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绿茶多酚和桑色素对低密度脂蛋白氧化修饰的抑制作用(英文) 总被引:9,自引:0,他引:9
许多研究报告表明,低密度脂蛋白(LDL)可经多种途径被氧化修饰成ο-LDL,巨噬细胞对ο-LDL的降解速率较LDL快3~10倍,动脉粥样硬化损伤部位的泡沫细胞是由巨噬细胞聚集了大量的胆固醇而形成的,LDL的氧化修饰以及由此导致的巨噬细胞吞噬的增加,对泡沫细胞的形成起到重要作用,本项研究采用紫外线照射和Cu~(2+)-PBS系统分别对LDL进行氧化修饰并且观察了绿茶多酚(10μg·ml~(-1))和黄酮类化合物桑色素(8.5μg·ml~(-1))对这一化学过程的抑制作用,其结果表明,两者均对LDL的氧化修饰具有显著抑制作用,主要实验证据为,它们可使琼脂糖电泳迁移率,硫代巴比妥酸反应物和激发光为360 nm,发射光为420 nm时的荧光强度等的增加量抑制50%左右并使小鼠腹腔巨噬细胞降解o-LDL的速率抑制70%,绿茶多酚和桑色素分别存在于绿茶和蔬菜中,因此它们防止LDL的氧化修饰对于动脉粥样硬化的预防和治疗具有一定的临床意义。 相似文献
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云芝多糖对脑、肝组织的抗氧化作用研究 总被引:16,自引:0,他引:16
目的 探讨中药云芝多糖对脑、肝组织抗氧化作用的影响及机制。方法 以SD大鼠和昆明小鼠为动物模型 ,采用Fe H2 O2 诱导大脑皮层组织和肝组织匀浆的脂氢过氧化反应及黄嘌呤氧化酶体系释放自由基超氧阴离子 (O·2 ) ,以改良的邻苯三酚自氧化法、DNTB直接法测定脑组织抗氧化酶活性及原位杂交法检测脑组织硒谷胱甘肽过氧化物酶 (SeG Px)mRNA表达。结果 云芝多糖有提高脑组织超氧化物歧化酶 (SOD)、SeGPx和非硒谷胱甘肽过氧化物酶 (non SeGPx)抗氧化酶活性 ,增加SeGPxmRNA表达 ,降低脑、肝组织Fe H2 O2 引发的脂氢过氧化反应和黄嘌呤氧化酶体系产生的O·2 。结论 云芝多糖可提高鼠大脑皮层、肝组织的抗氧化作用 ,对开发应用多糖类药物防治神经系统疾病、延缓衰老提供实验依据 相似文献
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刘乃丰 《Acta pharmacologica Sinica》1994,(2)
本文用放射配体法观察了维拉帕米(Ver)对恒河猴肾上皮细胞LDL受体活性的影响,发现Ver以浓度和时间依赖的方式明显增强受体介导的结合和内移过程,对降解的影响不显著。Ver作用浓度为44 mmol·L~(-1)效应最明显。 相似文献
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目的 观察地拉卓(血管扩张及抗血小板药)对人类单核细胞株(THP-1)源性巨噬细胞摄取乙酰化低密度脂蛋白(Ac-LDL)的影响.方法 以不加入地拉卓为对照组,以分别加入50、100μmol·L-1地拉卓为实验组;用细胞摄取Ac-LDL及Northern印迹方法,观察地拉卓对THP-1源性巨噬细胞受体摄取Ac-LDL以及对巨噬细胞清道夫受体-A mRNA表达的影响.结果 与对照组比较,巨噬细胞对Ac-LDL结合量和降解量随地拉卓浓度的增加而被明显抑制(均P<0.01);巨噬细胞ScR-A mRNA表达随地拉卓浓度的增加而减弱.结论 地拉卓抑制THP-1源性巨噬细胞对Ac-LDL结合和降解的作用是通过抑制ScR-A mRNA的表达来实现,其对动脉粥样硬化形成早期可能具有抑制作用. 相似文献
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低密度脂蛋白及其作为新型药物载体的研究进展 总被引:1,自引:0,他引:1
低密度脂蛋白(Low Density Lipoprotein, LDL)是一类血浆脂蛋白,携带人体血液中三分之二以上的胆固醇。LDL系经持异性LDL受体途径被细胞膜上受体识别、入胞和利用。细胞膜上LDL受体的活性和数量受细胞自身条件和对胆固醇需求的差异表现有很大差别。国外研究显示,LDL可携带同位素(如:~(99m)锝)经体循环后,分布到动脉粥样硬化的斑块、肾上腺骨质增生及癌变部位等;同时,LDL作为治疗药物载体可使携带药物靶向到癌细胞;或在体内增加药物的清除半衰期。本文旨在综述国外对LDL及其作为药物载体的近期研究进展 相似文献
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目的研究炎症介质-脂多糖(LPS)诱导的炎症应激是否通过扰乱固醇调节元件结合蛋白裂解激活蛋白-固醇调节元件结合蛋白2(SCAP-SREBP2)复合物介导的低密度脂蛋白受体(LDLr)负反馈调控,增加THP-1巨噬细胞对非修饰低密度脂蛋白胆固醇(LDL)摄取,导致泡沫细胞形成。方法诱导分化成功的THP-1巨噬细胞在无血清培养基中培养4 h后,分为对照组(继续无血清培养),高脂组(加入LDL负荷,终浓度为25 mg·L-1),高脂加炎症刺激组(加入LDL负荷,终浓度为25 mg·L-1,同时加入炎症介质LPS,终浓度200μg·L-1),单纯炎症刺激组(加入炎症介质LPS,终浓度200μg·L-1),以上各组细胞培养24 h后收获。ELISA法检测细胞培养基中TNF-α浓度,酶化学法检测细胞内胆固醇浓度,琼脂糖电泳检测LDL氧化程度,Real time PCR法检测LDLr、SREBP2和SCAP mRNA表达水平,Western blot法检测LDLr、SREBP2和SCAP蛋白表达,激光共聚焦检测SCAP在内质网与高尔基体间的转位情况。结果细胞内胆固醇测定发现,炎症介质LPS通过增加THP-1巨噬细胞对非修饰LDL摄取,导致巨噬细胞转变为泡沫细胞。在无炎症介质LPS时,25 mg·L-1LDL减少LDLr mRNA和蛋白表达(P<0.05)。然而,LPS增加LDLr mRNA和蛋白表达,逆转25 mg·L-1LDL对LDLr的抑制效应,不恰当的增加了巨噬细胞对LDL摄取(P<0.05),LPS刺激也导致了SCAP和SREBP2的mRNA和蛋白过表达(P<0.05),同时促进了SCAP从内质网转移到高尔基体。这些结果提示LPS干扰了胆固醇介导的LDLr负反馈调控,使非修饰LDL在巨噬细胞内堆积,导致泡沫细胞形成。结论本研究提示,在LPS诱导的炎症应激状态条件下,天然LDL可以通过LDLr被巨噬细胞大量摄取入细胞内,导致泡沫细胞形成,这可能是巨噬细胞泡沫化的另一条通路。 相似文献
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云芝多糖是从担子菌杂色云芝培养物中提出的多糖。胞内多糖(IPPV)是从云芝深层培养菌丝体细胞内提出的一种匍聚糖,小鼠口服或腹腔注射,可显著保护流感病毒静脉感染所致死亡和肝脏病理损伤,口服最小有效量500mg/kg一次或每日一次 3日都有效;腹腔注射50~200mg/kg一次有效,多次给药无效。腹腔注射100mg/kg一次,对小鼠疤疹病毒静脉注射所致死亡和肝病变有23.8~28.6%的保护作用,但无统计学意义。胞内多糖腹腔注射50mg/kg一次,可促进小鼠肝Kupfer细胞吞噬功能,防止静脉注射流感和疱疹病毒所引起的Kupfer细胞吞噬功能抑制。胞内多糖和自云芝深层培养液提出的胞外多糖(EPPV)腹腔注射小鼠,可诱生血清干扰素,胞外多糖诱生干扰素滴度高于胞内多糖。进一步工作有可能提高云芝多糖的疗效。 相似文献
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目的 建立酵母多糖诱导小鼠流产的模型并初步探讨巨噬细胞表型及功能的变化.方法 利用腹腔注射酵母多糖建立小鼠模型.采用流式细胞术及ELISA检测巨噬细胞表型及细胞因子和共刺激分子的表达.结果 通过腹腔静脉注射酵母多糖250 μg/g是理想的小鼠流产建模剂量.在体内试验中,酵母多糖组子宫替代活化的巨噬细胞(M2)比例明显低于对照组,差异有统计学意义(P<0.05),对经典活化的巨噬细胞(M1)无明显差别;在体外实验中,酵母多糖组刺激的子宫巨噬细胞M1比例均明显增多,M2比例明显均减少,差异有统计学意义(P<0.05).血清检测出酵母多糖组的IL-4减少,IL-2,IL-6和IFN增加,差异有统计学意义(P<0.05).酵母多糖组子宫巨噬细胞表面CD80和CD86增多,差异有统计学意义(P<0.05).结论 酵母多糖可在小鼠诱导流产,该模型可应用于感染相关流产的研究;酵母多糖注射后孕鼠流产可能与巨噬细胞相关的抑制性免疫功能减弱有关. 相似文献
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Preincubation of rat peritoneal macrophages with d-penicillamine increased their uptake of labelled aggregated human gamma globulin ([125I]AHG) without affecting the rate of degradation of the aggregates. Administration of d-penicillamine (50 mg.kg?1. day?1 p.o.) to normal rats resulted in increased uptake of [25I]AHG by peritoneal macrophages after 4 days of treatment, but not after 14 and 28 days of treatment. In contrast, macrophages from rats with adjuvant arthritis treated with d-penicillamine (50 mg.kg?1. day?1 p.o.) exhibited an increased uptake of [125I]AHG throughout the course of the disease. Administration of d-penicillamine in vivo had no effect on the rate of degradation of [125I]AHG by freshly prepared macrophages. Culture for 24 hr in vitro prior to incubation with [125I]AHG led to a decrease in the rate of degradation of the labelled aggregates by macrophages from untreated or d-penicillamine-treated rats and from rats with adjuvant arthritis, but not by macrophages from d-penicillamine-treated adjuvant arthritic rats. It is suggested that d-penicillamine may exert a stimulatory effect on the reticuloendothelial function during chronic inflammatory disease, and that this effect may be mediated via an interaction with the macrophage plasma membrane. 相似文献
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Song Gao Xiaozheng Zhong Jingjing Ben Xudong Zhu Yuan Zheng Yan Zhuang Hui Bai Li Jiang Yaoyu Chen Yong Ji Qi Chen 《Clinical and experimental pharmacology & physiology》2009,36(9):940-944
- 1 Activation of macrophages plays an important role in atherosclerosis. In order to investigate the effect of endoplasmic reticulum (ER) stress on cytokine release from macrophages, the RAW 264.7 mouse macrophage cell line was treated with 0.2 mmol/L 6‐aminonicotinamide (6‐AN) for 36 h and the secretion of tumour necrosis factor (TNF)‐α determined. In addition, Raw 264.7 cells were incubated in the presence of 10 µg/mL acetylated low‐density lipoprotein (acLDL) at 37°C for 8 h.
- 2 Secretion of TNF‐α from RAW 264.7 cells was stimulated by both loading of cells with acLDL and following 6‐AN treatment. In addition, the expression of glucose‐regulated protein (GRP) 78 was increased in 6‐AN‐treated cells (by 165%).
- 3 In separate experiments, PD98059, a specific inhibitor of the mitogen‐activated protein kinase kinase (MEK) pathway, blocked acLDL‐ and/or 6‐AN‐induced TNF‐α secretion, whereas LY294002, which blocks the AKT signalling pathway, had no effect. On the basis of these results, we speculate that acLDL/6‐AN‐induced secretion of TNF‐α from RAW 264.7 cells may be regulated by activation of the MEK signalling pathway.
- 4 The present study suggests that the accumulation of lipids in cells and/or ER stress could lead to macrophage apoptosis as a result of the increased production of TNF‐α, which integrates into atherosclerosis.
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Esters of elliptinium with stearic (ST-NME), palmitic (PAL-NME) or oleic (OL-NME) acids, a series of lipophilic derivatives of ellipticine, were synthetized, in order to evaluate their incorporation into Low Density Lipoprotein (LDL). Among the three derivatives, OL-NME shows the most potent incorporation (83 micrograms/mg protein LDL) compared to ST-NME (37 micrograms/mg protein LDL) and PAL-NME (58 micrograms/mg protein LDL). The size of OL-NME-LDL was determined by size distribution particles, showing their homogeneity compared to native LDL. When culture normal human fibroblasts were incubated with [125I]LDL incorporated drug, they bound to the LDL receptor with the same affinity as native LDL and were internalized and degraded intracellularly. The presence of excess native LDL inhibited the cellular uptake and degradation of [125I]drug-LDL. We have used [125I]acetyl-LDL as a probe for a binding site on macrophages that mediated the uptake and degradation of chemically altered or denatured LDL. Mouse peritoneal macrophages were shown to take up and degrade [125I]acetyl-LDL at rates that were greater than those for the uptake and degradation of native [125I]LDL and [125I]drug-LDL. The in vitro cytotoxic test on L1210 murine leukemic cells demonstrated that the complex was cytotoxic and was more effective than the free drug. This cytotoxic activity of the drug-LDL complex depends on the LDL high affinity receptor since the addition of native LDL reduces the killing power. In contrast, methylated LDL, which does not bind to the LDL receptor, has no effect on it. We conclude that it is possible to incorporate a large amount of cytotoxic drug into LDL without modifying their cellular metabolism via the high affinity LDL receptor pathway. It indicates also that the delivery of lipophilic drugs using LDL might provide distinct advantages over the use of synthetic carriers. 相似文献
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Metabolism of endothelin-1 and big endothelin-1 by recombinant neutral endopeptidase EC.3.4.24.11. 总被引:2,自引:2,他引:0
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Z. A. Abassi E. Golomb R. Bridenbaugh H. R. Keiser 《British journal of pharmacology》1993,109(4):1024-1028
1. Inhibitors of neutral endopeptidase EC.3.4.24.11 (NEP) have been shown to attenuate the hypertensive effect of big-endothelin-1 (BET-1) in rats. To determine whether NEP converts BET-1 to endothelin-1 (ET-1), the effect of a recombinant NEP (rNEP) on BET-1 and on ET-1 was assessed in vitro. 2. Incubation of [125I]-ET-1 with 1 microgram ml-1 of rNEP resulted in degradation of the peptide within minutes. Increase in the amount of rNEP to 10 micrograms ml-1 led to total cleavage of [125I]-ET-1 within seconds. 3. Phosphoramidon (10 microM) or SQ-28,603 (100 microM) totally suppressed the degradation of [125I]-ET-1 by rNEP. 4. The degradation of [125I]-BET-1 by either 1 or 10 micrograms ml-1 of rNEP was much slower than that of [125I]-ET-1. Again, both phosphoramidon and SQ 28,603 protected the peptide from degradation. 5. Intact [125I]-ET-1 was not observed when [125I]-BET-1 was incubated with rNEP. 6. These data show that neutral endopeptidase EC.3.4.24.11 is not an endothelin converting enzyme. 相似文献
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Specific and non-specific effects of beta-adrenoceptor agonists on guinea pig alveolar macrophage function 总被引:1,自引:0,他引:1
P A Henricks B Van Esch A J Van Oosterhout F P Nijkamp 《European journal of pharmacology》1988,152(3):321-330
The existence of beta-adrenoceptors on guinea pig alveolar macrophage membranes was determined by means of radioligand binding studies. Saturable binding with [125I]cyanopindolol demonstrated 38 +/- 6 fmol binding sites per 10(6) alveolar macrophages with a Kd of 0.85 +/- 0.15 nM. With timolol, atenolol and ICI 118.551 for competition of [125I]cyanopindolol binding it became clear that guinea pig alveolar macrophages possessed adrenergic binding sites of the beta 2-subtype. The cyclic AMP levels of alveolar macrophages could be increased by selective beta 2-adrenoceptor agonists but not by selective beta 1-adrenoceptor agonists. The influence of non-selective beta- and selective beta 1- and beta 2-adrenoceptor agonists on the phagocytic and metabolic responsiveness of alveolar macrophages was also studied. Addition of beta-adrenoceptor agonists had no effect on the uptake of bacteria by alveolar macrophages. Incubation of alveolar macrophages with increasing amounts of non-selective and selective beta 1-agonists resulted in a dose-dependent decrease in the detection of hydrogen peroxide released by alveolar macrophages. This effect was due to the scavenging properties of these drugs. The selective beta 2-receptor agonists, salbutamol and terbutaline, had no effect on the oxidative metabolism of alveolar macrophages. We conclude that guinea pig alveolar macrophages possess beta 2-adrenoceptors on their cell surface and that these receptors are not involved in the phagocytic activity of alveolar macrophages. 相似文献
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Dagmar Fischer Berit Osburg Holger Petersen Thomas Kissel Ulrich Bickel 《Drug metabolism and disposition》2004,32(9):983-992
The in vivo body distribution and the pharmacokinetics of a 20mer double-stranded nuclear factor kappaB decoy oligodeoxynucleotide (ODN) complexed with 25-kDa poly(ethylene imine) (PEI), low molecular weight 2.7-kDa PEI, and PEGylated PEI [bPEI(25k)-glPEG(550)(50)] after intravenous injection were studied in BALB/c mice using a double-labeling technique to follow simultaneously the distribution of both complex components. The polymers were radioactively labeled with (125)I by Bolton-Hunter reagent and the decoys with [gamma-(32)P]ATP by an enzymatic 5'-end-labeling technique. After i.v. bolus injections into the jugular vein, organ samples were taken after 15 min, 2 h and 12 h. For pharmacokinetic studies blood and plasma samples were collected from 20 s up to 2 h. Uncomplexed decoy was found to be degraded already after 15 min and was rapidly eliminated renally into urine. Complexation with the homopolymers increased the organ levels and circulation time of ODN after 15 min, with similar organ distribution profiles for (125)I and (32)P. In contrast to the behavior of free ODN, the complexes were mainly distributed into liver and spleen. Whereas the organ concentrations of (125)I remained high over 12 h, the (32)P values of ODN decreased in a time-dependent manner, likely due to separation of the complexes and degradation of the DNA. Although PEGylated PEI demonstrated a slower (125)I-uptake into the RES organs compared with 25-kDa PEI due to the shielding effect of PEG [poly(ethylene glycol)], it was not able to better stabilize the complexes in the circulation or protect DNA from degradation. 相似文献
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Hideyoshi Harashima Noriko Hirai Hiroshi Kiwada 《Biopharmaceutics & drug disposition》1995,16(2):113-123
The objective of this study was to quantify and model the degradation process of liposomes in peritoneal macrophages (PMs). Iodinated albumin (125I-alb) was chosen to be the marker of liposome degradation. The time course of the degradation of free 125I-alb after pinocytosis by PMs followed first-order kinetics with a half-life of 23 min. The degradation of liposomally encapsulated 125I-alb was also quantified. Kinetic modelling of liposome degradation indicated the existence of two kinetically different processes, one with a half-life of 13 min and the other with a half-life of 7.5 h. Comparing the degradation of liposomal and free 125I-alb suggested that 125I-alb was delivered to lysosomes much faster through phagocytosis than pinocytosis. These results indicate that the intracellular degradation kinetics of pinosomes and phagosomes is different. This method can quantify the rate and extent of liposomal degradation in macrophages and provide kinetic information on the intracellular destiny of liposomally encapsulated compounds. 相似文献
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Two novel polysaccharides, Plumula nelumbinis (P. nelumbinis) polysaccharide I (LNP I) and P. nelumbinis polysaccharide II (LNP II), were extracted and purified from P. nelumbinis, and a sulfated polysaccharide, P. nelumbinis polysaccharide III (LNP III), with a substitution degree of 0.62 was prepared from LNPI. The structures of the LNPs were preliminarily characterized using high performance size exclusion chromatography (HPSEC), gas chromatography-mass spectrometry (GC–MS), Fourier transformed infrared spectrometry (FT-IR), and nuclear magnetic resonance (NMR) spectrometry. In addition, evaluation of the antioxidant activity of the LNPs showed that they could significantly increase the proliferation of RAW264.7 macrophages (P?<?0.05) and improve the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) based on cell model of H2O2-induced oxidative damage. This suggested that these LNPs may be used as potential antioxidants. 相似文献
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米糠多糖抗肿瘤作用及其作用的部分机制 总被引:21,自引:0,他引:21
目的研究稻糠中提取物米糠多糖(ricebranpolysaccharose,RBS)对Balb/c小鼠Meth-A纤维肉瘤有无抑瘤作用以及有关细胞免疫学机制。方法设立米糠多糖处理组,环磷酰胺处理组及空白对照组。对各组小鼠的抑瘤情况,腹腔巨噬细胞吞噬能力,巨噬细胞表面Fc受体数量以及外周血中T细胞所占比例进行检测对比。结果米糠多糖组Balb/c小鼠同空白对照组和环磷酰胺处理组比较,有明显抑瘤作用;小鼠腹腔巨噬细胞吞噬能力,巨噬细胞表面Fc受体数量以及外周血中T细胞所占比例均有明显改善。结论米糠多糖对Balb/c小鼠Meth-A纤维肉瘤有明显抑瘤作用,该作用与提高细胞免疫功能有关。 相似文献