The Beneficial Effects of CGK012 Against Lipopolysaccharide-Induced Inflammation.

Abstract

This study investigates the protective effects of CGK012 [(7S)-(+)-cyclopentyl carbamic acid 8,8-dimethyl-2-oxo-6,7-dihydro-2H,8H-pyrano[3,2-g]chromen-7-yl-ester], a small-molecule inhibitor targeting the Wnt/β-catenin signaling pathway, against inflammatory responses elicited by lipopolysaccharide (LPS). The study evaluated the influence of CGK012 on heme oxygenase (HO)-1, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) expressions in LPS-stimulated human endothelial cells. It examined its effects on iNOS, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β in LPS-challenged mice. CGK012 treatment resulted in increased HO-1 production, inhibited nuclear factor-kappa B activation, and decreased the levels of COX-2/PGE2 and iNOS/NO. Additionally, CGK012 reduced signal transducer and activator of transcription-1 phosphorylation and facilitated Nrf2 nuclear translocation and binding to antioxidant response elements, culminating in reduced IL-1β production in LPS-exposed human umbilical vein endothelial cells. Notably, the inhibitory effect of CGK012 on iNOS/NO was reversed upon HO-1 knockdown via RNA interference. In vivo, CGK012 markedly attenuated iNOS expression in lung tissue and decreased TNF-α levels in bronchoalveolar lavage fluid. These findings underscore the anti-inflammatory potential of CGK012, suggesting its therapeutic promise for conditions characterized by pathological inflammation.