REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, N° 228, 4050-213 Porto, Portugal.
Chemistry Centre, School of Sciences, University of Minho, 4710-057 Braga, Portugal.
Int Immunopharmacol. 2023 Jun;119:110178. doi: 10.1016/j.intimp.2023.110178. Epub 2023 Apr 15.
Inflammation and endoplasmic reticulum (ER) stress are often hand in hand in the context of chronic disease. Both are activated upon perceived disturbances in homeostasis, being deleterious when intensely or chronically activated. Fisetin (FST) is a dietary flavonol that is known to possess multiple relevant bioactivities, raising the question of its potential health benefits and even its use in novel pharmacological approaches against ER stress and inflammation. To attain this prospect, some limitations to this molecule, namely its poor bioavailability and solubility, must be addressed. In an attempt to improve the biological properties of the parent molecule, we have synthesized a set of FST derivatives. These new molecules were tested along with the original compound for their ability to mitigate the activation of the signaling pathways underlying inflammation and ER stress. By reducing LPS-induced nuclear factor-kappa B (NF-κB) activation, cytokine release, inflammasome activation and reactive oxygen species (ROS) generation, FST has proven to be effective against the onset of inflammation. The molecule also decreases the activation of the unfolded protein response (UPR), as evidenced by the reduced expression of relevant UPR-related genes upon ER stress induction. Some of the tested derivatives are novel inhibitors of targets associated to inflammation and ER stress signaling, in some cases more potent than the parent compound. Furthermore, the reduced cytotoxicity of some of these molecules enabled the use of higher concentrations than that of FST, resulting in the observation of enhanced bioactivities.
在慢性疾病的背景下，炎症和内质网（ER）应激通常是密切相关的。当稳态感知到干扰时，两者都会被激活，当它们强烈或慢性激活时，就会产生有害影响。漆黄素（FST）是一种饮食类黄酮，已知具有多种相关的生物活性，这引发了人们对其潜在健康益处的关注，甚至对其在针对 ER 应激和炎症的新型药理学方法中的应用的关注。为了实现这一前景，必须解决该分子的一些局限性，即其较差的生物利用度和溶解度。为了改善母体分子的生物学特性，我们合成了一系列 FST 衍生物。这些新分子与原始化合物一起进行了测试，以评估它们减轻炎症和 ER 应激相关信号通路激活的能力。FST 通过降低 LPS 诱导的核因子-κB（NF-κB）激活、细胞因子释放、炎症小体激活和活性氧（ROS）生成，已被证明可有效对抗炎症的发生。该分子还降低了未折叠蛋白反应（UPR）的激活，这表现在 ER 应激诱导时相关 UPR 相关基因的表达减少。一些测试的衍生物是与炎症和 ER 应激信号转导相关的靶标的新型抑制剂，在某些情况下比母体化合物更有效。此外，这些分子中的一些降低了细胞毒性，使我们能够使用比 FST 更高的浓度，从而观察到增强的生物活性。
