PDF(Pubmed)
Abstract：
In recent decades, the interest in natural products with immunomodulatory properties has increased due to their therapeutic potential. These products have a wider range of pharmacological activities and demonstrate lower toxicity levels when compared to their synthetic counterparts. Therefore, this study aimed to investigate the immunomodulatory effects of sesquiterpenoids (SQs) and sesquiterpenoid dimers (SQDs) isolated from Dysoxylum parasiticum (Osbeck) Kosterm. stem bark on human and murine cells, particularly focusing on toll-like receptor 4 (TLR4). Utilizing the secreted alkaline phosphatase (SEAP) assay on engineered human and murine TLR4 of HEK-Blue cells, antagonist TLR4 compounds were identified, including SQs 6, 9, and 10, as well as SQDs 17 and 22. The results showed that 10-hydroxyl-15-oxo-α-cadinol (9) had a potent ability to reduce TLR4 activation induced by LPS stimulation, with minimal toxicity observed in both human and murine cells. The SEAP assay also revealed diverse immune regulatory effects for the same ligand. For instance, SQs 12, 14, and 16 transitioned from antagonism on human to murine TLR4. The SQs (4, 7, 11, and 15) and SQDs (18-20) offered partial antagonist effect exclusively on murine TLR4. Furthermore, these selected SQs and SQDs were assessed for their influence on the production of proinflammatory cytokines TNF-α, IL-1α, IL-1β, and IL-6 of the NF-κB signaling pathway in human and murine macrophage cell lines, showing a dose-dependent manner. Additionally, a brief discussion on the structure-activity relationship was presented.
摘要：
近几十年来,对具有免疫调节特性的天然产物的兴趣由于其治疗潜力而增加。与它们的合成对应物相比,这些产品具有更宽范围的药理活性并且表现出更低的毒性水平。因此,本研究旨在研究从寄生菌（Osbeck）Kosterm中分离的倍半萜（SQs）和倍半萜二聚体（SQDs）的免疫调节作用。人和鼠细胞上的树皮，特别关注Toll样受体4（TLR4）。利用分泌的碱性磷酸酶（SEAP）测定对HEK-Blue细胞的工程人和鼠TLR4，拮抗剂TLR4化合物被鉴定，包括第6、9和10季度，以及第17和22季度。结果表明,10-羟基-15-氧代-α-cadinol(9)对LPS刺激诱导的TLR4活化有较强的抑制作用,在人和鼠细胞中观察到最小的毒性。SEAP测定还揭示了相同配体的不同免疫调节作用。例如,SQ12、14和16从对人的拮抗作用转变为鼠TLR4。SQs（4、7、11和15）和SQD（18-20）仅对鼠TLR4具有部分拮抗作用。此外，评估这些选定的SQs和SQDs对促炎细胞因子TNF-α产生的影响，IL-1α,IL-1β,人和鼠巨噬细胞系NF-κB信号通路的IL-6，表现出剂量依赖性。此外,简要讨论了构效关系。
