Using bio-orthogonally catalyzed lethality strategy to generate mitochondria-targeting anti-tumor metallodrugs in vitro and in vivo

Synthetic lethality was proposed nearly a century ago by geneticists and recently applied to develop precision anti-cancer therapies. To exploit the synthetic lethality concept in the design of chemical anti-cancer agents, we developed a bio-orthogonally catalyzed lethality (BCL) strategy to generate targeting anti-tumor metallodrugs both in vitro and in vivo. Metallodrug Ru-rhein was generated from two non-toxic species Ru-N₃ and rhein-alkyne via exclusive endogenous copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction without the need of an external copper catalyst. The non-toxic species Ru-arene complex Ru-N₃ and rhein-alkyne were designed to perform this strategy, and the mitochondrial targeting product Ru-rhein was generated in high yield (>83%) and showed high anti-tumor efficacy in vitro. This BCL strategy achieved a remarkable tumor suppression effect on the tumor-bearing mice models. It is interesting that the combination of metal-arene complexes with rhein via CuAAC reaction could transform two non-toxic species into a targeting anti-cancer metallodrug both in vitro and in vivo, while the product Ru-rhein was non-toxic towards normal cells. This is the first example that exclusive endogenous copper was used to generate metal-based anti-cancer drugs for cancer treatment. The anti-cancer mechanism of Ru-rhein was studied and autophagy was induced by increased reactive oxygen species and mitochondrial damage. The generality of this BCL strategy was also studied and it could be extended to other metal complexes such as Os-arene and Ir-arene complexes. Compared with the traditional methods for cancer treatment, this work presented a new approach to generating targeting metallodrugs in vivo via the BCL strategy from non-toxic species in metal-based chemotherapy.     

银杏叶槲皮素对人肝癌HepG2细胞增殖与凋亡的影响

目的探讨银杏叶黄酮单体成分槲皮素体外对人肝癌细胞HepG2增殖与凋亡的影响。方法将银杏叶黄酮单体成分槲皮素作用于体外培养的人肝癌细胞HepG2,MTT法检测其对HepG2细胞增殖的影响,缺口末端核苷标记（TUNNEL）法检测其对HepG2细胞凋亡的影响。结果银杏叶黄酮单体成分槲皮素使体外培养的人肝癌细胞HepG2的增殖效率下降,使凋亡细胞数增加（P〈0.01）,两者均呈剂量依赖效应。结论银杏叶黄酮单体成分槲皮素具有与银杏叶总黄酮相似的作用,对体外培养的人HepG2细胞增殖有抑制作用,并能诱导细胞凋亡。     

银杏叶总黄酮对人肝癌HepG2细胞凋亡的影响及其机制研究

目的探讨银杏叶总黄酮对体外培养的人肝癌HepG2细胞凋亡的促进作用及其分子机理。方法采用TUNEL法检测银杏叶总黄酮对HepG2细胞凋亡的影响,提取Bcl-2基因的mRNA,以RT-PCR法研究银杏叶总黄酮对Bcl-2基因表达的影响。结果银杏叶总黄酮使人HepG2细胞凋亡指数增加（P〈0．01）,且呈剂量依赖效应;Bcl-2基因mRNA水平随银杏叶总黄酮浓度升高而降低。结论银杏叶总黄酮可促进人HepG2细胞的凋亡过程,并使Bcl-2基因mRNA水平降低,从而起到抗肿瘤的治疗作用。     

强制戒毒的现制调整与合理定位——实施《禁毒法》的两大要点

随着《禁毒法》的实施,统一强制隔离戒毒的管理体制将促使劳教退出现制;戒毒的双重特性是绝大多数成瘾人员因吸毒过错负有接受治疗的义务,因脑部疾患拥有被治疗的权利;强制隔离旨在治疗而非惩戒或者贬损性教育,因而传统的管控模式须让位于真正意义上的治疗模式;但限于制度成本和客观可能,场所强戒应限于有治愈可能且具须与隔离的吸毒成瘾人员。     

‘Two's up and poncing fags’: young women's smoking practices,reciprocity and friendship

Over the past decade much has been written by journalists, policy makers, and academics, about young women's leisure time pursuits. A great deal of this interest has focused around a concern that teenage girls in the UK are taking up smoking in larger numbers than their male peers. This paper draws on findings from my small‐scale doctoral research into teenage girls' use of tobacco and alcohol in a town in southern England. I examine young women's use of cigarettes as an informal social currency, and as a way of thinking about such tobacco use beyond the deficit model of the young female smoker common to many drugs education interventions. In this paper I draw upon theoretical material from the social theories of exchange to explore how young women's reciprocal networks of cigarettes operate to underpin friendships and mobilise power within girls' social networks. I explore how smoking as a reciprocal gift‐giving practice supports and maintains friendship groups and particular gendered practices. My argument is that teen girls create and sustain bonds of friendship through their use and exchange of cigarettes. I want to suggest that within the girls' friendship groups, the flow of branded cigarettes as a resource highlights alliances, inter‐group rivalries, and provides space for the production and negotiation of teenage ‘cool’ femininities.     

Evaluation of pelvic lymph node coverage of conventional radiotherapy fields based on bony landmarks in Chinese cervical cancer patients using CT simulation

ncer. CT simulation may be a feasible technique for planning pelvic fields optimally and individually.     

Anti-angiogenesis effect of generation 4 polyamidoamine/vascular endothelial growth factor antisense oligodeoxynucleotide on breast cancer in vitro

Objective: To study the effects of the generation 4 polyamidoamine/vascular endothelial growth factor antisense oligodeoxynucleotide (G4PAMAMNEGFASODN) compound on the expressions of vascular endothelial growth factor (VEGF) and its mRNA of breast cancer cells and on the inhibition of vascular endothelial cells. Methods: We examined the morphology of G4PAMAM/VEGFASODN compound and its pH stability, in vitro transfection efficiency and toxicity, and the expressions of VEGF and its mRNA. Methyl thiazolyl tetrazolium assay was used to detect the inhibitory function of the compound on vascular endothelial cells. Results: The compound was about 10 nm in diameter and was homogeneously netlike. From pH 5 to 10, it showed quite a buffered ability. The 48-h transfection rate in the charge ratio of 1:40 was 98.76%, significantly higher than that of the liposome group (P<0.05). None of the transfection products showed obvious toxicity on the cells. The expressions of both VEGF protein and its mRNA after G4PAMAM/VEGFASODN transfection decreased markedly. Conclusion: With a low toxicity, high safety, and high transfection rate, G4PAMAMNEGFASODN could be a promising gene vector. Specifically, it inhibits VEGF gene expression efficiently, laying a basis for further in vivo animal studies.     

The Coercion Argument Against Performance-Enhancing Drugs

This paper is a critique of the coercion argument against performance-enhancing drugs (PEDs). According to this argument, lifting the ban on PEDs would undermine the autonomy of athletes by creating a situation where everyone must either use PEDs or not compete at the highest levels of sport. Four problems are raised for this argument and it is concluded that the argument fails. A variation on the coercion argument is also considered and rejected.     

Dietary supplements

For the athlete training hard, nutritional supplements are often seen as promoting adaptations to training, allowing more consistent and intensive training by promoting recovery between training sessions, reducing interruptions to training because of illness or injury, and enhancing competitive performance. Surveys show that the prevalence of supplement use is widespread among sportsmen and women, but the use of few of these products is supported by a sound research base and some may even be harmful to the athlete. Special sports foods, including energy bars and sports drinks, have a real role to play, and some protein supplements and meal replacements may also be useful in some circumstances. Where there is a demonstrated deficiency of an essential nutrient, an increased intake from food or from supplementation may help, but many athletes ignore the need for caution in supplement use and take supplements in doses that are not necessary or may even be harmful. Some supplements do offer the prospect of improved performance; these include creatine, caffeine, bicarbonate and, perhaps, a very few others. There is no evidence that prohormones such as androstenedione are effective in enhancing muscle mass or strength, and these prohormones may result in negative health consequences, as well as positive drug tests. Contamination of supplements that may cause an athlete to fail a doping test is widespread.     

广西产十种有毒中药急性毒性实验研究

目的:观测小鼠依次口服大剂量曼陀罗、闹羊花、马钱子、斑蝥等10种广西产有毒中药的半数致死量,以评价其安全性。方法:每种中药在死亡率0%(Dn)和100%(Dm)范围内确定5～7个给药剂量,每个剂量组用20只小鼠进行观察7天,用Bliss法计算出半数致死量(LD50)等数据。结果:从半数致死量看,半夏的毒性在所有10种受试中药中最低;斑蝥毒性最高。毒性大小顺序为:斑蝥>蟾酥>马钱子>曼陀罗>闹羊花>木鳖子>山豆根>蛇床子>木通>半夏。结论:①多数受试有毒中药与药典标注的毒性程度基本相符;②根据不同毒性中药的半数致死量,可为中毒案件的侦破和定论提供科学的依据。