青蒿琥酯毒性作用机理初探

<正> 用电子自旋共振法(ESR)测定青蒿琥酯在体内、外代谢转化过程中是否产生自由基,用硫代巴比妥酸(TBA)法测定Wistar大鼠iv该药后肠、肝组织内丙二醛含量,以光学和电子显微镜观察抗氧化剂维生素E是否能对抗该药对肠、肝造成的病理损伤。结果表明,该药在体内、外代谢过程中均产生自由基;肠、肝组织中丙二醛的含量药后明显增高,且持续达6 d之久,增高程度与给药剂量呈正相关,药后24 h的相关系数(r)肠、肝     

青蒿酯钠的毒性机理及其对弓形虫的作用

青蒿酯钠的毒性机理及其对弓形虫的作用王京燕徐在海王明道（军事医学科学院微生物学流行病学研究所，北京１０００７１）青蒿酯钠是我国首创的高效低毒抗疟药．已经证明青蒿酯钠在体内产生自由基，引起脂质过氧化；但可由提高体内维生素Ｅ含量予以对抗．弓形虫和疟原虫同...     

青蒿琥酯诱发的自由基对孕鼠与胎鼠造血细胞的毒性

采用妊娠d 13-14 AMS小鼠骨髓和胎肝细胞微核和染色体畸变分析的联合试验方法观察青蒿琥酯对造血细胞的毒性, 并用电子自旋共振技术测定孕鼠和胚胎肝内自由基. 结果表明, 青蒿琥酯不但能诱发孕鼠骨髓细胞微核, 抑制骨髓造血, 而且能通过胎盘屏障损伤胎肝有核细胞. 但未发现对孕鼠骨髓和胎肝细胞的致染色体畸变作用. 青蒿琥酯给药能诱发孕鼠肝和胎肝内自由基信号增强. 本结果提示, 青蒿琥酯诱发经胎盘转运造血母细胞核质损伤和造血抑制可能与药物在体内形成的自由基有关.     

青蒿琥酯对非小细胞肺癌A549放射增敏的初步研究

目的初筛青蒿素及其衍生物联合放射线对非小细胞肺癌A549细胞的放射增敏效应,并以青蒿琥酯为主要研究对象,研究其对A549细胞的体内、外放射增敏效应,初步探讨其对A549细胞的放射增敏作用机制。方法通过MTT法初筛低毒剂量的青蒿素及其衍生物对非小细胞肺癌细胞株A549的放射增敏作用,发现青蒿琥酯具有较强放射增敏效应;采用裸鼠移植瘤模型,观察青蒿琥酯联合β电子线对荷痛裸鼠移植瘤生长抑制作用。同时采用Giemsa染色、流式细胞术,观察青蒿琥酯联合电子线对A549细胞的形态学变化以及细胞周期、凋亡的影响,初步探讨青蒿琥酯联合电子线对肿瘤细胞A549的放射增敏作用机制。结果MTT法得到青蒿素及其衍生物对非小细胞肺癌A549细胞生长抑制的IC10,以IC10为剂量参考,发现青蒿琥酯、双氢青蒿素具有放射增敏效应：联合射线后20rtM和40州的青蒿琥酯对A549细胞有生长抑制作用（p〈0．05）并呈一定量效关系,10μM、20μM和40μM的双氧青蒿素也有一定放射增敏作用（p〈0．05）。体内移植瘤实验结果表明青蒿琥酯（30mg／kg）可显著增加荷瘤裸鼠肿瘤组织B放射线的敏感性,肿瘤生长抑制率达50．90％。体外Giemsa染色结果表明,80μM的青蒿琥酯可以引起A549细胞出现显著的凋亡形态学变化;流式细胞术结果提示,20μM青蒿琥酯可将A549细胞周期阻滞于G2仃订期;凋亡结果分析,20μM青蒿琥酯联合放射线不引起A549细胞凋亡。结论青蒿素衍生物中双氢青蒿素、青蒿琥酯对A549细胞有一定的放射增敏作用。青蒿琥酯联合放射线在体内、外实验中均表现出较强的放射增敏效应,其放射增敏作用机制可能与青蒿琥酯的过氧桥断裂,产生自由基导致细胞周期的延迟以及诱导细胞凋亡相关,其具体机制与青蒿琥酯剂量之间的联系有待进一步研究。     

青蒿琥酯的药理和毒理学研究进展

目的：了解青蒿琥酯的药理和毒学研究进展。方法：查阅有关文献，综述了我国开发的抗疟新药青蒿琥酯的药理与毒理及其作用机制的研究进展。结果与结论：青蒿琥酯既有高效、速效的抗疟作用，还有免疫调节、抗肿瘤、保肝、抗炎、松驰平滑肌等作用。药动学研究显示其吸收快、分布广、代谢与排泄快。青蒿琥酯的耐受性好，其毒性作用的靶组织是骨髓造血系统，可逆性的网织红细胞减少是青蒿酯的剂量限制性毒作用，无其他严重的不良反应。     

维生素E对氯丁二烯亚急性中毒大鼠肝细胞钙稳态的保护作用

氯丁二烯是氯丁橡胶和聚氯丁二烯产品的单体,其突出的毒性作用是损害肝脏。有实验表明,氯丁二烯通过在体内产生自由基,增加脂质过氧化而影响细胞的正常功能。维生素E(VE)具有高效抗氧化作用,能保护生物膜免遭过氧化物的损害。我室前述工作已提示氯丁二烯亚急性中毒造成     

戎酒对酒精性肝病治疗的影响

摄入体内的乙醇除了极少量由呼吸和尿液排泄外,95％以上在体内分解,而肝脏是乙醇代谢的最主要器官。长期过量饮酒能引起肝脏炎症、纤维化,直至进展成为肝硬化、肝癌。过量的酒精摄入后,乙醇在肝脏代谢过程中产生大量的自由基,这些自由基可造成肝细胞的损伤。氧化应激可造成线粒体DNA缺失或突变,从而造成线粒体功能障碍。乙醇代谢过程中的中间产物乙醛也能促使脂质过氧化,与蛋白形成加合物诱发免疫反应等,从而引起肝细胞损伤。     

山茛菪碱对内毒素血症家兔血浆脂质过氧化物含量的影响

严重的细菌性感染时体内可能产生大量的氧、自由基和脂类自由基,使组织细胞膜损伤,脂质过氧化物含量增高。我们采用大肠杆菌内毒素致家兔产生内毒素血症,并给予山茛菪碱治疗,测定血浆脂质过氧化物代谢产物丙二醛的含量变化,观察山茛菪喊在严重感染时对脂质过氧化反应的影响。     

实验性PVR中脂质过氧化反应及玻璃体内注入维生素E对其作用的研究

目的 :研究实验性增生性玻璃体视网膜病变 (PVR)形成过程是否与自由基引发的脂质过氧化反应密切联系以及玻璃体内注射维生素E是否对PVR形成过程中发生的脂质过氧化反应产生抗氧化作用。方法 :18只健康家兔行气体压迫玻璃体术 ,3d后分三组 (每组 12只兔眼 )行气液交换。模型对照组给予 0 .5mL平衡盐溶液 ;5 0 μg维生素E组给予 0 .5mL含 5 0 μg维生素E的平衡液溶液 ;10 0 μg维生素E组给予 0 .5mL含 10 0 μg维生素E的平衡液溶液。同时 ,三组玻璃体内还注入 0 .1mL含 2 .5× 10 5的成纤维细胞悬液。气液交换后 15d及 30d分别从三组中随机各取 6只兔眼 ,抽取 0 .6mL玻璃体 ,并另取 6只正常兔眼作为正常对照组 ,也抽取 0 .6mL玻璃体 ,然后测量脂质过氧化物(LPO)及超氧化物歧化酶 (SOD)的含量。结果 :模型对照组在PVR模型建立 15d及 30d ,玻璃体内LPO及SOD较正常对照组明显升高 (P <0 .0 1)。当玻璃体内注入维生素E后 ,两给药组的LPO较模型对照组明显降低 (P <0 .0 1) ,SOD亦降低 (P <0 .0 5 )。结论 :PVR形成过程中存在着显著的脂质过氧化反应 ,玻璃体内注入维生素E能抑制PVR形成过程中的脂质过氧化反应 ,发挥强大的抗氧化作用     

青蒿琥酯在大鼠体内外抗肝纤维化的作用

目的观察青蒿琥酯(artesunate,Art)对大鼠肝纤维化的治疗作用及其对大鼠原代肝星状细胞(hepatic stellate cells,HSCs)增殖的影响,并探讨其作用机制。方法建立牛血清白蛋白(bovine serum albumin,BSA)免疫性肝纤维化大鼠模型,分为正常对照组、模型对照组及青蒿琥酯低、中、高剂量组;给药组分别给予不同剂量的青蒿琥酯灌胃,正常和模型对照组给予同体积蒸馏水灌胃,每日1次,连续2个月;酸水解法检测其肝组织胶原蛋白含量,测定血清白蛋白(albumin,Alb)、丙氨酸氨基转移酶(alanine amino transferase,ALT)及天门冬氨酸氨基转移酶(aspartate amino transferase,AST)水平;苏木精-伊红染色法(hematoxylin-eosin staining,HE染色)和胶原染色法对肝组织切片染色。分离大鼠HSCs,以培养活化HSCs。用MTT法测定HSCs增殖率,消化法测定细胞培养上清液中的羟脯氨酸(hydroxyproline,Hyp)含量,Western blot和RT-PCR法检测HSCs p53表达。结果与正常对照组相比,模型对照组大鼠血清Alb水平降低(P<0.05),ALT、AST水平增高(P<0.05);与模型对照组相比,青蒿琥酯低、中、高剂量组血清AST水平降低(P<0.05),大鼠肝组织胶原蛋白含量降低(P<0.05)。青蒿琥酯对培养活化的HSCs有抑制作用,且呈剂量和时间依赖性(P<0.05);青蒿琥酯作用24 h后,HSCs分泌羟脯氨酸减少(P<0.05),p53 mRNA表达增加(P<0.05)。结论青蒿琥酯在大鼠体内、体外均有抗肝纤维化作用,该作用与其增加HSCs p53的表达有关。     

异莲心碱的体外抗氧化活性

目的研究异莲心碱对氧自由基的清除作用及其对脂质过氧化反应(LPO)的抑制作用。方法羟自由基由Fenton体系产生,超氧阴离子自由基由邻苯三酚自氧化法产生,通过比色法测定LPO的终产物 丙二醛(MDA)的相对含量来反映异莲心碱对LPO的影响。结果异莲心碱对羟自由基和超氧阴离子自由基有较强的清除作用,达到5 0 %清除率所需药物浓度(EC50 )分别为0 .90 ,1.82mg/ml,可抑制小鼠肝匀浆脂质过氧化反应,EC50 为0 .6 7mg/ml。结论异莲心碱对氧自由基有清除作用,对脂质过氧化有抑制作用,其活性与剂量呈正相关     

Chelating and free radical scavenging mechanisms of inhibitory action of rutin and quercetin in lipid peroxidation

Inhibitory effects of flavonoids rutin and quercetin on ferrous ion-dependent lipid peroxidation of lecithin liposomes and NADPH- and CCl4-dependent lipid peroxidation in rat liver microsomes were studied to elucidate the chelating and free radical scavenging activities of these compounds. The interaction of rutin with superoxide ion and ferrous ions and the reaction of quercetin with lipid peroxy radicals were also studied. Both flavonoids were significantly more effective inhibitors of iron ion-dependent lipid peroxidation systems due to chelating iron ions with the formation of inert iron complexes unable to initiate lipid peroxidation. At the same time, iron complexes of flavonoids retained their free radical scavenging activities. The chelating mechanism of inhibition was more important for rutin than for quercetin. The mutual effect of rutin and ascorbic acid on non-enzymatic lipid peroxidation was also studied. It was concluded that rutin and quercetin are able to suppress free radical processes at three stages: the formation of superoxide ion, the generation of hydroxyl (or cryptohydroxyl) radicals in the Fenton reaction and the formation of lipid peroxy radicals.     

四氯化碳诱导肝损伤大鼠自由基及微量元素含量的动态变化(英文)

为探讨微量元素与自由基代谢的关系,本实验采用四氯化碳诱导肝损伤的大鼠模型,研究了中毒大鼠体内自由基和微量元素含量的动态变化。结果大鼠经四氯化碳致毒后,肝组织自由基浓度增加,肝脏中Cu,Zn-SOD含量增加,存在着自由基底物对超氧化物歧化酶的诱导合成作用。肝脏出现明显的脂质过氧化增强现象,MDA浓度增加,GSH降低和GSSG升高。实验还观察到脑组织亦发生轻度脂质过氧化增强。在上述变化的同时,与自由基代谢有关的微量元素Zn、Cu、Fe、Mn和Se也发生了明显的改变,其中肝脏中Zn、Cu和Se含量显著降低,而肝Fe却明显增高,在脑组织中表现为Zn的降低和Se升高。上述结果说明微量元素改变在肝损伤时的自由基代谢中具有一定的作用。     

Inhibition by uric acid of free radicals that damage biological molecules

To clarify the antioxidative role of uric acid, its ability to scavenge carbon-centered and peroxyl radicals and its inhibitory effect on lipid peroxidation induced by various model systems were examined. Uric acid efficiently scavenged carbon-centered and peroxyl radicals derived from the hydrophilic free radical generator 2,2'-azobis-(2-amidinopropane)-dihydrochloride (AAPH). All damage to biological molecules, including protein, DNA and lipids induced by AAPH, was strongly prevented by uric acid. In contrast, alpha-tocopherol had little effect on damage to biological molecules. Lipid peroxidation by the lipophilic free radical generator 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN) was little inhibited by uric acid, but not by alpha-tocopherol. Copper-induced lipid peroxidation was inhibited by uric acid and alpha-tocopherol. NADPH- and ADP-Fe(3+)-dependent microsomal lipid peroxidation was efficiently inhibited by alpha-tocopherol, but not by uric acid. Uric acid seems to scavenge free radicals in hydrophilic conditions to inhibit lipid peroxidation on the lipid-aqueous boundary, and the antioxidation is only little in lipophilic conditions.     

脑出血患者血浆及脑血肿引流物ET、MDA、SOD、LPO对照研究

目的研究内皮素(ET)、丙二醛(MDA)、超氧化物歧化酶(SOD)、脂质过氧化物(LPO)脑出血患者含量改变的临床意义。方法分析脑出血患者血浆及脑血肿引流物ET、MDA、SOD、LPO含量改变。结果血浆和脑血肿引流物ET、MDA、LPO明显增高 ,其中脑血肿引流物增高更为显著。而血浆和脑血肿引流物SOD均明显降低 ,以脑血肿引流物降低更明显。结论脑出血时血管收缩因子增加 ,而舒张因子减少 ,同时脑内自由基产生增多 ,而清除自由基能力下降 ,这可能是脑出血时比较重要的病理机制     

Antioxidative constituents fromPaeonia lactiflora

The ethanol extract of the peony root (Paeonia Lactiflora Pall, Paeoniaceae) as well as its major active components including gallic acid and methyl gallate were evaluated for their protective effects against free radical generation and lipid peroxidation. In addition, the protective effects against hydrogen peroxide-induced oxidative DNA damage in a mammalian cell line were examined. The ethanol extracts of the peony root (PREs) and its active constituents, gallic acid and methyl gallate, exhibited a significant free radical scavenging effect against 1,1-diphenyl-2-picryl hydrazine (DPPH) radical generation and had an inhibitory effect on lipid peroxidation, as measured by the level of malondialdehyde (MDA) formation. The PREs did not have any pro-oxidant effect. They strongly inhibited the hydrogen peroxide-induced DNA damage from NIH/3T3 fibroblasts, as assessed by single cell gel electrophoresis. Furthermore, the oral administration of 50% PRE (50% ethanol extract of peony root), gallic acid and methyl gallate potently inhibited the formation of micronucleated reticulocytes (MNRET) in the mouse peripheral blood induced by a KBrO3 treatment in vivo. Therefore, PREs containing gallic acid and methyl gallate may be a useful antigenotoxic antioxidant by scavenging free radicals, inhibiting lipid peroxidation and protecting against oxidative DNA damage without exhibiting any pro-oxidant effect.     

The preventive inhibition of chondroitin sulfate against the CCI<Subscript>4</Subscript>-lnduced oxidative stress of subcellular level

Our work in this study was made in the microsomal fraction to evaluate the lipid peroxidation by measuring superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and malondialdehyde (MDA) and to elucidate the preventive role of CS in the CCl4-induced oxidative stress. The excessive lipid peroxidation by free radicals derived from CCl4 leads to the condition of oxidative stress which results in the accumulation of MDA. MDA is one of the end-products in the lipid peroxidation process and oxidative stress. MDA, lipid peroxide, produced in this oxidative stress causes various diseases related to aging and hepatotoxicity, etc. Normal cells have a number of enzymatic and nonenzymatic endogenous defense systems to protect themselves from reactive species. The enzymes in the defense systems, for example, are SOD, CAT, and GPx. They quickly eliminate reactive oxygen species (ROS) such as superoxide anion free radical *O2(-), hydrogen peroxide H2O2 and hydroxyl free radical *OH. CS inhibited the accumulation of MDA and the deactivation of SOD, CAT and GPx in the dose-dependent and preventive manner. Our study suggests that CS might be a potential scavenger of free radicals in the oxidative stress originated from the lipid peroxidation of the liver cells of CCl4-treated rats.     

丁基苯酞对血管性痴呆患者自由基及血液流变学的影响

目的探讨丁基苯酞对VD患者自由基的清除作用及对血液流变学的影响。方法选择60例VD患者,另选健康老人120例,其中空白对照组60例,健康组60例。观察治疗前后血清超氧化物岐化酶(SOD)、过氧化脂质(LPO)、丙乙醛(MDA)、谷胱甘肽氧化物酶(GSH-Px)活性变化及血液流变学指标。结果治疗后SOD、GSH-Px升高,MDA、LPO降低(P<0.05),治疗后血液流变学各项指标均有明显改善。结论丁基苯酞软胶囊有抗MDA,LPO等自由基损伤和激活SOD,GSH-Px等抗脂质过氧化作用,并可明显降低TC、TG、LDL-C,升高HDL,改善血液流变学异常指标。     

银杏叶片对血管性痴呆患者自由基及血液流变学的影响

目的：探求银杏叶片对VD患者自由基的清除作用及对血液流变学的影响。方法：选择60例VD患者，其中男34例，女26例，年龄56～81岁，病程2个月～3年，另选健康老人120例，其中空白对照组60例，健康组60例。观察治疗前后血清超氧化物歧化酶（SOD）、过氧化脂质（LPO）、丙乙醛（MDA）、谷胱甘肽氧化物酶（GSH-PX）活性变化及血液流变学指标。结果：治疗后SOD、GSH-PX升高，MDA、LPO降低（P〈0．05）。治疗后血液流变学各项指标均有明显改善（P〈0．05，P〈0.01）。结论：银杏叶片有抗MDA、LPO等自由基损伤和激活SOD、GSH-PX等抗脂质过氧化作用，并且可明显降低TC、TG、LDLC，升高HDL，改善血液流变学异常指标。     

知母总黄酮对溴酸钾诱导小鼠肾损伤的保护作用

目的探讨知母总黄酮对溴酸钾诱导小鼠肾损伤的保护作用。方法200mg.kg-1溴酸钾腹腔注射诱导小鼠肾损伤模型,采用高效液相色谱仪测定小鼠血清中肌酐含量及肾组织中谷胱甘肽、半胱氨酸和维生素C含量,TBARS法测定小鼠肾组织中丙二醛含量,荧光酶标仪测定知母总黄酮的体外抗氧化活性及小鼠肾组织的抗氧化能力指数。结果与肾损伤模型组相比,知母总黄酮可以有效降低血清肌酐水平和肾组织中丙二醛含量,提高肾损伤小鼠肾组织的抗氧化能力指数、谷胱甘肽、半胱氨酸及维生素C水平,并在体外显示出较强的抗氧化能力。结论知母总黄酮对溴酸钾诱导的小鼠肾损伤具有一定的保护作用,其作用机制可能与知母总黄酮通过消除自由基缓解溴酸钾诱发的肾组织过氧化状态有关。