Felix Franciel Batista, Vago Juliana Priscila, Fernandes Débora de Oliveira, Martins Débora Gonzaga, Moreira Isabella Zaidan, Gonçalves William Antonio, Costa Walyson Coelho, Araújo Jessica Maria Dantas, Queiroz-Junior Celso Martins, Campolina-Silva Gabriel Henrique, Soriani Frederico Marianetti, Sousa Lirlândia Pires, Grespan Renata, Teixeira Mauro Martins, Pinho Vanessa
Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Front Pharmacol. 2021 Apr 26;12:662308. doi: 10.3389/fphar.2021.662308. eCollection 2021.
Biochanin A (BCA) is a natural organic compound of the class of phytochemicals known as flavonoids and isoflavone subclass predominantly found in red clover (). It has anti-inflammatory activity and some pro-resolving actions, such as neutrophil apoptosis. However, the effect of BCA in the resolution of inflammation is still poorly understood. In this study, we investigated the effects of BCA on the neutrophilic inflammatory response and its resolution in a model of antigen-induced arthritis. Male wild-type BALB/c mice were treated with BCA at the peak of the inflammatory process (12 h). BCA decreased the accumulation of migrated neutrophils, and this effect was associated with reduction of myeloperoxidase activity, IL-1β and CXCL1 levels, and the histological score in periarticular tissues. Joint dysfunction, as seen by mechanical hypernociception, was improved by treatment with BCA. The resolution interval (Ri) was also quantified, defining profiles of acute inflammatory parameters that include the amplitude and duration of the inflammatory response monitored by the neutrophil infiltration. BCA treatment shortened Ri from ∼23 h observed in vehicle-treated mice to ∼5.5 h, associated with an increase in apoptotic events and efferocytosis, both key steps for the resolution of inflammation. These effects of BCA were prevented by H89, an inhibitor of protein kinase A (PKA) and G15, a selective G protein-coupled receptor 30 (GPR30) antagonist. In line with the data, BCA also increased the efferocytic ability of murine bone marrow-derived macrophages. Collectively, these data indicate for the first time that BCA resolves neutrophilic inflammation acting in key steps of the resolution of inflammation, requiring activation of GPR30 and via stimulation of cAMP-dependent signaling.
生物chanin A（BCA）是一种天然有机化合物，属于植物化学物质类黄酮和异黄酮亚类，主要存在于红三叶草中。它具有抗炎活性和一些促炎症消退作用，如中性粒细胞凋亡。然而，BCA在炎症消退中的作用仍知之甚少。在本研究中，我们在抗原诱导的关节炎模型中研究了BCA对中性粒细胞炎症反应及其消退的影响。雄性野生型BALB/c小鼠在炎症过程的高峰期（12小时）接受BCA治疗。BCA减少了迁移中性粒细胞的积累，这种作用与髓过氧化物酶活性、IL-1β和CXCL1水平的降低以及关节周围组织的组织学评分降低有关。通过机械性痛觉过敏观察到的关节功能障碍通过BCA治疗得到改善。还对消退间隔（Ri）进行了量化，确定了急性炎症参数的概况，包括通过中性粒细胞浸润监测的炎症反应的幅度和持续时间。BCA治疗将Ri从载体处理小鼠中观察到的约23小时缩短至约5.5小时，这与凋亡事件和吞噬作用的增加有关，这两者都是炎症消退的关键步骤。BCA的这些作用被蛋白激酶A（PKA）抑制剂H89和选择性G蛋白偶联受体30（GPR30）拮抗剂G15所阻断。与这些数据一致，BCA还增加了小鼠骨髓来源巨噬细胞的吞噬能力。总的来说，这些数据首次表明BCA通过作用于炎症消退的关键步骤来消退中性粒细胞炎症，这需要GPR30的激活并通过刺激cAMP依赖性信号传导。
