量其超氧化物歧化酶（SOD）活性、丙二醛（MDA）含量和羟自由基（.OH）抑制能力。实验期间观察小鼠一般情况,记录实验前后小鼠体质量。结果热环境（38或40℃）暴露使小鼠烦躁不安,活动量明显增加,摄水量降低,体质量减轻。与不同环境温度暴露的对照组相比,热应激复合DDVP中毒组小鼠全血AChE活性和心、脑和肝组织SOD活性和羟自由基抑制能力均明显下降（P〈0.05）,而MDA含量明显升高（P〈0.05）。热应激和DDVP中毒对上述指标的影响有交互作用。结论在本实验条件下,热应激和DDVP中毒对小鼠乙酰胆碱酯酶有显著的抑制作用,同时可引起组织脂质过氧化增强,提示氧化应激机制与高热复合DDVP中毒的加重效应有关。     

瑞士球训练为中心的组合力量训练与传统阻力训练对人体平衡能力作用的比较

目的:比较以瑞士球训练为中心的组合力量训练与传统阻力训练对人体平衡能力的影响。方法:选取30名普通女大学生,随机分为实验组和对照组,每组15人。实验共进行10周,每周3次,每次60分钟。实验组进行以瑞士球、平衡盘、悬吊等为中心的组合力量训练,对照组进行以杠铃、哑铃、组合力量训练器为主的传统阻力训练。实验前后,运用BIODEX动态平衡系统分别测试并分析两组受试者睁眼和闭眼状态下的动态平衡能力,测试难度系数8级。结果:10周训练结束后,两组受试者睁眼和闭眼状态下的动态测试总体稳定指数(OSI)、前后方向稳定指数(API)和左右方向稳定指数(RLI)较实验前均发生不同程度的变化。与训练前相比,实验组受试者睁眼和闭眼状态下双脚OSI、API、RLI显著降低(P<0.05),降低幅度分别为45.2%、48.2%、53.1%和65.8%、73.9%、58.5%;对照组实验后睁眼和闭眼状态下OSI、API、RLI较实验前也有所变化,降低幅度分别为27.0%、-5.6%、0%和2.3%、2.0%、-6.6%,但无统计学意义(P>0.05)。两组受试者实验后三项指标组间比较差异显著(P<0.05)。实验后实验组受试者睁眼和闭眼状态下OSI、API、RLI三项指标分别为0.57±0.26、0.44±0.26、0.30±0.16和0.94±0.75、0.72±0.62、0.59±0.41;对照组分别为0.89±0.2、0.75±0.29、0.77±0.56和2.09±1.32、1.93±1.53、1.29±0.66,睁眼和闭眼状态下三项指标比较差异显著(P<0.05)。结论:相对于传统力量训练方法,以瑞士球训练为中心的组合力量训练对于增强人体平衡能力、提高不稳定状态下的姿态保持具有显著作用。     

Tissue factor haploinsufficiency during endotoxin induced coagulation and inflammation in mice.

Intervention studies blocking tissue factor (TF) driven coagulation show beneficial effects on survival in endotoxemia models by reducing cytokine production. It is unknown, however, if moderately reduced TF levels influence endotoxemia. The objective was to investigate whether TF haploinsufficiency reduces endotoxin-induced cytokine production in murine cells or in mice. We analyzed the intrinsic capacity of heterozygous TF deficient (TF+/-) leukocytes to produce cytokines. In addition, we determined the consequences of TF haploinsufficiency on endotoxin-induced inflammation during murine endotoxemia. Endotoxin induced the production of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and keratinocyte-derived chemokine (KC) in both whole blood and macrophages. Heterozygous TF deficiency reduced endotoxin induced IL-6 and KC levels about two-fold, while TNF-alpha levels were indistinguishable between TF+/- and wild-type cells. In vivo, endotoxin induced a biphasic coagulant response and significant increases in cytokine levels. Surprisingly, both the inflammatory and the coagulant responses were indistinguishable between wild-type and TF+/- mice. At baseline tissues of TF+/- mice showed a 50% reduction in TF activity compared to wild type. Upon endotoxin administration, TF activity increased and the difference between TF+/- and wild-type mice disappeared after 4 h. After 12 h the baseline difference in TF activity was re-established. TF deficiency reduces cytokine production in vitro, but an enhanced induction of TF during murine endotoxemia eliminates this effect in vivo.     

Effects of 4-Methylpyrazole on Ethanol Neurobehavioral Toxicity in CD-1 Mice

OBJECTIVES: 4-Methylpyrazole (4-MP), an alcohol dehydrogenase (ADH) antagonist, is used for the treatment of ethylene glycol and methanol ingestions. However, ethanol is frequently co-ingested by those who ingest these more toxic alcohols. Several in vitro and in vivo studies have shown a decrease in the elimination rate of ethanol after the administration of 4-MP, but none has evaluated the effects of 4-MP administration on the neurobehavioral toxicity of ethanol. This was a study to determine whether ADH blockade with 4-MP prolongs ethanol neurobehavioral toxicity in a murine model. METHODS: D-1 mice were pretreated with 4-MP, with observation of its effect on ethanol dose-response curves. 4-MP (25 mg/kg) or an equal volume of saline was administered intraperitoneally. Ten minutes later, incremental ethanol doses of 1-5 g/kg were administered intraperitoneally. Pretreated and control groups were composed of ten mice each for each dose of ethanol tested. Outcomes for assessing ethanol neurobehavioral toxicity were successful performance on the rotarod test and presence of the righting reflex, two established and validated outcome measures for ethanol-induced neurobehavioral toxicity in mice. RESULTS: The dose of ethanol at which 50% of the animals failed a particular outcome test (toxic dose 50 [TD(50)]) was decreased with 4-MP administration for both the rotarod test and the righting reflex. The TD(50) intergroup differences (control vs. 4-MP) were statistically significant at 60, 120, and 180 minutes (p < 0.05). CONCLUSIONS: Pretreatment with 4-MP significantly prolonged ethanol neurobehavioral toxicity in CD-1 mice, presumably by inhibiting its metabolism by ADH. Further investigation is warranted to evaluate this interaction.     

Neonatal tumor necrosis factor alpha promotes diabetes in nonobese diabetic mice by CD154-independent antigen presentation to CD8(+) T cells

Neonatal islet-specific expression of tumor necrosis factor (TNF)-alpha in nonobese diabetic mice promotes diabetes by provoking islet-infiltrating antigen-presenting cells to present islet peptides to autoreactive T cells. Here we show that TNF-alpha promotes autoaggression of both effector CD4(+) and CD8(+) T cells. Whereas CD8(+) T cells are critical for diabetes progression, CD4(+) T cells play a lesser role. TNF-alpha-mediated diabetes development was not dependent on CD154-CD40 signals or activated CD4(+) T cells. Instead, it appears that TNF-alpha can promote cross-presentation of islet antigen to CD8(+) T cells using a unique CD40-CD154-independent pathway. These data provide new insights into the mechanisms by which inflammatory stimuli can bypass CD154-CD40 immune regulatory signals and cause activation of autoreactive T cells.     

黄蜀葵花黄酮成分F-6对四氯化碳致小鼠急性肝损伤的保护作用

目的观察黄蜀葵花黄酮成分F-6对四氯化碳致小鼠急性肝损伤的保护作用。方法实验分为6组:空白对照组、四氯化碳模型组、联苯双酯阳性对照组、F-6低、中、高剂量组。连续给药7 d后,用四氯化碳制备小鼠急性肝损伤模型。测定各组小鼠血清中谷丙转氨酶、谷草转氨酶活性,测定肝组织匀浆中丙二醛含量、超氧化物歧化酶活性;HE染色观察肝组织病理形态学的改变。结果 F-6能显著降低四氯化碳所致肝损伤小鼠血清中谷丙转氨酶、谷草转氨酶活性及肝组织中丙二醛含量,提高超氧化物歧化酶活性;F-6能减轻四氯化碳引起小鼠肝、脾肿大程度;F-6治疗组小鼠肝组织受损程度显著减轻。结论 F-6对四氯化碳所致的小鼠急性肝损伤具有保护作用,其保肝降酶作用显著,其机制可能与清除自由基、抑制脂质过氧化反应有关。     

PKH26标记单核细胞衍生的肝样细胞体内示踪研究

目的 探讨人外周血单核细胞向肝样细胞潜能及单核细胞衍生的肝样细胞移植的有效示踪剂,并进一步观察受体鼠移植后肝样细胞存活、分布与转归情况.方法 分别设立A、B两组.A组为阴性对照组,在细胞培养过程中不添加诱导细胞分化肝细胞生长因子(HGF)和成纤维细胞生长因子-4 (FGF-4);B组应用HGF和FGF-4体外联合诱导人外周血单核细胞向肝干细胞分化.鉴定和判断细胞分化的变化,采用免疫荧光细胞化学染色法检测细胞甲胎蛋白(alpha fetoprotein,AFP)和细胞角蛋白19(cytokeratin 19,CK19)表达.以红色荧光染料PKH26标记单核细胞衍生的肝样细胞,尾静脉注入受体鼠体内作为实验组.对照组注射等量生理盐水.分别于移植2周后取肝组织,通过荧光显微镜观察实验组肝样细胞向肝脏迁移与转归的情况.采用免疫荧光细胞化学染色法检测移植的肝样细胞白蛋白(albumin,ALB)的表达.结果 A组细胞随培养时间延长,单核细胞由刚分离出的较均一的圆形逐渐变得不规则,呈条索状、纤维样改变,少部分细胞呈圆形,细胞发生凋亡,裂解.B组细胞随诱导分化培养时间延长,细胞变大、变圆,呈集落生长,增殖活性强.B组有AFP和CK19阳性表达,而A组则没有表达.动物实验组受体鼠肝组织冰冻切片可见大量PKH26标记阳性的肝样细胞,对照组未发现PKH26标记阳性的肝样细胞.移植2周后行免疫荧光细胞化学染色法检测实验组肝样细胞ALB表达阳性.结论 在HGF和FGF-4体外联合诱导条件下,人外周血单核细胞具有向肝样细胞分化的潜能.并且,PKH26可作为肝样细胞移植的一种有效示踪剂.移居肝组织的肝样细胞2周后开始向成熟肝细胞分化,发挥肝细胞功能,表达白蛋白.     

PS-341对小鼠重症急性胰腺炎核因子-κB活化的影响

目的观察PS-341对重症急性胰腺炎(SAP)小鼠胰腺组织核因子-κB(NF-κB)活化的影响,阐明PS-341对SAP的作用机制。方法采用连续7次腹内注射雨蛙素(每次间隔1h)及脂多糖制作小鼠SAP模型,将60只ICR雌性小鼠随机分为PS-341治疗组(注射脂多糖前0.5h腹内注射0.5mg/kgPS-341),模型对照组(注射脂多糖前0.5h腹内注射50%DMSO),空白对照组(生理盐水制模)。最后一次注射雨蛙素后2h麻醉小鼠,取血检测血淀粉酶,光镜下观察小鼠胰腺和肺脏的病理形态,测定胰腺组织中髓过氧化物酶水平,实时荧光定量PCR测定胰腺组织中黏附分子(ICAM-1)的含量,免疫印迹法(Westernblotting)检测胰腺组织中IκBα的表达,电泳迁移率实验(EMSA)测定NF-κB活性。结果 PS-341治疗组和模型对照组比较,胰腺组织中I-κB降解减少,NF-κB活性显著下降,血清淀粉酶、MPO、胰腺组织中细胞黏附分子ICAM-1的表达都明显降低(P<0.05)。胰腺和肺脏组织病理学有明显的改善(P<0.05)。结论 PS-341通过抑制胰腺内NF-κB活化而抑制炎症反应。PS-341可能是治疗SAP的一个新措施。