2006 Annual Report 1.What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? Why does it matter? What major problem or issue is being resolved and how are you resolving it? Natural products offer a vast and virtually unlimited source of new agents for both the pharmaceutical and agrochemical industries. The National Center for Natural Products Research (NCNPR) was created to bring together an alliance of academia, government, and the pharmaceutical and agrochemical industries to integrate research, development, and commercialization of potentially useful natural products. The overall goal of this project is to discover new bioactive natural products from higher plants with potential to become lead compounds for development as new agrochemicals and pharmaceuticals, and to examine the biological and chemical properties of medicinal plants in order to develop them as alternative crops. The specific research objectives include: Objective 1: Discover secondary metabolites from natural resources with anti-infective and anti-cancer activities based on molecular and cell-based assays. Objective 2: Characterize mechanisms of action, selectivity, toxicity, and functional activity for the best candidate compounds with anti-microbial and anti-cancer properties in secondary assays and in animal models. Objective 3: Selection, agronomics, and analysis of medicinally important plants and their derived products. This project is aligned with National Program 302 "Plant Biological and Molecular Processes". This research allows scientists from USDA and the university to work together to identify new molecular targets for the discovery of agrochemicals and pharmaceuticals and to share resources, including specimens of plants and marine organisms collected from worldwide sources, that facilitate the discovery of novel bioactive natural products that can serve as lead compounds for development of new toxicologically safe, environmentally benign pest management agents and new pharmaceuticals. This research also allows scientists from USDA and the university to work together to solve problems related to the production of high quality medicinal plants that produce drugs or precursors to drugs, or are sold as dietary supplements. How serious is the problem? Why does it matter? Description of the Problem to be Solved – Cancer, infectious disease and neurodegenerative disease are still leading causes of morbidity and mortality in the US and around the world. Natural products have a proven track record in providing novel treatment approaches for these disorders, and offer a vast and virtually unlimited source of new agents for both the pharmaceutical and agrochemical industries. Many segments of the biosphere are largely unexplored, and in many parts of the world, our biodiversity is being lost at an alarming rate. The overall goal of this project is to discover, develop and commercialize new bioactive natural products from higher plants and other natural sources. Such technologies can provide new products for human/animal health and agricultural productivity, provide incentives for conservation of biodiversity, and stimulate economic development. Despite significant advances in drug discovery in the last half-century, there remain important unmet therapeutic needs. Likewise, there is an urgent need to identify new and safer pest management agents. Natural products offer a virtually unlimited source of potential new pharmaceuticals and agrochemicals, largely because of the remarkable diversity of both chemical structures and biological activities of naturally occurring secondary metabolites. Over 50% of prescription drugs on the US market were derived from natural products. Additionally, the utility of novel bioactive natural products as biochemical probes, the development of novel and sensitive techniques to detect biologically active natural products, improved techniques to isolate, purify, and structurally characterize these active constituents, and advances in solving the demand for supply of complex natural products collectively provide a compelling justification to search for bioactive natural products with potential pharmaceutical and agricultural applications. Ultimately, commercially available plant-derived pharmaceuticals and agrochemicals could create a demand for such plants as alternative crops. Additionally, a wide array of plant-based substances (i.e., botanical dietary supplements, 'herbal remedies') are consumed by millions of people daily in the US. The US market for botanical dietary supplements is estimated to be between 4 and 5 billion dollars. There is a critical ongoing need for quality, research-based scientific information to provide the basis for establishing standards and monitoring the quality and safety of botanical products consumed by the public, to guide health care professionals and the consuming public in their decisions regarding the use of these products, for introducing new products that have a firm research underpinning, and for assessing the potential of such products to become alternative crops for US farmers. 2.List by year the currently approved milestones (indicators of research progress) Objective 1: Discover secondary metabolites from natural resources with anti-infective and anti-cancer activities based on molecular and cell-based assays. Milestone 1.1: Expansion of the natural products repository through collections and strategic partnerships with other institutions; Milestone 1.2: Enhancement of throughput for the isolation, identification and analysis of important plant-derived natural products with pharmaceutical or agricultural applications. Objective 2: Characterize mechanisms of action, selectivity, toxicity, and functional activity for the best candidate compounds with anti-microbial and anti-cancer properties in secondary assays and in animal models. Milestone 2.1: Enhance the capacity to characterize isolated lead natural products to assess their suitability as drug or agrichemical development candidates in preliminary profiling assays; Milestone 2.2: Enhance the capacity to do detailed assessments on isolated lead natural products to assess their suitability for advancement into formal early development studies as pharmaceuticals or agrichemicals; Milestone 2.3: Advance lead candidates into early development studies. Objective 3: Selection, agronomics, and analysis of medicinally important plants and their derived products. Milestone 3.1: Develop analytical methods on botanicals of interest for supply of pharmaceuticals or agrichemicals or their precursors or of importance as botanical supplements; Milestone 3.2: Develop reference materials [authenticated plant specimens, standardized extracts, or chemical reference standards] on botanicals that are of commercial, economic, or public health importance; Milestone 3.3: Conduct horticultural and agronomic studies on candidate medicinal plants to assess suitability for crop development. 4a.List the single most significant research accomplishment during FY 2006. A patent was issued on our natural product-derived anticancer compounds in preclinical assessment at the National Cancer Institute. These agents showed promise against several cancers in animal models, most significantly the treatment of leukemias, and the prevention liver metastases in sarcomas. 4b.List other significant research accomplishment(s), if any. Our antimalarial drug candidate was advanced with external funding through exploratory toxicology and primate efficacy trials, with positive results. In FY 07, the regulatory toxicology should be completed, and clinical trials anticipated in the spring of 2007. 4c.List significant activities that support special target populations. None. 4d.Progress report. None. 5.Describe the major accomplishments to date and their predicted or actual impact. Many joint projects between USDA and university scientists have been initiated. These projects have led to a total of three issued U.S. patents. There is also currently one U.S. patent application pending. During FY 2005-2006, one patent issued and the referenced pending application received a Notice of Allowance. In addition, 7 joint publications have originated from the collaboration in 2006. The plant specimen acquisition project has continued to expand with a total of over 7,750 samples in the natural product repository. These samples are being characterized on an ongoing basis for biological activity and the chemical constituents responsible for the biological effects are being identified and isolated. In addition, collaborations with external collection groups have been established to enhance our internal capabilities, most notably with the Missouri Botanical Garden, the New York Botanical Garden and the Kenya Academy of Sciences. Additional biological assays, including functional genomic-based assays, have been utilized to identify potentially useful bioactive natural products. Several new biological assays for plant and human pathogens have been added. Emphasis has been placed on the discovery of antifungals, anticancer, antiinflammatory agents and immunomodulating agents. Over 3,374 natural product crude extracts, semi-purified fractions and purified compounds were screened in 2005-2006 for biological activities against specific molecular targets and/or whole cell systems. Significant progress continues to be made in determining antifungal lead compounds for pharmaceutical use from several novel classes of compounds. In addition, promising agrochemical lead compounds have been identified from the sampangine class of antifungals and a joint USDA/University of Mississippi patent application has been filed. A commercial partner is currently investigating the market potential of these compounds. Progress continues to be made on the development of a promising 8-aminoquinoline derivative for the treatment of PCP infections in AIDS patients and malaria. Scale-up and preclinical toxicology of the compound is ongoing in collaboration with the National Institutes of Health (NIH) and the Medicines for Malaria Venture in Geneva, Switzerland. A patent application was filed on a promising new class of compounds that have potent antifungal activity. This class will be investigated for potential pharmaceutical and agrochemical applications. We continue to develop new analytical and biological screening methods to characterize the chemical constituents responsible for biological activity of botanicals consumed as dietary supplements. This work forms the foundation for all studies that determine the correlation of pharmaceutical profiles and chemical profiles with observed therapeutic effects and conditions of cultivation and harvesting of medicinal plants. Work continues on a grant obtained from the NIH to continue our research on Echinacea to determine genetic variability in several medicinal plants of commercial interest. This project is aimed at understanding genetic and phenotypic factors that contribute to consistent high quality medicinal plant material, including the optimal conditions for the cultivation, harvest, and post-harvest processing and storage of medicinal plants to ensure maximum yield of valuable chemicals and/or therapeutic effect. A patent application has been filed and a second application is in the draft stage of development. Two license agreements were executed with pharmaceutical companies to commercialize potent immunostimulants isolated from blue green algae and aloe. Our “Living Collection” of medicinal plants has grown from about 400 to 900 species over the period of 2002-2006. In addition, our seedbank of medicinal plants now stands at 450 species. Demonstration plots of several medicinal herbs are grown each year in our Medicinal Plant Garden. A commercial partner is evaluating the market potential of an anthraquinone derivative as a potential algaecide. A jointly owned USDA/University of Mississippi patent application was filed on the compound that has been shown to have selective activity against the blue green algae responsible for the development of the off-flavor in catfish. 6.What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end-user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? Procedures for isolating purified reference compounds from popular dietary supplement ingredients and analytical methods for characterizing the compounds have been licensed to ChromaDex, Incorporated. ChromaDex is currently selling these standards to the dietary supplement and functional food industries. A process for extracting a novel immunostimulatory ingredient from blue green algae was transferred to Nordic Phytopharma. The company is currently conducting clinical trials. A process for extracting a novel immunostimulatory ingredient from aloe was transferred to AHMC, Inc. The company is currently scaling up production of the ingredient. The results of our research are disseminated through presentations at scientific meetings, publications in scientific journals, and/or patents. The information is thus available to the scientific community immediately upon presentation or publication. For patented technology, efforts to identify licensing partners commence immediately upon filing for patent application (or sooner in some cases), and it is expected that it will be 5–10 years before the technology (especially new pharmaceuticals) will be available to the end user. Constraints in developing pharmaceuticals are related principally to the rigorous regulatory requirements mandated by the Food and Drug Administration. The cost of developing a pharmaceutical product has been estimated to exceed $800 million. In order for a pharmaceutical company to be interested in licensing one of our lead compounds we must conduct sufficient pharmacology and toxicology studies to give an indication that the compound is a likely candidate for full development and has advantages over existing drugs and compounds in industrial pipelines. 7.List your most important publications in the popular press and presentations to organizations and articles written about your work. (NOTE: List your peer reviewed publications below). Articles in popular press: Moraes, R.M. Partners Video Magazine – http://www.csrees.usda.gov/newsroom/partners/partners.html Partners is a video magazine produced by the Cooperative State Research, Education, and Extension Service (CSREES). It highlights the programs and accomplishments of the partnership between CSREES and the Land Grant University System in the areas of research, education, and extension. CSREES-USDA/NRI-Wild Medicine – episode 14, In Mississippi, researchers are exploring the full medicinal wonders of the Mayapple, a plant that already produces chemicals used in anti-cancer drugs. Presentations: Wang X, Haasch ML, Dasmahapatra AK, “Ethanol perturbs alcohol dehydrogenase enzyme mRNA expression in Japanese medaka embryo”, 45th Annual Meeting of the Society of Toxicology, San Diego, CA, March 5-9, 2006. Argote K, Chaudhary A, Weston J, Khan SI, Willett KL, “Toxicological Analyses of Mississippi Coastal Water and Sediment Samples following Hurricane Katrina”, Society of Toxicology Meeting, San Diego, CA, June 28, 2005. Herath HMTB, Nanayakkara NPD, “Stereoselective synthesis of fire ant venom alkaloids, solenopsins and isosolenopsins”, Annual Meeting of the American Society of Pharmacognosy, Corvallis, OR, July 23-27, 2005. Jayasinghe L, Nanayakkara NPD, Jacob M, Abbas H, “Antimicrobial compounds from Fusarium polypialidicum”, Annual Meeting of the American Society of Pharmacognosy, Corvallis, OR, July 23-27, 2005. Nanayakkara NPD, Jayasinghe L, Jacob M, Abbas H, “Antimicrobial compounds from Alternaria alternate”, Annual Meeting of the American Society of Pharmacognosy, Corvallis, OR, July 23-27, 2005. Li XC, Jacob MR, Agarwal AK, Smillie TJ, Khan SI, Nagle DG, Clark AM, “New cycloartenone triterpenes from the green alga Penicillus capitatus that enhance fluconazole activity in eflux pump-overexpressing Saccaromyces cerevisiae”, Annual Meeting of the American Society of Pharmacognosy, Corvallis, OR, July 23-27, 2005. Zhou YD, Kim YP, Li XC, Baerson SR, Agarwal AK, Hodges T, Ferreira D, Nagle DG, “Hypoxia-inducible factor-1 activation by (-)-epicatechin gallate: Potential adverse effects of cancer chemoprevention with high-dose green tea extracts”, Annual Meeting of the American Society of Pharmacognosy, Corvallis, OR, July 23-27, 2005. Baerson SR, Dayan FE, Rimando AM, Pan Z, Cook D, Nanayakkara NPD, Duke S, “A Functional Genomics Approach for the Identification of Genes Involved in the Biosynthesis of the Allelochemical Sorgoleone”, ACS Symposium Series, 2005. Zhu XY, Jacob MR, Khan SI, Walker LA, Ablordeppey SY, “Bis-Indoloquinolines: New Antiinfection Agents with Low Cytotoxicity”, ACS National Meeting, Washington, DC, August 28-September 1, 2005. Avula B, Joshi V, Weerasooriya A, Khan IA, “Quantitative Determination and Separation of Adrenergic Amines and Flavonoids from Poncirus trifoliatus Raf. Fruits at Different Growth Stages by High Performance Liquid Chromatography”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Khan SI, Avula B, Puella S, Choi YW, Khan IA, “Bioavailability and Intestinal Transport of Lignans from Schisandra Chinensis”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Khan SI, Avula B, Navarrete A, Khan IA, “Bioavailability and Intestinal Transport of triterpenoids from ampiptherygium adstringens”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Choi YW, Takamatsu S, Khan SI, Srinivas PV, Ferreira D, Zhao J, Khan IA, “Structure-Antioxidant Activity Relationships of Lignans from Schisandra Chinensis”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. ElSohly MA, Gul W, Feng S, Nanayakkara NPD, Clark AM, Khan SI, Cogswell FB, Walker LA, “GC/MS Analysis of the 8-Aminoquinoline Antimalarial [NPC 1161] and its Carboxy Metabolite in Plasma and Red Blood Cells of Primates”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Avula B, Tripathi LM, Khan SI, Tekwani BL, Nanayakkara NPD, Gul W, ElSohly MA, Khan IA, “HPLC Method for the determination of NPC 1161, Primaquine and their metabolites in various biological systems”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Avula B, Navarrete A, Ji X, Hersh P, Khan IA, “Quantitative Determination of Triterpenes from Amphiptherygium adstringens by HPLC and HPTLC”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Shukla Y, Schaneberg B, Pawar R, Avula B, Khan IA, “Phytochemical Investigation of Hoodia gordonii, a South African Succulent Plant with Anorectic Activity”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Avula B, Upparapalli SK, Goldman P, Khan IA, “Identification of Quercetin, Amentoflavone, Sesamin and GA-1 in Ginkgo Products by Liquid Chromatography”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Avula B, Khan IA, “Simultaneous Quantification of Benzethonium Chloride, Methyl Paraben and Triclosan in Grapefruit Seed Extracts by HPLC”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Avula B, Upparapalli SK, Khan IA, “Enantiomeric Separation and Determination of Adrenergic Amines in Citrus aurantium, Various Citrus species, Related Genera and Dietary Supplements by High Perfomance Capillary Electrophoresis”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Avula B, Upparapalli Sk, Navarrete A, Khan IA, “Simultaneous Quantification of Adrenergic Amines and Flavonoids in Various Citrus Species and Dietary Supplements by Liquid Chromatography”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Avula B, Navarrete A, Upparapalli SK, Khan IA, “Simultaneous Analysis of Synephrine, and other Adrenergic Amines and Flaonoids in Citrus Peel Jams and Fruit Juices by Liquid Chromatography”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Avula B, Navarrete A, Joshi VC, Khan IA, “Quantification of Parthenolide in Tanacetum species by LC-UV/LC-MS and Microscopic Comparison of Mexican/US Feverfew Samples”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Ugalde M, Reza V, Gonzalez-Trujan E, Avula B, Khan IA, “Isobolographic analysis of the sedative interaction between six central nervous system depressant drugs and Valeriana edulis hydroalcoholic extract in mice”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Avula B, Navarrete A, Choi YW, Khan IA, “Chemical Fingerprinting of Valeriana Species: Simultaneous Determination of Valerenic Acids, Flavonoids and Phenylpropanoids using HPLC with UV-detection”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Herath WHMW, “Microbial Metabolism of 3-Hydroxyflavone and 7-Hydroxyflavone”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Balachandran P, Khan IA, Pasco DS, “Botanicals of FDA concern: Screening for cytotoxicity and apoptosis induction in vitro”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Mehmedic Z, Chandra S, Martin J, Foster S, Khan IA, ElSohly MA, “Delta9-THC and other Cannabinoids content of confiscated marijuana: Potancy trends, 1993-2004”, IACM 3rd International Conference on Cannabinoids in Medicine, Leiden University, September 9-10, 2005. Mehmedic Z, Chandra S, Martin J, Foster S, Khan IA, ElSohly MA, “Delta9-THC and other Cannabinoids content of confiscated marijuana: Potancy trends, 1993-2004”, NCNPR Annual Poster Session, University, MS, October 21, 2005. Stanford D, ElSohly MA, Chandra S, Juergens JP, “Techniques for a viable plant inventory for regulatory compliance”, NCNPR Annual Poster Session, University, MS, October 21, 2005. Chandra S, Joshi SC, “Effect of altitude on photosynthetic and biochemical characteristics of Podophyllum hexandrum and Aconitum balfourii, two Alpine endangered medicinal herb from Central Himalaya”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Muhammad I, Samoylenko V, Gafur MA, Ross SA, Mossa JS, Tekwani BL, Dunbar DC, Bosselaers J, ElSohly MA, ElFeraly FS, “Antiparasitic, Nematicidal and Antifouling Constituents from Juniperus Berries”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Samoylenko V, Dunbar DC, Rushing JW, Khan IA, Muhammad I, “Two new constituents of Morinda citrifolia (NONI) fruit juice”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Agarwal AK, Jacob MR, Li XC, Feng Q, Walker LA, Clark AM, “Genomic, genetic and molecular approaches to identify MOA of antifungal compounds”, NCNPR Annual Poster Session, University, MS, October 21, 2005. Singh K, Agarwal AK, Khan SI, Walker LA, Tekwani BL, “Comparative in vitro drug susceptibility and gene expression profiling of Plasmodium falciparum grown in culture medium supplemented with human serum or Albumax”, NCNPR Annual Poster Session, University, MS, October 21, 2005. Li XC, Jacob MR, Agarwal AK, Smillie TJ, Khan SI, Nagle DG, Clark AM, “Cycloartanone Triterpenes from the Green Alga Penicillus captatus that enhance Fluconazole Activity in Efflux Pump-Overexpressing Saccharomyces cerevisiae”, NCNPR Annual Poster Session, University, MS, October 21, 2005. Digirolamo J, Li XC, Jacob MR, Smillie TJ, Khan SI, Ferreira D, Agarwal AK, Clark AM, “Isolation, structure elucidation, and reversal of fluconazole resistance of sterol sulfates from Trachyopsis sp.”, NCNPR Annual Poster Session, University, MS, October 21, 2005. Huang TL, Eynde JJV, Mayence A, Khan SI, Tekwani BL, “Antiprotozoal activities of a library of bixbenzamidines”, Pacifichem, Honolulu, HA, December 15-20, 2005. Willett KL, Chaudhary A, Khan SI, Singh S, Azua A, Gardinali P, “Assessment of toxicological potential in marine coastal areas using YES assay and chemical analyses”, SETAC, Baltimore, MD, November 1, 2005. Tekwani BL, Tripathi LM, Khan SI, Avula B, Khan IA, ElSohly MA, Nanayakkara NDP, Walker LA, “Biotransformation of primaquine and NPC 1161 to carboxymetabolites: role of semicarbazide sensitive amine oxidase”, ASTMH Annual Meeting, Washington DC, December 11-15, 2005. Huang TL, Eynde JJV, Mayence A, Khan SI, Tekwani BL, “Antiplasmodial and Antileishmanial activities of Pentamidine congeners”, 45th Annual ICAAC Meeting,Washington DC, December 16-19, 2005. Telang NS, Illendula A, Tekwani BL, Khan SI, Avery M, “Design, Synthesis and Biological Evaluation of Isoflavones as Antigiardial Agents”, Regional Meeting, November 1-4, 2005. Smillie TJ, “The Natural Product Repository and Natural Products Quality Control”, Phytochemical Society of North America National Meeting, The Salk Institute, La Jolla, CA, July 30 - August 3, 2005. Slattery M, Gochfeld D, Lesser MP, “Ecology and bioactiity of Deep-Reef Sponge Communities in the Bahamas”, 7th International Sponge Symposium, Buzios Brazil, Buzios, Brazil, May 7-13, 2006. Gochfeld D, Harrison L, Olson J, Lesser M, Ankisetty S, Slattery M, “Allelopathic effects of the Caribbean sponge Svenzea zeai on the coral Montastraea annularis”, 7th International Sponge Symposium, Buzios Brazil, Buzios, Brazil, May 7-13, 2006. Scloeder C, Thacker R, Gochfeld D, “Effect of Anthropogenic Disturbance on Sponge Communicty Structure and Disease Incidence”, 7th International Sponge Symposium, Buzios Brazil, Buzios, Brazil, May 7-13, 2006. Gochfeld D, Slattery M, Olson JB, “Aplysina red band syndrome: a new condition affecting Caribbean sponges”, 7th International Sponge Symposium, Buzios Brazil, Buzios, Brazil, May 7-13, 2006. Gochfeld D, Avery BA, Marsh KE, Thacker RW, Slattery M, “Chemical Ecology of Caribbean sponges: habitat-specific variability in chemical defenses”, Annual Meeting of the American Society of Pharmacognosy, Corvallis, OR, July 23-27, 2005. Slattery M, Gochfeld D, Ankisetty S, Miller J, Rimoldi JR, Willett KL, Smillie TJ, Jacob MR, Best AM, Chambliss WG, Walker LA, “The NIUST Ocean Biotechnology Center & Repository”, Annual Meeting of the American Society of Pharmacognosy, Corvallis, OR, July 23-27, 2005. Purcell J, Slattery M, Gochfeld D, “Determining the Bioactivity of a Marine Sponge Extract against Leishmania”, Annual Biomedical Research Conference for Minority Students, Atlanta, GA, November 2-4, 2005. Gochfeld D, Miller J, Olson JB, “Variability in Susceptibility and Response to Dark Spot Syndrome in Siderastrea siderea”, 13th Ocean Sciences Meeting, Honolulu, Hawaii, February 20-24, 2006. Miller J, Olson JB, Gochfeld D, “Histological Examination of Siderastrea siderea Affected by Dark Spot Syndrome”, 13th Ocean Sciences Meeting, Honolulu, Hawaii, February 20-24, 2006. Khan, IA, “Challenges in Assessing the Quality and Safety of Botanicals: A Global Co-operation is needed”, International Conference on Quality and Safety Issues Related to Botanicals, Oxford, MS, August 15-18, 2005. Khan, IA, “Quality and Safety of Botanicals - Global Cooperation Perspective”, Indo-US Symposium, New Delhi, India, October 3-6, 2005. Khan, IA, “Challenges in Assessing the Quality and Safety of Botanicals: A Global Co-operation is needed”, Bio Forum 2005, Shanghai, China, April 26-28, 2005. Khan, IA, “Quality and safety issues related to herbal medicine”, 10th International Symposium on Traditional Medicine in Toyama, Toyama, Japan, July 14-15, 2005. Khan, IA, “Natural Products Research at NCNPR”, University of Hong Kong, Hong Kong, June 8, 2005. Publications: Puella SV, Takamatsu S, Khan SI, Khan IA, “Isolation of lignans and biological activity studies of Ephedra viridis”, Planta Medica, 71(8):789-791, (2005). Puella SV, Choi YW, Khan SI, Khan IA, “New acylated clionasterol glycosides from Valeriana officinalis”, Planta Medica, 71(10):960-961, (2005). Arbiser J, Li XC, Hossain CF, Nagle DG, Smith D, Miller P, Govindarajan B, DiCarlo J, Landis-Piwowar K, Dou QP, “Naturally Occurring Proteasome Inhibitors from Mate Tea (Ilex paraguayensis)Serve as Models for Topical Proteasome Inhibitors”, The Society for Investigative Dermatology, 125:207-212, (2005). Ferreira D, Slade D, Marias J, “Flavans and Proanthocyanidins”, Flavanoids: Chemisty, Biochemisty and Applications, pages 553-616, (2005). Ferreira D, Slade D, Marias J, “Bi-, Tri-, Tetra-, Penta- and Hexaflavonoids”, Flavanoids: Chemisty, Biochemisty and Applications, pages 1101-1128, (2005). Marais J, Deavours B, Dixon RA, Ferreira D, “The Stereochemistry of Flavonoids”, The Science of Flavanoids, pages 1-46, (2005). Swamy RC, Kunert O, Schuhly W, Bucar F, Ferreira D, Rani VS, Kumar BR, Rao AVNA, “Structurally Unique Biflavonoids from Selaginella chrysocaulos and Selaginella bryopteris”, Chemistry and Biodiversity, 3:405-413, (2006). Cushman KE, Maqbool M, Bedir E, Lata H, Khan IA, Moraes RM, “Podophyllotoxin content and yield of American mayapple leaves in sun and shade”, HortScience, 40: 60-63, (2005). Weerasooriya A, Saunders RMK, “The Genus Mitrephora (Annonaceae) in Cambodia, Laos, and Vietnam”, Systematic Botany, 30(2):248-262, (2005). Avula B, Choi YW, Srinivas PV, Khan IA, “Quantitative Determination of Lignan Constituents from Schisandra chinensis by Liquid Chromatography”, Chromatographia, 61(9):515-518, (2005). Jacob MR, Walker LA, “Natural Products and Antifungal Drug Discovery”, Methods in Moledular Medicine: Antifungal Agents: Methods and Protocols, 118:83-109, (2005). Avula B, Joshi VC, Weerasooriya A, Khan IA,, “Liquid Chromatography for Separation and Quantitative Determination of Adrenergic Amines and Flavonoids from Poncirus trifoliatus Raf. Fruits at Different Stages of Growth”, Chromatographia, 62(7):379-383, (2005). Ahmed A, Bishr M, El-Shanawany M, Attia E, Ross SA, Pare P, “Rare trisubstituted sesquiterpenes daucanes from the wild Daucus carota”, Phytochemistry, 66:1680-1684, (2005). Master HE, Khan SI, Poojari KA, “Design and synthesis of low molecular weight compounds with complement inhibition activity”, Bioorganic & Medicinal Chemistry, 13(16):4891-4899, (2005). Ross SA, Al-Azeib MA, Krishnaveni KS, Fronczek F, Burandt CL, “Alkamides from the Leaves of Zanthoxylum syncarpum”, Journal of Natural Products, 68(8):1297-1299, (2005). Goud PM, Sheri A, Desai P, Watkins B, Tekwani BL, Sabnis Y, Gut J, Rosenthal P, Avery MA, “Design, Synthesis and Evaluation of Trisubstituted Thiazoles Targeting Plasmodium Falciparum Cysteine Proteases”, Medicinal Chemistry Research, 14(2):74-105, (2005) . Ojwang J, Wang YH, Wyde P, Fischer N, Schuely W, Appleman J, Hinds S, Shimasaki C, “A novel inhibitor of respiratory syncytial virus isolated from ethnobotanicals”, Antiviral Research, 68(3):163-172, (2005). Desai P, Patny A, Gut J, Rosenthal P, Tekwani BL, Srivastava A, Avery MA, “Identification of Parasitic Cysteine Protease Inhibitors by Use of Virtual Screening. 2. The Available Chemical Directory”, Journal of Medicinal Chemistry, 49:1576-1584, (2006). Wang Q, Williams E, Haasch M, Dasmahapatra A, “Japanese Medaka (Oryzias latipes): Development Model for the Study of Alcohol Teratology”, Birth Defects Research (Part B): Developmental and Reproductive Toxicology, 77(1):29-39, (2006). Tatsimo S, Tane P, Srinivas Pv, Sondengam B, Jacob M, Okunji C, Schuster B, Iwu M, Khan IA, “Novel Antimicrobial Diterpenoids from Turraeanthus africanus”, Planta Medica, 71:1145-1151, (2005). Tatsimo S, Tane P, Srinivas Pv, Sondengam B, Jacob M, Okunji C, Schuster B, Iwu M, Khan IA, “Antimicrobial Principle from Afranomum longifolius”, Planta Medica, 72:132-135, (2006). Repka MA, ElSohly MA, Munjal M, Ross SA, “Temperature Stability and Bioadhesive Properties of Delta9-Tetrahydrocannabiinol Incorporated Hydroxypropylcellulose Polymer Matrix Systems”, Journal of Drug Development and Industrial Pharmacy, 32:21-32, (2006). Slattery M, Gochfeld DJ, Kamel HN, “Hybrid soft coral aquaculture to produce novel "pharmaceutical factories"”, Global Aquaculture Advocate, 8(6):42-43, (2005). Gochfeld DJ, Olson JB, Slattery M, “Colony and population variation in susceptibility and resistance to Dark Spot Syndrome in the Caribbean coral Siderastrea siderea”, Diseases of Aquatic Organisms, 69:53-65, (2006). Reguera RM, Tekwani BL, Balana-Fouce R, “Polyamine transport in parasites: A potential target for new antiparasitic drug development”, Comparative Biochemistry and Physiology, Part C, 140:151-164, (2005). Bharate SB, Bhutani KK, Khan SI, Tekwani BL, Jacob MR, Khan IA, Singh IP, “Biomimetic synthesis, antimicrobial, antileishmanial and antimalarial activities of euglobals and their analogs”, Bioorganic & Medicinal Chemistry, 14(6):1750-60, (2005). Jain M, Khan SI, Tekwani BL, Jacob MR, Singh S, Singh P, Jain R, “Synthesis, antimalarial, antileishmanial, and antimicrobial actvities of some 8-quinolinamine analogues”, Bioorganic & Medicinal Chemistry, 13(14):4458-4466, (2005). Balachandran P, Pugh N, Ma G, Pasco DS, “Toll-like receptor 2-dependent activation of monocytes by Spirulina polysaccharide and its immune enhancing action in mice”, International Immunopharmacology, (2006). Avula B, Upparapalli SK, Khan IA, “Enantiomeric Separation of Adrenergic Amines in Citrus Species, Related General and Dietary Supplements by Capillary Electrophoresis”, Chromatographia, 62(3):151-157, (2005). Xiahong Ji, Khan I, Mosjidis JA, Wang H, Livant P, “Variability for the presence of pyrrolizidine alkaloids in Crotolaria juncea l.”, Pharmazie, 60(8):620-622, (2005). Gutierrez-Zepeda A, Santell R, Wu Z, Brown M, Wu YJ, Khan IA, Link CD, Zhao B, Luo Y, “Soy isoflavone glycitein protects against beta amyloid-induced toxicity and oxidative stress in transgenic Caenorhabditis elegans”, BMC Neuroscience, page 54, (2005). Yalcin FN, Ersoz T, Bedir Erdal, Sahpaz S, Bailleul F, Khan IA, Donmez AA, Calis I, “Phlinoside F, a New Phenylethanoid Glycoside from Phlomis angustissima”, Turk J. Chem, 29(4):417-423, (2005). Taskin MK, Caliskan OA, Anil H, Abou-Gazar H, Khan IA, Bedir Erdal, “Triterpene Saponins from Nigella sativa L.”, Turk J. Chem, 29(5):561-569, (2005). Demirci B, Baser KHC, Crockett SL, Khan IA, “Analysis of the Volatile Constituents of Asian Hypericum L. (Clusiaceae, Hyperidoidear) Species”, J. Essent. Oil Res., 17:659-663, (2005). Joshi VC, Navarrete A, Khan, IA, “Authentication of Valeriana procera Kunth and comparative account of five Valeriana species”, Journal of AOAC, 88(6):1621-1625, (2005). Avula B, Upparapalli SK, Navarrete A, Khan IA, “Simultaneous quantification of adrenergic amines and flavonoids in C. aurantium, various Citrus species, and dietary supplements by liquid chromatography.”, Journal of AOAC, 88(6):1593-1606, (2005). Calis I, Bedir E, Kirmizibekmez H, Ersoz T, Donmez AA, Khan IA, “Secondary Metabolites from Phlomisoppositiflora”, Natural Products Research, 19(5):493-501, (2005). Ji X, Khan IA, “Quantitative Determination of Usnic Acid in Usnea lichen and Its Products by Reversed-Phase Liquid Chromatography with Photodiode Array Detector”, Journal of AOAC, 88(5):1265-1268, (2005). Greenblatt D, Von Moltke LL, Luo Y, Perloff ES, Horan KA, Bruce A, Reynolds RC, Harmatz JS, Avula BH, Khan IA, Goldman P, “Ginkgo biloba Does Not Alter Clearance of Flurbiprofen, a Cytochrome P450-2C9 Substrate”, J. Clin Pharmacol, 46(2):214-221, (2006). Navarrete A, Avula B, Choi YW, Khan IA, “Chemical fingerprinting of valeriana species: simultaneous determination of valerenic acids, flavonoids, and phenylpropanoids using liquid chromatography with ultraviolet detection”, Journal of AOAC, 89(1):8-15, (2006). Navarrete A, Avula B, Joshi VC, Ji X, Hersh P, Khan IA, “Quantitative determination of triterpenes from Amphiptherygium adstringens by liquid chromatography and thin-layer chromatography and morphological analysis of cuachalalate preparations”, Journal of AOAC, 89(1):1-7, (2006). Bharate SB, Bhutani KK, Khan SI, Tekwani BL, Jacob MR, Khan IA, Singh IP, “Biomimetic synthesis, antimicrobial, antileishmanial and antimalarial activities of euglobals and their analgues”, Bioorganic & Medicinal Chemistry, 14(6):1750-1760, (2006). Khan, IA, “Issues related to botanicals”, Life Sciences, 78(18):2033-2038, (2006). Avula B, Wang YH, Pawar RS, Shukla YJ, Schaneberg B, Khan IA, “Determination of the Appetite Suppressant P57 in Hoodia gordonii Plant Extracts and Dietary Supplements by Liquid Chromatography/Electrospray Ionization Mass Spectrometry (LC-MSD-TOF) and LC-UV methods”, Journal of AOAC International, 89(3):606-611, (2006). Crockett SL, Schaneberg B, Khan IA, “Phtyochemical Profiling of New and Old World Hypericum (St. John's Wort) species”, Phytochemical Analysis, 16(6):479-485, (2005). Galal AM, Ross SA, Jacob MR, ElSohly MA, “Antifungal Activity of Artemisinin Derivatives”, Journal of Natural Products, 68(8):1274-1276, (2005). Li XC, ElSohly HN, Walker LA, Clark AM, “Phenolic Glycosides from Potalia amara”, Planta Medica, 71(10):977-979, (2005). Choi YW, Takamatsu S, Khan SI, Srinivas PV, Ferreira D, Zhao J, Khan IA, “Schisadrene, a Dibenzocyclooctadiene Lignan from Schisandra chinensis:Structue-Antioxidant Activity Relationships of Dibenzocyclooctadiene Lignans”, Journal of Natural Products, 69(3):356-359, (2006). Ankisetty SR, ElSohly H, Li XC, Khan SI, Tekwani BL, Smillie T, Walker LA, “Aromatic Constituents of Uvaria grandiflora”, Journal of Natural Products, 69(4):692-694, (2006). Herath WHMW, Mikell J, Hale A, Ferreira D, Khan IA, “Microbial Metabolism. Part 6. Metabolites of 3- and 7-Hydroxyflavones”, Chem. Pharm. Bull., 54(3):320-324, (2006). Li XC, Jacob MR, Ding Y, Agarwal A, Smillie TJ, Khan SI, Nagle DG, Ferreira D, Clark AM, “Capisterones A and B, which Enhance Fluconazole Activity in Saccharomyces cerevisiae, from the Marine Green Alga Penicillus capitatus”, Journal of Natural Products, 69(4):542-546, (2006). Mora F, Jones D, Desai P, Patny A, Avery MA, Feller DR, Smillie T, Zhou YD, Nagle DG, “Bioassay for the Identification of Natural Product-Based Activators of Peroxisome Proliferator-Activated Receptor-y (PPARy): The Marine Sponge Metabolite Psammaplin A Actvates PPARy and Induces Apoptsis in Human Breast Tumor Cells”, Journal of Natural Products, 69(4):547-552, (2006). Gormann R, Kaloga M, Ferreira D, Marais J, Kolodziej H, “Newbouldiosides A-C, phenylethanoid glycosides from the stem bark of Newbouldia laevis”, Phytochemistry, 67:805-811, (2006). Tekwani BL, Walker LA, “Targeting the hemozoin synthesis pathway for new antimalarial drug discovery: technologies for in vitro beta-hematin formation assay”, Combinatorial Chemistry & High Throughput Screening, 8(1):61-77, (2005). Moraes RM, Momm H, Silva B, Maddox V, Easson G, Lata H, Ferreira D, “Geographical information system method for assessing chemo-diversity in medicinal plants”, Planta Medica, 71:1157-1164, (2005). Jayasinghe L, Abbas HK, Jacob MR, Herath WHMW, Nanayakkara NPD, “N-Methyl-4-hydroxy-2pyridinone Analogues from Fusarium oxysporum”, Journal of Natural Products, 69(3):439-442, (2006). Mbwambo ZH, Kapingu MC, Moshi MJ, Machumi F, Apers S, Cos P, Ferreira D, Marais J, Bs Lerghe DV, Maes L, Vlietinick A, Pieters L, “Antiparasitic Activity of Some Zanthones and Biflavonoids from the Root Bark of Garcinia livingstonei”, Journal of Natural Products, 69(3):369-372, (2006). Yang CR, Zhang Y, Jacob M, Khan S, Zhang YJ, Li XC, “Antifungal Activity of C-27 Steroidal Saponins”, Antimicrobial Agents and Chemotherapy, 50(5):1710-1714, (2006). Smillie TJ, “International Conference on Quality and Safety Issues Related to Botanicals”, Chronica Horticulturae, 46(1):35-37, (2006). Joint USDA & NCNPR published manuscripts July 1, 2005 - June 30, 2006: Tabanca N, Bedir Erdal, Alankus-Caliskan O, Khan IA, “Cycloartane Triterpene gylocides from the roots of Astragalus gilvus Boiss”, Biochemical Systematics and Ecology, 33:1067-1070, (2005). Tabanca N, Demirci B, Kirimer N, Baser HC, Bedir Erdal, Khan IA, Wedge DE, “Gas chromatographic-mass spectrometric analysis of essential oils from Pimpinella aurea, Pimpinella corymbosa, Pimpinella peregrina and Pimpinella puberula gathered from Eastern and Southern Turkey”, Journal of Chromatogrpahy A, 1097:192-198, (2005). Tabanca N, Demirci B, Kirimer N, Baser HC, Bedir Erdal, Khan IA, Wedge DE, “Gas chromatographic–mass spectrometric analysis of essential oils from Pimpinella species gathered from Central and Northern Turkey”, Journal of Chromatogrpahy A, 1117(2):194-205, (2005). Techen N, Khan IA, Pan Z, Scheffler B, “The Use of Polymerase Chain Reaction (PCR) for the Identification of Ephedra DNA in Dietary Supplements”, Planta Medica, 72:241-247, (2006). Tabanca N, Douglas AW, Bedir Erdal, Dayan FE, Kirimer N, Base KHC, Aytac Z, Khan IA, Scheffler BE, “Patterns of essential oil relationships in Pimpinella(Umbelliferae) based on phylogenetic relationships using nuclear and chloroplast sequences”, Plant Genetic Resosurces, 3(2):149-169, (2005). Hossain CF, Kim YP, Baerson SR, Zhang L, Bruick R, Mohammed K, Agarwal AK, Nagle DG, Zhou YD, “Saururus cernuuslignans - Potent small molecule inhibitors of hypoxia-inducible factor-1”, Biochemical and Biophysical Research Communications, 333:1026-1033, (2005). Sampson BJ, Tabanca N, Nes'e K, Demirci B, Baser KHC, Khan IA, Spiers JM, Wedge DE, “Insecticidal activity of 23 essential oils and their major compounds against adult Lipaphis pseudobrassicae (Davis) (Aphididae: Homoptera)”, Pest Management Science, 61(11):1122-1128, (2005).