Rufino Ana Teresa, Lucas Mariana, Silva Artur M S, Ribeiro Daniela, Fernandes Eduarda
LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal.
LAQV, REQUIMTE, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
Pharmaceutics. 2023 Feb 26;15(3):780. doi: 10.3390/pharmaceutics15030780.
Rheumatoid arthritis (RA) is characterized by systemic immune and chronic inflammatory features, leading to the destruction of the joints. Presently, there are no effective drugs able to control synovitis and catabolism in the process of RA. 2-Styrylchromones (2-SC) are a small group of compounds characterized by the attachment of a styryl group to the chromone core that have already been associated to a wide range of biological activities, including antioxidant and anti-inflammatory activities. The present study investigated the effect of a set of six 2-SC on the interleukin-1β (IL-1β)-induced increase of nitric oxide (NO), inducible form of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-3 (MMP-3) expression levels in human fibroblast-like synoviocytes (HFLS), pointing to the role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in the process. From a set of six 2-SC, presenting hydroxy and methoxy substituents, the one presenting two methoxy substituents at C-5 and C-7 of A ring and a catechol group on B ring, significantly reduced NO production and the expression of its inducible synthase (iNOS). It also significantly reduced the catabolic MMP-3 protein expression. This 2-SC inhibited the NF-κB pathway by reversing the IL-1β - induced levels of cytoplasmatic NF-kB inhibitor alpha (IκBα), and decreasing the p65 nuclear levels, suggesting the involvement of these pathways in the observed effects. The same 2-SC significantly increased the COX-2 expression, which may indicate a negative feedback loop mechanism of action. The properties of 2-SC may be of great value in the development of new therapies with improved efficacy and selectivity towards RA, and thus deserve further exploitation and evaluation to disclose the full potential of 2-SC.
类风湿性关节炎（RA）的特征是具有全身免疫和慢性炎症特性，会导致关节破坏。目前，尚无有效的药物能够控制RA病程中的滑膜炎和分解代谢。2-苯乙烯基色酮（2-SC）是一小类化合物，其特征是苯乙烯基连接到色酮核心上，已被证实具有广泛的生物活性，包括抗氧化和抗炎活性。本研究调查了一组六种2-SC对白细胞介素-1β（IL-1β）诱导的人成纤维细胞样滑膜细胞（HFLS）中一氧化氮（NO）、诱导型一氧化氮合酶（iNOS）、环氧化酶-2（COX-2）和基质金属蛋白酶-3（MMP-3）表达水平升高的影响，指出活化B细胞核因子κB轻链增强子（NF-κB）激活在此过程中的作用。在一组具有羟基和甲氧基取代基的六种2-SC中，在A环的C-5和C-7位具有两个甲氧基取代基且在B环上具有邻苯二酚基团的化合物，能显著降低NO的产生及其诱导型合酶（iNOS）的表达。它还能显著降低分解代谢性MMP-3蛋白表达。这种2-SC通过逆转IL-1β诱导的细胞质NF-κB抑制因子α（IκBα）水平并降低p65核水平来抑制NF-κB途径，表明这些途径参与了所观察到的效应。同一2-SC显著增加了COX-2的表达，这可能表明存在负反馈环作用机制。2-SC的特性在开发对RA具有更高疗效和选择性的新疗法方面可能具有重要价值，因此值得进一步探索和评估，以揭示2-SC的全部潜力。
