Current developments in the discovery and design of new drug candidates from plant natural product leads

This review article will emphasize recent research in the Natural Products Laboratory, School of Pharmacy, University of North Carolina at Chapel Hill, on various classes of plant-derived compounds that possess potent antitumor or anti-HIV activity. These compounds were obtained by bioactivity- and mechanism of action-directed isolation and characterization coupled with rational drug design-based modification and analogue synthesis. Structural modification, SAR, and mechanism of action studies are discussed.     

Potential for interaction of kava and St. John's wort with drugs

The present interest and widespread use of herbal remedies has created the possibility of interaction between them and pharmaceutical drugs if they are used simultaneously. Before the recent reports of apparent hepatotoxicity associated with its use, kava (Piper methysticum Forst. F.), was one of the top 10 selling herbal remedies in Europe and North America. This adverse effect was not previously encountered with the traditional beverage which was prepared as a water infusion in contrast to the commercial products which are extracted with organic solvents. Kavalactones, the active principles in kava, are potent inhibitors of several of the CYP 450 enzymes, suggesting a high potential for causing pharmacokinetic interactions with drugs and other herbs which are metabolized by the same CYP 450 enzymes. Furthermore, some kavalactones have been shown to possess pharmacological effects, such as blockade of GABA receptors and sodium and calcium ion channels, which may lead to pharmacodynamic interactions with other substances which possess similar pharmacological proprieties. St. John's wort (Hypericum perforatum L.), used extensively for the treatment of mild to moderate clinical depression, has long been considered safer than the conventional pharmaceutical agents. However, its ability, through its active constituents hypericin, pseudohypericin and hyperforin, to induce intestinal P-glycoprotein/MRD1 and both intestinal and hepatic CYP3A4 enzyme, could markedly reduce the distribution and disposition of their co-substrates. In addition, St. John's wort is a potent uptake inhibitor of the neurotransmitters serotonin, norepinephrine and dopamine all of which have a role in mood control. Consequently, the very real potential for a pharmacodynamic interaction between the herb and pharmaceutical drugs which share this mechanism of action and, like St. John's wort, are used for mood elevation. However, presently there is very little evidence to substantiate actual pharmacokinetic and/or pharmacodynamic interaction between drugs and kava or St. John's wort. This review provides a brief overview of the existing data on interactions of kava and St. John's wort with pharmaceutical agents and as a result reveals the urgent need for detailed investigations to identify clinically significant interactions for these herbal remedies that have the potential to cause adverse effects.     

Pharmacological activity of three commercial Hypericum perforatum preparations in mice

St John's Wort (Hypericum perforatum) is the main herbal species used to treat depression. The products available on the pharmaceutical and dietary supplement markets are obtained by a variety of preparation processes and their pharmacological effects may differ significantly. The purpose of this study therefore was to investigate the effect of different St John's Wort commercial preparations available on the French market. Only one preparation gave significant results in the forced swimming test.     

西苑医院科研成果申报与获奖情况分析

采用规范研究法分析中国中医科学院西苑医院2010—2014年科研奖励申报及获奖情况。从科研奖励申报情况看，各科室申报奖励的积极性较高，但申报科室相对集中，申报奖励数呈逐年递减趋势；各层次科研奖励的申报数分布相对不均。从所获科研奖励的基本特征看，获奖难度最大的是国家科学技术奖；所获科研奖项多是基于社会认可度和权威性较高的课题，且所获科研奖励的项目第一完成人均为正高级职称。本文认为，若要提高科研奖励申报的成功率，应从提升课题质量、加强课题成果交流与宣介入手，以科研团队建设为支撑，构建合理的科研成果考核机制。     

日照市海产品中副溶血性弧菌带菌状况调查

目的：了解日照市海产品中副溶血性弧菌（Vibrio parahaemolyticus,VP）带菌情况和耐药谱,为VP食源性疾病的监测提供科学依据.方法： 根据GB/T 4789.7-2003标准进行副溶血性弧菌的分离培养和鉴定,K-B法进行药敏实验.结果：160份样品中检出副溶血性弧菌54株,带菌率33.75% 药敏试验结果显示,54株副溶血性弧菌对青霉素类、内酰胺类、氨基糖苷类、磺胺类、喹诺酮类、头孢类药物都有耐药株出现,部分菌株多重耐药,其中氨苄西林的耐药率最高,达58.7%.结论：日照市海产品VP污染严重,应引起我们的关注 同时加强水产品抗生素使用的管理,防止耐药菌株的传播.     

海绵药物的研究进展:化学和生物活性

近年来国际上对海洋天然产物的研究日益深入，依托现代大规模药理筛选，目前已有多种结构新颖、药理活性显著且作用机制特殊的海洋天然产物进入临床试验阶段或正在进行临床前研究。海绵种类繁多，代谢途径独特，生存环境多样，共生现象复杂而普遍，多年来一直是海洋天然产物领域最富成果的研究领域之一。本文简要介绍近几年海绵化学成份及其药理活性的研究进展，以供国内同行参考。     

受区炎性疤痕吻合血管游离皮瓣移植术中的手术要点

目的：探讨受区炎性疤痕吻合血管游离皮瓣移植手术的成功率。方法：受区炎性疤痕,需行游离皮瓣修复10例,其中桥式交叉吻合3例,血管移植4例,扩大清创至正常区域吻合3例。结果：所有皮瓣均完全存活,未出现血管危象,术后功能恢复良好。结论：受区慢性感染所致的炎性疤痕内的血管不可行血管吻合,吻合处应位于正常组织内,以提高皮瓣存活率,减少术后血管危象发生。     

海洋微生物次生代谢产物的结构特征和生物活性的研究进展

本文归纳了21世纪以来海洋微生物产生的次生代谢产物的结构类型及其抗菌、抗肿瘤、抗心脑血管疾病、抗炎症和酶抑制等生物活性,并展望了今后海洋微生物和海洋天然产物的发展方向。     

前沟藻属海洋甲藻的化学成分及生物活性研究进展

前沟藻属甲藻中含有丰富的结构新颖、生物活性多样的大环内酯类和长链多羟基多烯类化合物，其潜在的药用价值引起了人们的广泛关注.本文对1986年到2003年间有关前沟藻属甲藻的化学和生物活性研究进展进行综述，并在此基础上对这类海洋微生物的药用前景进行展望．     

现代生物技术在海洋药物研究中的应用

人类进入20世纪80年代以来，世界各国，特别是沿海国家的科研人员在全球范围展开了对海洋生物资源的开发工作，其中海洋生物活性物质和海洋药物的研究是开发中的热点。随着现代生物技术的发展，包括细胞培养、生物活性物质的分离纯化、高通量筛选、基因工程以及药物的修饰等在内的各种生物技术在其中发挥着重要作用。本文将结合我们在海洋药物研究中的工作，就现代生物技术在海洋天然产物和海洋药物研究领域中的应用作一综述。     

天然药物化学史话:来自海洋的药物

海洋独特的环境造就了海洋生物的多样性和海洋生物次生代谢产物的多样性,海洋天然产物新颖的化学结构和独特的生物活性成为新药研发先导化合物的宝库。主要针对近年来已经上市或者具有良好开发前景的海洋药物的发现过程及化学结构进行简要介绍,以期能引起更多专业工作者的兴趣,并借此激励有志于科学研究的年轻工作者。     

Phospholipase A2 inhibitors from marine organisms.

This review of phospholipase A2 (PLA2) inhibitors from marine organisms presents a compilation of research in this field over the past decade. As an introduction to the research on marine natural products, there is an overview of the role of PLA2 in inflammation that provides a rationale for seeking inhibitors of PLA2 as anti-inflammatory agents. A radiometric assay to measure inhibition of bee venom PLA2 is described in detail. Examples of marine natural products that inhibit PLA2 are manoalide and its derivatives, scalaradial and related compounds, the pseudopterosins, the vidalols, and a group of terpenoids that contain masked 1,4-dicarbonyl moieties.     

Challenges and rewards of research in marine natural products chemistry in Brazil

Brazil is blessed with a great biodiversity, which constitutes one of the most important sources of biologically active compounds, even if it has been largely underexplored. As is the case of the Amazon and Atlantic rainforests, the Brazilian marine fauna remains practically unexplored in the search for new biologically active natural products. Considering that marine organisms have been shown to be one of the most promising sources of new bioactive compounds for the treatment of different human diseases, the 8000 km of the Brazilian coastline represents a great potential for finding new pharmacologically active secondary metabolites. This review presents the status of marine natural products chemistry in Brazil, including results reported by different research groups with emphasis on the isolation, structure elucidation, and evaluation of biological activities of natural products isolated from sponges, ascidians, octocorals, and Opistobranch mollusks. A brief overview of the first Brazilian program on the isolation of marine bacteria and fungi, directed toward the production of biologically active compounds, is also discussed. The current multidisciplinary collaborative program under development at the Universidade de S?o Paulo proposes to establish a new paradigm toward the management of the Brazilian marine biodiversity, integrating research on the species diversity, ecology, taxonomy, and biogeography of marine invertebrates and microorganisms. This program also includes a broad screening program of Brazilian marine bioresources, to search for active compounds that may be of interest for the development of new drug leads.     

海洋来源药食同源品开发利用研究进展

海洋蕴含着丰富的生物资源,是药食同源品研究与开发的重要宝库。近年来,以虾青素及海藻多糖为代表的海洋活性成分成为健康领域的关注热点,体现了海洋来源药食同源品的独特应用潜力。以目前研究较多的几类海洋来源脂质、多糖、多肽及皂苷类药食同源品为例,分别介绍其来源、结构、生物活性、开发利用潜力等方面的研究概况,以期为海洋来源药食同源品的深入开发和利用提供参考。     

The 1990 United States-Japan seminar on bioorganic marine chemistry, meeting report.

The second U.S.-Japan Seminar on "Bioorganic Marine Chemistry" was held in Honolulu, Hawaii, 3-7 December, 1990. Twenty-one invited lecturers and fourteen observers from the two countries attended. Recent results in the areas of (a) new bioactive natural products, (b) biological and pharmacological activity of marine natural products, and (c) biosynthesis of marine natural products were presented and discussed. Summaries of the presentations and relevant chemical structures are presented in this report.     

大学校园高品质学生学术文化建设的实践与思考

从2001年开始,北京中医药大学相继推出了大学生科技创意大赛、创业方案大赛、科研课题招标、学术成果展览、知识竞赛、科技论文大赛、学术讲座等多项活动。到2005年年底,我校已经形成了上半学年举行大学生科研课题招标,下半学年举行大学生科研课题结题、科技论文大赛和创业计划大赛,“杏林阡陌”“博导论坛”学术讲座贯穿于全学年的学生学术工作平台,搭建了学生学术传承、探讨的平台,这对塑造严谨创新的学风和校风、对大学生的成长成才以及营造浓郁的学生学术文化氛围具有重要的意义。     

Rise and Fall of Oral Health Products with Canadian Bloodroot Extract†

The rhizome of Sanguinaria canadensis (SC, bloodroot) contains an active principle with antimicrobial, antiinflammatory, antioxidative and immunomodulatory effects. For this reason SC extract has been added to toothpastes and mouthwashes in various concentrations. When tested separately, neither the toothpastes nor the mouthwashes with SC extract had any demonstrable clinical effectiveness against dental plaque and gingivitis. Although using them together twice a day seemed more effective than using placebo, more recent studies have shown conflicting results. Preclinical safety studies up to 2000, which did not include studies longer than 6 months, were thought not to indicate any appreciable potential for harm – to the oral mucosa in particular. In 2003, the FDA Subcommittee on Oral Health Care Drug Products for Over‐the‐Counter Human Use concluded from a review that using SC‐containing products is safe. However, for reasons unknown, the review failed to consider publications between 1999 and 2001 that suggested a possible link between the use of SC‐containing products and the pre‐neoplastic lesion, leukoplakia. As it happened, bloodroot had already been removed (in 2001) from the formula of one of the most widely used products in question and the brand has since then disappeared altogether from the worldwide market. Copyright © 2012 John Wiley & Sons, Ltd.     

The Immunostimulating Role of Lichen Polysaccharides: A Review

The immune system has capacity to suppress the development or progression of various malignancies including cancer. Research on the immunomodulating properties of polysaccharides obtained from plants, microorganisms, marine organisms, and fungi is growing rapidly. Among the various potential sources, lichens, symbiotic systems involving a fungus and an alga and/or a cyanobacterium, show promise as a potential source of immunomodulating compounds. It is well known that lichens produce an abundance of structurally diverse polysaccharides. However, only a limited number of studies have explored the immunostimulating properties of lichen polysaccharides. Published studies have shown that some lichen polysaccharides enhance production of nitrous oxide (NO) by macrophages and also alter the production levels of various proinflammatory and antiinflammatory cytokines (IL‐10, IL‐12, IL‐1β, TNF‐α, and IFN‐α/β) by macrophages and dendritic cells. Although there are only a limited number of studies examining the role of lichen polysaccharides, all results suggest that lichen polysaccharides can induce immunomodulatory responses in macrophages and dendritic cells. Thus, a detailed evaluation of immunomodulatory capacity of lichen polysaccharides could provide a unique opportunity for the discovery of novel therapeutic agents. Copyright © 2014 John Wiley & Sons, Ltd.     

The cephalostatin way of apoptosis

The cephalostatins, bis-steroidal natural products from the marine tube worm Cephalodiscus gilchristi, were isolated by Dr. G. R. Pettit and his group. These compounds show a unique cytotoxicity profile in the in vitro screen of the National Cancer Institute, suggesting a novel mechanism of action. Indeed, cephalostatin 1 ( 1) is an extremely powerful agent that acts via an unusual apoptosis pathway. It induces selective Smac/DIABLO, but no cytochrome c release from mitochondria. Nevertheless, caspase-9 is required for apoptosis induction. Interestingly, caspase-9 is activated without the participation of the apoptosome, leading to the question of its mechanism of activation. We found that endoplasmic reticulum stress-associated caspase-4 contributes to nonclassical cephalostatin-mediated caspase-9 activation, additionally pointing out the unusual pathway used by this substance. Cephalostatin 1 ( 1), therefore, provides a very good tool to discover novel apoptotic pathways, which might be important in the understanding and treatment of chemo-resistant cancer.     

Bacterial production of the tunicate-derived antitumor cyclic depsipeptide didemnin B

Natural products obtained from marine invertebrates such as sponges and tunicates are attractive sources of drugs. However, a critical obstacle in the development of these compounds is the problem of supply. In most cases, neither chemical synthesis nor mariculture of invertebrates is economically feasible. Due to structural similarities, many marine natural products are suspected to be produced by associated microorganisms. A favorable strategy for the production of such compounds is to use culturable microorganisms. Here we report that didemnin B, a tunicate-derived depsipeptide, has been isolated from a culturable bacterium, Tistrella mobilis YIT 12409.