Antioxidant botanicals and antimicrobial defenses/Kevin Fritsche

这个项目的主要目的是对选定的抗氧化剂植物药物进行临床前筛选 在体内调节抗微生物和抗病毒活性的潜力。粗提物和推定的生物活性 每种植物的成分都将在体内和体外进行测试。两种小鼠细菌感染模型 (即共同//介导性脓毒症和系统性李斯特菌病)和一种新的小鼠艾滋病毒模型。临床上 将监测相关结果，如发烧、进食、嗜睡和细菌/病毒清除。 具有一组共同的炎症/感染生物标志物(例如，肿瘤坏死因子-α、白介素IP、白介素6、单核细胞趋化蛋白-1、白介素12、白介素10)。这个 工作假说是，具有强大抗氧化活性的植物性物质会影响宿主的氧化还原状态 吞噬细胞，使炎症、抗细菌和抗病毒反应发生改变。结果就是 在这种改变的细胞氧化还原过程中，宿主将体验到明显的好处(例如，低烧、增强 病原体清除，减少全身炎症)。令人兴奋和新奇的初步发现表明 紫苏木和接骨木提取物影响细菌清除和在大肠杆菌败血症模型中的存活。一个 小鼠巨噬细胞系RAW 264.7细胞将被用于描述细胞事件的变化 对炎症、抗细菌和抗病毒途径在植物学反应中的重要性 化合物包括：NADPH氧化酶(NOX)和诱导型一氧化氮合酶(INOS)活性，核因子-KB 激活和Nri‘2-Keap1信号转导。此外，在细胞中有条件删除Keapl的小鼠 髓系(即吞噬细胞)将被用来评估Nrf2依赖基因之间的相互作用 植物抗氧化剂在影响宿主对感染反应中的表达。患有髓系特异性白血病的小鼠 Keap1的缺失应该大大增强了吞噬细胞中的Nri‘2信号，从而使体内的氧化还原状态 这些先天免疫细胞被改变，导致炎症减轻。这些独特的老鼠将被用来 吞噬细胞中Nrf2信号的相互作用及不同植物药对先天感染的影响 免疫系统和宿主对感染的反应。

The primary aim ofthis project is to conduct pre-clinical screening of selected antioxidant botanicals for their potential to modulate in vivo anti-microbial and anti-viral activity. Crude extracts as well as putative bioactive components of each botanical will be tested both in vivo and in vitro. Two murine bacterial infection models (i.e., ¿ co//-mediated sepsis and systemic listeriosis) and a novel murine HIV model will be used. Clinically relevant outcomes, such as fever, food intake, lethargy, and bacterial/viral clearance will be monitored along with a common set of inflammation/infection biomarkers (e.g., TNF-a, IL-ip, IL-6, MCP-1, IL-12, IL-10). The working hypothesis is that botanicals with potent antioxidant activity will affect the redox status of host phagocytes such that inflammatory, anti-bacterial and anti-viral responses will be altered. As a consequence of this altered cellular redox the host will experience discernable benefits (e.g., lower fever, enhanced pathogen clearance, reduced systemic inflammation). Exciting and novel preliminary findings show that Sutheriandia and elderberry extracts affect bacterial clearance and survival in the ¿ coli sepsis model. A murine macrophage cell line, RAW 264.7 cells, will be used to profile alterations in cellular events of importance to the inflammatory, anti-bacterial, and anti-viral pathways in response to the botanical compounds including: NADPH oxidase (NOX) and inducible nitric oxide synthase (INOS) activity, NF-KB activation and Nri'2-Keapl signaling. Additionally, mice with a conditional deletion of Keapl in cells from the myeloid lineage (i.e., phagocytes) will be used to evaluate the interaction between Nrf2-dependent gene expression and antioxidant botanicals in shaping host response to infection. Mice with a myeloid-specific deletion of Keapl should have greatly enhanced Nri'2 signaling in phagocytes such that redox status within these innate immune cells is altered resulting in diminished inflammation. These unique mice will be used to explore interactions between Nrf2 signaling in phagocytes and effects of various botanicals on the innate immune system and the host response to infection.