Jahan, Humera and Fatima, Urooba and Asad, Sana and Zahoor, Sidra and Tufail, Priya and Zainab, Dania and Siddiqui, Nimra Naz and Ullah, Aaqib and Pizzi, Marina and Choudhary, M. Iqbal (2026) IQ-RKT Formulation mitigates cardiomyocytes injury by targeting AGEs-RAGE-ROS-dependent TRAF3IP2/JNK apoptotic nexus in diabetes. Free Radical Biology and Medicine, 246. 456 - 475.

Text IQ-RKT Formulation mitigates cardiomyocytes injury by targeting.pdf Restricted to Registered users only Download (18MB) | Request a copy

Abstract

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in diabetic populations. Elevated advanced glycation end products (AGEs) in diabetes foster the on-set, and progression of CVDs. However, the underlying AGEs-induced signaling nexus, involved in cardiomyocytes apoptosis, remain unexplored. Currently no anti-AGEs drug available to address CVDs in diabetes. Indeed, natural products remained a major sources of new medicine, and currently being focused in the drug development. The objective of this study was to explore the mechanism of AGEs-associated apoptotic pathway in cardiomyocytes. Additionally, to harness the medicinal properties of natural products, a newly developed formulation, comprised of rutin, kaempferol, and thymoquinone, named IQ-RKT, was characterized for its anti-apoptotic potential against AGEs-induced cardiotoxicity. We studied the role of MGO-, and glucose-AGEs in cardiomyocytes apoptosis under diabetic environment in H9c2 cells in vitro, as well as in SD diabetic rats in vivo. The inhibition of AGEs-induced apoptosis of cardiomyocytes was investigated by a treatment with IQ-RKT. Using H9c2 cells, as well as SD diabetic rats models in vivo, we found that AGEs-induced elevated levels of RAGE was reduced by a treatment with IQ-RKT. AGEs stimulate intracellular ROS generation, TRAF3 interacting protein 2 (TRAF3IP2) expression, and TRAF3IP2-dependent-JNK activation. TRAF3IP2/JNK causes transactivation of AP-1/NF-κB transcription factors. AGEs increase Bax, cytochrome c, and activate caspase-3, and suppress anti-apoptotic Bcl-2. IQ-RKT significantly inhibited this apoptotic pathway, and tilted the balance towards anti-apoptosis. Moreover, IQ-RKT decreased lipid peroxidation, cardiac injury, and glycooxidative biomarkers in the plasma of diabetic rats. Interestingly, this effect of IQ-RKT was independent of hyperglycemic environment in diabetic rats. The IQ-RKT also appeared as a stable formulation at different pH, and temperature ranges. The study provides experimental evidences that AGE-RAGE axis is likely associated with cardiomyocytes death via ROS-dependent TRAF3IP2/JNK pathway. Therefore, targeting this pathway appeared to have therapeutic potential. The newly developed formulation IQ-RKT was identified as an effective anti-apoptotic cardioprotective agent to be further investigated through pre-clinical, and clinical studies. © 2026 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Actions (login required)

View Item