Maedeh HAMZEH, Fereshteh TALEBPOUR AMİRİ, Saeed YAGHUBİ BEKLER, Seyed Jalal HOSSEİNİMEHR

Nephroprotective effect of cerium oxide nanoparticles on cyclophosphamide-induced nephrotoxicity via antiapoptotic and antioxidant properties in BALB/c mice

Cyclophosphamide [CP], as alkylating agents has side effects such as nephrotoxicity. Cerium oxide nanoparticles [nanoceria; NC], as an antioxidant, are effective at reduction oxidative stress. This study evaluated the protective effect of nanoceria in nephrotoxicity induced CP. 32 BALB/c mice were randomly divided into four equal groups. Control, NC, CP and NC+CP. NC and CP injected intraperitoneally respectively in dose of 100 μg/kg for 3 days and 200 mg/kg single dose on 3th day of study. Two days after the final treatment, histochemical, serum biochemical, histopathological and immunohistochemical examinations were performed for determination effects of NC on nephrotoxicity. Oxidative stress and renal injury induced in CP treated mice were proved by the significantly elevation of urea and creatinine and alteration in oxidative stress markers [MDA and GSH levels]. Consequently, histopathological changes and apoptosis were markedly increased. NC was able to reduce MDA, urea , creatinine and increase GSH content. In addition, NC pretreatment could alleviated immunoreactivity of caspase-3. NC revealed a strong antioxidant in nephrotoxicity following CP treatment. This study suggests that NC through antioxidant and antiapoptotic properties have protective effect against CP-induced nephrotoxicity.

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[1] Unnikrishnan A, Glover S, Norkina O, Wingard J, Norkin M. Complete resolution of severe ulcerative colitis after haploidentical hematopoietic stem cell transplantation followed by post-transplant high-dose cyclophosphamide. Bone Marrow Transplant. 2017; 52: 1204-1205.

[2] Lim SR, Hyun SH, Lee SG, Kim JY, Kim SH, Park SJ, Moon KS, Sul D, Kim DH, Choi HK. Potential urinary biomarkers of nephrotoxicity in cyclophosphamide‐treated rats investigated by NMR‐based metabolic profiling. J Biochem Mol Toxicol. 2017; 31(3): e21871

[3] Wahlang B, Falkner KC, Cave MC, Prough RA. Chapter One-Role of Cytochrome P450 Monooxygenase in Carcinogen and Chemotherapeutic Drug Metabolism. Adv Pharmacol. 2015; 74: 1-33.

[4] Zarei M, Shivanandappa T. Amelioration of cyclophosphamide-induced hepatotoxicity by the root extract of Decalepis hamiltonii in mice. Food Chem Toxicol. 2013; 57:179-184.

[5] Bhattacharjee A, Basu A, Ghosh P, Biswas J, Bhattacharya S. Protective effect of Selenium nanoparticle against cyclophosphamide induced hepatotoxicity and genotoxicity in Swiss albino mice. J Biomater Appl. 2014; 29(2): 303- 317

[6] Sharma S, Sharma P, Kulurkar P, Singh D, Kumar D, Patial V. Iridoid glycosides fraction from Picrorhiza kurroa attenuates cyclophosphamide-induced renal toxicity and peripheral neuropathy via PPAR-γ mediated inhibition of inflammation and apoptosis. Phytomedicine. 2017; 36:108-117.

[7] Ruggiero A, Ferrara P, Attinà G, Rizzo D, Riccardi R. Renal toxicity and chemotherapy in children with cancer nephrotoxicity and cancer treatment. Br J Clin Pharmacol. 2017. 83:2605-2614.

[8] Goudarzi M, Kalantari H, Kalantar M, Foruozandeh H. Protective effects of hydroalcoholic extract of Capparis spinosa L. against cyclophosphamide-induced nephrotoxicity in mice. Toxicol. Lett. 2016; 258: S283-S284.

[9] Gagnon J, Fromm KM. Toxicity and protective effects of cerium oxide nanoparticles (nanoceria) depending on their preparation method, particle size, cell type, and exposure route. Eur J Inorg Chem. 2015; 2015(27): 4510-4517.

[10] Liu T, Li L, Teng X, Huang X, Liu H, Chen D, Ren J, He J, Tang F. Single and repeated dose toxicity of mesoporous hollow silica nanoparticles in intravenously exposed mice. Biomaterials. 2011; 32(6): 1657-1668.

[11] Korsvik C, Patil S, Seal S, Self WT. Superoxide dismutase mimetic properties exhibited by vacancy engineered ceria nanoparticles. Chem Commun (Camb). 2007; 10: 1056-1058.

[12] Pirmohamed T, Dowding JM, Singh S, Wasserman B, Heckert E, Karakoti AS, King JES, Seal S, Self WT. Nanoceria exhibit redox state-dependent catalase mimetic activity. Chem Commun (Camb). 2010; 46(16): 2736-2738.

[13] Hashem RM, Rashd LA, Hashem KS, Soliman HM. Cerium oxide nanoparticles alleviate oxidative stress and decreases Nrf-2/HO-1 in D-GALN/LPS induced hepatotoxicity. Biomed Pharmacother.2015; 73:80-86.

[14] González-Flores D, De Nicola M, Bruni E, Caputo F, Rodríguez AB, Pariente JA, Ghibelli L. Nanoceria protects from alterations in oxidative metabolism and calcium overloads induced by TNFα and cycloheximide in U937 cells: pharmacological potential of nanoparticles. Mol Cell Biochem. 2014; 397(1-2): 245-253.

[15] Forest V, Leclerc L, Hochepied J-F, Trouvé A, Sarry G, Pourchez J. Impact of cerium oxide nanoparticles shape on their in vitro cellular toxicity. Toxicol In Vitro. 2017; 38:136-141.

[16] Xu P, Maidment 3rd B, Antonic V, Jackson I, Das S, Zodda A,Zhang x, Seal S, Vujaskovic Z. Cerium Oxide Nanoparticles: A Potential Medical Countermeasure to Mitigate Radiation-Induced Lung Injury in CBA/J Mice. Radiat Res.2016; 185(5): 516-526.

[17] Ouyang Z, Mainali MK, Sinha N, Strack G, Altundal Y, Hao Y, Winningham TA, Sajo E, Celli J, Ngwa W. Potential of using cerium oxide nanoparticles for protecting healthy tissue during accelerated partial breast irradiation (APBI). Phys Med. 2016; 32(4): 631-635.

[18] Sack M, Alili L, Karaman E, Das S, Gupta A, Seal S,Brenneisen P. Combination of conventional chemotherapeutics with redox-active cerium oxide nanoparticles—A novel aspect in cancer therapy. Mol Cancer Ther. 2014; 13(7): 1740- 1749.

[19] Chen S, Hou Y, Cheng G, Zhang C, Wang S, Zhang J. Cerium oxide nanoparticles protect endothelial cells from apoptosis induced by oxidative stress. Biol Trace Elem Res. 2013; 154(1): 156-166.

[20] Celardo I, De Nicola M, Mandoli C, Pedersen JZ, Traversa E, Ghibelli L. Ce3+ ions determine redox-dependent antiapoptotic effect of cerium oxide nanoparticles. ACS Nano. 2011; 5(6): 4537-4549.

[21] Mikyšková R, Indrová M, Vlková V, Bieblová J, Šímová J, Paračková Z, Piasecka EP, Rossowska J, Reinis M . DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment. J Leukoc Biol. 2014; 95 743-753. (5) .

[22] Murali VP, Kuttan G. Curculigo orchioides Gaertn Effectively Ameliorates the Uro-and Nephrotoxicities Induced by Cyclophosphamide Administration in Experimental Animals. Integr Cancer Ther.2016; 15(2): 205-215.

[23] Huang Z, Roy P, Waxman DJ. Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing Ndechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol. 2000; 59(8): 961-972.

[24] Lamb EJ, Brettell EA, Cockwell P, Dalton N, Deeks JJ, Harris K,Higgins T, Kalra PA, Khunti K, Loud F, Ottridge RS, Sharpe CC, Sitch AJ, Stevens PE, Sutton AJ, Taal MW . The eGFR-C study: accuracy of glomerular filtration rate (GFR) estimation using creatinine and cystatin C and albuminuria for monitoring disease progression in patients with stage 3 chronic kidney disease-prospective longitudinal study in a multiethnic population. BMC Nephrol. 2014; 15(1): 13.

[25] Guney T, Kanat İF, Alkan A, Alisik M, Akinci S, Silay K, Neselioglu S, Dilek I, Erel O. Assessment of serum thiol/disulfide homeostasis in multiple myeloma patients by a new method. REDOX REP. 2017; 22(6): 246-251.

[26] Aquilano K, Baldelli S, Ciriolo MR. Glutathione: new roles in redox signaling for an old antioxidant. Front Pharmacol. 2014; 5:196.

[27] Singh JC, Mamtani A, Barrio A, Morrow M, Sugarman S, Jones LW, Yu AF, Argolo D, Smyth LM, Modi S, Schweber S, Boafo C, Patil S, Norton L, Baselga J, Hudis CA, Dang C. Pathologic Complete response with neoadjuvant Doxorubicin and Cyclophosphamide followed by Paclitaxel with Trastuzumab and Pertuzumab in patients with HER2‐positive early stage breast cancer: A single center experience. Oncologist. 2017; 22(2): 139-143.

[28] Sheweita SA, El-Hosseiny LS, Nashashibi MA. Protective effects of essential oils as natural antioxidants against hepatotoxicity induced by cyclophosphamide in mice. PLoS One. 2016; 11(11): e0165667.

[29] Zhang H, Liu Y-y, Jiang Q, Li K-r, Zhao Y-x, Cao C,Yao J. Salvianolic acid A protects RPE cells against oxidative stress through activation of Nrf2/HO-1 signaling. Free Radic Biol Med. 2014; 69:219-228.

[30] Reinhardt K, Winkler H. Cerium mischmetal, cerium alloys, and cerium compounds. Ullmann's encyclopedia of industrial chemistry. 2002.

[31] Heckert EG, Karakoti AS, Seal S, Self WT. The role of cerium redox state in the SOD mimetic activity of nanoceria. Biomaterials. 2008; 29(18): 2705-2709.

[32] Scholes F, Hughes A, Hardin S, Lynch P, Miller P. Influence of hydrogen peroxide in the preparation of nanocrystalline ceria. Chem. Mater. 2007; 19(9): 2321-2328.

[33] Guzman J, Carrettin S, Corma A. Spectroscopic evidence for the supply of reactive oxygen during CO oxidation catalyzed by gold supported on nanocrystalline CeO2. J Am Chem Soc. 2005; 127(10): 3286-3287.

[34] Karakoti A, Singh S, Dowding JM, Seal S, Self WT. Redox-active radical scavenging nanomaterials. Chem Soc Rev. 2010; 39(11): 4422-4432.

[35] Yokel RA, Unrine JM, Wu P, Wang B, Grulke EA. Nanoceria biodistribution and retention in the rat after its intravenous administration are not greatly influenced by dosing schedule, dose, or particle shape. Environ Sci Nano. 2014; 1(6):

[36] Dowding J, Song W, Bossy K, Karakoti A, Kumar A, Kim A,Bossy B, Seal S, Ellisman MH, Perkins G, Self WT, Bossy- Wetzel E. Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death. Cell Death Differ. 2014; 21(10): 1622-1632.

[37] Xia T, Kovochich M, Liong M, Mädler L, Gilbert B, Shi H,Yeh JI, Zink JI, Nel AE. Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS nano. 2008; 2(10): 2121-2134.

[38] Schubert D, Dargusch R, Raitano J, Chan S-W. Cerium and yttrium oxide nanoparticles are neuroprotective. Biochem Biophys Res Commun. 2006; 342(1): 86-91.

[39] Colon J, Hsieh N, Ferguson A, Kupelian P, Seal S, Jenkins DW, Baker CH. Cerium oxide nanoparticles protect gastrointestinal epithelium from radiation-induced damage by reduction of reactive oxygen species and upregulation of superoxide dismutase 2. Nanomed Nanotech Biol Med (Other). 2010; 6(5): 698-705.

[40] Colon J, Herrera L, Smith J, Patil S, Komanski C, Kupelian P, Seal S, Jenkins W, Baker CH. Protection from radiationinduced pneumonitis using cerium oxide nanoparticles. Nanomed Nanotech Biol Med (Other) .2009; 5(2): 225-231.

[41] Cheng G, Guo W, Han L, Chen E, Kong L, Wang L, Ai W, Song N, Li H, Chen H. Cerium oxide nanoparticles induce cytotoxicity in human hepatoma SMMC-7721 cells via oxidative stress and the activation of MAPK signaling pathways. Toxicol In Vitro. 2013; 27(3): 1082-1088.

[42] Kumari M, Singh SP, Chinde S, Rahman MF, Mahboob M, Grover P. Toxicity study of cerium oxide nanoparticles in human neuroblastoma cells. Int J Toxicol. 2014; 33(2): 86-97.

[43] Asati A, Santra S, Kaittanis C, Perez JM. Surface-charge-dependent cell localization and cytotoxicity of cerium oxide nanoparticles. ACS nano. 2010; 4(9): 5321-5331.

[44] Grulke E, Reed K, Beck M, Huang X, Cormack A, Seal S. Nanoceria: factors affecting its pro-and anti-oxidant properties. Environ Sci Nano. 2014; 1(5): 429-444.

[45] Becker S, Soukup J, Gallagher J. Differential particulate air pollution induced oxidant stress in human granulocytes, monocytes and alveolar macrophages. Toxicol In Vitro. 2002; 16(3): 209-218.

[46] Kwon HJ, Cha M-Y, Kim D, Kim DK, Soh M, Shin K, Hyeon T, Mook-Jung I. Mitochondria-targeting ceria nanoparticles as antioxidants for Alzheimer’s disease. ACS Nano. 2016; 10(2): 2860-2870.

[47] Kong L, Cai X, Zhou X, Wong LL, Karakoti AS, Seal S, McGinnis JF. Nanoceria extend photoreceptor cell lifespan in tubby mice by modulation of apoptosis/survival signaling pathways. Neurobiol Dis. 2011; 42(3): 514-523.

[48] Zhang X, Zhu Y, Duan W, Feng C, He X. Allicin induces apoptosis of the MGC-803 human gastric carcinoma cell line through the p38 mitogen-activated protein kinase/caspase-3 signaling pathway. Mol Med Rep. 2015; 11(4): 2755- 2760.

[49] Das J, Choi Y-J, Han JW, Reza AMMT, Kim J-H. Nanoceria-mediated delivery of doxorubicin enhances the antitumour efficiency in ovarian cancer cells via apoptosis. Sci Rep. 2017; 7(1): 9513.

[50] Akhtar MJ, Ahamed M, Alhadlaq HA, Khan MM, Alrokayan SA. Glutathione replenishing potential of CeO 2 nanoparticles in human breast and fibrosarcoma cells. J Colloid Interface Sci. 2015; 453 21-27.

[51] Khaksar MR, Rahimifard M, Baeeri M, Maqbool F, Navaei-Nigjeh M, Hassani S, Moeini-Nodeh S, Kebriaeezadeh A, Abdollahi M. Protective effects of cerium oxide and yttrium oxide nanoparticles on reduction of oxidative stress induced by sub-acute exposure to diazinon in the rat pancreas. J Trace Elem Med Biol. 2017; 41:79-90.

[52] Serebrovska Z, Swanson R, Portnichenko V, Shysh A, Pavlovich S, Tumanovska L,Dorovskych A, Lysenko V, Tertykh V, Bolbukh Y, Dosenko V. Anti-inflammatory and antioxidant effect of cerium dioxide nanoparticles immobilized on the surface of silica nanoparticles in rat experimental pneumonia. Biomed Pharmacother. 2017; 92:69-77.

[53] Mansour DF, Salama AA, Hegazy RR, Omara EA, Nada SA. Whey protein isolate protects against cyclophosphamide-induced acute liver and kidney damage in rats. J appl pharm sci. 2017; 7(06): 111-120.

[54] Ghabaee DNZ, Amiri FT, Moghaddam AE, Khalatbary AR, Zargari M. Administration of zinc against arsenicinduced nephrotoxicity during gestation and lactation in rat model. J Nephropathol. 2017; 6(2): 74.

[55] Naeimi RA, Amiri FT, Khalatbary AR, Ghasemi A, Zargari M, Ghesemi M, Hosseinimehr SJ. Atorvastatin mitigates testicular injuries induced by ionizing radiation in mice. Reproductive Toxicol. 2017; 72: 115-122.