Baicalein inhibits the polarization of microglia/macrophages to the M1 phenotype by targeting STAT1 in EAE mice.

Microglia/macrophage polarization modulation plays a key role in the pathogenesis of multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE). M1 microglia/macrophages secrete a variety of cytokines that cause inflammation and facilitate demyelination in the central nervous system (CNS). Baicalein (5,6,7-trihydroxyflavone, C15H10O5, BAI), a natural flavonoid isolated from the roots of the traditional Chinese medicine Scutellaria baicalensis Georgi, has been suggested to have a wide range of biological effects, including antioxidant, anti-inflammatory, and neuroprotective properties. In this study, flow cytometry, Western blotting, immunofluorescence and other methods were used to investigate whether BAI could reduce the demyelination and inflammatory response of the spinal cord in EAE mice induced by MOG35-55 and affect the polarization of spinal microglia/macrophages. Our results showed that BAI treatment delayed the onset of EAE and alleviated clinical symptoms, demyelination and inflammatory cell infiltration. Meanwhile, BAI inhibited the overactivation of M1 microglia/macrophages in vivo and in vitro, significantly decreased the expression of proinflammatory cytokines in M1 microglia/macrophages, and inhibited the activation of STAT1. Subsequently, molecular docking, pull-down and immunofluorescence experiments confirmed that BAI has the ability to bind to the SH2 domain of STAT1 and that BAI colocalizes with p-STAT1 in the cytoplasm rather than being transferred to the nucleus during inflammatory stimulation. This study showed that BAI might inhibit the polarization of microglia/macrophages to the M1 phenotype in EAE mice by targeting STAT1. This new discovery lays a theoretical and experimental foundation for the clinical application of BAI in the treatment of MS.

Adverse Events Associated With the Addition of Aspirin to Direct Oral Anticoagulant Therapy Without a Clear Indication.

Importance: It is unclear how many patients treated with a direct oral anticoagulant (DOAC) are using concomitant acetylsalicylic acid (ASA, or aspirin) and how this affects clinical outcomes. Objective: To evaluate the frequency and outcomes of prescription of concomitant ASA and DOAC therapy for patients with atrial fibrillation (AF) or venous thromboembolic disease (VTE). Design, Setting, and Participants: This registry-based cohort study took place at 4 anticoagulation clinics in Michigan from January 2015 to December 2019. Eligible participants were adults undergoing treatment with a DOAC for AF or VTE, without a recent myocardial infarction (MI) or history of heart valve replacement, with at least 3 months of follow-up. Exposures: Use of ASA concomitant with DOAC therapy. Main Outcomes and Measures: Rates of bleeding (any, nonmajor, major), rates of thrombosis (stroke, VTE, MI), emergency department visits, hospitalizations, and death. Results: Of the study cohort of 3280 patients (1673 [51.0%] men; mean [SD] age 68.2 [13.3] years), 1107 (33.8%) patients without a clear indication for ASA were being treated with DOACs and ASA. Two propensity score-matched cohorts, each with 1047 patients, were analyzed (DOAC plus ASA and DOAC only). Patients were followed up for a mean (SD) of 20.9 (19.0) months. Patients taking DOAC and ASA experienced more bleeding events compared with DOAC monotherapy (26.0 bleeds vs 31.6 bleeds per 100 patient years, P = .01). Specifically, patients undergoing combination therapy had significantly higher rates of nonmajor bleeding (26.1 bleeds vs 21.7 bleeds per 100 patient years, P = .02) compared with DOAC monotherapy. Major bleeding rates were similar between the 2 cohorts. Thrombotic event rates were also similar between the cohorts (2.5 events vs 2.3 events per 100 patient years for patients treated with DOAC and ASA compared with DOAC monotherapy, P = .80). Patients were more often hospitalized while undergoing combination therapy (9.1 vs 6.5 admissions per 100 patient years, P = .02). Conclusion and Relevance: Nearly one-third of patients with AF and/or VTE who were treated with a DOAC received ASA without a clear indication. Compared with DOAC monotherapy, concurrent DOAC and ASA use was associated with increased bleeding and hospitalizations but similar observed thrombosis rate. Future research should identify and deprescribe ASA for patients when the risk exceeds the anticipated benefit.