2,4,5-trimethoxy-2'-trifluoromethylchalcone Attenuates Oxidative Stress and Inflammasome-Associated Inflammation in Experimental Models of Crystal-Induced Inflammation.

Crystal-induced arthropathies, including gout and calcium pyrophosphate deposition disease, are characterized by activation of inflammatory and oxidative pathways involving nuclear factor-kappa B (NF-κB) signaling, inflammasome activation, and reactive oxygen species (ROS) generation. This study evaluated the anti-inflammatory and antioxidant effects of 2,4,5-trimethoxy-2'-trifluoromethylchalcone (CH) in experimental models of crystal-induced inflammation and gouty arthritis. CH was evaluated in lipopolysaccharide (LPS)/adenosine 5'-triphosphate (ATP)-stimulated murine peritoneal macrophages and in murine models of CPPD crystal-induced air pouch inflammation and monosodium urate (MSU)-induced gouty arthritis. Cytokine production was determined by ELISA, whereas NF-κB and caspase-1 activation were evaluated by Western blot. ROS generation and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) were also assessed. CH reduced interleukin (IL)-1β, IL-18, tumor necrosis factor (TNF)-α, and IL-6 production in activated macrophages and attenuated lactate dehydrogenase release associated with pyroptosis. Mechanistically, CH reduced p65 NF-κB phosphorylation, caspase-1 activation, and ROS generation while promoting Nrf2 nuclear translocation. In vivo, CH reduced leukocyte infiltration, myeloperoxidase activity, inflammatory cytokine levels, and paw edema in CPPD- and MSU-induced models. These findings suggest that CH acts as a multitarget compound capable of simultaneously modulating inflammatory and oxidative pathways involved in crystal-induced arthropathies, which may represent a potential advantage over approaches targeting a single inflammatory pathway.