氧化应激中ROS对FOXO3a转录因子的调控作用研究进展

活性氧(reactive oxygen species,ROS)介导的氧化应激参与多种细胞信号转导过程,FOXO3a转录因子是氧化应激中多个信号通路的交汇点,ROS对FOXO3a存在着复杂的调控作用。由于FOXO3a在细胞增殖、细胞周期阻滞、ROS清除和诱导细胞凋亡中发挥复杂而重要的作用,已经成为氧化应激损伤的研究热点之一。该文对氧化应激损伤中FOXO3a的活性调节机制及其靶基因进行了综述,为FOXO3a靶向调控氧化应激和临床治疗相关疾病开辟了新的思路。     

白杨素通过SIRT1/AMPK信号通路缓解乙醇诱导的酒精性肝损伤

酒精性肝病(alcoholic liver disease,ALD)是长期饮酒引起的肝脏损害,是进展期肝脏疾病非常重要的原因之一。ALD疾病谱酒精性脂肪肝的发病率也逐渐增高,若得不到有效治疗可导致酒精性肝炎、酒精性肝纤维化、肝硬化,对患者身体健康有着严重影响[1]。因此,探明ALD的发病机制,以期为探索有效的ALD治疗靶点提供坚实的理论依据尤为重要。白杨素(chrysin,CHR)是广泛存在于蜂蜜、蔬菜、水果中的天然黄酮类化合物,具有抗氧化、抗炎、抗癌的活性[2]。该研究采用小鼠Lieber-DeCarli酒精液体饲料联合单剂酒精灌胃模型,探讨白杨素对酒精性肝损伤中SIRT1/AMPK信号通路的调控作用。     

酒精性肝病动物模型的研究进展

酒精性肝病（alcohol liver disease,ALD）的发病机制较为复杂,目前尚不清楚,可能与酒精及其代谢产物对肝脏的毒性作用、氧化应激、内毒素、免疫异常等多种因素有关。为了深入研究酒精性肝病的发病机制和筛选防治酒精性肝病的药物,酒精性肝病动物模型的选择至关重要,本文就酒精性肝病动物模型的研究现状作一简要综述。     

C-藻蓝蛋白对肝脏损伤的保护作用及机制研究进展

C-藻蓝蛋白（C-PC）是一种来自海洋藻类的含色素蛋白质，在多种炎性疾病和肿瘤治疗中表现出良好的效果。其对药物或毒性物质引起的肝损害、非酒精性脂肪性肝病、肝纤维化和肝脏缺血再灌注损伤等多种肝病具有保护作用。C-PC对肝损伤的保护作用主要是通过调节核因子（NF）-κB、磷脂酰肌醇3激酶/蛋白激酶B(PI3K/Akt)和AMP依赖的蛋白激酶（AMPK）等信号通路及抑制氧化应激等机制实现的，且对正常细胞没有毒性。因此，C-PC作为一种潜在的天然保肝海洋活性物质具有广阔的应用前景。就近年来C-PC对肝脏损伤的保护作用及机制的研究进展进行综述。     

丹皮酚通过调控JAK2/STAT3信号通路改善酒精性肝损伤小鼠肝脏炎症与氧化应激损伤

目的 探讨丹皮酚基于JAK2/STAT3信号通路改善急性酒精刺激所致小鼠肝脏炎症和氧化应激损伤的作用机制。方法 C57BL/6小鼠随机分为对照组、模型组、水飞蓟宾组(36.8 mg·kg^-1)、丹皮酚低、中、高(120、240、480 mg·kg^-1)剂量组,造模组小鼠自由饮用Lieber-DeCarli酒精液体饲料,造模第二日起灌胃给药,连续10 d。测定小鼠血脂、肝功能、炎症因子以及氧化应激水平;利用HE、油红O染色观察各组小鼠肝脏病理形态变化,Western blot及免疫组化法检测丹皮酚对小鼠肝组织JAK2/STAT3信号通路相关蛋白表达水平的影响。结果 与模型组相比,中、高剂量丹皮酚明显降低酒精诱导的肝损伤小鼠的血脂、肝功能、氧化应激水平,降低IL-6、IL-1β、TNF-α表达,且明显改善肝脏的病理状态。中、高剂量丹皮酚组小鼠肝脏组织p-JAK2、p-STAT3蛋白表达水平降低,SOCS3蛋白表达水平升高。结论 丹皮酚可明显减轻酒精性肝损伤小鼠肝脏炎症和氧化应激损伤,其机制可能是通过调控JAK2/STAT3信号通路实现的。     

氧化应激与2型糖尿病的研究现状与反思

2004年美国糖尿病学会(American Diabetes Association ADA)年会提出了糖尿病及其慢性并发症都是同一发病机制.即高糖损伤的共同基础——氧化应激[1].胰岛B细胞暴露在持续高血糖环境下,刺激信号转导通路产生了过量的活性氧(reactive oxygen species,ROS).导致B细胞功能障碍和凋亡[2].近年来,氧化应激成为研究的新热点与方向.     

丹酚酸B通过介导SIRT3/FOXO1信号通路减轻非酒精性脂肪肝的氧化应激反应（英文）

丹酚酸B (Salvianolic acid B, Sal B)是一种多酚类抗氧化剂,已被证明在多种疾病中具有抗脂质积累、抗炎和清除氧自由基的活性。我们旨在研究Sal B是否可以改善非酒精性脂肪性肝病(Non-alcoholic fatty liver disease, NAFLD)的疾病进展并探索其可能的机制。通过油酸诱导Hep G2细胞建立NAFLD模型组细胞,SalB干预模型细胞建立治疗组细胞,进行生化分析及油红O染色检测各组细胞内脂质含量,通过免疫荧光及流式细胞仪检测细胞内活性氧(reactiveoxygen species, ROS)含量;试剂盒及酶标仪定量细胞内脂氧化物丙二醛(Malonydialdehyde, MDA)的含量;通过蛋白质印迹分析、RT-q PCR和免疫沉淀(Immunoprecipitation, IP)检测参与氧化应激的信号通路蛋白,包括SIRT3、SOD2和FOXO1通路蛋白。研究发现,油酸(Oleicacid,OA)可以诱导细胞内脂质、过氧化物及脂氧化物的积累,降低SIRT3的表达,并促进FOXO1乙酰化。然而Sal B治疗后显著扭转了这些趋势。进一...     

扇贝多肽对UVB辐射小鼠胸腺淋巴细胞PI3K/Akt和ASK1-JNK信号通路的影响

目的 研究扇贝多肽(polypeptide from Chlamys farreri,PCF)对紫外线B(UVB)辐射损伤小鼠胸腺淋巴细胞后P13K/Akt和ASK1-JNK信号通路的影响.方法 UVB辐射小鼠胸腺淋巴细胞,用比色法测定胸腺淋巴细胞活性氧(reactive oxygen species,ROS)水平;western-blot检测Akt的活性,预先加入或不加入P13K/Akt通路特异性抑制剂LY294002检测细胞凋亡信号调节激酶Ⅰ(apoptosis signal regulating kinase-1,ASK1)、JNK的活性、线粒体膜电位(ACM)和DNA ladder.结果 PCF能激活AKT的活性,抑制UVB对小鼠胸腺淋巴细胞ASK1凋亡通路的活化.结论 PCF通过降低细胞内活性氧的含量,提高AKT的活性,引起ASK1的降解,导致ASK1-JNK诱导的细胞凋亡抑制.     

酒精性脂肪肝脂质代谢研究进展

酒精性脂肪肝(AFL)是长期大量饮用酒精引发的肝脏损害性病变,可逆转也可进一步发展为肝纤维化和肝硬化。众多的脂肪细胞因子如瘦素(Leptin)、抵抗素(Resistin)和肿瘤坏死因子-α(TNF-α)在脂肪肝的发病中起到一定的促进作用,脂联素(Adiponectin)能改善脂质代谢,延缓脂肪肝的发生;脂联素通过腺苷酸活化蛋白激酶(AMPK)调节糖脂代谢、改善胰岛素敏感性。脂联素/AMPK信号通路是酒精在肝脏的作用靶点、也是调节PPARγ作用的重要信号通路;脂肪分化相关蛋白(ADRP)调节脂质代谢、促进酒精性脂肪肝的形成;过氧化物酶增殖体激活受体γ(PPARγ)参与机体脂质稳态的调节,脂肪肝时PPARγ表达增高,肝纤维化时PPARγ表达减少。对酒精性脂肪肝脂质代谢的深入研究,有助于阐明酒精性脂肪肝发病机制并为临床防治ALD及脂质代谢相关疾病提供新策略。     

内质网应激在酒精诱导的中枢神经毒性中的作用

目的综述内质网应激(endoplasmic reticulum stress,ERS)在酒精诱导的中枢神经毒性中的作用。方法通过查阅相关文献对其进行归纳总结。从ERS诱导细胞凋亡的通路、酒精诱导ERS的机制、ERS在酒精所致脑损伤中与细胞凋亡、自噬和炎症反应的关系等几个方面进行介绍。结果系统总结了ERS诱导细胞凋亡的通路;酒精诱导ERS的作用机制与乙醛加合物的存在、钙离子的稳态和氧化应激等有关;酒精诱导ERS后可引起细胞凋亡、自噬和炎症反应。结论 ERS在酒精诱导中枢神经毒性中发挥重要作用。     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

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.     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

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.     

Interindividual variability in metabolic activation in humans in vivo

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.     

Theophylline kinetics in peripheral tissues in vivo in humans

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 (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-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 - t_max Time to peak concentration - c_max Peak concentration     

休克时血中氧自由基的变化

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。     

Changes in angiopoietin expression in glomeruli involved in glomerulosclerosis in rats with daunorubicin-induced nephrosis

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.     

Trichinellosis in immigrants in Switzerland

We describe a case of trichinellosis diagnosed at the Division of Infectious Diseases, Hospital of Lugano, in January 2009. This case was associated with a cluster of cases and was traced to the consumption of contaminated meat after a wild boar hunt in Bosnia.