Contributions of host and gut microbial mediated metabolism to the antiviral activity of elderberry

摘要 大约百分之八十的人使用草药膳食补充剂和药物作为主要的医疗保健形式 世界人口的一半。在美国，这些植物药的使用量正在增加，占11.26美元 仅去年一年的销售额就达10亿美元。尽管广泛和越来越多的使用，草药膳食补充剂和 与西药相比，对药物的监管严重不足。确切的机制，活性化合物 代谢物、药代动力学和安全性特征尚未完全了解。这项研究的重点是顶部- 2020年在美国销售草药膳食补充剂，接骨木果（Sambucus nigra L.），这 具有抗病毒作用。许多天然产品可能表现出较差的生物利用度，因此尽管有希望， 体外抗病毒功效不等同于体内相关药理学作用。代谢降解 然而，由宿主代谢或肠道微生物组代谢产生的产物可以表现出增加的代谢产物。 生物利用度和药理学作用。很少有研究检查代谢产物，生物利用度， 和药理作用的代谢产物接骨木，没有这样做时，关于其抗病毒 活动因此，该提案提供了药代动力学和生药学方面的新研究培训， 用于抗病毒功效的接骨木提取物的代谢生物转化产物。该提案将发展 复杂植物混合物的宿主和肠道微生物代谢的方法和能力，并提供 关于接骨木果的抗病毒功效的药理学意义。接骨木果的代谢产物会 在体外模型中表征并在体内验证。将使用以下方法分离生成的代谢物： 制备高效液相色谱法及其抗流感病毒活性的评价 模型抗病毒化合物和代谢物将使用高分辨率质谱法进行表征 （HRMS）、核磁共振（NMR）和X射线晶体学（如适用）。生物利用度和 肠道微生物组的贡献将使用gnotobiotic鼠模型来评估。这些研究将确定 从接骨木中提取的代谢物具有抗病毒能力和生物利用度，有助于建立 其他植物代谢评估的基础设施。这将促进理解， 草药的特性，促进我作为一个独立科学家的职业发展 能够在生药学和药理学领域进行相关研究，造福人类 健康

ABSTRACT Herbal dietary supplements and medicines are used as the primary form of health care for about eighty percent of the world’s population. In the United States, the use of these botanicals is increasing, accounting for $11.26 billion in sales in the past year alone. Despite widespread and increasing use, herbal dietary supplements and medicines are severely underregulated compared to western medicine. Exact mechanisms, active compounds and metabolites, pharmacokinetics, and safety profiles are not fully understood. This study focuses on the top- selling herbal dietary supplement in the year 2020 in the United States, elderberry (Sambucus nigra L.), which exhibits antiviral effects. Many natural products can exhibit poor bioavailability and thus despite the promise of antiviral efficacy in vitro, do not equate to relevant pharmacological effects in vivo. Metabolic degradation products resulting from host metabolism or gut microbiome metabolism can, however, exhibit increased bioavailability and pharmacological effects. Few studies have examined the metabolic products, bioavailability, and pharmacological effects of metabolites of elderberry, and none have done so when regarding its antiviral activities. Thus, this proposal provides novel research training in pharmacokinetics and pharmacognosy to test metabolic biotransformation products of elderberry extracts for antiviral efficacy. This proposal will develop the methods and capabilities for host and gut microbial metabolism of complex botanical mixtures and provide pharmacological significance regarding the antiviral efficacy of elderberry. Metabolic products of elderberry will be characterized in vitro models and validated in vivo. Isolation of metabolites generated will be conducted using preparative high-performance liquid chromatography and their antiviral activity assessed against influenza models. Antiviral compounds and metabolites will be characterized using high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR), and X-ray crystallography where applicable. Bioavailability and contributions of the gut microbiome will be assessed using a gnotobiotic murine model. These studies will identify metabolites from elderberry exhibiting both antiviral capacities and bioavailability and help establish an infrastructure for metabolic assessment of other botanicals. This will advance the understanding and characterization of herbal medicines and promote the development of my career as an independent scientist capable of conducting relevant research in the fields of pharmacognosy and pharmacology to benefit human health.