Antiapoptotic and antioxidative effects of cerium oxide nanoparticles on the testicular tissues of streptozotocin-induced diabetic rats: An experimental study


Background: Cerium dioxide nanoparticles (CNPs) due to the antidiabetic and antioxidant activities are proposed for the treatment of oxidative stress-associated diseases.

Objective: To examine the impact of CNPs on hyperglycemia-induced apoptosis and oxidative stress in the testis of diabetic rats.

Materials and Methods: Twenty-four male rats were divided into four groups (n = 6/each) as diabetic rats, CNPs group, diabetic + CNPs rats, and controls. The control group was fed only mouse food and water. Rats became diabetic through receiving streptozotocin (STZ) 60 mg/kg. CNPs were given to the rats at a dose of 30 mg/kg daily for 2 wk. Malondialdehyde and total thiol group (TTG) levels were measured using spectrofluorometer. Expression of b-cell lymphoma protein 2-associated X protein (BAX) and b-cell lymphoma protein 2 (Bcl-2) were investigated using quantitative real-time polymerase chain reaction. Western blot analysis was used to examine caspase 3 protein levels.

Results: The content of malondialdehyde significantly increased in the STZ-diabetic rats, while TTG levels demonstrated a remarkable decrease. Caspase-3, BAX, and BAX/Bcl-2 mRNA ratio raised significantly in the STZ-diabetic rats. On the other hand, Bcl-2 mRNA levels reduced in the testis of diabetic rats (p = 0.006). Intervention with CNPs caused a substantial increase in the TTG levels, while the malondialdehyde contents, caspase-3, BAX levels, as well as BAX/Bcl-2 mRNA ratio were considerably decreased following CNPs treatment. Administration of CNPs increased mRNA levels of Bcl-2 (p < 0.0001).

Conclusion: CNPs treatment attenuates testicular apoptosis and oxidative stress induced by diabetes. This nanoparticle might be suggested for the treatment of diabetes-associated reproductive disorders.

Key words: Apoptosis, Nanoceria, Diabetes, Oxidative stress, Testis.

[1] Minaz N, Razdan R, Hammock BD, Mujwar S, Goswami SK. Impact of diabetes on male sexual function in streptozotocin-induced diabetic rats: Protective role of soluble epoxide hydrolase inhibitor. Biomed Pharmacother 2019; 115: 108897. 1–6.

[2] Cai L, Chen S, Evans T, Deng DX, Mukherjee K, Chakrabarti S. Apoptotic germ-cell death and testicular damage in experimental diabetes: Prevention by endothelin antagonism. Urol Res 2000; 28: 342–347.

[3] Huang X, Shi X, Zhou J, Li S, Zhang L, Zhao H, et al. The activation of antioxidant and apoptosis pathways involved in damage of human proximal tubule epithelial cells by PM 2.5 exposure. Environ Sci Eur 2020; 32: 1–3.

[4] Barati E, Nikzad H, Karimian M. Oxidative stress and male infertility: Current knowledge of pathophysiology and role of antioxidant therapy in disease management. Cell Mol Life Sci 2020; 77: 93–113.

[5] Choudhury H, Pandey M, Hua ChK, Mun ChS, Jing JK, Kong L, et al. An update on natural compounds in the remedy of diabetes mellitus: A systematic review. J Tradit Complement Med 2017; 8: 361–376.

[6] Naganuma T, Traversa E. Stability of the Ce 3+ valence state in cerium oxide nanoparticle layers. Nanoscale 2012; 4: 4950–4953.

[7] Celardo I, De Nicola M, Mandoli C, Pedersen JZ, Traversa E, Ghibelli L. Ce3+ ions determine redoxdependent anti-apoptotic effect of cerium oxide nanoparticles. ACS Nano 2011; 5: 4537–4549.

[8] Khurana A, Tekula S, Godugu C. Nanoceria suppresses multiple low doses of streptozotocininduced Type 1 diabetes by inhibition of Nrf2/NF-κB pathway and reduction of apoptosis. Nanomedicine 2018; 13: 1905–1922.

[9] Artimani T, Amiri I, Soleimani Asl S, Saidijam M, Hasanvand D, Afshar S. Amelioration of diabetesinduced testicular and sperm damage in rats by cerium oxide nanoparticle treatment. Andrologia 2018; 50: e13089.

[10] Celardo I, Pedersen JZ, Traversa E, Ghibelli L. Pharmacological potential of cerium oxide nanoparticles. Nanoscale 2011; 3: 1411–1420.

[11] Rubio L, Marcos R, Hernandez A. Nanoceria acts as antioxidant in tumoral and transformed cells. Chem Biol Interact 2018; 291: 7–15.

[12] Grulke E, Reed K, Beck M, Huang X, Cormack A, Seal S. Nanoceria: Factors affecting its pro-and antioxidant properties. Environ Sci: Nano 2014; 1: 429– 444.

[13] Hasanvand D, Amiri I, Soleimani Asl S, Saidijam M, Shabab N, Artimani T. Effects of CeO2 nanoparticles on the HO-1, NQO1, and GCLC expression in the testes of diabetic rats. Can J Physiol Pharmacol 2018; 96: 963–969.

[14] Yagi K. Assay for blood plasma or serum. Methods Enzymol 1984; 105: 328–331.

[15] Abshenas R, Artimani T, Shahidi S, Ranjbar A, Komaki A, Salehi I, et al. Treadmill exercise enhances the promoting effects of preconditioned stem cells on memory and neurogenesis in Aβ- induced neurotoxicity in the rats. Life Sci 2020; 249: 117482. 1–13.

[16] Long L, Wang J, Lu X, Xu Y, Zheng S, Luo C, et al. Protective effects of scutellarin on type II diabetes mellitus-induced testicular damages related to reactive oxygen species/Bcl-2/Bax and reactive oxygen species/microcirculation/staving pathway in diabetic rat. J Diabetes Res 2015; 2015: 252530. 1–12.

[17] Khosravi Z, Sedaghat R, Baluchnejadmojarad T, Roghani M. Diosgenin ameliorates testicular damage in streptozotocin-diabetic rats through attenuation of apoptosis, oxidative stress, and inflammation. Int Immunopharmacol 2019; 70: 37–46.

[18] Ghaznavi H, Najafi R, Mehrzadi S, Hosseini A, Tekyemaroof N, Shakeri-Zadeh A, et al. Neuroprotective effects of cerium and yttrium oxide nanoparticles on high glucose-induced oxidative stress and apoptosis in undifferentiated PC12 cells. Neurol Res 2015; 37: 624–632.

[19] Shoorei H, Khaki A, Khaki AA, Ali Hemmati A, Moghimian M, Shokoohi M. The ameliorative effect of carvacrol on oxidative stress and germ cell apoptosis in testicular tissue of adult diabetic rats. Biomed Pharmacother 2019; 111: 568–578.

[20] Mohasseb M, Ebied S, Yehia MAH, Hussein N. Testicular oxidative damage and role of combined antioxidant supplementation in experimental diabetic rats. J Physiol Biochem 2011; 67: 185– 194.

[21] Heeba GH, Hamza AA. Rosuvastatin ameliorates diabetes-induced reproductive damage via suppression of oxidative stress, inflammatory and apoptotic pathways in male rats. Life Sci 2015; 141: 13–19.

[22] Das S, Dowding JM, Klump KE, McGinnis JF, Self W, Seal S. Cerium oxide nanoparticles: Applications and prospects in nanomedicine. Nanomedicine 2013; 8: 1483–1508.

[23] Talebpour Amiri F, Hamzeh M, Yaghubi Beklar S, Hosseinimehr SJ. Anti-apoptotic and antioxidant effect of cerium oxide nanoparticles on cyclophosphamide-induced hepatotoxicity. Erciyes Med J 2018; 40: 148–154.

[24] Tian Y, Song W, Xu D, Chen X, Li X, Zhao Y. Autophagy induced by ROS aggravates testis oxidative damage in diabetes via breaking the feedforward loop linking p62 and Nrf2. Oxid Med Cell Longev 2020; 2020: 7156579. 1–9.

[25] Chen Sh, Hou Y, Cheng G, Zhang C, Wang Sh, Zhang J. Cerium oxide nanoparticles protect endothelial cells from apoptosis induced by oxidative stress. Biol Trace Elem Res 2013; 154: 156–166.

[26] Zhao Y, Tan Y, Dai J, Li B, Guo L, Cui J, et al. Exacerbation of diabetes-induced testicular apoptosis by zinc deficiency is most likely associated with oxidative stress, p38 MAPK activation, and p53 activation in mice. Toxicol Lett 2011; 200: 100–106.

[27] Hentzen NB, Mogaki R, Otake S, Okuro K, Aida T. Intracellular photoactivation of Caspase-3 by molecular glues for spatiotemporal apoptosis induction. J Am Chem Soc 2020; 142: 8080–8084.

[28] Hajnoczky G, Csordas G, Das S, Garcia-Perez C, Saotome M, Sinha Roy S, et al. Mitochondrial calcium signalling and cell death: Approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis. Cell Calcium 2006; 40: 553–560.

[29] Heckert EG, Karakoti AS, Seal S, Self WT. The role of cerium redox state in the SOD mimetic activity of nanoceria. Biomaterials 2008; 29: 2705–2709.

[30] Kobyliak NM, Falalyeyeva TM, Kuryk OG, Beregova TV, Bodnar PM, Zholobak NM, et al. Antioxidative effects of cerium dioxide nanoparticles ameliorate age-related male infertility: Optimistic results in rats and the review of clinical clues for integrative concept of men health and fertility. EPMA J 2015; 6: 1–22.