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

Abstract

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-triazoles 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 proinflammatory mediators in THP-1 monocytes. Among all the synthesized carbazole-linked 1,2,3 triazoles, compounds 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.

• Authors: Humera Jahan, Nimra Naz Siddiqui, Shazia Iqbal, Fatima Z Basha, Sadia Shaikh, Marina Pizzi, M Iqbal Choudhary
• Journal: Cellular signalling (Cell Signal) Vol. 97 Pg. 110372 (09 2022) ISSN: 1873-3913 [Electronic] England
• PMID: 35640822 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022. Published by Elsevier Inc.

Chemical References

• Carbazoles
• Glycation End Products, Advanced
• NF-kappa B
• Reactive Oxygen Species
• Triazoles
• Pyruvaldehyde
• Cyclooxygenase 2
• Glucose
• Dinoprostone

Topics

• Carbazoles (metabolism, pharmacology)
• Cyclooxygenase 2 (metabolism)
• Diabetic Angiopathies (metabolism)
• Dinoprostone (metabolism)
• Glucose (metabolism)
• Glycation End Products, Advanced
• Humans
• Monocytes (metabolism)
• NF-kappa B (metabolism)
• Pyruvaldehyde (pharmacology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Triazoles (pharmacology)