{"references": ["Rasoulian B, Kaeidi A, Pourkhodadad S, Dezfoulian O, Rezaei M, Wahhabaghai H, Alirezaei M (2014) Effects of pretreatment with single-dose or intermittent oxygen on Cisplatin-induced nephrotoxicity in rats Nephro-urology monthly 6:e19680 doi:10.5812/numonthly.19680.", "Uozumi J, Ueda T, Yasumasu T, Koikawa Y, Naito S, Kumazawa J, Sueishi K (1992) Platinum accumulation in the kidney and liver following chemotherapy with cisplatin in humans, International urology and nephrology 25:215-220.", "Cozzaglio L, Doci R, Colella G, Zunino F, Casciarri G, Gennari L, Colla G (1990) A feasibility study of high-dose cisplatin and 5-fluorouracil with glutathione protection in the treatment of advanced colorectal cancer Tumori 76:590-594.", "Wang Y et al. (2010) Specific hemosiderin deposition in spleen induced by a low dose of cisplatin: altered iron metabolism and its implication as an acute hemosiderin formation model Current drug metabolism 11:507", "Dong Z, Atherton S (2007) Tumor necrosis factor-\u03b1 in cisplatin nephrotoxicity: A homebred foe? Kidney international 72:5-7.", "Rao M, Rao M (1998) Protective effects of cystone, a polyherbal ayurvedic preparation, on cisplatin-induced renal toxicity in rats Journal of ethnopharmacology 62:1-6.", "Barbaro B, Toietta G, Maggio R, Arciello M, Tarocchi M, Galli A, Balsano C (2014) Effects of the olive-derived polyphenol oleuropein on human health International journal of molecular sciences 15:18508-18524 doi:10.3390/ijms151018508.", "Fabiani R, Rosignoli P, De Bartolomeo A, Fuccelli R, Servili M, Montedoro GF, Morozzi G (2008) Oxidative DNA damage is prevented by extracts of olive oil, hydroxytyrosol, and other olive phenolic compounds in human blood mononuclear cells and HL60 cells The Journal of nutrition 138:1411-1416.", "Casamenti F, Grossi C, Rigacci S, Pantano D, Luccarini I, Stefani M (2015) Oleuropein Aglycone: A Possible Drug against Degenerative Conditions. In Vivo Evidence of its Effectiveness against Alzheimer's Disease Journal of Alzheimer's disease: JAD 45:679-688.\n[10]\tQuirantes\u2010Pin\u00e9 R, Lozano\u2010S\u00e1nchez J, Herrero M, Ib\u00e1\u00f1ez E, Segura\u2010Carretero A, Fern\u00e1ndez\u2010Guti\u00e9rrez A (2013) HPLC\u2013ESI\u2013QTOF\u2013MS as a Powerful Analytical Tool for Characterising Phenolic Compounds in Olive\u2010leaf Extracts Phytochemical Analysis 24:213-223.\n[11]\tSrivastava R, Farookh A, Ahmad N, Misra M, Hasan S, Husain M (1996) Evidence for the involvement of nitric oxide in cisplatin-induced toxicity in rats Biometals 9:139-142.\n[12]\tWaseem M, Bhardwaj M, Tabassum H, Raisuddin S, Parvez S (2015) Cisplatin hepatotoxicity mediated by mitochondrial stress Drug and chemical toxicology:1-8 doi:10.3109/01480545.2014.992437.\n[13]\tAdemiluyi AO, Oboh G, Agbebi OJ, Boligon AA, Athayde ML (2014) Sorghum (Sorghum bicolor (L.) Moench) Leaf Sheath Dye Protects Against Cisplatin-Induced Hepatotoxicity and Oxidative Stress in Rats Journal of medicinal food 17:1332-1338.\n[14]\tAndreadou I et al. (2009) Metabonomic identification of novel biomarkers in doxorubicin cardiotoxicity and protective effect of the natural antioxidant oleuropein NMR in Biomedicine 22:585-592.\n[15]\tYagi K (1984) Assay for blood plasma or serum Methods Enzymol 105:328-331.\n[16]\tGil H-W, Seok S-J, Jeong D-S, Yang J-O, Lee E-Y, Hong S-Y (2010) Plasma level of malondialdehyde in the cases of acute paraquat intoxication Clinical toxicology 48:149-152.\n[17]\tBolukbas C, Bolukbas FF, Horoz M, Aslan M, Celik H, Erel O (2005) Increased oxidative stress associated with the severity of the liver disease in various forms of hepatitis B virus infection BMC infectious diseases 5:95.\n[18]\tLi D et al. (2014) Exercises in Hot and Humid Environment Caused Liver Injury in a Rat Model PLoS One 9:e111741.\n[19]\tAbdel-Wahab B, Metwally M (2011) Ginkgo biloba enhances the anticonvulsant and neuroprotective effects of sodium valproate against kainic acid-induced seizures in mice J Pharmacol Toxicol 6:679-690.\n[20]\tZubair A, Jamal S, Mubarik A (2009) Morphometric analysis of hepatic steatosis in chronic hepatitis C infection Saudi journal of gastroenterology: official journal of the Saudi Gastroenterology Association 15:11.\n[21]\tCheong HH, Masilamani J, Chan CYE, Chan SY, Phan TT (2013) Metabolically functional hepatocyte-like cells from human umbilical cord lining epithelial cells Assay and drug development technologies 11:130-138.\n[22]\tTeixeira RB, Kelley J, Alpert H, Pardo V, Vaamonde CA (1982) Complete protection from gentamicin-induced acute renal failure in the diabetes mellitus rat Kidney international 21:600-612.\n[23]\tCure E, Kirbas A, Tumkaya L, Cure MC, Kalkan Y, Yilmaz A, Yuce S (2015) Protective effect of infliximab on methotrexate-induced liver injury in rats: Unexpected drug interaction Journal of cancer research and therapeutics 11:164.\n[24]\tDu F et al. (2015) Morphology and Molecular Mechanisms of Hepatic Injury in Rats under Simulated Weightlessness and the Protective Effects of Resistance Training PLoS One 10.\n[25]\tBrackett J, Schafer ES, Leung DH, Bernhardt MB (2014) Use of allopurinol in children with acute lymphoblastic leukemia to reduce skewed thiopurine metabolism Pediatric blood & cancer 61:1114-1117.\n[26]\tPalipoch S, Punsawad C, Koomhin P, Suwannalert P (2014) Hepatoprotective effect of curcumin and alpha-tocopherol against cisplatin-induced oxidative stress BMC complementary and alternative medicine 14:111.\n[27]\tHesketh M, Twaddell T, Finn A A possible role for cisplatin (DDP) in the transient hepatic enzyme elevation noted after ondansetron administration. In: Proc Am Assoc Clin Oncol, 1990. vol 323. p b28.\n[28]\tOleszko A et al. (2015) Application of FTIR-ATR Spectroscopy to Determine the Extent of Lipid Peroxidation in Plasma during Haemodialysis BioMed research international 2015.\n[29]\tRahman K (2007) Studies on free radicals, antioxidants, and co-factors Clinical interventions in aging 2:219.\n[30]\tAttia SM (2010) Deleterious effects of reactive metabolites Oxidative medicine and cellular longevity 3:238-253.\n[31]\tPons DG, Nadal-Serrano M, Torrens-Mas M, Valle A, Oliver J, Roca P (2015) UCP2 inhibition sensitizes breast Cancer cells to therapeutic agents by increasing oxidative stress Free Radical Biology and Medicine\n[32]\tKim HJ et al. (2015) Glutamine protects against cisplatin-induced nephrotoxicity by decreasing cisplatin accumulation Journal of pharmacological sciences 127:117-126 doi:10.1016/j.jphs.2014.11.009.\n[33]\tHassen I, Casabianca H, Hosni K (2014) Biological activities of the natural antioxidant oleuropein: Exceeding the expectation\u2013A mini-review Journal of Functional Foods.\n[34]\tDekanski D, Janicijevic-Hudomal S, Ristic S, Radonjic NV, Petronijevic ND, Piperski V, Mitrovic DM (2009a) Attenuation of cold restraint stress-induced gastric lesions by an olive leaf extract Gen Physiol Biophys 28:135-142.\n[35]\tDekanski D, Risti\u0107 S, Mitrovi\u0107 D (2009b) Antioxidant effect of dry olive (Olea europaea L.) leaf extract on ethanol-induced gastric lesions in rats Mediterranean Journal of Nutrition and Metabolism 2:205-211.\n[36]\tDekanski D, Selakovi\u0107 V, Piperski V, Radulovi\u0107 \u017d, Koreni\u0107 A, Radenovi\u0107 L (2011) Protective effect of olive leaf extract on hippocampal injury induced by transient global cerebral ischemia and reperfusion in Mongolian gerbils Phytomedicine 18:1137-1143.\n[37]\tDekanski D, Mihailovi\u0107-Stanojevi\u0107 N, Milanovi\u0107 GJ, Jovovi\u0107 \u0110, Miloradovi\u0107 Z (2014) Effects of high dose olive leaf extract on haemodynamic and oxidative stress parameters in normotensive and spontaneously hypertensive rats Journal of the Serbian Chemical Society 79:1085-1097.\n[38]\tKim Y, Choi Y, Park T (2010) Hepatoprotective effect of oleuropein in mice: mechanisms uncovered by gene expression profiling Biotechnology journal 5:950-960.\n[39]\tOliveras-L\u00f3pez M-J, Molina JJM, Mir MV, Rey EF, Mart\u00edn F, de la Serrana HL-G (2013) Extra virgin olive oil (EVOO) consumption and antioxidant status in healthy institutionalized elderly humans Archives of gerontology and geriatrics 57:234-242.\n[40]\t\u00c7oban J, \u00d6ztezcan S, Do\u011fru\u2010Abbaso\u011flu S, Bing\u00fcl I, Ye\u015fil\u2010Mizrak K, Uysal M (2014) Olive leaf extract decreases age\u2010induced oxidative stress in major organs of aged rats Geriatrics & gerontology international 14:996-1002.\n[41]\tde la Puerta R, Ruiz Gutierrez V, Hoult JR (1999) Inhibition of leukocyte 5-lipoxygenase by phenolics from virgin olive oil Biochemical pharmacology 57:445-449.\n[42]\tZbidi H, Salido S, Altarejos J, Perez-Bonilla M, Bartegi A, Rosado JA, Salido GM (2009) Olive tree wood phenolic compounds with human platelet antiaggregant properties Blood cells, molecules & diseases 42:279-285 doi:10.1016/j.bcmd.2009.01.001.\n[43]\t Kodama A et al. (2014) Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity Biochimica et Biophysica Acta (BBA)-General Subjects 1840:1152-1162.\n[44]\tGhanema IA, Sadek KM (2012) Olive leaves extract restored the antioxidant perturbations in red blood cells hemolysate in streptozotocin induced diabetic rats World Academy of Science, Engineering & Technology 64:159-165.\n[45]\tBenavente-Garc\u0131a O, Castillo J, Lorente J, Ortuno A, Del Rio J (2000) Antioxidant activity of phenolics extracted from Olea europaea L. leaves Food Chemistry 68:457-462.\n[46]\tRoberto Fabiani, Patrizia Rosignoli, Angelo De Bartolomeo, Raffaela Fuccelli, Maurizio Servili, Gian Francesco Montedoro and Guido Morozzi (2008) Oxidative DNA Damage Is Prevented by Extracts of Olive Oil, Hydroxytyrosol, and Other Olive Phenolic Compounds in Human Blood Mononuclear Cells and HL60 Cells, The Journal of Nutrition 138(8):1411-1416.\n[47]\tTurkez H, Togar B (2011) Olive (Olea europaea L.) leaf extract counteracts genotoxicity and oxidative stress of permethrin in human lymphocytes The Journal of toxicological sciences 36:531-537.\n[48]\tMohamadi M, Afzali D, Esmaeili-Mahani S, Mostafavi A, Torkzadeh-Mahani M (2015) Spectroscopic and electrochemical studies of the interaction between oleuropein, the major bio-phenol in olives, and salmon sperm DNA Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 148:260-265.\n[49]\tZheng X-N et al. (2013) Pu-erh Tea Powder Preventive Effects on Cisplatin-Induced Liver Oxidative Damage in Wistar Rats Asian Pacific journal of cancer prevention: APJCP 15:7389-7394.\n[50]\tXu Y, Li J, Wang R (2012) Change in gastrocnemius dystrophin and metabolic enzymes and increase in high-speed exhaustive time induced by hypoxic training in rats, Sheng li xue bao:(Acta physiologica Sinica) 64:455-462.\n[51]\tEl-Demerdash F, Yousef M, El-Naga NA (2005) Biochemical study on the hypoglycemic effects of onion and garlic in alloxan-induced diabetic rats Food and Chemical Toxicology 43:57-63.\n[52]\tKaminskyy VO, Piskunova T, Zborovskaya IB, Tchevkina EM, Zhivotovsky B (2012) Suppression of basal autophagy reduces lung cancer cell proliferation and enhances caspase-dependent and-independent apoptosis by stimulating ROS formation Autophagy 8:1032-1044.\n[53]\tFouraschen SM et al. (2013) mTOR signaling in liver regeneration: Rapamycin combined with growth factor treatment World journal of transplantation 3:36.\n[54]\tPaiva\u2010Martins F et al. (2009) Effects of olive oil polyphenols on erythrocyte oxidative damage Molecular nutrition & food research 53:609-616.\n[55]\tPaiva-Martins F, Gordon MH, Gameiro P (2003) Activity and location of olive oil phenolic antioxidants in liposomes Chemistry and physics of lipids 124:23-36.\n[56]\tNasr AY (2013) Morphological, biochemical, histological, and ultrastructural protective effects of misoprostol on cisplatin induced-hepatotoxicity in adult male rats Saudi medical journal 34:1237-1247.\n[57]\tDhouib IE-B, Lasram MM, Annabi A, Gharbi N, El-Fazaa S (2015) A comparative study on toxicity induced by carbosulfan and malathion in Wistar rat liver and spleen Pesticide Biochemistry and Physiology.\n[58]\tDomitrovi\u0107 R, Jakovac H, Marchesi VV, \u0160ain I, Romi\u0107 \u017d, Raheli\u0107 D (2012) Preventive and therapeutic effects of oleuropein against carbon tetrachloride-induced liver damage in mice Pharmacological Research 65:451-464.\n[59]\tNarayana K (2012) Effects of l-ascorbic acid on two cycles of cisplatin-induced DNA double-strand breaks and phosphorylation of p53 in the liver Experimental and Toxicologic Pathology 64:495-502.\n[60]\tKobatake K, Kato M, Mita K (2015) Advanced testicular cancer associated with life-threatening tumour lysis syndrome and choriocarcinoma syndrome Canadian Urological Association Journal 9:62.\n[61]\tJiang Y et al. (2014) Effects of cisplatin on the contractile function of thoracic aorta of Sprague\u2011Dawley rats, Biomedical reports 2:893-897.\n[62]\tLapi D, Di Maro M, Mastantuono T, Battiloro L, Sabatino L, Muscariello E, Colantuoni A (2015) Effects of Oleuropein and Pinoresinol on Microvascular Damage Induced by Hypoperfusion and Reperfusion in Rat Pial Circulation Microcirculation 22:79-90.\n[63]\tNaqshbandi A, Khan W, Rizwan S, Khan F (2012) Studies on the protective effect of flaxseed oil on cisplatin-induced hepatotoxicity Human & experimental toxicology 31:364-375.\n[64]\tAdejuwon A, Femi-Akinlosotu O, Omirinde J, Owolabi O, Afodun A (2014) Launaea taraxacifolia ameliorates cisplatin-induced hepato-renal injury Eur J Medicinal Plants 4:528-541.\n[65]\tWaseem M, Pandey P, Tomar B, Raisuddin S, Parvez S (2014) Ameliorative Action of Curcumin in Cisplatin-mediated Hepatotoxicity: An in vivo Study in Wistar Rats Archives of medical research 45:462-468."]}

Cisplatin (CIS) is one of the most effective an anticancer drug and also toxic to cells by activating oxidative stress. Oleuropein (OLE) has key role against oxidative stress in mammalian cells, but the role of this antioxidant in the toxicity of CIS remains unknown. The aim of the present study was to investigate the efficacy of OLE on CIS-induced liver damages in male rats. With this aim, male Sprague Dawley rats were randomly assigned to one of eight groups: Control group; the group treated with 7 mg/kg/day CIS; the groups treated with 50, 100 and 200 mg/kg/day OLE (i.p.); and the groups treated with OLE for three days starting at 24 h following CIS injection. After 4 days of injections, serum was provided to assess the blood AST, ALT and LDH values. The liver tissues were removed for histological, biochemical (TAC, TOS and MDA) and genotoxic evaluations. In the CIS treated group, the whole liver tissue showed significant histological changes. Also, CIS significantly increased both the incidence of oxidative stress and the induction of 8-hydroxy-deoxyguanosine (8-OH-dG). Moreover, the rats taking CIS have abnormal results on liver function tests. However, these parameters reached to the normal range after administration of OLE for 3 days. Finally, OLE demonstrated an acceptable high potential and was effective in attenuating CIS-induced liver injury. In this trial, the 200 mg/kg dose of OLE firstly appeared to induce the most optimal protective response.