PDF(Pubmed)
Abstract：
The endoplasmic reticulum (ER) is determinant to maintain cellular proteostasis. Upon unresolved ER stress, this organelle activates the unfolded protein response (UPR). Sustained UPR activates is known to occur in inflammatory processes, deeming the ER a potential molecular target for the treatment of inflammation. This work characterizes the inflammatory/UPR-related molecular machinery modulated by an in-house library of natural products, aiming to pave the way for the development of new selective drugs that act upon the ER to counter inflammation-related chronic diseases. Starting from a library of 134 compounds of natural occurrence, mostly occurring in medicinal plants, nontoxic molecules were screened for their inhibitory capacity against LPS-induced nuclear factor kappa B (NF-κB) activation in a luciferase-based reporter gene assay. Since several natural products inhibited NF-κB expression in THP-1 macrophages, their effect on reactive oxygen species (ROS) production and inflammasome activation was assessed, as well as their transcriptional outcome regarding ER stress. The bioactivities of several natural products are described herein for the first time. We report the anti-inflammatory potential of guaiazulene and describe 5-deoxykaempferol as a novel inhibitor of inflammasome activation. Furthermore, we describe the dual potential of 5-deoxykaempferol, berberine, guaiazulene, luteolin-4\'-O-glucoside, myricetin, quercetagetin and sennoside B to modulate inflammatory signaling ER stress. Our results show that natural products are promising molecules for the discovery and pharmaceutical development of chemical entities able to modulate the inflammatory response, as well as proteostasis and the UPR.
摘要：
内质网(ER)是维持细胞蛋白质稳定的决定因素。在未解决的ER压力下，这种细胞器激活未折叠的蛋白质反应（UPR）。已知持续的UPR激活发生在炎症过程中，认为ER是治疗炎症的潜在分子靶标。这项工作描述了由内部天然产物库调节的炎症/UPR相关分子机制，旨在为开发新的选择性药物铺平道路，这些药物作用于ER以对抗炎症相关的慢性疾病。从134个天然存在的化合物库开始，主要发生在药用植物中，在基于荧光素酶的报告基因分析中，筛选了无毒分子对LPS诱导的核因子κB（NF-κB）激活的抑制能力。由于几种天然产物抑制NF-κB在THP-1巨噬细胞中的表达，评估了它们对活性氧（ROS）产生和炎性体活化的影响，以及它们关于ER应激的转录结果。本文首次描述了几种天然产物的生物活性。我们报告了愈创木烯的抗炎潜力，并描述了5-脱氧山奈酚作为一种新型的炎性小体激活抑制剂。此外，我们描述了5-脱氧山奈酚的双重电势，小檗碱,guaiazulene,木犀草素-4\'-O-葡萄糖苷，杨梅素,槲皮素和人参皂苷B调节炎症信号ER应激。我们的结果表明，天然产物是发现和药物开发能够调节炎症反应的化学实体的有前途的分子，以及proteostasis和UPR。
