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

摘要 约80%的人使用草药膳食补充剂和药物作为主要的保健形式 占世界人口的1/3。在美国，这些植物药的使用量正在增加，占11.26美元 仅在过去一年的销售额就达到了10亿美元。尽管使用广泛且不断增加，草药膳食补充剂和 与西药相比，药品监管严重不足。确切的机制，活性化合物 代谢物、药代动力学和安全性还不完全清楚。这项研究的重点是顶层- 2020年在美国销售草药膳食补充剂，接骨木(Sambuus ngra L.) 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，因此尽管承诺 体外抗病毒效果，不等同于体内相关药理作用。代谢降解 然而，由宿主代谢或肠道微生物组代谢产生的产品可能会增加 生物利用度和药理作用。很少有研究检查代谢产物、生物利用度、 以及接骨木代谢产物的药理作用，但关于其抗病毒作用，还没有人这样做 活动。因此，这项建议提供了新的药代动力学和生药学方面的研究培训以供测试 接骨木提取物的代谢生物转化产物的抗病毒效果。这项建议将发展 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 接骨木抗病毒作用的药理学意义。接骨木的代谢产物 在体外模型中进行表征，并在体内进行验证。分离产生的代谢物将使用 制备高效液相色谱法及其抗流感病毒活性评价 模特们。抗病毒化合物和代谢物将使用高分辨率质谱仪进行表征 (Hrms)、核磁共振(Nmr)和X射线结晶学(如适用)。生物利用度和 肠道微生物组的贡献将使用诺生菌小鼠模型进行评估。这些研究将确定 接骨木中的代谢物具有抗病毒能力和生物利用度，并有助于建立 其他植物新陈代谢评估的基础设施。这将增进对中国的了解和 草药的特性，并促进我作为一名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.