植物来源天然小分子化合物防治骨质疏松症的研究进展

摘要：骨质疏松症是一种以骨量减少、骨质量下降和骨微结构退化为特征的全身性骨病,其病因主要是骨代谢障碍,即破骨细胞的过度形成,导致骨吸收增加和成骨形成不足所致。传统中草药等植物来源的天然小分子化合物由于来源丰富、结构多样、不良反应少等特性可作为预防和治疗骨质疏松症的替代药物。本文综述了近年来发现的具有骨保护作用的植物来源的天然小分子化合物的研究进展,以期为预防和治疗骨质疏松药物的开发提供新思路。     

天然产物促进药物发现（英文）

Natural products or natural product derived drugs comprised 32% of small molecule approved drugs between 1981 and 2010.In the same period of time,16% of small molecule approved drugs were synthetic or natural mimics based on the study of pharmacophores related to natural products.Indisputably,natural products provide diverse structural diversity and intricate carboskeletal frameworks.As it is believed that nature has evolved optimized biologically active compounds-the secondary metabolites-to ensure survival of the species that produce them,natural products are perceived by some to be more′drug-like′than totally synthetic compounds.As such,natural products may provide us with the′best′lead compounds yet for drug discovery,giving rise to natural product inspired drug design.This talk will provide an overview of some of my research in this area.Specifically,I will outline the challenges and some of the lessons learnt in this quest to develop natural products as leads to potential drugs.     

赖氨酸甲基转移酶SETD6在肿瘤发生发展中的研究进展

甲基化酶SET家族是治疗肝癌、乳腺癌、非小细胞肺癌等肿瘤潜在的基因靶点,近年来,其重要家族成员赖氨酸甲基转移酶SETD6的功能及作用引起人们的关注。SETD6不仅能够提高肿瘤细胞的生存、增殖及迁移能力,还能维持胚胎干细胞的自我更新、维持干细胞特性。其机制与SETD6通过甲基化PAK4蛋白激活Wnt/β-catenin通路,以及影响和调控NF-κB通路相关联。该文综述了SETD6在肿瘤发生、发展中的功能及其相关的分子基础、信号通路等研究,探讨其作为治疗肿瘤新靶点的应用前景。     

谷胱甘肽S转移酶π（GST-π）在非霍奇金淋巴瘤中的表达及意义

目的探讨谷胱甘肽S转移酶π（GST-π）与非霍奇金淋巴瘤（NHL）分期及病理分型及预后的关系。方法对30例NHL患者进行谷胱甘肽S转移酶π（GST-π）检测。结果中高度恶性与低度恶性组间谷胱甘肽转化酶差异有显著性，谷胱甘肽S转移酶订阳性，提示预后不良。结论GST-π是预测NHL分期、恶性程度及预后的重要指标。     

开发天然产物药物的尝试与困难（英文）

The development of natural product based drugs for antitumor therapy is fraught with problems of supply,unless the agent is ato provide enough for early preclinical studies.In this presentation I will give examples from three sources,one of which NCI worked on extensively,the others are examples of work by small companies from an Australian aboriginal usage of a plant,and some very clever work by an academic chemist at Yale University.The story of Picatois the one from an Australian aboriginal lead and shows how compounds can come from odd places.The second,Kyprolisis a tour-de-force from an academic laboratory,and the third,Eribulinis the one that started from a very small amount of material from a Japanese sponge and ultimately led to the most complex totally synthesized drug for any disease.Highlights and″lessons learned″will be discussed for each of these as the overall problems,though similar,were addressed successfully in different ways.     

鉴定植物天然产物生物活性组分的新方法（英文）

Countless studies have been devoted to the scientific evaluation of the safety and/or efficacy of botanical natural products.Investigators involved in such studies face a unique set of challenges.Natural products differ from their pharmaceutical counterparts in that they are typically complex mixtures,for which the identities and quantities of components present are not known.To further complicate matters,the composition of these mixtures will vary depending on source material and method of preparation.Investigators conducting clinical trials with complex botanical natural products must choose from a myriad of potential preparations,which may vary greatly in composition.In making such decisions,it is extremely useful to know which components of the mixture are most likely to be responsible for its purported biological activity(theactive constituents).The gold standard approach for identifying active constituents of botanical natural products is bioassay-guided fractionation,in which the mixture is subjected to successive rounds of purification and bioassays until an active compound is identified.Bioassay guided fractionation has historically played a critical role in drug discovery,but is,nonetheless,fraught with challenges.The process is biased towards the most abundant and easily isolatable mixture components,which may not be the most biologically active.Furthermore,if multiple compounds contribute either additively,antagonistically,or synergistically to the observed biological activity of the mixture,activity may be lost upon isolation.As a complementary strategy to bioassay-guided fractionation,our research group has developed untargeted metabolomics strategies to aid in the identification of bioactive mixture components.These strategies involve profiling botanical mixtures using ultraperformance chromatography coupled to high resolving power mass spectrometry.The resulting chemical data is then integrated with biological assay data using biochemometric data analysis strategies.Several case studies will be presented illustrating how this approach can be applied,including for the identification of compounds from the botanical green(Camellia sinensis)that inhibit drug metabolizing enzymes.Such studies are being conducted as part of the Center for Excellence in Natural Product Drug Interaction Studies(Na PDI),which is supported by a cooperative agreement with the National Center for Complementary and Integrative Health,a component of the National Institutes of Health.     

为天然的微生物工厂开发程序化生物功能（英文）

Synthetic biology aims to engineer genetically modified biological systems that perform novel functions that do not exist in nature,with reusable,standard interchangeable biological parts.The use of these standard biological parts enables the exploitation of common engineering principles such as standardization,decoupling,and abstraction for synthetic biology.With this framework in place,synthetic biology has the potential to make the construction of novel biological systems a predictable,reliable,systematic process.Recent efforts to implement a highly systematic frame work in biological engineering have provided long-awaited evidence that engineering principles can facilitate the construction of novel biological systems.Synthetic biology has so far demonstrated that its framework can be applied to a wide range of areas such as energy,environment,and health care.In this talk,our recent efforts to develop recombinant microbial cells with programmable biological functionalities will be presented.In particular,an emphasis will be placed on our development of auto-regulatory genetic circuits that transformed microbes into cell factories that autonomously monitor biosynthetic activities.     

比较多巴胺和左旋多巴对大鼠肝脏芳基硫酸转移酶和雌激素硫酸转移酶的诱导作用（英文）

硫酸转移酶是主要的II相药物代谢酶之一。芳基硫酸转移酶包括rSULT1A1和rSULT1E1,能够催化酚类化合物发生硫酸化。多巴胺是中枢神经系统重要的神经递质,并且能调控各种外周功能。本研究旨在探究多巴胺和左旋多巴对大鼠肝脏硫酸转移酶（rSULT1A1,rSULT1E1）的作用。分别给予雄性大鼠、雌性大鼠不同浓度多巴胺（0,2,10,100 mg/kg/d）及左旋多巴（0,5,25,125 mg/kg/d）。采用real-time PCR以及western blot方法测定rSULT1A1和rSULT1E1的mRNA和蛋白表达;采用PNPS以及放射性的方法测定rSULT1A1和rSULT1E1活性。结果表明：多巴胺增加两种性别大鼠肝脏中rSULT1A1的表达和活性,而对rSULT1E1无显著作用;左旋多巴仅对雄性大鼠肝脏的rSULT1E1有诱导作用,但对两种大鼠肝脏中rSULT1A1以及雌性大鼠的rSULT1E1未产生显著作用。研究结果说明多巴胺在外周和中枢神经系统对rSULTA1和rSULTE1的诱导作用是不同的。     

国际药理学联合会,导向药理学与天然产物（英文）

The pharmaceutical industry has struggled to provide new drugs for stroke and neurodegenerative disease using classical medicinal chemistry approaches.However there is a disconnect between single molecular targets and such severe diseases.Life style changes,particularly exercise,and some natural products,may extend life span:but what are the molecular targets?IUPHAR has built a database of the molecular targets within the human genome which is freely available,with gold standard ligands:the IUPHAR/BPS GuidetoPHARMACOLOGY(GtoP)database(see GuideToPharmacology.org).The database is unique containing information reviewed by the >90NC-IUPHAR expert committees with their publications(H-index72).These expert committees consider features beyond the capability of machine-based data trawling,such as what we know and don′t know,variables affecting drug receptor affinity,the crucial challenges of multiple gene products,alternative splicing,epigenetics,allostery,disease and drug ontologies.The database is being actively promoted worldwide by the main pharmacological societies,resulting in a large international user-base.This can now be extended to the molecular targets of natural products.Natural products also markedly affect cellular metabolism and I will also cover how recent human evolution selected certain molecular pathways,allowing metabolomics analysis to develop new directions for the treatment of neurodegenerative disease.IUPHAR can be a partner in developing new therapeutic paradigms,by expert assessmentof complex research areas at clinical and preclinical levels.This is a unique cooperative international initiative.Key words:pharmacology;molecular targets;natural products     

Small molecule interleukin-8 modulators

The correlation between the production of IL-8, along with many chemokines and inflammatory diseases, has been well documented. Therefore, modulation of IL-8 production is a viable approach to drug discovery for the treament of inflammatory diseases. Two general approaches to regulate IL-8 production are most prevalent. One is direct inhibition of IL-8 receptors, CXCR₁ and/or CXCR₂. The other is downstream regulation of IL-8 production via inhibition of p38 kinase. This review accounts the patent literature published between 1998 and 2001, covering small molecule IL-8 modulators using both approaches.     

Small molecule allosteric modulators of phosphodiesterase 4

Phosphodiesterase 4 (PDE4) inhibitors have shown benefit in human clinical trials but dosing is limited by tolerability, particularly because of emesis. Novel cocrystal structures of PDE4 catalytic units with their regulatory domains together with bound inhibitors have revealed three different PDE4 conformers that can be exploited in the design of novel therapeutic agents. The first is an open conformer, which has been employed in the traditional approach to the design of competitive PDE4 inhibitors. The second is an asymmetric dimer in which a UCR2 regulatory helix from one monomer is placed in a closed conformation over the opposite active site in the PDE4 dimer (trans-capping). Only one active site can be closed by an inhibitor at a time with the consequence that compounds exploiting this conformer only partially inhibit PDE4 enzymatic activity while retaining potency in cellular and in vivo models. By placing an intrinsic ceiling on the magnitude of PDE4 inhibition, such compounds may better maintain spatial and temporal patterning of signaling in cAMP microdomains with consequent improved tolerability. The third is a symmetric PDE4 conformer in which helices from the C-terminal portion of the catalytic unit cap both active sites (cis-capping). We propose that dual-gating of PDE4 activity may be further fine tuned by accessory proteins that recognize open or closed conformers of PDE4 regulatory helices.     

Small molecule kinase inhibitors as anti-cancer therapeutics

Protein kinases have emerged as the most important class of targets in oncology drug discovery because of their major roles in regulating cellular growth and survival. At least, 11 kinase inhibitors have received FDA approval to be used as cancer treatments, and there are continuous efforts to bring more candidates from laboratory benches to the clinic. Although many protein kinase inhibitors directly interact with the ATP binding site, other can alter the kinase conformation to prevent productive ATP binding. Herein we discuss the different mechanisms of action of kinase inhibitors and provide classification of the inhibitors according to their binding sites. Some of these are allosteric inhibitors, ATP competitive inhibitors, protein substrate competitive inhibitors, and covalent bond forming inhibitors. This review provides a broad overview of the relation between mechanism of action and the issues of target selectivity and resistance. Special attention was given to the kinase inhibitors currently in clinical trials.     

Small molecule drugs - optimizing DNA damaging agent-based therapeutics

DNA-targeted chemotherapies remain fundamental in clinical management of both common solid tumours and hematologic malignancies. Recent studies indicate that novel combinations of cytotoxic chemotherapy may have significant activity even in tumours regarded as being resistant to conventional chemotherapy. In addition, the search for more selective and efficacious drugs that can deliver critical DNA damage with minimal side effects continues. Trabectedin, bendamustine and the pyrrolobenzodiazepine dimer SG2000 exemplify three different classes of DNA targeted agent undergoing clinical evaluation. Increasingly, DNA damaging drugs are being used in combination with novel agents such as small molecule inhibitors or antibodies targeting receptor tyrosine kinases. Understanding the mechanistic basis for interactions of these novel targeted agents with DNA-interactive drugs will inform design of optimal combinations for future studies and is critical to maximize benefit in the clinic.     

Small molecule and biologic modulators of the immune response to hepatitis C virus

Hepatitis C virus represents a major global health problem, with approximately 3% of the world population infected. Immune-response modifiers represent the standard of care, given the lack of approved antiviral agents having direct activity against the viral proteins. Although in recent years, improvements in therapy have been attained by combined treatment with pegylated interferon and ribavirin, the discovery and development of next-generation small molecule and biologic agents is ongoing. Several of these newer therapeutics are focused on modulating Toll-like receptors, interferon-alpha signaling, and the pro-inflammatory cytokine balance. A comprehensive account of the lead compounds in development, the bioassays used for optimization of these immune response modifiers and their clinical status is presented.