Cyclooxygenase-2 Inhibitor Parecoxib Was Disclosed as a PPAR-γ Agonist by In Silico and In Vitro Assay.

In a search for effective PPAR-γ agonists, 110 clinical drugs were screened via molecular docking, and 9 drugs, including parecoxib, were selected for subsequent biological evaluation. Molecular docking of parecoxib to the ligand-binding domain of PPAR-γ showed high binding affinity and relevant binding conformation compared with the PPAR-γ ligand/antidiabetic drug rosiglitazone. Per the docking result, parecoxib showed the best PPAR-γ transactivation in Ac2F rat liver cells. Further docking simulation and a luciferase assay suggested parecoxib would be a selective (and partial) PPAR-γ agonist. PPAR-γ activation by parecoxib induced adipocyte differentiation in 3T3-L1 murine preadipocytes. Parecoxib promoted adipogenesis in a dose-dependent manner and enhanced the expression of adipogenesis transcription factors PPAR-γ, C/EBPα, and C/EBPß. These data indicated that parecoxib might be utilized as a partial PPAR-γ agonist for drug repositioning study.

Effects of prostaglandin E1 infused via the superior mesenteric artery on partially resected, dearterialized canine liver.

This study was performed to determine whether the infusion of prostaglandin E1 (PGE1) via the superior mesenteric artery (SMA) lessens hypoxic hepatic injury in beagle dogs subjected to major hepatectomy and dearterialization. Changes in systemic and hepatic hemodynamics by infusion of PGE1 were measured in intact and dearterialized dogs. The effects of infusion at 0.02 microg/kg/min were also studied in dogs that underwent resection of 55% of the liver and complete dearterialization. PGE1 infusion significantly increased portal vein flow and hepatic oxygen delivery. Hepatic dearterialization remarkably decreased delivery, but infusion at 0.02 microg/kg/min significantly restored it to 88% of the pre-dearterialized value. In hepatectomized animals, complete dearterialization provoked fatal hepatic damage, but infusion remarkably improved hepatic parenchymal and non-parenchymal injury. PGE1 through SMA might be useful for patients who have undergone major hepatectomy and combined arterial resection without reconstruction.