Impact of NiO2 Nanoparticles and Curcumin on Testis Torsion/Detorsion Injury: Role of miR-34 and circRNA 0001518

  • Shabnam Zarei Moradi 1. Department of Genetics, Faculty of Biosciences, Islamic Azad University, North Tehran Branch, Tehran, Iran
  • Seyed Abdolhamid Angaji 2. Department of Cell and Molecular Biology, Faculty of Biosciences, Kharazmi University, Tehran, Iran
  • Mitra Salehi 3. Department of Microbiology, Faculty of Biosciences, Islamic Azad University, North Tehran Branch, Tehran, Iran
  • Mehrdad Hashemi 4. Department of Genetics, Faculty of Advanced Science and Technology, Islamic Azad University, Tehran Medical Sciences, Tehran, Iran 5. Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
Keywords: Testicle, Torsion, Rat, Bcl-x, MiR-34, circRNA


Background: Testicular torsion is one cause of infertility without proper treatment. In this study, we investigate the effects of NiO2 nanoparticles (NPs) and curcumin on sperm parameters in rats and the expressions of genes involved in the apoptotic pathway, as well as expressions of miR-34 and circRNA 0001518. Materials and Methods: Forty-eight rats were randomly divided into eight groups: control (healthy rats), control rats that received NiO2-NPs, healthy rats that received curcumin, rats that received simultaneous NiO2-NPs and curcumin, untreated testicular ischemia/reperfusion (I/R) rats, testicular I/R rats that received NiO2-NPs, testicular I/R rats that received curcumin, and testicular I/R rats that received NiO2-NPs and curcumin. Then, sperms were extracted from the rats' epididymides to analyze concentration, viability, morphology, and motility. The cellular apoptosis level was studied using flow cytometry. Also, Bad and Bcl-X gene expressions and miR-34 and circRNA 0001518 levels were measured. Results: We observed improved sperm parameters in the testicular I/R) rats that received curcumin and NiO2-NPs. Administration of NiO2-NPs to healthy rats increased both apoptosis and the Bad/Bcl-X expression ratio. However, its administration to testicular I/R rats alone or with curcumin decreased apoptosis and the Bad/Bcl-X expression ratio and increased expressions of miR-34 and circRNA 0001518. Conclusion: Administration of NiO2-NPs and curcumin, alone or in combination, can have therapeutic effects in testicular I/R conditions by altering the expressions of genes in the mitochondrial apoptotic pathway and their regulatory elements. [GMJ.2021;10:e2342]


Hamed GM, Ahmed RM, Emara MM, Mahmoud MH. Effect of erythropoietin on experimental unilateral testicular torsion detorsion in rat model. Life Sci J. 2011;8(2):405-12.

Shimizu S, Saito M, Dimitriadis F, Kinoshita Y, Shomori K, Satoh I, et al. Protective effect of ischaemic post‐conditioning on ipsilateral and contralateral testes after unilateral testicular ischaemia‐reperfusion injury. Int J Androl. 2011;34(3):268-75.


Vakili A, Eianali MR, Bandegi AR. The protective effects of Saffron against the oxidative damage in a transient model of focal cerebral ischemia in rats. Tehran University Medical Journal. 2011:405-12.

Yun SS, Kim SP, Kang MY, Nam SH. Inhibitory effect of curcumin on liver injury in a murine model of endotoxemic shock. Biotechnol Lett. 2010;32(2):209-14.


Azza M, El-Wakf M, Elhabiby M, El-kholy E, El-Ghany E. Use of tumeric and curcumin to alleviate adverse reproductive outcomes of water: Nitrate pollution in male rats. Nat Sci. 2011;9:229-39.

Ilbey YO, Ozbek E, Cekmen M, Simsek A, Otunctemur A, Somay A. Protective effect of curcumin in cisplatin-induced oxidative injury in rat testis: mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways. Hum Reprod. 2009;24(7):1717-25.


Yu W-G, Xu G, Ren G-J, Xu X, Yuan H-Q, Qi X-L, et al. Preventive action of curcumin in experimental acute pancreatitis in mouse. Indian J Med Res. 2011;134(5):717.

PMid:22199113 PMCid:PMC3249972

Gouda SG, Khalil MS, Naim MM. Curcumin protects against testicular damage and genotoxicity induced by acrylamide in male albino mice. Egyptian Journal of Histology. 2011;34(2):333-45.

Sharma P, Singh R. Protective role of curcumin on lindane induced reproductive toxicity in male Wistar rats. Bull Environ Contam Toxicol. 2010;84(4):378-84.


Takhtfooladi MA, Asghari A, Takhtfooladi HA, Shabani S. The protective role of curcumin on testicular tissue after hindlimb ischemia reperfusion in rats. Int Urol Nephrol. 2015;47(10):1605-10.


Fallahi S, Hooshmandi Z, Setorki M. The effects of Fe4NiO4Zn nanoparticles on thyroid tissue and serum level of T3, T4 and TSH. Journal of Shahrekord University of Medical Sciences. 2017;18(6):115-24.

Jain TK, Reddy MK, Morales MA, Leslie-Pelecky DL, Labhasetwar V. Biodistribution, clearance, and biocompatibility of iron oxide magnetic nanoparticles in rats. Mol Pharm. 2008;5(2):316-27.


Scandorieiro S, de Camargo LC, Lancheros CA, Yamada-Ogatta SF, Nakamura CV, de Oliveira AG, et al. Synergistic and Additive Effect of Oregano Essential Oil and Biological Silver Nanoparticles against Multidrug-Resistant Bacterial Strains. Front Microbiol. 2016;7:760.

PMid:27242772 PMCid:PMC4876125

Muñoz A, Costa M. Elucidating the mechanisms of nickel compound uptake: a review of particulate and nano-nickel endocytosis and toxicity. Toxicol Appl Pharmacol. 2012;260(1):1-16.

PMid:22206756 PMCid:PMC3306469

Lan Z, Yang WX. Nanoparticles and spermatogenesis: how do nanoparticles affect spermatogenesis and penetrate the blood-testis barrier. Nanomedicine (Lond). 2012;7(4):579-96.


Wahid F, Shehzad A, Khan T, Kim YY. MicroRNAs: synthesis, mechanism, function, and recent clinical trials. Biochim Biophys Acta. 2010;1803(11):1231-43.


Hermeking H. The miR-34 family in cancer and apoptosis. Cell Death Differ. 2010;17(2):193-9.


Pigazzi M, Manara E, Baron E, Basso G. miR-34b targets cyclic AMP-responsive element binding protein in acute myeloid leukemia. Cancer Res. 2009;69(6):2471-8.


Chen Q-R, Yu L-R, Tsang P, Wei JS, Song YK, Cheuk A, et al. Systematic proteome analysis identifies transcription factor YY1 as a direct target of miR-34a. J Proteome Res. 2011;10(2):479-87.

PMid:21182263 PMCid:PMC3679541

Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell. 2007;26(5):731-43.


Panda AC. Circular RNAs act as miRNA sponges. Adv Exp Med Biol. 2018:67-79.


Lin F, Zhao G, Chen Z, Wang X, Lv F, Zhang Y, et al. circRNA‑miRNA association for coronary heart disease. Mol Med Rep. 2019;19(4):2527-36.

PMid:30720076 PMCid:PMC6423602

Shan C, Zhang Y, Hao X, Gao J, Chen X, Wang K. Biogenesis, functions and clinical significance of circRNAs in gastric cancer. Mol Cancer. 2019;18(1):1-15.

PMid:31519189 PMCid:PMC6743094

Organisation WH. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction: Cambridge university press; 1999.

Zare Z, Eimani H, Mohammadi M, Mofid M, Dashtnavard H. The Effect of Orally Administered L-carnitine on Testis Tissue, Sperm Parameters and Daily Sperm Production in Adult Mice. Yakhteh medical journal. 2010;11(4).

Mallick IH, Yang W, Winslet MC, Seifalian AM. Ischemia-reperfusion injury of the intestine and protective strategies against injury. Dig Dis Sci. 2004;49(9):1359-77.


Carden DL, Granger DN. Pathophysiology of ischaemia-reperfusion injury. J Pathol 2000;190(3):255-66.<255::AID-PATH526>3.0.CO;2-6

Oldenburg O, Qin Q, Krieg T, Yang XM, Philipp S, Critz SD, et al. Bradykinin induces mitochondrial ROS generation via NO, cGMP, PKG, and mitoKATP channel opening and leads to cardioprotection. Am J Physiol Heart Circ Physiol. 2004;286(1):H468-76.


Unal D, Yeni E, Erel O, Bitiren M, Vural H. Antioxidative effects of exogenous nitric oxide versus antioxidant vitamins on renal ischemia reperfusion injury. Urol Res. 2002;30(3):190-4.


Sneha P, Ramtej V. Protective Effect of Curcumin on Diethanolamine-Induced Toxic Effects on Human Spermatozoa: An in Vitro Study.

Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect.2005;113(8):1056-61.

PMid:16079079 PMCid:PMC1280349

Khaki A, Khaki AA, Hajhosseini L, Golzar FS, Ainehchi N. The antioxidant effects of ginger and cinnamon on spermatogenesis dys-function of diabetes rats. Afr J Tradit Complement Altern Med. 2014;11(4):1-8.

PMid:25392573 PMCid:PMC4202389

Fetouh FA, Azab AES. Ameliorating effects of curcumin and propolis against the reproductive toxicity of gentamicin in adult male guinea pigs: Quantitative analysis and morphological study. American Journal of Life Sciences. 2014;2(3):138-49.

Aziz N, Saleh RA, Sharma RK, Lewis-Jones I, Esfandiari N, Thomas Jr AJ, et al. Novel association between sperm reactive oxygen species production, sperm morphological defects, and the sperm deformity index. Fertil Steril. 2004;81(2):349-54.


Santhoshkumar T, Rahuman AA, Jayaseelan C, Rajakumar G, Marimuthu S, Kirthi AV, et al. Green synthesis of titanium dioxide nanoparticles using Psidium guajava extract and its antibacterial and antioxidant properties. Asian Pac J Trop Med. 2014;7(12):968-76.

Pourmorad F, Hosseinimehr S, Shahabimajd N. Antioxidant activity, phenol and flavonoid contents of some selected Iranian medicinal plants. African journal of biotechnology. 2006;5(11).

Taghizadeh L, Eidi A, Mortazavi P, Rohani AH. Effect of selenium on testicular damage induced by varicocele in adult male Wistar rats. J Trace Elem Med Biol. 2017;44:177-85.


Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002 Sep;2(9):647-56.


Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell. 1995;80(2):285-91.

Krajewski S, Krajewska M, Shabaik A, Wang HG, Irie S, Fong L, et al. Immunohistochemical analysis of in vivo patterns of Bcl-X expression. Cancer Res. 1994;54(21):5501-7.

Boise LH, González-García M, Postema CE, Ding L, Lindsten T, Turka LA, et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993;74(4):597-608.

Misso G, Di Martino MT, De Rosa G, Farooqi AA, Lombardi A, Campani V, et al. Mir-34: a new weapon against cancer? Mol Ther Nucleic Acids. 2014 Sep 23;3(9):e194.

PMid:25247240 PMCid:PMC4222652

Li N, Wang K, Li P-F. MicroRNA-34 family and its role in cardiovascular disease.Crit Rev Eukaryot Gene Expr. 2015;25(4):293-7.


Maroof H, Salajegheh A, Anthony Smith R, King-Yin Lam A. MicroRNA-34 family, mechanisms of action in cancer: a review. Curr Cancer Drug Targets. 2014;14(8):737-51.


Zhong Y, Du Y, Yang X, Mo Y, Fan C, Xiong F, et al. Circular RNAs function as ceRNAs to regulate and control human cancer progression. Mol Cancer. 2018;17(1):1-11.

PMid:29626935 PMCid:PMC5889847

Abi A, Farahani N, Molavi G, Hayat SMG. Circular RNAs: epigenetic regulators in cancerous and noncancerous skin diseases. Cancer Gene Ther. 2020;27(5):280-93.


How to Cite
Zarei Moradi, S., Angaji, S. A., Salehi, M., & Hashemi, M. (2021). Impact of NiO2 Nanoparticles and Curcumin on Testis Torsion/Detorsion Injury: Role of miR-34 and circRNA 0001518 . Galen Medical Journal, 10, e2342.
Original Article