Suppression of COX-2/PGE2 levels by carbazole-linked triazoles via modulating methylglyoxal-AGEs and glucose-AGEs – induced ROS/NF-κB signaling in monocytes

Chronic hyperglycemia favours the formation of advanced glycation end products (AGEs) which are responsible of many diabetic vascular complications. Keeping in view the medicinal properties of the1,2,3-triazole- conjugated analogs, the present study was designed to evaluate the possible effect of carbazole-linked 1,2,3-tri- azoles 2–16 against glucose- and methylglyoxal-AGEs-induced inflammation in human THP-1 monocytes. In vitro antiglycation, and metabolic assays were used to determine antiglycation, and cytotoxicity activities. DCFH-DA, immunostaining, immunoblotting, and ELISA techniques were employed to study the ROS and levels of proin- flammatory mediators in THP-1 monocytes. Among all the synthesized carbazole-linked 1,2,3 triazoles, com- pounds 2, 7, 8, and 11–16 showed antiglycation activity in glucose- and MGO-modified bovine serum albumin models, whereas parent compound 1 only exhibited activity in glucose-BSA model. The metabolic assay demonstrated the non-toxic profile of compounds 1–2, 11–13, and 15 up to 100 μM concentration in both HepG2 and THP-1 cell lines. We found that compounds 11–13, and 15 attenuated AGEs-induced ROS formation (P < 0.001), and halted NF-ĸB translocation (P < 0.001), likewise standard drugs, PDTC, rutin, and quercetin, in THP- 1 monocytes. Among the derivatives, compounds 12, and 13 also suppressed the AGEs-induced elevation of COX- 2 (P < 0.001) and PGE2 (P < 0.001). Our data show that the carbazole-linked triazoles 12, and 13 hampering the formation of glycation products, prevent the activation of AGEs-ROS-NF-κB signaling pathway, and limit the proinflammatory COX-2 protein, and PGE2 induction in human THP-1 monocytes. Both these compounds can thus serve as leads for further studies towards the treatment and prevention of diabetic vascular complications