The impact of PPAR-γ/Nrf-2/HO-1, NF-κB/IL-6/ Keap-1, and Bcl-2/caspase-3/ATG-5 pathways in mitigation of DOX-induced cardiotoxicity in an animal model: The potential cardioprotective role of oxyresveratrol and/or dapagliflozin

• Published in: Food and chemical toxicology 2024-09, Vol.191, p.114863, Article 114863
• Main Authors: El-Sawy, Waleed S.M., El‐Bahrawy, Ali H., Messiha, Basim A.S., Hemeida, Ramadan A.M., Khalaf, Marwa M.
• Format: Article
• Language: English
• Subjects: animal models; Animals; Antioxidants - pharmacology; Benzhydryl Compounds - toxicity; blood serum; Cardiotonic Agents - pharmacology; Cardiotoxicity; Cardiotoxicity - drug therapy; Cardiotoxicity - etiology; Cardiotoxicity - prevention & control; Caspase 3 - genetics; Caspase 3 - metabolism; caspase-3; caudal vein; Dapagliflozin; Disease Models, Animal; Doxorubicin; Doxorubicin - toxicity; gene expression; Glucosides - pharmacology; heart; Heme Oxygenase (Decyclizing) - genetics; Heme Oxygenase (Decyclizing) - metabolism; histopathology; interleukin-6; Interleukin-6 - genetics; Interleukin-6 - metabolism; intravenous injection; Kelch-Like ECH-Associated Protein 1 - genetics; Kelch-Like ECH-Associated Protein 1 - metabolism; Male; males; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB/IL-6/ Keap-1; Oxyresveratrol; Plant Extracts - pharmacology; PPAR gamma - genetics; PPAR gamma - metabolism; PPAR-γ/Nrf-2/HO-1; protein synthesis; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Wistar; reference standards; Signal Transduction - drug effects; Stilbenes - pharmacology; vitamin E
• ISSN: 0278-6915; 1873-6351; 1873-6351
• DOI: 10.1016/j.fct.2024.114863

Antioxidants given concurrently with chemotherapy offer an effective strategy for reducing the negative effects of the drug. One remaining obstacle to the use of doxorubicin (DOX) in chemotherapy is cardiotoxicity. Using vitamin E (Vit. E) as a reference standard, our study focuses on the potential preventive benefits of oxyresveratrol (ORES) and/or dapagliflozin (DAPA) against DOX-induced cardiac injury. Acute cardiotoxicity was noticed after a single intravenous injection of a male rat's tail vein with 10 mg/kg of DOX. Oral doses of ORES (80 mg/kg), DAPA (10 mg/kg), and Vit. E (1 g/kg) were given, respectively. Pretreatment of animals with Vit. E, ORES and/or DAPA revealed a considerable alleviation of heart damage, as evidenced by histopathological change mitigation and a notable drop in serum AST, LDH, CK, CK-MB, and cardiac contents of MDA and NO2−. Also, serum TAC, tissue GSH, and SOD showed substantial increases. Additionally, tissue caspase-3, serum IL-6, and TNF-α were considerably reduced. Moreover, a downregulation in cardiac gene expression of ATG-5, Keap-1, and NF-κB in addition to an upregulation of Bcl-2 gene expression and HO-1, Nrf-2, and PPAR-γ protein expression clearly appeared. Ultimately, ORES and/or DAPA have an optimistic preventive action against severe heart deterioration caused by DOX. [Display omitted] •The most often administered anthracycline antibiotic during chemotherapy is doxorubicin (DOX).•Acute cardiotoxicity is one of DOX's primary adverse effects.•Oxyresveratrol (ORES) and/or dapagliflozin (DAPA) have a number of biological and pharmacological activities.•Either ORES or DAPA inhibited the expression of TNF-α, IL-6, Keap-1, NF-κB, caspase-3, and ATG-5.•HO-1, Bcl-2, PPAR-γ, and Nrf-2 were all elevated by ORES and/or DAPA.