The Impact of NF-κB and Keap1/Caspase-3 Signaling Pathway on protective Effects of sitagliptin in a Rat Model of Doxorubicin-Induced Cardiac Dysfunction.

mostafa, mahmoud; Kasem, Enas M.; Mohammed, Walaa H.; Elkholy, Manar A.; Elsayed, Alzahraa Z.; Faruk, Eman Mohamed; el awam, mona kamal

doi:10.21608/besps.2025.362914.1204

	The Impact of NF-κB and Keap1/Caspase-3 Signaling Pathway on protective Effects of sitagliptin in a Rat Model of Doxorubicin-Induced Cardiac Dysfunction.
Bulletin of Egyptian Society for Physiological Sciences
Volume 45, Issue 3, July 2025, Page 347-361 PDF (826.5 K)
Document Type: Original Article
DOI: 10.21608/besps.2025.362914.1204
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Authors
mahmoud mostafa ¹; Enas M. Kasem¹; Walaa H. Mohammed¹; Manar A. Elkholy²; Alzahraa Z. Elsayed²; Eman Mohamed Faruk³; mona kamal el awam¹
¹Department of Physiology, Faculty of Medicine, Benha University, Benha, Egypt.
²Department of Pharmacology, Faculty of Medicine, Benha University, Qalubiya, Egypt.
³Anatomy Department, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia, Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Benha, Egypt
Abstract
Background: Doxorubicin (DOX) treatment is a primary cause of chemotherapy-induced cardiotoxicity. Antidiabetic sitagliptin (STG) has been shown to improve cardiovascular functions through anti-inflammatory, antioxidant, and anti-apoptotic effects. Oxidative stress plays a crucial role in the development of various cardiovascular diseases, especially those related to endothelial dysfunction. The transcription factor nuclear factor erythroid-2-like 2 (Nrf2) is the main regulator of antioxidant defense mechanisms. Nrf2, along with its suppressor protein Kelch-like ECH-associated protein 1 (Keap1), controls the levels of reactive oxygen species (ROS). Objective: This study aimed to evaluate the role of the Nrf2/caspase-3 signaling pathway in the cardiotoxic effect of DOX and the potential role of sitagliptin (STG). Materials and Methods: Rats were divided into four groups, each comprising eight animals (n=8): a control group, an STG group (receiving 10 mg/kg/day for 21 days), a DOX group (receiving 1mg/kg i.p per day for five injections \ week for 3 weeks) and STG+DOX group (treated by STG and DOX as previously mentioned). Results: The effect of DOX on cardiac tissue detected a significant reduction in ABP, and deviated ST segment, while STG improved DOX-induced cardiotoxicity markers, oxidative stress and inflammatory markers. Also, STG regulate cardiovascular hemodynamics and reduce both cardiac caspase-3, Keap-1 and upregulates NrF2 gene expression levels Conclusion: STG administration can exert protective effects against doxorubicin-induced cardiac toxicity through anti-inflammatory, antioxidant, and anti-apoptotic properties, in addition to promoting the Nrf2 signaling pathway.
Keywords
cardiac toxicity; nuclear factor erythroid 2-related factor 2 (Nrf2); Doxorubicin; caspase-3


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