Mast cells are essential regulators of inflammation most recognized for their central role in allergic inflammatory disorders. Signaling via the high-affinity immunoglobulin E (IgE) receptor, FcεRI, leads to rapid degranulation of preformed granules and the sustained release of newly synthesized proinflammatory mediators. Our group recently established rosemary extract as a potent regulator of mast cell functions, attenuating MAPK and NF-κB signaling. Carnosic acid (CA)-a major polyphenolic constituent of rosemary extract-has been shown to exhibit anti-inflammatory effects in other immune cell models, but its role as a potential modulator of mast cell activation is undefined. Therefore, we sought here to determine the modulatory effects of CA in a mast cell model of allergic inflammation. We sensitized bone marrow-derived mast cells with anti-trinitrophenyl IgE and activated with allergen (TNP-BSA) under stem cell factor potentiation, in addition to treatment with CA. Our results indicate that CA significantly inhibits allergen-induced early phase responses including Ca²⁺ mobilization, ROS production, and subsequent degranulation. We also show CA treatment reduced late phase responses, including the release of all cytokines and chemokines examined following IgE stimulation and corresponding gene expression excepting that of CCL2. Importantly, we determined that CA mediates its inhibitory effects through modulation of tyrosine kinase Syk and downstream effectors TAK1 (Ser412) and Akt (Ser473) as well as NFκB signaling, while phosphorylation of FcεRI (γ chain) and MAPK proteins remained unaltered. These novel findings establish CA as a potent modulator of mast cell activation, warranting further investigation as a putative anti-allergy therapeutic.

Inhibiting glycogen synthase kinase 3 (GSK3) improves muscle function, metabolism, and bone health in many diseases and conditions; however, whether GSK3 should be targeted for Duchenne muscular dystrophy (DMD), a severe muscle wasting disorder with no cure, remains unknown. Here, we show the effects of GSK3 inhibition in male DBA/2J (D2) and C57BL/10 (C57) mdx mice. Treating D2 mdx mice with GSK3 inhibitors alone or in combination with aerobic exercise improves muscle strength, endurance, and morphology, attenuates the hypermetabolic phenotype, and enhances insulin sensitivity. GSK3 inhibition in C57 mdx mice also improves muscle fatigue resistance and increases cage ambulation. Moreover, muscle-specific GSK3 knockdown in mdx mice augments muscle force production and endurance. In both mdx strains, GSK3 inhibition increases bone mineral content and density. Overall, these improvements to muscle, metabolic, and bone health with GSK3 inhibition in mdx mice may have clinical implications for patients with DMD, where the current standard of care, glucocorticoids, delay the loss of ambulation but increase the risk for insulin resistance and osteoporosis. Along with our observation of lowered β-catenin content in DMD myoblasts, a known cellular target for GSK3, this study provides ample evidence in support of inhibiting GSK3 for this disease.

Adverse childhood experiences (ACEs) are associated with dysregulation of inflammation and cortisol. The objectives of this study were to use principal component analysis to explore the inflammatory biomarker data to create inflammation composite variables; to examine the relationship between these composite measures of inflammation with ACEs and cortisol; and to assess whether these relationships were moderated by sex. The analysis included 232 young adults from the Niagara Longitudinal Heart Study (NLHS). After adjusting for covariates, higher exposure to ACEs significantly predicted higher low-grade inflammation. These results further support the use of multiple biomarkers to understand the complex relationships among ACEs, cortisol, and inflammation, which should be further examined in longitudinal studies to study biomarker trajectories.