Carnosol modulates mPGES-1/PPAR-γ biological axis: from in silico to in vivo clinical imaging and investigations

The onset and progression of the inflammatory response and reaction are complex mechanisms dependent on the balance of activity between different and counteracting targets and enzymatic systems. The understanding and, even more importantly, the identification of new protein networks and their respective modulators represent a challenging strategy for treating inflammation and inflammation-based diseases. Natural products are a valuable source of bioactive compounds. In this field, carnosol and carnosic acid from Salvia species (spp.) displayed anti-inflammatory and analgesic effects, acting as modulators of several targets of the arachidonic acid cascade. In this work, through a multimodal approach based on in silico, biophysical, in vivo, in vivo small-animal imaging, and ex vivo approaches, we brought further structural and biological insights into the pharmacological profile of these promising diterpenoids. We attributed the superior anti-inflammatory activity of carnosol, compared to carnosic acid, in a zymosan-induced chronic inflammation model to its ability to function as a direct or partial PPAR-γ agonist. This effect is linked to the recently discovered role of the mPGES-1/PPAR-γ pathway in regulating inflammatory and/or cancer processes.