Cyclosporine A induces testicular injury via mitochondrial apoptotic pathway by regulation of mir-34a and sirt-1 in male rats: The rescue effect of curcumin. (25th August 2020)

• Record Type: Journal Article
• Authors: Ghazipour, Amir Mohammad; Shirpoor, Alireza; Ghiasi, Rafighe; Pourheydar, Bagher; Khalaji, Naser; Naderi, Roya
• Is Part Of: Chemico-biological interactions. Volume 327(2020)
• Publication Date: 2020-08-25
• Subjects: Cyclosporine A -- Testis -- Apoptosis -- Curcumin -- Mir-34a -- Sirt-1; CsA cyclosporine A -- Bax Bcl2-associated X -- Bcl-2 B-cell lymphoma-2 -- c-Caspase-3 cleaved Caspase-3 -- p-Caspase-3 pro Caspase-3 -- ROS reactive oxygen species -- miRNAs microRNAs -- mir-34a mirRNA34a -- sirt-1 sirtuin 1 -- NIH National Institutes of Health -- Con Control -- 8-OHdg 8-hydroxy-2' –deoxyguanosine -- DMSO Dimethyl sulfoxide solution -- Nox4 NADPH oxidase 4 -- HRP Horseradish Peroxidase -- TUNEL Terminal deoxynucleotidyl transferase dUTP nick-end labeling -- FFPE formalin-fixed paraffin-embedded -- MDA malondialdehyde -- GSH Glutathione -- GSH-PX Glutathione peroxidase -- CAT Catalase -- NO nitric oxide; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2020.109180
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Testicular damage contributes to cyclosporine A (CsA) induced male infertility. However, the exact underlying molecular mediators involved in CsA-induced testis disorder remains unclear. The present study aimed to characterize the role of mir-34a/sirt-1 in CsA induced testicular injury alone or in combination with curcumin. A total of twenty-eight male Wistar rats were subdivided into four groups: control (Con), sham, cyclosporine A (CsA), cyclosporineA + curcumin (CsA + cur). The animals received cyclosporine A (30 mg/kg) and curcumin (40 mg/kg) for 28 days by oral gavage. At the end of the experiment, CsA administration significantly resulted in a decrease in testis weight and testis coefficient. The molecular analysis demonstrated that CsA exposure increased 8-OHdg and Nox4 protein contents in the testis tissue. TUNEL staining indicated that CsA caused the number of apoptotic cells to increase in the testes of male rats. In addition, exposure to CsA resulted in an increased expression of Bax, and a decreased expresion in that of Bcl-2, with a concomitant up-regulation of the Bax/Bcl-2, c-Caspase-3/p-Caspase-3 ratio and cytochrome c level. Meanwhile, exposure to CsA increased the expression of mir-34a and decreased sirt-1 protein level in the testis tissue samples compared to the control group. Taken together, our findings suggested that CsA can cause damage to testicular germ cells via oxidative stress and mitochondrial apoptotic pathway, and probably mir-34a/sirt-1 play a crucial role in this process. It also demonstrates that these negative effects of CsA can be reduced by using curcumin as an antioxidant and anti-inflammatory agent. Graphical abstract: Image 1 Highlights: Cyclosporine A increased oxidative stress manifestations in testis of rats. Cyclosporine A increased apoptotic cells by mitochondrial apoptotic pathway in testis of rats. Cyclosporine A increased the expression of mir-34a and decreased sirt-1 (sirtuin-1) protein level in the testis tissue. Curcumin alleviated genes and protein expression alterations in testis of rats.