|Year : 2018 | Volume
| Issue : 3 | Page : 671-678
Therapeutic effects of oleuropein on cisplatin-induced pancreas injury in rats
Murat Bakir, Fatime Geyikoglu, Kubra Koc, Salim Cerig
Department of Biology, Faculty of Science, Ataturk University, Erzurum, Turkey
|Date of Web Publication||12-Jun-2018|
Dr. Kubra Koc
Department of Biology, Faculty of Science, Ataturk University, Erzurum
Source of Support: None, Conflict of Interest: None
Aims: Cisplatin (CIS) is an influential chemotherapeutic agent in the treatment of several types of malignant solid tumors, but its clinical use is related with ototoxicity. Oleuropein (OLE) is a natural antioxidant and scavenging free radicals. Here, we first explore the efficacy of OLE in pancreas against to the toxicity of CIS and also analyses its mechanism.
Materials and Methods: Fifty-six Sprague-Dawley rats were equally divided into eight groups, including, control group which received 7 mg/kg/day CIS intraperitoneally (i.p.) for 24 h, groups treated with doses of 50, 100, and 200 mg/kg OLE i.p. for 3 days, and groups which received same dose of CIS with three doses of OLE. After the treatments, animals were sacrificed. The oxidative DNA damage (8-hydroxy-2'-deoxyguanosine [8-OHdG]), total oxidative stress (TOS), total antioxidant status (TAS), and malondialdehyde (MDA) levels were evaluated in the pancreas. The histopathology of the pancreas was examined using three different staining methods: hematoxylin-eosin, periodic acid–Schiff, and alcian blue. Serum was provided to assess pancreatic function the lipase and amylase values.
Results: The results showed that CIS significantly increased the level of TOS, MDA, and 8-OHdG in tissue as compared to the control group. Moreover, severe tissue damages were detected in the pancreas. Whereas, OLE at high dose significantly decreased the formations of 8-OHdG, the level of MDA, and increased levels of TAS in tissue samples. In the CIS group, the levels of amylase and lipase increased compared with the control group. However, there were statistically significant differences among the CIS group and the CIS + OLE groups in the values of both amylase and lipase. In addition, histopathological findings observed in CIS group in the pancreatic tissue alleviated in CIS + OLE groups.
Conclusion: We hope that the results of this study will provide an impetus for future investigations of novel treatment strategies for OLE in pancreas due to CIS.
Keywords: Antioxidant activity, cisplatin, histopathology, oleuropein, oxidative DNA damage, pancreas
|How to cite this article:|
Bakir M, Geyikoglu F, Koc K, Cerig S. Therapeutic effects of oleuropein on cisplatin-induced pancreas injury in rats. J Can Res Ther 2018;14:671-8
| > Introduction|| |
Cisplatin (CIS) is one of the important chemotherapeutic drugs having a high level and a broad spectrum of antitumor activity commonly used to treat head, neck, lung, testis, ovary, and breast cancers. On the other hand, several side effects have been shown, such as nephrotoxicity, infertility, ototoxicity, and neurotoxicity.,
Olive leaves contain a wide variety of phenolic compounds belonging to phenolic acids, phenolic alcohols, flavonoids, and secoiridoids. Recently, the useful effects of olive oil have been ascribed to the content of polyphenols, which exert antioxidant, anti-inflammatory, anti-cancer, antimicrobial, antiviral, anti-atherogenic, hypoglycemic, and neuroprotective effects., Since the uncontrolled production of free radicals has been hypothesized as contributing to the pathogenesis of diseases, such as coronary heart disease and cancer. The ability of polyphenols to scavenge free radicals could be important in explaining how polyphenols may play a role in preventing these diseases. Oleuropein (OLE) is the most prevalent phenolic component in olive leaves, seed, pulp, and peel of unripe olives (up to 14% of the dry weight). OLE has documented useful pharmacological effects, such as cardioprotective effect, antioxidant, anti-inflammatory, anti-cancer, anti-atherogenic activity, anti-microbial properties, and neuroprotective effect.,,,,,,
The main aims of this study were (i) to determine the effects of OLE on CIS-induced pancreas toxicity in the rat. In this regard, histopathological and biochemical evaluations of the pancreas tissue were performed. (ii) To evaluate the genotoxicity of CIS and to investigate the antigenotoxic potential of OLE against CIS-induced oxidative DNA damage in rat pancreas.
| > Materials and Methods|| |
This study was carried out in the Experimental Animals Research Centre of Atatürk University. The experiments were approved by the Local Ethics Committee for Experiments on Animals of Atatürk University (protocol number: B.30.2.ATA.0.23.85-11). All experiments were carried out in accordance with the Guide for the Care and Use of Laboratory Animals published by the Institute of Laboratory Animal Resources Commission on Life Sciences.
Fifty-six adult male Spraque-Dawley rats (weighing 200–250 g) obtained from Medical Experimental Application and Research Center, Atatürk University were used. Animals were housed inside polycarbonate cages in an air-conditioned room (22 ± 2°C) with 12 h light-dark cycle. Standard rat feed and water were provided ad libitum. The rats were allowed to acclimatize to the laboratory environment for 7 days before the start of the experiment.
The fifty-six rats were randomly assigned into eight groups (seven rats each). In Group 1 (control), rats received 1 mL of distillated water as vehicle. In Group 2 (CIS), rats received 7 mg CIS/kg body weight, diluted in distillated water (1 mL). In Groups 3, 4, and 5 (OLE), rats received 1 mL of OLE solution (50, 100, and 200 mg/kg/day). In Groups 6, 7, and 8 (CIS + OLE), the animals received 1 mL of preparations of OLE following CIS administration. The injections of CIS were given using a single dose, through intraperitoneal (i.p.) route for 24 h. The OLE and CIS + OLE groups received i.p. injections with a single daily dose for a total period of 3 days. On day 4 after injections, the rats were anesthetized with isoflurane. Blood samples were collected for biochemical studies. At the end of this application, rats were immediately sacrificed by cervical decapitation. After cervical dislocation under anesthesia, the pancreas specimens were gathered for further analyses.
Preparation of pancreas tissue homogenates
Fresh pancreas tissues were rinsed with ice-cold saline and immediately stored at −80°C. The tissue specimens were weighed and then homogenized in a 50-mM phosphate buffered saline at pH 7.0. Homogenized pancreas tissues were then centrifuged at 10.000 rpm at 4°C over 15 min to isolate the supernatant for subsequent analysis.
Amylase and lipase measurement for pancreatic function assessment
Blood samples were taken immediately before rats were killed for measurement amylase and lipase values. Serum amylase and lipase levels were determined spectrophotometrically using an automated analyzer (Olympus AU 600, Diamond Diagnostic, Holliston, USA). All chemicals were obtained from Sigma (Sigma, St Louis MO, USA).
Determination of 8-hydroxy-2'-deoxyguanosine level
8-hydroxy-2'-deoxyguanosine (8-OHdG) assay kits were purchased from Cayman Chemical for determining 8-OHdG levels in the pancreas samples. Since it is a competitive assay that can be used for the quantification of 8-OHdG in homogenates and recognizes both free 8-OHdG and DNA-incorporated 8-OHdG, many types of research are being performed to use this protocol. This assay depends on the competition between 8-OHdG and 8-OHdG-acetylcholinesterase conjugate for a limited amount of 8-OHdG monoclonal antibody. All procedures were carried out in accordance with the provider manual.
Determination of lipid peroxidation
Quantitative measurement of malondialdehyde (MDA) was performed following the thiobarbituric acid (TBA) test. Pancreas homogenate (2 mL) was mixed with 1 mL of 20% (v/v) TCA and 1 mL of 0.67% (v/v) TBA and then boiled for 10 min. After cooling, the mixture was filtered through Whatman filter paper and reading of the filtrate was done at 530 nm. The amount of MDA formed was quantitated with TBA and used as an index of lipid peroxidation. The results were expressed as nanomoles of MDA per milligram of protein using molar extinction coefficient (1.56 × 105 cm 2/mmol).
Measurement of total antioxidant capacity and total oxidant status
Total antioxidant status (TAS) and total oxidative stress (TOS) levels were measured using a colorimetric method that was introduced by Erel. The results were expressed as millimolar Trolox equivalent per liter (mmol Trolox equivalent/g protein) for TAS and micromolar hydrogen peroxide equivalent per liter (μmol H2O2 equivalent/g protein) for TOS. The ratio of TOS to TAS was accepted as the OSI. For the calculation, the resulting unit of TAS was converted to μmol/g protein, and the OSI value was calculated according to the following formula.
OSI (arbitrary unit) = (TOS [μmol H2O2 equivalent/g protein]/TAS [μmol Trolox equivalent/g protein]) × 100.
The pancreas tissues of rats were fixed in buffered 10% formalin solution for 24 h and embedded in a paraffin wax. Tissues were then sectioned at 5-μm, stained with hematoxylin-eosin (H and E), periodic acid–Schiff (PAS) and alcian blue methods. A semiquantitative evaluation of pancreas tissue was accomplished by scoring the degree of severity according to the formerly published criteria. For each pancreas section, whole slide was examined for dilated acini, fibrosis, focal necrosis of Islets of Langerhans More Details, degeneration of Langerhans, infiltration, and congestion were observed under bright field using an Olympus BX60 microscope equipped with a digital CCD. In addition, high-resolution pictures (×200) of samples were taken under the same microscope. The pancreas damage was scored with a maximum score of 18. The maximum score for the other pathological findings was 3.
For statistical analysis, we used SPSS for Windows 13.0 (SPSS Inc., Chicago, IL, USA). The experimental data were analyzed using one-way analysis of variance followed by Tukey post hoc test for multiple comparisons. Results are presented as mean ± standard error and values of P < 0.05 were considered statistically significant.
| > Results|| |
8-OHdG was used as a marker of oxidative DNA damage. As presented in [Table 1], in control group and OLE treated groups, the levels of 8-OHdG was similar. On the other hand, the levels of 8-OHdG in rat pancreas were markedly increased after CIS administration. A dose-dependent a decrease in 8-OHdG was observed in the CIS + OLE groups and levels of 8-OH-dG increased by CIS were normalized in the pancreas by a dose of 200 mg/kg OLE.
|Table 1: The effects of OLE on pancreas 8-OHdG levels after treated with cisplatin|
Click here to view
[Table 2] shows the effect of CIS administration on TAS, TOS, and MDA levels in pancreatic tissues of rats. TOS and MDA levels in the pancreases of CIS group were higher than those of the control group while TAS level was significantly lower than those of the control group (P < 0.05). In only OLE treated groups, the levels of biochemical parameters were similar compared with control group. The supplementation of rats with OLE resulted in a reversal of biochemical parameters when compared with the CIS groups. Moreover, these effects were associated with the increasing doses of OLE therapy.
|Table 2: The effects of OLE on pancreas MDA, TAS and TOS levels after treated with cisplatin|
Click here to view
Pancreatic amylase and lipase values were found to be significantly increased in the CIS group compared with the control group (P < 0.05). Pancreatic amylase and lipase values in the CIS + OLE groups were found to be significantly decreased compared to the CIS group (P < 0.05). In addition, i.p. injection of OLE alone, the amylase and lipase levels were not changed [Table 3].
|Table 3: The effects of OLE on pancreas serum amylase and lipase levels after treated with cisplatin|
Click here to view
In control group, the normal architecture of tissue in sections stained with H and E [Figure 1] and [Figure 2], PAS [Figure 3], alcian blue [Figure 4] are shown. In sections stained with H and E, CIS group showed significant pancreatic changes as compared with control group; dilated acini, fibrosis, infiltration, focal necrosis of islets of Langerhans, congestion, degeneration of Langerhans [Figure 1] and [Figure 2]. However, the treatment of OLE was able to reduce the pancreas damage. Moreover, this positive impact was notably correlated with increased OLE doses. In 50 and 100 mg/kg CIS + OLE groups, above mentioned pathological findings were alleviated. There were more congestion, infiltration, dilated acini, and fibrosis in 50 mg/kg CIS + OLE group than in 100 mg/kg CIS + OLE group. Moreover, in 200 mg/kg CIS + OLE group, pancreas tissue showed a normal structure and orderly arrangement and resembled those of control rats [Figure 2]. Histopathological scores of the groups are summarized in [Table 4]. Moreover, the analysis of histopathological data demonstrated significant differences between the groups (P < 0.05).
|Figure 1: The pancreas histology in control and cisplatin groups rats; (a) Control group, Langerhans islet (l). (b-g) The pancreas degenerations in 7 mg/kg cisplatin group (b) Dilated acini (arrows) (c) Fibrosis (f) (d) Infiltration (i) (e) Focal necrosis of islets of Langerhans (arrow), (f) Congestion (c) and (g) Degeneration of islet cells (arrow) (H and E, ×200)|
Click here to view
|Figure 2: The pancreas histology in cisplatin + oleuropein group rats; (a-c) cisplatin + 50 mg/kg oleuropein group, Infiltration (i), Congestion (c), Arrows: Dilated acini, Fibrosis (f) (d) cisplatin + 100 mg/kg oleuropein group, Dilated acini (arrows), (e) Congestion (c), Infiltration (arrow) and (f) cisplatin + 200 mg/kg oleuropein group (H and E, ×200)|
Click here to view
|Figure 3: The pancreas histology in control, cisplatin, and cisplatin + oleuropein group rats, (a) Control group, (b) The decreased glycogen content in pancreas of cisplatin group compared with control group, (c and d) The increased glycogen content in pancreas of cisplatin + 50 mg/kg and cisplatin + 100 mg/kg oleuropein groups, (e) The glycogen content in pancreas of cisplatin + 200 mg/kg oleuropein group similar to control (PAS, ×200)|
Click here to view
|Figure 4: (a) Control group, (b) cisplatin group and (c) cisplatin + 200 mg/kg oleuropein group, Ductal mucin (arrows), (Alcian Blue, ×200)|
Click here to view
|Table 4: Histopathological scores of pancreas pathology in cerulein-induced AP|
Click here to view
PAS staining clearly revealed depletion of glycogen in CIS group compared with control group [Figure 3]a and [Figure 3]b. Treatment with OLE for 7 days revealed a dose-dependent increase of glycogen of pancreas [Figure 3]c and [Figure 3]d. In OLE 200 mg/kg group, pancreas glycogen content was similar with the control group [Figure 3]e. In sections stained with alcian blue method, there were not any change in mucin content of ductal walls in studied all groups [Figure 4].
| > Discussion|| |
CIS is a chemotherapeutic agent that is widely used in cancer treatment. Numerous side effects have been detected. CIS has many side effects, including bone marrow toxicity, renal toxicity, gastrointestinal toxicity, peripheral neuropathy, and ototoxicity. In this study, we established whether the pharmacological treatment with OLE provides a protective effect against CIS damage in the pancreas of rats. CIS chemotherapy is limited due to the development of myelosuppression and genotoxicity which may lead to secondary cancer. Moreover, it has been revealed that significant dose-dependent increase in genotoxicity with respect to DNA damage as a result of CIS treatment. As a cytotoxic agent, CIS interferes with DNA synthesis and causes DNA cross-linking that modulates cell cycle progression, thus ultimately inducing tumor cell apoptosis.
8-OHdG is the most common marker of DNA oxidation produced by oxidation of DNA bases. In CIS therapy, the 8-OHdG levels are elevated, therefore in previous studies, it has frequently been utilized as a reliable biomarker of oxidative stress-related DNA damage. There was no scoring system for the report of the intensity of CIS-induced 8-OHdGs in the pancreas. For the first time, we here demonstrate that 7 mg/kg/day CIS administration induced significant DNA damages to pancreas cells. According to our results, 8-OHdG score is a good predictor for detecting the protective role of OLE against CIS-induced toxicity in rats. In this study, i.p. injection of CIS resulted in an apparent increase in 8-OHdG formations; however, OLE was observed to protect pancreas cells of rats from CIS-induced DNA damage. This study is the first to demonstrate a vital role of OLE in the suppression of 8-OHdG formations in pancreas cells.
It is established that the products of lipid peroxidation, especially the cytotoxic aldehydes like MDA, are important because they can also induce damage DNA and the highly active hydroxyl radicals can break the DNA threads creating (8-OHdG). The previous studies showed that CIS-induced an excessive production of MDA.,,,, In this study, CIS increased MDA (a secondary product of lipid peroxidation) and decreased antioxidant content in the pancreas homogenates. We detected that the application of OLE significantly ameliorates endogenous antioxidant activity in studied tissues by decreasing MDA. MDA level was lower in the 50 and 100 mg/kg OLE groups as compared to the CIS group. A significant inhibition of lipid peroxidation in pancreas cells was obtained in the presence of 200 mg/kg OLE (P < 0.05).
CIS can generate reactive oxygen species such as superoxide and hydroxyl radicals.,, It has been reported that chemotherapy with CIS creates a reduce the plasma concentrations of various antioxidants. This decrease can cause a failure of the antioxidant defence mechanisms against organ damage. Previous studies have shown that the administration of antioxidants can reduce the side effects associated with CIS.,,,,
OLE derived from numerous plants, particularly from the olive tree, Olea europaea L. (Oleaceae), is a biophenol with many biological activities. Some studies have shown that OLE possesses a wide range of pharmacologic and health-promoting properties including antiarrhythmic, immune-stimulant, cardioprotective, anti-inflammatory, and antioxidant, effects.,, Many of these properties have been defined as resulting from the antioxidant feature of OLE.
We investigated on pancreas the effects of TAS and TOS in relation to our pathological study. According to our findings, the measurements of TAS in biological tissues will allow to understand if the protective effect displayed by antioxidants reflect an improvement in endogenous antioxidant defenses and a reduction of chemotherapy risk. We established that OLE administration dose-dependently increased antioxidant capacity (50 and 100 mg/kg). Especially, 200 mg/kg OLE exhibited powerful antioxidant activity in pancreas against CIS exposure. According to our findings, OLE could protect tissue from harmful effects of CIS by increasing the level of reduced TAS. OLE increased the cells antioxidant capacity by stimulating the synthesis of antioxidant enzymes and helped maintain their activity during oxidative stress.
CIS has been widely and effectively used for chemotherapy against a number of tumor types; however, the drug induces a series of side effects in various organs. It is reported that CIS may generate oxygen free radicals in the body. Moreover, the free radicals may cause changes in cell structure and function, thereby affecting tissue and organ function. In this context, our results revealed that CIS treatment resulted in significant attenuation of pancreas dysfunction (decreased amylase and lipase levels). Similarly, the finding was reported after transcatheter arterial infusion with CIS for advanced hepatocellular carcinoma. On the contrary, elevated levels of amylase and lipase in pancreas cells were normalized by OLE treatment in this study. At this point, we proposed that the antioxidant role of OLE could be a therapeutic agent for protection from CIS toxicity in enzyme-secreting cells, as well as in other cell types.
In this study, pathological changes in pancreas induced by CIS and the treatment of pancreas with OLE were used as a reference. Our histopathological findings in CIS-treated rats were dilated acini, fibrosis, focal necrosis of islets of Langerhans, degeneration of Langerhans, infiltration, congestion, and decreased glycogen. Pancreatic fibrosis is defined by the overgrowth and excess deposition of extracellular matrix components, including collagen. Tissue collagen is investigated as a free radical-induced fibrosis marker, and as an effect of chemotherapy, it is increased substantially in all tissues. Our histopathological scoring system indicates that 7 mg/kg/day CIS application remarkable increases collagen content and other pathological findings in the pancreas. Results of this study show that the 200 mg/kg dose of OLE, by its antioxidant properties, alleviates oxidative injury, and fibrosis-induced by CIS in the pancreas. Hence, this study might be the first report on the effect of OLE on pancreas fibrosis in an experimental model. Olive polyphenols have been claimed to play a significant protective role in cancer and other inflammation-related diseases. Both inflammatory and cancer cell models have demonstrated that olive leaf polyphenols are anti-inflammatory and protect against DNA damage initiated by free radicals. Our study's results show that OLE decreases CIS-induced lymphocyte infiltration in the pancreas. From the pathological score, we can see that 200 mg/kg OLE are much more effective against CIS toxicity than 100 mg/kg OLE.
In this study, CIS reduced activities of gluconeogenesis enzymes in the pancreas. However, OLE resulted in the entire development of glycogenesis as evident by higher of glycogen deposits as compared to CIS group. Moreover, consistent with the detections of the present study, in the pancreas of the animals treated with CIS was recorded diffuse degenerative changes and necrosis. However, high dose of OLE could reduce the degree of necrosis. There were no significant changes in mucin content between OLE and CIS groups.
The results of the current study indicated that treatment with OLEextract at 200 mg/kg significantly reduced the histopathological findings in the treatment group. Moreover, administration of OLE at 100 and 50 mg/kg in treatment group alleviated the histopathological findings.
| > Conclusion|| |
In summary, OLE can decrease CIS-induced pancreas toxicity by inhibiting lipid peroxidation and ROS; and this method has good clinical applicability. This means that OLE combined with CIS may be applied to tumor patients to improve chemotherapy efficiency in the near future. On the basis of long-term experience and extensive clinical data, OLE may represent a candidate for the management of CIS-induced DNA damages, pathological lesions, and functional disorders in the pancreas.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Wang R, MoYung KC, Zhao YJ, Poon K. A mechanism for the temporal potentiation of genipin to the cytotoxicity of cisplatin in colon cancer cells. Int J Med Sci 2016;13:507-16.
Baek N, Seo OW, Lee J, Hulme J, An SS. Real-time monitoring of cisplatin cytotoxicity on three-dimensional spheroid tumor cells. Drug Des Devel Ther 2016;10:2155-65.
Tharavichitkul E, Lorvidhaya V, Kamnerdsupaphon P, Sukthomya V, Chakrabandhu S, Klunklin P, et al.
Combined chemoradiation of cisplatin versus carboplatin in cervical carcinoma: A single institution experience from Thailand. BMC Cancer 2016;16:501.
Palmeri R, Monteleone JI, Spagna G, Restuccia C, Raffaele M, Vanella L, et al.
Olive leaf extract from sicilian cultivar reduced lipid accumulation by inducing thermogenic pathway during adipogenesis. Front Pharmacol 2016;7:143.
Cicerale S, Lucas L, Keast R. Biological activities of phenolic compounds present in virgin olive oil. Int J Mol Sci 2010;11:458-79.
Barbaro B, Toietta G, Maggio R, Arciello M, Tarocchi M, Galli A, et al.
Effects of the olive-derived polyphenol oleuropein on human health. Int J Mol Sci 2014;15:18508-24.
Visioli F, Bellomo G, Galli C. Free radical-scavenging properties of olive oil polyphenols. Biochem Biophys Res Commun 1998;247:60-4.
Edgecombe SC, Stretch GL, Hayball PJ. Oleuropein, an antioxidant polyphenol from olive oil, is poorly absorbed from isolated perfused rat intestine. J Nutr 2000;130:2996-3002.
Andreadou I, Iliodromitis EK, Mikros E, Constantinou M, Agalias A, Magiatis P, et al.
The olive constituent oleuropein exhibits anti-ischemic, antioxidative, and hypolipidemic effects in anesthetized rabbits. J Nutr 2006;136:2213-9.
Visioli F, Bellosta S, Galli C. Oleuropein, the bitter principle of olives, enhances nitric oxide production by mouse macrophages. Life Sci 1998;62:541-6.
Hamdi HK, Castellon R. Oleuropein, a non-toxic olive iridoid, is an anti-tumor agent and cytoskeleton disruptor. Biochem Biophys Res Commun 2005;334:769-78.
Manna C, Migliardi V, Golino P, Scognamiglio A, Galletti P, Chiariello M, et al.
Oleuropein prevents oxidative myocardial injury induced by ischemia and reperfusion. J Nutr Biochem 2004;15:461-6.
Visioli F, Galli C. Antiatherogenic components of olive oil. Curr Atheroscler Rep 2001;3:64-7.
Bisignano G, Tomaino A, Lo Cascio R, Crisafi G, Uccella N, Saija A. On the in-vitro
antimicrobial activity of oleuropein and hydroxytyrosol. J Pharm Pharmacol 1999;51:971-4.
Bazoti FN, Bergquist J, Markides KE, Tsarbopoulos A. Noncovalent interaction between amyloid-beta-peptide (1-40) and oleuropein studied by electrospray ionization mass spectrometry. J Am Soc Mass Spectrom 2006;17:568-75.
Institute for Laboratory Animal Research, National Research Council. Guide for the Care and Use of Laboratory Animals. Washington, DC: National Academy Press; 2010. p. 248.
Abdel-Wahab BA, Metwally ME. Ginkgo biloba enhances the anticonvulsant and neuroprotective effects of sodium valproate against kainic acid-induced seizures in mice. J Pharmacol Toxicol Methods 2011;6:679-90.
Wills ED. Evaluation of lipid peroxidation in lipids and biological membranes. In: Snell K, Mullock B, editors. Biochemical Toxicology: A Practical Approach. Oxford, England: IRL Press; 1987. p. 138-40.
Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004;37:277-85.
Esen C, Alkan BA, Kirnap M, Akgül O, Isikoglu S, Erel O. The effects of chronic periodontitis and rheumatoid arthritis on serum and gingival crevicular fluid total antioxidant/oxidant status and oxidative stress index. J Periodontol 2012;83:773-9.
Akyazi I, Eraslan E, Gülçubuk A, Ekiz EE, Cirakli ZL, Haktanir D, et al.
Long-term aspirin pretreatment in the prevention of cerulein-induced acute pancreatitis in rats. World J Gastroenterol 2013;19:2894-903.
Demir MG, Altintoprak N, Aydin S, Kösemihal E, Basak K. Effect of transtympanic injection of melatonin on cisplatin-induced ototoxicity. J Int Adv Otol 2015;11:202-6.
Basu A, Ghosh P, Bhattacharjee A, Patra AR, Bhattacharya S. Prevention of myelosuppression and genotoxicity induced by cisplatin in murine bone marrow cells: Effect of an organovanadium compound vanadium (III)-l-cysteine. Mutagenesis 2015;30:509-17.
Dasari SR, Velma V, Yedjou CG, Tchounwou PB. Preclinical assessment of low doses of cisplatin in the management of acute promyelocytic leukemia. Int J Cancer Res Mol Mech 2015;1:1-15.
Leung AW, Hung SS, Backstrom I, Ricaurte D, Kwok B, Poon S, et al.
Combined use of gene expression modeling and siRNA screening identifies genes and pathways which enhance the activity of cisplatin when added at no effect levels to non-small cell lung cancer cells in vitro
. PLoS One 2016;11:e0150675.
Persson T, Popescu BO, Cedazo-Minguez A. Oxidative stress in Alzheimer's disease: Why did antioxidant therapy fail? Oxid Med Cell Longev 2014;2014:427318.
Kodama A, Watanabe H, Tanaka R, Kondo M, Chuang VT, Wu Q, et al.
Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity. Biochim Biophys Acta 2014;1840:1152-62.
Liu Q, Zhou Y, Duan R, Wei H, Jiang S, Peng J. Lower dietary n-6:n-3 ratio and high-dose vitamin E supplementation improve sperm morphology and oxidative stress in boars. Reprod Fertil Dev 2016;2016:A-J.
Atessahin A, Sahna E, Türk G, Ceribasi AO, Yilmaz S, Yüce A, et al.
Chemoprotective effect of melatonin against cisplatin-induced testicular toxicity in rats. J Pineal Res 2006;41:21-7.
Pratibha R, Sameer R, Rataboli PV, Bhiwgade DA, Dhume CY. Enzymatic studies of cisplatin induced oxidative stress in hepatic tissue of rats. Eur J Pharmacol 2006;532:290-3.
Meng X, Chen H, Wang G, Yu Y, Xie K. Hydrogen-rich saline attenuates chemotherapy-induced ovarian injury via regulation of oxidative stress. Exp Ther Med 2015;10:2277-82.
Soni KK, Zhang LT, You JH, Lee SW, Kim CY, Cui WS, et al.
The effects of MOTILIPERM on cisplatin induced testicular toxicity in Sprague-Dawley rats. Cancer Cell Int 2015;15:121.
Omar HA, Mohamed WR, Arab HH, Arafa ESA. Tangeretin alleviates cisplatin-induced acute hepatic injury in rats: Targeting MAPKs and apoptosis. PLoS One 2016;11:e0151649.
Yoshida M, Fukuda A, Hara M, Terada A, Kitanaka Y, Owada S. Melatonin prevents the increase in hydroxyl radical-spin trap adduct formation caused by the addition of cisplatin in vitro
. Life Sci 2003;72:1773-80.
Weijl NI, Hopman GD, Wipkink-Bakker A, Lentjes EG, Berger HM, Cleton FJ, et al.
Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients. Ann Oncol 1998;9:1331-7.
Antunes LM, Darin JD, Bianchi MD. Protective effects of Vitamin C against cisplatin-induced nephrotoxicity and lipid peroxidation in adult rats: A dose-dependent study. Pharmacol Res 2000;41:405-11.
Leonetti C, Biroccio A, Gabellini C, Scarsella M, Maresca V, Flori E, et al.
Alpha-tocopherol protects against cisplatin-induced toxicity without interfering with antitumor efficacy. Int J Cancer 2003;104:243-50.
Pace A, Savarese A, Picardo M, Maresca V, Pacetti U, Del Monte G, et al.
Neuroprotective effect of Vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol 2003;21:927-31.
Wozniak K, Czechowska A, Blasiak J. Cisplatin-evoked DNA fragmentation in normal and cancer cells and its modulation by free radical scavengers and the tyrosine kinase inhibitor STI571. Chem Biol Interact 2004;147:309-18.
Dos Santos GC, Mendonça LM, Antonucci GA, Dos Santos AC, Antunes LM, Bianchi Mde L. Protective effect of bixin on cisplatin-induced genotoxicity in PC12 cells. Food Chem Toxicol 2012;50:335-40.
Kyriazis ID, Koutsoni OS, Aligiannis N, Karampetsou K, Skaltsounis AL, Dotsika E. The leishmanicidal activity of oleuropein is selectively regulated through inflammation- and oxidative stress-related genes. Parasit Vectors 2016;9:441.
Andrikopoulos NK, Antonopoulou S, Kaliora AC. Oleuropein inhibits LDL oxidation induced by cooking oil frying by-products and platelet aggregation induced by platelet-activating factor. LWT Food Sci Technol 2002;35:479-84.
Jemai H, El Feki A, Sayadi S. Antidiabetic and antioxidant effects of hydroxytyrosol and oleuropein from olive leaves in alloxan-diabetic rats. J Agric Food Chem 2009;57:8798-804.
Visioli F, Poli A, Gall C. Antioxidant and other biological activities of phenols from olives and olive oil. Med Res Rev 2002;22:65-75.
Yao W, Hu Q, Ma Y, Xiong W, Wu T, Cao J, et al.
Human adipose-derived mesenchymal stem cells repair cisplatin-induced acute kidney injury through antiapoptotic pathways. Exp Ther Med 2015;10:468-76.
Lou XY, Cheng JL, Zhang B. Therapeutic effect and mechanism of breviscapine on cisplatin-induced nephrotoxicity in mice. Asian Pac J Trop Med 2015;8:873-7.
Hagihara A, Ikeda M, Ueno H, Morizane C, Kondo S, Nakachi K, et al.
Phase I study of combination chemotherapy using sorafenib and transcatheter arterial infusion with cisplatin for advanced hepatocellular carcinoma. Cancer Sci 2014;105:354-8.
Lin WR, Lim SN, Yen TH, Alison MR. The influence of bone marrow-secreted IL-10 in a mouse model of cerulein-induced pancreatic fibrosis. Biomed Res Int 2016;2016:4601532.
Trujillo J, Molina-Jijón E, Medina-Campos ON, Rodríguez-Muñoz R, Reyes JL, Loredo ML, et al.
Curcumin prevents cisplatin-induced decrease in the tight and adherens junctions: Relation to oxidative stress. Food Funct 2016;7:279-93.
Boss A, Bishop KS, Marlow G, Barnett MP, Ferguson LR. Evidence to support the anti-cancer effect of olive leaf extract and future directions. Nutrients 2016;8. pii: E513.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]