Synergistic effect of Ebselen and gamma radiation on breast cancer cells

Purpose: To explore the synergistic effect of a seleno-organic compound Ebselen (Ebs) and/or γ-radiation to exert antitumor effects on human breast cancer (MCF-7) cell line in vitro.

Materials and methods: Ebs cytotoxicity at various concentrations (10, 25, 50 and 75 μg), cell proliferation and clonogenic assay of Ebs and/or γ-radiation (at 1, 3 and 6?Gy), expression of p-IκBα and NF-κB, inflammatory cytokines levels (TNF-α, IL-2, INF-γ, IL-10 and TGF-β), apoptotic factors (Caspase-3, Granzyme-B and TRAIL) and angiogenic factor (VEGF) were investigated.

Results: The results showed that the effective dosage of this combination was observed at 25 μg/ml of Ebs with γ-radiation at 6?Gy. Data displayed a significant reduction in NF-κB mRNA along with an elevation in granzyme-B mRNA and TRAIL mRNA expression. Furthermore, protein expression of caspase-3 was elevated, whereas p-IκBα and p-NF-κB(p65) protein expression was reduced significantly. Also, a significant decline in TNF-α, IL-2, INF-γ, TGF-β with a significant increase in IL-10 levels were revealed. Meanwhile, a significant decrease in VEGF level and proliferation capacity were observed.

Conclusions: We conclude that a combination of Ebs with radiotherapy has a major antitumor efficiency in inducing apoptosis and inhibiting cancer cell progression, due to the synergistic effect in regulating gene and protein expression, and in a modulating response of pro-and anti-inflammatory cytokines.     

Ebselen对妊娠铅负荷干预

目的：探讨防止宫内铅暴露对婴儿健康影响,方法,应用原子吸收测定孕妇血铅,对志愿采用Ebselen进行干预流行病学调查,结果：至38周干预组血铅增加21．5％,显低于对照组（64．5％）,Zn含量（13.39umol/L→17.35umol/L和GSH－Px活性（73．5U/L→95.4U/L)增加,LPO含量（6.82nmol/L→5.22nmol/L)降低,差异有极显性（P均＜0．01）,结论：Ebselen对盈妇期铅增高的趋势有阻遏作用,Ebselen中的Se不参加贮存而具有增强抗氧化活性,但能促进Zn的储备,Ebselen有用于预防婴儿铅中毒的可能。     

Ebselen对Cu2+、Fe2+及巨噬细胞氧化修饰人LDL的抑制作用

目的:研究Ebselen对Cu2+、Fe2+及巨噬细胞氧化修饰人低密度脂蛋白(LDL)的抑制作用及其可能机制.方法:采用紫外分光光度法检测人LDL中硫代巴比妥酸反应物(TBARS)及共轭双烯(CD)的含量来表示LDL的被氧化程度.结果:Cu2+、Fe2+及体外培养的小鼠腹腔巨噬细胞(MPM)都能氧化修饰人LDL,使其中的TBARS和CD含量显著升高.Ebselen(0.5～4.0 μmol/L)能剂量依赖性降低人LDL中TBARS和CD含量,其中2umol/L的Ebselen能完全抑制Cu2、Fe2+及MPM升高LDL中TBARS含量的作用.单用谷胱甘肽(GSH,0.5 mmol/L)对LDL中TBARS含量没有显著的影响,但GSH能显著增强Ebselen对TBARS生成的抑制作用.结论:Ebselen能抑制Cu2+、Fe2+及MPM氧化修饰人LDL,GSH能明显增强Ebselen的这种抑制作用.     

Effect of ebselen,a scavenger of reactive oxygen species,on chondrocyte metabolism

Abstract

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a synthetic heterocyclic seleno-organic compound, has been shown to act as a scavenger of reactive oxygen species (ROS). We have previously reported that interleukin-1 (IL-1) inhibited proteoglycan (PG) synthesis and induced the production of ROS in cartilage explants and isolated chondrocyte cultures. In this study, we report the protective effect of ebselen against IL-1-mediated inhibition of PG synthesis and ROS induction in cultured cartilage explants and chondrocytes. Ebselen also reversed the inhibition of PG synthesis in mechanically stressed cultured chondrocytes. These data suggest that the use of the antioxidant ebselen may be a useful tool for studying the mechanisms of cartilage degradation.     

Azaanalogues of ebselen as antimicrobial and antiviral agents: synthesis and properties

The different analogues of ebselen-unsubstituted benzisoselenazol-3(2H)-one (2a) 2-pyridylbenzisoselenazol-3(2H)-ones (2b-h) and 7-azabenzisoselenazol-3(2H)-ones (3a-j) were designed as new selenium-containing antiviral and antimicrobial agents and synthesized. Some of them were found in the antiviral assay in vitro to be strong inhibitors of cythopatic activity of herpes simplex virus type 1--HSV-1 (compounds 2a,b,f,h, 3a-j) and encephalomyocarditis virus--EMCV (compounds 2a,h, 3a-f,k,l). The compounds 2a,h and 3a-e,j were found to have an appreciable activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus) in vitro, some of them inhibited growth of pathogenic yeasts (Candida albicans) (3a,b) and filamentous fungi (3a-e,f).     

依布硒固体分散体的制备及体外溶出度研究

目的提高依布硒的体外溶出速率。方法以固体分散技术制备依布硒固体分散体,并测定其体外溶出度,采用差示扫描量热法(DSC)进行物相分析。结果DSC分析表明,依布硒是以非晶体状态存在,用水溶性载体普朗尼克制备的分散体体外溶出60min大于60%。结论制备依布硒固体分散体可以提高其体外溶出度。     

依布硒啉对大鼠心肌缺血再灌注损伤后磷酸肌醇-3激酶/蛋白激酶B信号通路的影响

目的探讨依布硒啉预处理对大鼠心肌缺血再灌注后磷酸肌醇-3激酶/蛋白激酶B（P13K/Akt）信号及其内质网应激的影响。 方法将30只大鼠分成对照组,缺血再灌注组及依布硒啉组,每组10只。对照组大鼠冠状动脉左室支左心耳下缘约0.5 cm处只穿线,不结扎,常规腹腔注射生理盐水2 ml;缺血再灌注组大鼠缺血再灌注前30 min腹腔注射生理盐水2 ml;依布硒啉组大鼠缺血再灌注前30 min腹腔注射依布硒啉溶液5 mg/kg。每组各取8只大鼠,采用酶联免疫吸附试验（ELISA）检测各组血清炎症因子高迁移率族蛋白1（HMGB1）、丙二醛、超氧化物歧化酶（SOD）、天冬氨酸转氨酶（AST）及乳酸脱氢酶（LDH）的表达,Tunel法检测缺血心肌细胞凋亡指数,Western-blotting检测各组心肌心肌葡萄糖调节蛋白78（GRP78）蛋白表达及P13K/Akt通路磷酸化水平。 结果三组大鼠间HMGB1、丙二醛、SOD、AST及LDH水平比较,差异均有统计学意义（F = 63.755、73.023、99.220、110.439、120.557,P均< 0.05）,进一步比较发现,缺血再灌注组及依布硒啉组的HMGB1[（9.2 ± 2.7）、（5.5 ± 1.1）、（2.2 ± 0.3）U/L]、丙二醛[（7.2 ± 0.4）、（5.6 ± 0.7）、（4.1 ± 0.9）μmol/L]、AST [（1 011 ± 226）、（813 ± 82）、（671 ± 60）U/L]及LDH [（2 783 ± 674）、（2 043 ± 489）、（1 528 ± 524）U/L]水平较对照组均明显升高,SOD水平[（249 ± 28）、（149 ± 10）、（172 ± 17）kU/L]较对照组明显降低（P均< 0.05）。三组大鼠间的凋亡指数（F = 139.942,P < 0.001）、GRP78蛋白表达（F = 177.846,P < 0.001）及P13K/Akt磷酸化水平（F = 86.286,P < 0.001）比较差异均存在统计学意义,进一步比较发现,缺血再灌注组和依布硒啉组凋亡指数[（38.1 ± 4.6）、（25.4 ± 3.9）、（8.2 ± 1.5）%]明显高于对照组,且I/R组更高（P均< 0.05）。 结论依布硒啉预处理可以抑制大鼠内质网应激,可能与调节P13K/Akt信号通路磷酸化水平有关。     

依布硒啉对肝性脑病大鼠的保护作用

目的  探讨依布硒啉对肝性脑病(HE)大鼠的保护作用并探讨其机制。方法  Wistar大鼠随机分为4组：空白对照组(Ⅰ),HE模型组(Ⅱ),依布硒啉处理组(Ⅲ)和溶剂对照组(Ⅳ)。用硫代乙酰胺(TAA)腹腔注射,建立Ⅱ期HE模型后分别给予生理盐水、依布硒啉和二甲基亚砜(DMSO)灌胃1周。检测各组血清3-硝基酪氨酸(3 NT)、谷丙转氨酶(ALT)、丙二醛(MDA)的含量及超氧化物歧化酶(SOD)的活性;观察肝脏的病理改变。结果  Ⅲ组大鼠HE症状较Ⅱ组和Ⅳ组进展缓慢;Ⅲ组与Ⅱ组、Ⅳ组比较各血清指标差异均有统计学意义(P<0.05),与Ⅰ组比较差异无统计学意义(P>0.05)。结论  依布硒啉对TAA诱导的HE大鼠有一定的保护作用,可减缓HE的发展。其机制可能与依布硒啉能够清除体内过氧亚硝酸阴离子且阻止酪氨酸硝基化有关     

依布硒林减轻无心跳大鼠供者供肺的缺血再灌注损伤

目的 探讨依布硒林减轻大鼠无心跳供者(NHBD)肺缺血再灌注损伤(IRI)的作用及其机制.方法 取SD大鼠20只作为无心跳供者,获取供肺.取SD大鼠20只作为受者,并按配对比较法随机分为依布硒林组和移植对照组,每组10只,两组受鼠于移植前1h分别给予含依布硒林(剂量为500 mg/kg)和环孢素A的生理盐水和仅含环孢素A的生理盐水.移植后1h,检测支气管肺泡灌洗液(BALF)中总蛋白质含量、白细胞数量及中性粒细胞(PMN)百分比,测定移植肺组织中丙二醛(MDA)和髓过氧化物酶(MPO)含量,并计算移植肺组织干/湿质量比(W/D).结果 两组肺移植手术均获得成功,术后1h受鼠存活率均为100％.依布硒林组和移植对照组BALF中蛋白质含量分别为(0.41±0.12)和(0.93±0.32) rmg/ml,PMN百分比分别为(3.3±2.0)％和(5.1±2.3)％,移植肺组织中MDA含量分别为(0.631±0.23)和(0.766±0.82) nmol/mg蛋白,MPO含量分别为(25.09±1.19)％和(35.14±0.92)％,W/D分别为(0.359±0.017)和(0.339±0.011),两组间上述指标的比较,差异均有统计学意义(P＜0.05).结论 依布硒林可能通过抑制氧化应激反应,从而有效减轻大鼠NHBD肺的缺血再灌注损伤.