抗癌抗生素格尔德霉素衍生物17AAG的研究进展

格尔德霉素是一种苯醌安莎霉素类抗生素,有极强的抗肿瘤活性,其衍生物 17AAG (17- 丙烯胺 -17- 去甲氧基格尔德霉素 ) 是 格尔德霉素的 17 位甲氧基被烯丙胺基取代所得,与格尔德霉素相比,其毒性更低,抗癌活性更高。综述 17AAG 的作用机制、治疗应用、 药代动力学、毒性等研究进展。     

格尔德霉素抑制高致病性禽流感病毒增殖及其所介导炎性反应研究

对高致病性禽流感病毒感染最为有效的治疗应采用抗病毒和抗炎症的联合治疗．本试验用流感病毒H5N1感染不同细胞株(A549细胞和MDCK细胞),采用不同浓度格尔德霉素对病毒感染细胞培养物作用不同时长,检测流感病毒滴度;ELISA检测格尔德霉素作用于流感病毒H5N1感染A549细胞12 h、24 h促炎性细胞因子IFN-α、TNF-α和IL-6水平．结果显示,流感病毒H5N1感染A549细胞和MDCK细胞,格尔德霉素极显著地抑制了流感病毒H5N1在细胞培养物的增殖(P < 0.01),而在病毒感染36 h和48 h,格尔德霉素并没有显著抑制流感病毒在MDCK细胞上的增殖(P > 0.05)．促炎性细胞因子分析结果显示,格尔德霉素在流感病毒感染A549细胞12 h和24 h均显著降低了促炎性细胞因子IFN-α、TNF-α和IL-6的分泌(P < 0.05)．上述实验结果显示,格尔德霉素具有抑制流感病毒H5N1增殖及其所介导的炎性反应的双重效应,为格尔德霉素成为应对流感病毒流行的备选药物提供基础科学依据．     

高效液相色谱-串联质谱分析微量格尔德霉素类似物

安莎类抗生素例如利福霉素和安丝菌素,通常由一组化学结构相似的组分组成。格尔德霉素为苯安莎类抗生素,已经发现4个组分。本研究采用高效液相色谱-串联质谱方法对格尔德霉素(GDM)制品中的微量组分进行了分析,发现5个新的和1个已知的GDM类似物。依据质谱数据、结合GDM生物合成机制,对6个GDM类似物的化学结构进行了推测:分子式为C29H42N2O10的新化合物3个,分别为GDM安莎链上C2-C3、C4-C5和C8-C9之间的C-C双键变为单键并同时单羟基化的GDM衍生物;分子式为C28H38N2O8的新化合物2个,其中1个为17(或12,或4)-去甲氧基格尔德霉素,另1个为4,5-双氢-10,11-脱水-17-去甲基-17-羟基格尔德霉素;分子式为C29H42N2O9的已知化合物1个,为4,5-双氢格尔德霉素。这些GDM类似物的发现有助于加深对GDM生物合成的认识,并对通过基因阻断、组合生物合成技术获得GDM衍生物的研究有启示作用。     

吸水链霉菌Streptomyces hygroscopicus 17997中噬菌体基因转移系统的建立及其应用

由吸水链霉菌Streptomyces hygroscopicus 17997产生的格尔德霉素geldanamycin(GA)属安莎类抗生素,具有良好的抗肿瘤和抗病毒活性。本文应用链霉菌温和噬菌体ΦC31衍生的KC515载体,在吸水链霉菌S．hygroscopicus 17997中建立并优化了S．hygroscopicus 17997的基因转染体系。利用所建立的基因转染体系,以基因阻断技术从S．hygroscopicus 17997基因文库含有多组PKS基因柯斯质粒中,鉴定了与GA PKS生物合成相关基因的柯斯质粒,该工作为GA生物合成基因簇的克隆奠定了基础。     

Sterptomyces rochei4089的L基因阻断变株的构建及功能研究

运用同源重组技术破坏了一株格尔德霉素产生菌Sterptomyces rochei 4089的L基因,该基因编码氧化还原酶.以Sterptomyces rochei 4089基因组总DNA为模板,PCR扩增AHBA-KLM基因簇,采取Red/ET重组技术,构建L基因阻断质粒pKC1139-KLM-KmR.采用大肠杆菌与链霉菌的结合转移将阻断质粒含AHBA-KLM基因簇和Kan表达单元的3.0 kb线性片段转化Sterptomyces rochei 4089菌株,在卡纳霉素的平板上筛选卡纳霉素抗性转化子,经PCR检测分离到L基因阻断突变菌株.对原、变株的发酵液进行TLC和HPLC分析显示,Sterptomyces rochei 4089基因组中的L基因失活后,导致该菌株不能合成安莎类抗生素格尔德霉素.通过阻断L基因,为筛查这类放线菌产生安莎类抗生素提供了明确的组分指示作用.     

格尔德霉素生物合成的调控基因

从吸水链霉菌17997中克隆了格尔德霉素(Geldanamycin, Gdm)生物合成酶基因簇, 通过生物信息学分析发现两个LAL(Large ATP-binding regulators of the LuxR family)家族的调控基因gdmRI和gdmRII, 基因阻断和基因回复实验证实这两个基因产物都正调控Gdm的生物合成。     

格尔德霉素生物合成的调控基因

从吸水链霉菌17997中克隆了格尔德霉素(Geldanamycin, Gdm)生物合成酶基因簇, 通过生物信息学分析发现两个LAL(Large ATP-binding regulators of the LuxR family)家族的调控基因gdmRI和gdmRII, 基因阻断和基因回复实验证实这两个基因产物都正调控Gdm的生物合成。     

吸水链霉菌Streptomyces hygroscopicus 17997中噬菌体基因转移系统的建立及其应用

由吸水链霉菌Streptomyces hygroscopicus 17997产生的格尔德霉素geldanamycin(GA)属安莎类抗生素, 具有良好的抗肿瘤和抗病毒活性。本文应用链霉菌温和噬菌体C31衍生的KC515载体,在吸水链霉菌S.hygroscopicus 17997中建立并优化了S. hygroscopicus　17997的基因转染体系。利用所建立的基因转染体系,以基因阻断技术从S. hygroscopicus 17997基因文库含有多组PKS基因柯斯质粒中,鉴定了与GA PKS生物合成相关基因的柯斯质粒,该工作为GA生物合成基因簇的克隆奠定了基础。     

盐霉素抗肿瘤作用研究进展

盐霉素(salinomycin)特异性杀伤肿瘤干细胞(cancer stem cell,CSC)作用的发现,引起了国内外学者的广泛关注.最近的研究表明,盐霉素能高选择性杀死小鼠身上的人乳腺癌CSC并且其效力比紫杉醇高100倍.盐霉素这种靶向作用于CSC的能力及较好的成药性,使其具有研发为一种新型的抗癌药物的潜能.通过手术及术后化疗抗癌的传统方法已经难以对抗肿瘤的复发或转移.然而,利用离子型载体抗生素即盐霉素杀伤肿瘤干细胞这一特性,消除肿瘤复发与转移的”根源”,从而达到治愈”癌症”这一顽疾的目的在理论上是可行的.多项研究已证实盐霉素能对抗多种肿瘤干细胞,因此我们认为盐霉素是一种广谱抗肿瘤药物,这些结论将推动临床抗肿瘤研究进入一个崭新的阶段,为防癌治癌工作提供实验依据和新的思路.本文将系统阐述盐霉素抗肿瘤药效学及其作用机制的研究进展,以期为后续临床研发抗癌新化合物提供参考.     

吸水链霉菌17997格尔德霉素部分生物合成基因簇的克隆和分析

吸水链霉菌17997(Streptomyceshy groscopicus17997)是我所从中国云南土壤中分离到的格尔德霉素(geldanamycin,GDM)产生菌,GDM具有良好的抗肿瘤和抗病毒活性,但其肝毒性和水溶性差的缺点限制了其在临床上的应用。为了实现对GDM结构的生物学改造,首先要获得GDM的生物合成基因。根据GDM后修饰基因——氨甲酰基转移酶基因(gdmN)的保守序列筛选S.hygroscopicus17997的柯斯质粒基因组文库,共获得6个阳性克隆,选择CT-4阳性柯斯质粒进行亚克隆和测序,又通过PCR延伸的方法获得了与CT4连锁的将近5kb的外源序列,共获得28.356kb的外源DNA序列,其中包含了13个可能阅读框架,通过同源比较证实该序列与S.hygroscopicusNRRL3602中的GDM生物合成基因有很高的同源性。为进一步研究GDM生物合成基因的功能,并通过组合生物学的方法改造GDM的结构奠定了基础。     

Vaccines to treat cancer--an old approach whose time has arrived

There are extensive DNA changes in tumor cells and the genes of tumor cells continuously mutate at a high rate. While this can provide therapeutic targets, it makes it unlikely that an agent that is selective for a single target will work against all cells in a tumor. However, it may be possible to use tumor epitopes as sentinels to engage adaptive and innate immunological mechanisms and create a tumor destructive environment effective also against variant cells that have lost a given antigen or their ability to present it. We hypothesize that therapeutic tumor vaccines, in combination with the targeting, to tumors, of costimulatory molecules such as anti-CD137scFv, or lymphokines such as GMCSF, will expand anti-tumor responses for therapeutic benefit when used as an adjunct to surgery and chemotherapy.     

The quantal theory of immunity

Exactly how the immune system discriminates between all environmental antigens to which it reacts vs. all selfantigens to which it does not, is a principal unanswered question in immunology. As set forth in this review, because of the advances in our understanding of the immune system that have occurred in the last 50 years, for the first time it is possible to formulate a new theory, termed the ＂Quantal Theory of Immunity＂, which reduces the problem from the immune system as a whole, to the individual cells comprising the system, and finally to a molecular explanation as to how the system behaves as it does.     

Two claims about potential human beings

It seems that at conception something is formed which, due to its genetic make-up, has the potentiality to develop into a full-blown human being. Many believe that in virtue of this potentiality, this organism, the human zygote or early embryo, has in instrinsic value which makes it wrong to use or produce it merely as a means to some end, e.g., some scientific end such as to produce embryonic stem cells. Against this it is here argued, first, that it does not follow from the fact that something has a potential to become a (fully developed) human being that it already is a human being (in a rudimentary sense). In fact, a human being begins to exist no earlier than a couple of weeks after conception, at the stage known as gastrulation. Thus, even granted the questionable assumption that something has instrinsic value in virtue of being a human being, the zygote will not have intrinsic value. Secondly, the value an embryo has in virtue of its potentiality to become a full-blown human being can only be instrumental, a value as a means. But of course it cannot be wrong to treat that which has merely instrumental value as a mere means or instrument to some end.     

You can run--or you can hide: optimal strategies for cryptic prey against pursuit predators

We consider the optimal behavior of a cryptic prey individualas it is approached by a predator searching for prey. Althoughthe predator has not yet discovered the prey, it has an increasinglikelihood of doing so as it gets closer to the prey. Further,the closer the predator is to the prey when it discovers it,the more likely the predator will be to capture the prey. Thesearguments suggest that the prey should flee before the predatordiscovers it. However, the act of fleeing will alert the predatorto the presence of the prey and trigger an attack that mightnot have occurred otherwise. We capture these conflicting outcomesin a mathematical model, which we then use to predict the optimalbehavior of the prey and predator. We argue that the optimalstrategy for the prey is either to run as soon as they detecta predator approaching or to only flee in response to havingbeen detected by the predator. Running as soon as the predatoris detected is associated with low predator search speeds, alow nonpredation cost to running, a large advantage to the preyin initiating chases rather than reacting, limited ability tospot the predator at distance, a high ability to spot prey bythe predator, and a high probability that chases will be successful.The optimal strategy for the predator depends on whether itscurrent trajectory is taking it closer to or further from theprey. In the latter case, the predator should attack immediatelyon discovering the prey; in the former case, it should delayits attack until it reaches the point on its current trajectorywhere distance to the prey is minimized.     

Extracellular functions of galectin-3

Galectin-3 has been suspected of modulating cell to extracellular matrix interactions in a novel fashion ever since it was first described. However, the rapid accumulation of research data in just the last 8 years alone has completely changed our perspective of this multifunctional protein. Its chimeric nature (consists of carbohydrate recognition and collagen like domains) somehow makes it suited to interact with a plethora of interesting extracellular matrix proteins some of which might enable it to cross the plasma membrane despite its lack of appropriate signal peptides. It is now becoming established as a mediator of signal transduction events on the cell surface as well as a mediator of a variety of extra-cellular processes such as kidney development, angiogenesis, neuronal functions, tumor metastasis, autoimmune disorders, endocytosis and possibly exocytosis. Nevertheless, it still retains its unique position as a mediator/modulator of cell to extracellular matrix adhesive interactions. Cells, particularly epithelial cells which lack galectin-3 expression, interact poorly with their extracellular matrices. In some of these processes, it functions as a matricellular protein, displaying both pro- and anti-adhesive properties.     

Extracellular functions of galectin-3

Galectin-3 has been suspected of modulating cell to extracellular matrix interactions in a novel fashion ever since it was first described. However, the rapid accumulation of research data in just the last 8 years alone has completely changed our perspective of this multifunctional protein. Its chimeric nature (consists of carbohydrate recognition and collagen like domains) somehow makes it suited to interact with a plethora of interesting extracellular matrix proteins some of which might enable it to cross the plasma membrane despite its lack of appropriate signal peptides. It is now becoming established as a mediator of signal transduction events on the cell surface as well as a mediator of a variety of extra-cellular processes such as kidney development, angiogenesis, neuronal functions, tumor metastasis, autoimmune disorders, endocytosis and possibly exocytosis. Nevertheless, it still retains its unique position as a mediator/modulator of cell to extracellular matrix adhesive interactions. Cells, particularly epithelial cells which lack galectin-3 expression, interact poorly with their extracellular matrices. In some of these processes, it functions as a matricellular protein, displaying both pro- and anti-adhesive properties. Published in 2004.     

Systemic Negligence: Why It Is Morally Important for Developing World Bioethics

In the context of clinical and non‐clinical biomedical practices, negligence is usually understood as a lapse of a specific professional duty by a healthcare worker or by a medical facility. This paper tries to delineate systemic negligence as another kind of negligence in the context of health systems, particularly in developing countries, that needs to be recognized and addressed. Systemic negligence is not just a mere collection of stray incidences of medical errors and system failures in a health system, but is proposed in this paper as a more pervasive kind of neglect. Several non‐medical factors, such as lack of social and political will, also contribute to it and hence is more difficult to address in a health system. This paper argues that recognizing systemic negligence and including it research agenda have special moral importance for researchers in developing world bioethics, public health ethics and for health activists in the developing world. For, it can be a potent health system barrier, and can seriously impair efforts to ensure patient safety, particularly in the weaker health systems. As it erodes accountability in a health system, addressing it is also important for the twin goals of ensuring patient safety and improving health system performance. Above all, it needs to be addressed because the tolerance of its persistence in a health system seems to undervalue health as a social good.     

Picasso-Hund - ein neuer Name für Lycaon pictus?

Lycaon pictus has been named by a variety of common names, such as “African Wild Dog”, “African Hunting Dog” and their adequates in other languages. The article summarizes the history of naming in that species concluding with a new recommendation by the SSP as well as the EEP for that species to rename it as Painted Dog. As the translation of that name into German is an unhandy term it is suggested to name it “Picasso-Hund” in that language.