NCCIH Priorities for Natural Products Research.

The National Center for Complementary and Integrative Health (NCCIH) is the lead agency within the U. S. federal government for complementary and integrative health research, which includes natural products. Although NCCIH is one of the smaller components of the National Institutes of Health (NIH), NCCIH funds a disproportionately high percentage of natural products research at NIH. This stems from NCCIH being the only NIH grant issuing component that includes natural products as an explicit part of its mission. This perspective provides an overview of the NCCIH mission and summarizes NCCIH funding priorities for natural products research across basic and mechanistic as well as clinical sectors. These priorities are guided by the recently released NCCIH strategic plan. A primary element of this new plan is a focus on whole person health instead of the frequent focus on the treatment of diseases. The NCCIH focus on whole person health includes how natural products and multicomponent therapeutic approaches, which often include natural products, can help move individuals towards health restoration and promotion.

National Center for Complementary and Integrative Health Perspectives on Clinical Research Involving Natural Products.

The sales of dietary supplements continue to increase year after year. Despite their use by a large percentage of Americans, there is little evidence for the vast majority of products regarding their safety or efficacy. National Center for Complementary and Integrative Health supports a broad range of research on dietary supplements, including clinical trials. Our experience with these trials has shaped our current policies and priorities for clinical research. This perspective outlines those policies and priorities that are shaping our investments going forward. SIGNIFICANCE STATEMENT: The sales of dietary supplements continue to increase year after year. Despite their use by a large percentage of Americans, there is little evidence for the vast majority of products regarding their safety or efficacy. National Center for Complementary and Integrative Health supports a broad range of research on dietary supplements, including clinical trials. Our experience with these trials has shaped our current policies and priorities for clinical research. This perspective outlines those policies and priorities that are shaping our investments going forward.

Improving natural product research translation: From source to clinical trial.

While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a September, 2018 transdisciplinary workshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.

Naturally complex: Perspectives and challenges associated with Botanical Dietary Supplement Safety assessment.

Due to the extensive use of botanical dietary supplements by consumers in the United States, there is a need for appropriate research and data to support safety assessments. Complexity and variability, both natural and introduced, of botanical dietary supplements make research on these products difficult. Botanical dietary supplements are regulated by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended by the 1994 Dietary Supplement Health and Education Act (DSHEA). They are regulated as a category of food, which differs from the regulation of pharmaceutical products. Both manufacturers and the FDA are faced with the challenge of determining the best approaches for evaluating and monitoring the safety of botanical products. High quality botanicals research requires accurate identification and characterization of the material being studied. Inconsistent results in efficacy studies of botanical dietary supplements have led to efforts to improve the rigor and reproducibility of research in the field. Addressing the challenges associated with botanical dietary supplement safety is a global effort requiring coordination between numerous stakeholders, including researchers, suppliers, manufacturers, and regulators, all of whom play a role in ensuring that high quality products are available on the market.

The Challenge of Reproducibility and Accuracy in Nutrition Research: Resources and Pitfalls.

Inconsistent and contradictory results from nutrition studies conducted by different investigators continue to emerge, in part because of the inherent variability of natural products, as well as the unknown and therefore uncontrolled variables in study populations and experimental designs. Given these challenges inherent in nutrition research, it is critical for the progress of the field that researchers strive to minimize variability within studies and enhance comparability between studies by optimizing the characterization, control, and reporting of products, reagents, and model systems used, as well as the rigor and reporting of experimental designs, protocols, and data analysis. Here we describe some recent developments relevant to research on plant-derived products used in nutrition research, highlight some resources for optimizing the characterization and reporting of research using these products, and describe some of the pitfalls that may be avoided by adherence to these recommendations.

Neopyrrolomycins with broad spectrum antibacterial activity.

Three new antibiotics, neopyrrolomycins B (1), C (2), and D (3), with potent activity against Gram-positive pathogens were discovered. They exhibited MIC values < 1 microg/mL versus a number of resistant strains. The compounds were obtained from the ethyl acetate extracts of a Streptomyces sp. after purification by column chromatography and RP-HPLC. Their structures were elucidated using X-ray crystallography (1) and NMR spectroscopy (2 and 3).

Citreamicins with potent gram-positive activity.

Two new xanthone antibiotics, citreamicin delta (1) and epsilon (2), with potent activity against Gram-positive pathogens including multidrug-resistant Staphylococcus aureus (MDRSA) were discovered. Compounds 1 and 2 exhibited MIC values < 1 microg/mL versus a number of resistant strains. The compounds were obtained from EtOAc extracts of Streptomyces vinaceus and were purified by countercurrent chromatography and reversed-phase HPLC. Their structures were elucidated using primarily NMR and mass spectroscopy.

Mutactimycin E, a new anthracycline antibiotic with gram-positive activity.

Resistance to currently available antibiotics has become a widely recognized crisis in the medical community. To address this, many companies and researchers are refocusing their attention towards natural products, which have an excellent track record of producing effective antibacterial drugs. The AMRI natural product library was screened for activity against multi-drug resistant Staphylococcus aureus (MDRSA). The active samples were counter screened for cytotoxicity against the human hepatocellular carcinoma HepG2 cell line to determine an in vitro therapeutic index (in vitro TI). Those samples with a high in vitro TI were selected for fractionation and dereplication. This led to the discovery of a new anthracycline structure. This metabolite, named mutactimycin E (1), exhibited moderate activity against several gram positive organisms. Here we report the isolation, structure elucidation and biological activities of this new compound.