Drug Design, Development and Therapy (Jul 2024)
Nootkatone Counteracts Melamine-Mediated Nephrotoxicity via Modulation of Intermediate Filament Proteins, Oxidative, Inflammatory, and Apoptotic Events
Abstract
Doaa Abdelrahaman,1 Ola A Habotta,2 Ahmed Ateya,3 Ahmed A Aldarmahi,4,5 Reham A El-Shafei,6 Mohamed M Badawy,7,8 Ahmed A El-Mansy,9,10 Thoraya M A-Elgadir,11 Aml M Nada,12 Mona G Elhadidy,13,14 Eman Hamza,15,16 Khairiah M Alwutayed,17 Mohamed El-Sherbiny,18 Liana Fericean,19 Florin Imbrea,20 Ahmed Abdeen21 1Department of Internal Medicine, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia; 2Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt; 3Department of Animal Husbandry and Wealth Development, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt; 4Department of Basic Science, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia; 5National Guard- Health Affairs, King Abdullah International Medical Research Centre, Jeddah, 21582, Saudi Arabia; 6Department of Pharmacology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt; 7Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 8Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Delta University for Science and Technology, Gamasa, Egypt; 9Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa, Jordan; 10Department of Medical Histology and Cell Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 11Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, Saudi Arabia; 12Department of Internal Medicine and Endocrinology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 13Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 14Department of Medical Physiology, Faculty of Medicine, Al-Baha University, Al Aqiq, Saudi Arabia; 15Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 16Department of Medical Biochemistry and Molecular Biology, Horus University, Damietta, Egypt; 17Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia; 18Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, 11597, Saudi Arabia; 19Department of Biology and Plant Protection, Faculty of Agriculture, University of Life Sciences “king Michael I” from Timișoara, Calea Aradului, Romania; 20Department of Crop Science, Faculty of Agriculture, University of Life Sciences “King Mihai I” from Timisoara, Calea Aradului, Romania; 21Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Benha University, Toukh, EgyptCorrespondence: Florin Imbrea, University of Life Sciences “King Mihai I” from Timisoara, 119, Calea Aradului, Timisoara, 300645, Romania, Email [email protected] Ahmed Abdeen, Benha University, Toukh, 13736, Egypt, Email [email protected]: Nootkatone (NK), a bioactive sesquiterpene ketone, is a major ingredient in grapefruit that has distinguished biological activities. Melamine (MM), a food adulterant, was reported to induce toxic effects including renal disorders. Hence, this protocol was devoted to evaluate the renoprotective impact of NK toward MM-evoked renal damage.Methods: Rats were either exposed to MM (700 mg/kg) or a combination of MM and two doses of NK (5 and 10 mg/kg).Results: The results showed that NK therapy notably decreased the kidney functional parameters, along with KIM-1 and NGAL expressions of MM group. Furthermore, a decrease in MDA and NO levels as well as an elevation in SOD, CAT, GSH, and SOD and NRF2 mRNA expression in the NK group demonstrated NK’s ability to enhance the renal antioxidant defense of the MM group. Significant suppression in renal inflammatory markers was achieved by NK via lessening of IL-1β and TNF-α, besides downregulation of NF-κB and IL-1β expressions. NK also downregulated vimentin, nestin, and desmin in the MM group. Additionally, in response to the MM exposure, NK hindered renal apoptosis by decreasing caspase-3 expression and restoring renal histopathological features.Conclusion: These outcomes suggest that NK can be considered as a prospective candidate to guard against MM exposure-mediated renal toxic effects.Keywords: apoptosis, inflammation, intermediate proteins, melamine nephrotoxicity, nootkatone, oxidative stress
