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Biochanin A Regulates Key Steps of Inflammation Resolution in a Model of Antigen-Induced Arthritis via GPR30/PKA-Dependent Mechanism.

ABSTRACT: Biochanin A (BCA) is a natural organic compound of the class of phytochemicals known as flavonoids and isoflavone subclass predominantly found in red clover (Trifolium pratense). 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 in vivo 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.

SUBMITTER: Felix FB

PROVIDER: S-EPMC8114065 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesRheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joint synovium. The traditional Chinese medicine Xinfeng capsule (XFC) has a remarkable alleviating effect on inflammatory symptoms, such as joint pain and swelling, in patients with RA. However, the underlying mechanism of action remains to be elucidated. This study intended to conduct network pharmacology, animal experiments, data mining, and molecular docking to explore the molecular mechanism through which XFC can improve the inflammatory symptoms of RA.MethodsThe Apriori association rules and a random walk model were employed to evaluate the effect of XFC on the clinical inflammatory indexes of RA. The active ingredients and the potential target genes of XFC were obtained from public databases. Based on the search tool for recurring instances of neighboring genes (STRING) database, the Database for Annotation, Visualization and Integrated Discovery (DAVID) database, Cytoscape software, and molecular docking method, the molecular mechanism by which XFC acts on RA was also analyzed. Finally, an adjuvant arthritis rat model was established to verify the effects of XFC on inflammation-related signaling pathways and inflammatory factors.ResultsXFC significantly reduced the level of C-reactive protein (CRP), vascular endothelial growth factor (VEGF), and the erythrocyte sedimentation rate (ESR). The docking space structures of the active ingredients in XFC, namely triptolide and quercetin, and the key targets were stable. Inflammation-related biological processes were identified as the key factors involved in the development of RA, and the regulation of the toll-like receptor (TLR) signaling pathway may be the key link for XFC toward improving the inflammatory state of RA. The expression levels of toll-like receptor 4 (TLR4), myeloid differentiation primary response protein MyD88 (MyD88), interleukin-1 receptor-associated kinase 1 (IRAK1), TNF receptor-associated factor 6 (TRAF6), TGF-beta-activated kinase 1 (TAK1), phospho-Inhibitor of NF-κB kinaseβ (p-IKKβ), phospho-Nuclear factor-k-gene binding (p-NF-κB), and interleukin-1β (IL-1β) can all be decreased by XFC. XFC improves joint inflammation symptoms by lowering pro-inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (INF-γ) levels.ConclusionsXFC could effectively improve the clinical inflammatory indexes of RA. The active ingredients of XFC improved the inflammatory state of RA by regulating the TLR-signaling pathway.

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Biochanin A Regulates Key Steps of Inflammation Resolution in a Model of Antigen-Induced Arthritis via GPR30/PKA-Dependent Mechanism.

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