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Original Article

Korean J Physiol Pharmacol 2021; 25(4): 341-354

Published online July 1, 2021 https://doi.org/10.4196/kjpp.2021.25.4.341

Copyright © Korean J Physiol Pharmacol.

Cardamonin exerts a protective effect against autophagy and apoptosis in the testicles of diabetic male rats through the expression of Nrf2 via p62-mediated Keap-1 degradation

Shereen M. Samir1, Mahmoud Elalfy2, Eman Mohamad El Nashar3,4, Mansour A. Alghamdi5,6, Eman Hamza7, Mohamed Saad Serria7, and Mona G. Elhadidy1,8,*

1Department of Medical Physiology, College of Medicine, Mansoura University, Mansoura 35511, Egypt, 2Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35511, Egypt, 3Department of Anatomy, Faculty of Medicine, King Khalid University, Abha 61421, Saudi Arabia, 4Department of Histology and Cell Biology, College of Medicine, Benha University, Benha 13511, Egypt, 5Department of Anatomy, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia, 6Genomics and Personalized Medicine Unit, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia, 7Medical Biochemistry Department, College of Medicine, Mansoura University, Mansoura 35511, Egypt, 8Department of Medical Physiology, College of Medicine, Al-Baha University, Al-Baha 65525, Saudi Arabia

Correspondence to:Mona G. Elhadidy
E-mail: mona.gaber2012@yahoo.com

Received: December 24, 2020; Revised: May 8, 2021; Accepted: May 27, 2021

Abstract

Cardamonin (CARD) is a chalconoid with anti-inflammatory and antioxidant properties, and it is present in several plants. We sought to explore whether CARD exerts any positive effects against hyperglycemia-induced testicular dysfunction caused by type 2 diabetes and aimed to identify its possible intracellular pathways. Adult male rats were subdivided into six groups: control, CARD, diabetic (DM), DM + glibenclamide (GLIB), DM + CARD and DM + GLIB + CARD. Type 2 DM induced a significant increase in blood glucose and insulin resistance, along with diminished serum insulin, testosterone and gonadotropins levels, which were associated with the impairment of key testicular androgenic enzymes and cellular redox balance. Administration of CARD at a dose of 80 mg/kg for 4 weeks effectively normalized all of these alterations, and the improvement was confirmed by epididymal sperm analysis. After treatment with CARD, the pathological changes in spermatogenic tubules were markedly improved. Significantly, CARD upregulated testicular glucose transporter-8 (GLUT-8) expression and had inhibitory effects on elevated autophagy markers and caspase-3 immunoreactive cells. Furthermore, our results revealed that CARD was able to attenuate damage via activation of Nrf2 through the p62-dependent degradation of testicular anti-Kelch-like ECH-associated protein-1 (Keap-1). In conclusion, this study suggests that CARD provides protection against diabetic stress-mediated testicular damage. The use of CARD with conventional anti-diabetic therapy was associated with improved efficacy compared with conventional therapy alone.

Keywords: Apoptosis, Autophagy, Glucose transporter, Gonadotropins, Insulin sensitivity, Reproductive capacity