Free Radic Biol Med. 2026 Jan 9:S0891-5849(26)00004-3. doi: 10.1016/j.freeradbiomed.2026.01.004. Online ahead of print.
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, and currently no anti-AGE drug available to address CVDs in diabetes. Indeed, natural products remained a major sources of modern medicine, and currently being recognized in the drug development. The objective of this study was to explore the mechanism of AGE-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. 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 caspase-3 activation, 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 evidence that AGE-RAGE axis is associated with cardiomyocytes death via ROS-dependent TRAF3IP2/JNK pathway. Therefore, targeting this pathway, the developed formulation IQ-RKT identified as an effective anti-apoptotic cardioprotective agent to be further investigated through clinical studies.
PMID:41520849 | DOI:10.1016/j.freeradbiomed.2026.01.004