Sajjan Rajpoot, Ashutosh Kumar, Vadim Gaponenko, Teresa Lm Thurston, Dolly Mehta, Syed M Faisal, Kam Yj Zhang, Hem C Jha, Gajanan N Darwhekar, Mirza S Baig
Background: Sepsis is a syndrome due to microbial infection causing impaired multiorgan function. Its underlying cause is immune dysfunction and macrophages play an essential role. Methods: TIRAP interaction with PKCδ in macrophage was studied, revealing downstream signaling by Western blot and quantitative reverse transcriptase PCR. Dorzolamide (DZD) disrupting TIRAP-PKCδ interaction was identified by virtual screening and validated in vitro and in septic mice. Results: The study highlights the indispensable role of TIRAP-PKCδ in p38 MAPK-activation, NF-κB- and AP-1-mediated proinflammatory cytokines expression, whereas DZD significantly attenuated the signaling...
April 27, 2023: Future Medicinal Chemistry