Exometabolome analysis identifies pyruvate dehydrogenase as a target for the antibiotic triphenylbismuthdichloride in multiresistant bacterial pathogens

The desperate need for new therapeutics against notoriously antibiotic-resistant bacteria has led to a quest for novel antibacterial target structures and compounds. Moreover, defining targets and modes of action of new antimicrobial compounds remains a major challenge with standard technologies. Here we characterize the antibacterial properties of triphenylbismuthdichloride (TPBC), which has recently been successfully used against device-associated infections. We demonstrate that TPBC has potent antimicrobial activity against many bacterial pathogens. Using an exometabolome profiling approach, a unique TPBC-mediated change in the metabolites of Staphylococcus aureus was identified, indicating that TPBC blocks bacterial pyruvate catabolism. Enzymatic studies showed that TPBC is a highly efficient, uncompetitive inhibitor of the bacterial pyruvate dehydrogenase complex. Our study demonstrates that metabolomics approaches can offer new avenues for studying the modes of action of antimicrobial compounds, and it indicates that inhibition of the bacterial pyruvate dehydrogenase complex may represent a promising strategy for combating multidrug-resistant bacteria.     

杨属植物化学成分和药理作用的研究进展

本文对杨属植物的化学成分和药理作用作了全面、系统的综述,为杨属植物药用价值的开发利用提供了科学的依据.     

Process‐Based Species Action Plans: an approach to conserve contemporary evolutionary processes that sustain diversity in taxonomically complex groups

Many endemic plant species belong to taxonomically complex groups. These endemics have often arisen as a consequence of recent and rapid evolutionary divergence facilitated by processes such as hybridization, polyploidy and/or breeding system transitions. The rapid and dynamic nature of divergence in taxonomically complex groups leads to problems in the implementation of traditional species‐based approaches for the conservation of the biodiversity that they contain. Firstly, the taxa of interest can be difficult to define and identify, leading to practical difficulties in implementing conservation measures. Secondly, a species‐based approach often fails to capture the complexity of diversity present in the taxonomically complex group. To accommodate these challenges, we have developed a Process‐Based Species Action Plan approach. This is designed to conserve the processes leading to the generation of biodiversity, rather than focusing on the preservation of individual named taxa. We illustrate the approach using a group of endemic tree species (Sorbus) on the Scottish island of Arran that have originated via a combination of multiple recent hybridization events and apomixis. The plan focuses on the optimization of habitat management to ensure the reproduction and regeneration of Sorbus in the zone in which these evolutionary processes operate, and to facilitate hybridization that will ensure the continued generation of diversity in this group. © 2011 The Linnean Society of London, Botanical Journal of the Linnean Society, 2012, 168 , 194–203.     

Hsp90 (heat shock protein 90) inhibitor occupancy is a direct determinant of client protein degradation and tumor growth arrest in vivo

Several Hsp90 (heat shock protein 90) inhibitors are currently under clinical evaluation as anticancer agents. However, the correlation between the duration and magnitude of Hsp90 inhibition and the downstream effects on client protein degradation and cancer cell growth inhibition has not been thoroughly investigated. To investigate the relationship between Hsp90 inhibition and cellular effects, we developed a method that measures drug occupancy on Hsp90 after treatment with the Hsp90 inhibitor IPI-504 in living cells and in tumor xenografts. In cells, we find the level of Hsp90 occupancy to be directly correlated with cell growth inhibition. At the molecular level, the relationship between Hsp90 occupancy and Hsp90 client protein degradation was examined for different client proteins. For sensitive Hsp90 clients (e.g. HER2 (human epidermal growth factor receptor 2), client protein levels directly mirror Hsp90 occupancy at all time points after IPI-504 administration. For insensitive client proteins, we find that protein abundance matches Hsp90 occupancy only after prolonged incubation with drug. Additionally, we investigate the correlation between plasma pharmacokinetics (PK), tumor PK, pharmacodynamics (PD) (client protein degradation), tumor growth inhibition, and Hsp90 occupancy in a xenograft model of human cancer. Our results indicate Hsp90 occupancy to be a better predictor of PD than either plasma PK or tumor PK. In the nonsmall cell lung cancer xenograft model studied, a linear correlation between Hsp90 occupancy and tumor growth inhibition was found. This novel binding assay was evaluated both in vitro and in vivo and could be used as a pharmacodynamic readout in the clinic.     

Current strategies for the treatment of inborn errors of metabolism

Inborn errors of metabolism (IEMs) are a large group of inherited disorders characterized by disruption of metabolic pathways due to deficient enzymes, cofactors, or transporters. The rapid advances in the understanding of the molecular pathophysiology of many IEMs, have led to significant progress in the development of many new treatments. The institution and continued expansion of newborn screening provide the opportunity for early treatment, leading to reduced morbidity and mortality. This review provides an overview of the diverse therapeutic approaches and recent advances in the treatment of IEMs that focus on the basic principles of reducing substrate accumulation, replacing or enhancing absent or reduced enzyme or cofactor, and supplementing product deficiency. In addition, the challenges and obstacles of current treatment modalities and future treatment perspectives are reviewed and discussed.     

Signaling events involved in interleukin 27 (IL-27)-induced proliferation of human naive CD4+ T cells and B cells

IL-27 induces stronger proliferation of naive than memory human B cells and CD4(+) T cells. In B cells, this differential response is associated with similar levels of IL-27 receptor chains, IL-27Rα and gp130, in both subsets and stronger STAT1 and STAT3 activation by IL-27 in naive B cells. Here, we show that the stronger proliferative response of CD3-stimulated naive CD4(+) T cells to IL-27 is associated with lower levels of IL-27Rα but higher levels of gp130 compared with memory CD4(+) T cells. IL-27 signaling differs between naive and memory CD4(+) T cells, as shown by more sustained STAT1, -3, and -5 activation and weaker activation of SHP-2 in naive CD4(+) T cells. In the latter, IL-27 increases G0/G1 to S phase transition, cell division and, in some cases, cell survival. IL-27 proliferative effect on naive CD4(+) T cells is independent of MAPK, but is dependent on c-Myc and Pim-1 induction by IL-27 and is associated with induction of cyclin D2, cyclin D3, and CDK4 by IL-27 in a c-Myc and Pim-1-dependent manner. In BCR-stimulated naive B cells, IL-27 only increases entry in the S phase and induces the expression of Pim-1 and of cyclins A, D2, and D3. In these cells, inhibition of Pim-1 inhibits IL-27 effect on proliferation and cyclin induction. Altogether, these data indicate that IL-27 mediates proliferation of naive CD4(+) T cells and B cells through induction of both common and distinct sets of cell cycle regulators.     

小球藻的营养及药用价值

微藻因具有丰富的营养价值和产油能力,因而已被广泛研究。小球藻属于单细胞绿藻,分布广泛,种类多达十余种,在食品、医药、饲料、能源和环保等多个领域具有广泛的应用价值。小球藻不仅可以光自养生长,还可以利用有机碳源进行异养生长。小球藻细胞壁坚厚,胞内含有丰富的蛋白质、必需氨基酸、多糖、色素、脂肪酸,并富含多种维生素,以及铁、钙、锌、钾等矿物元素,具有全面而均衡的营养价值。小球藻属中的蛋白核小球藻已被我国卫生部列为新资源食品。小球藻特有的促生长因子（CGF）具有提高免疫力、抗肿瘤等多种特殊功效,近年来研究证明小球藻在临床上可作为治疗多种疾病的辅助药物,被认为是绿色天然的营养保健食品。本文从小球藻的生物学特性、营养价值、药理和保健作用等方面进行了论述。     

Relaxing effects of beta-receptor stimulators in isolated, gravid human myometrium

The effects of isoprenaline and the selective β₂-receptor terbutaline were investigated on strips from human myometrium obtained at caesarean sections. In normally polarized preparations both amines (isoprenaline 0.02 – 0.4 μg/ml, terbutaline 0.2 – 8 μg/ml) decreased the frequency and the amplitude of the spontaneous contractile activity. This action was not affected by phenoxybenzamine, 0.5 μg/ml, but could be blocked by propranolol, 0.1 μg/ml. In myometrial strips, depolarized by increasing the extracellular potassium concentration, isoprenaline, 0.004 – 0.4 μg/ml, and terbutaline, 0.008 – 8 μg/ml, had relaxing effects that were unaffected by phenoxybenzamine, 0.5 μg/ml, but could be blocked by propranolol, 0.1 gm/ml. It is concluded that the effects of the tested amines are mediated by actions on β-adrenoceptors, probably β₂-receptors.     

抗菌肽的研究进展

抗菌肽是一类抗细菌、真菌、病毒、寄生虫及肿瘤细胞的小分子多肽,是生物抵御自然界中有害微生物侵染的重要因素,且具抗菌谱广、无免疫原性、作用机制独特、耐热性好等特性,有望成为抗生素的替代品。本文着重介绍了抗菌肽的性质、种类、作用机理等方面的研究进展,同时对其应用、目前存在的问题进行了讨论。     

灵长类动作理解的镜像神经机制研究进展

灵长类动作理解(understanding of actions)的神经机制是认知神经科学研究的重要内容,它的阐明对于揭示灵长类特有的一些高级认知行为的本质和过程具有重要意义。就灵长类动物而言,个体对其同类做出动作的识别以及理解是其一切社会行为的基础,但是迄今为止我们对其动作理解的神经机制还知之甚少。随着镜像神经元成为近年来国外认知神经科学与认知人类学研究的热点,人们通过神经生理学和脑成像等技术,陆续发现和证明了其在灵长类动作理解过程中的重要作用。本文综述了近年来关于灵长类动作理解的镜像神经机制的研究成果,介绍了镜像神经元在灵长类动作理解过程中的一些新认识及其在该能力进化和发育等方面的作用,并对当前一些实验中遗留的问题与灵长类动作理解领域的未来研究方向作了反思与展望。