Abstract
Zingerone (ZO), one of the active components of ginger (Zingiber officinale), is a phenolic alkanone with antioxidant, antiapoptotic, and anti-inflammatory properties. Cisplatin (CP) is a widely used chemotherapeutic drug for solid tumors, but its therapeutic use is limited due to dose-dependent nephrotoxicity. In the present study, we investigated the ameliorative effect of ZO against CP-induced nephrotoxicity. Intraperitoneal administration of single-dose CP (7 mg/kg body weight) on the first day enhanced kidney lipid peroxidation and reduced antioxidant enzyme activities such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH). CP increased serum urea and creatinine levels and disrupted histological integrity while causing a decrease aquaporin 1 (AQP1) level in the kidney tissues. CP induced inflammatory responses by elevating the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-33 (IL-33) and nuclear factor kappa B (NF-κB), and activities of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, it also caused oxidative DNA damage and activation of apoptotic pathway by increasing of 8-hydroxy-2′-deoxyguanosine (8-OHdG), p53, cysteine aspartate-specific protease-3 (caspase-3), and Bcl-2-associated x protein (bax) while decreasing B cell lymphoma-2 (Bcl-2). However, treatment with ZO at a dose of 25 and 50 mg/kg b.wt. for 7 days significantly decreased oxidative stress, apoptosis, inflammation, and histopathological alterations while increased AQP1 levels in the kidney tissue. The results of the current study suggested that ZO as an effective natural product attenuates CP-induced nephrotoxicity.
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References
Aebi H (1984): [13] Catalase in vitro, Methods Enzymol Elsevier, pp. 121–126
Ahmad B, Rehman MU, Amin I, Arif A, Rasool S, Bhat SA, Afzal I, Hussain I, Bilal S (2015) A review on pharmacological properties of zingerone (4-(4-hydroxy-3-methoxyphenyl)-2-butanone). Sci World J 2015
Akca G, Eren H, Tumkaya L, Mercantepe T, Horsanali MO, Deveci E, Dil E, Yilmaz A (2018) The protective effect of astaxanthin against cisplatin-induced nephrotoxicity in rats. Biomed Pharmacother 100:575–582
Alchin KF (2010) Ototoxicity in patients receiving concurrent cisplatin and cranial irradiation therapy for the treatment of head and neck cancers: an audiometric follow-up
Alibakhshi T, Khodayar MJ, Khorsandi L, Rashno M, Zeidooni L (2018) Protective effects of zingerone on oxidative stress and inflammation in cisplatin-induced rat nephrotoxicity. Biomed Pharmacother 105:225–232
Al-Kharusi N, Babiker H, Al-Salam S, Waly M, Nemmar A, Al-Lawati I, Yasin J, Beegam S, Ali B (2013) Ellagic acid protects against cisplatin-induced nephrotoxicity in rats: a dose-dependent study. Eur Rev Med Pharmacol Sci 17:299–310
Basu A, Krishnamurthy S (2010): Cellular responses to cisplatin-induced DNA damage. J Nucleic Acids 2010
Benzer F, Kandemir FM, Kucukler S, Comaklı S, Caglayan C (2018a) Chemoprotective effects of curcumin on doxorubicin-induced nephrotoxicity in wistar rats: by modulating inflammatory cytokines, apoptosis, oxidative stress and oxidative DNA damage. Arch Physiol Biochem, 1–10
Benzer F, Kandemir FM, Ozkaraca M, Kucukler S, Caglayan C (2018b) Curcumin ameliorates doxorubicin-induced cardiotoxicity by abrogation of inflammation, apoptosis, oxidative DNA damage, and protein oxidation in rats. J Biochem Mol Toxicol 32:e22030
Caglayan C, Kandemir FM, Yıldırım S, Kucukler S, Kılınc MA, Saglam YS (2018a) Zingerone ameliorates cisplatin-induced ovarian and uterine toxicity via suppression of sex hormone imbalances, oxidative stress, inflammation and apoptosis in female wistar rats. Biomed Pharmacother 102:517–530
Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S (2018b): Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Sci Pollut Res, 1–17
Caglayan C, Kandemir FM, Yildirim S, Kucukler S, Eser G (2019) Rutin protects mercuric chloride-induced nephrotoxicity via targeting of aquaporin 1 level, oxidative stress, apoptosis and inflammation in rats. J Trace Elem Med Biol 54:69–78
Domitrović R, Cvijanović O, Pugel EP, Zagorac GB, Mahmutefendić H, Škoda M (2013) Luteolin ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of platinum accumulation, inflammation and apoptosis in the kidney. Toxicology 310:115–123
Dong X, Wang Y, Zhou Y, Wen J, Wang S, Shen L (2016) Aquaporin 3 facilitates chemoresistance in gastric cancer cells to cisplatin via autophagy. Cell Death Dis 2:16087
dos Santos NAG, Rodrigues MAC, Martins NM, Dos Santos AC (2012) Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update. Arch Toxicol 86:1233–1250
Eldutar E, Kandemir FM, Kucukler S, Caglayan C (2017) Restorative effects of Chrysin pretreatment on oxidant–antioxidant status, inflammatory cytokine production, and apoptotic and autophagic markers in acute paracetamol-induced hepatotoxicity in rats: an experimental and biochemical study. J Biochem Mol Toxicol 31:e21960
Guerrero-Beltrán CE, Calderón-Oliver M, Tapia E, Medina-Campos ON, Sánchez-González DJ, Martínez-Martínez CM, Ortiz-Vega KM, Franco M, Pedraza-Chaverri J (2010) Sulforaphane protects against cisplatin-induced nephrotoxicity. Toxicol Lett 192:278–285
Gülçin I (2012) Antioxidant activity of food constituents: an overview. Arch Toxicol 86:345–391
Hagar H, El Medany A, Salam R, El Medany G, Nayal OA (2015) Betaine supplementation mitigates cisplatin-induced nephrotoxicity by abrogation of oxidative/nitrosative stress and suppression of inflammation and apoptosis in rats. Exp Toxicol Pathol 67:133–141
Han X, Yue J, Chesney RW (2009) Functional TauT protects against acute kidney injury. J Am Soc Nephrol 20:1323–1332
Helmy MM, Helmy MW, Allah DMA, Zaid AMA, El-Din MMM (2014) Selective ETA receptor blockade protects against cisplatin-induced acute renal failure in male rats. Eur J Pharmacol 730:133–139
Hemalatha K, Prince PSM (2015a) Preventive effects of zingerone on altered lipid peroxides and nonenzymatic antioxidants in the circulation of isoproterenol-induced myocardial infarcted rats. J Biochem Mol Toxicol 29:63–69
Hemalatha KL, Prince PSM (2015b) A biochemical and 2, 3, 5-triphenyl tetrazolium chloride staining study on the preventive effects of zingerone (vanillyl acetone) in experimentally induced myocardial infarcted rats. Eur J Pharmacol 746:198–205
Hemalatha K, Prince PSM (2016a) Anti-inflammatory and anti-thrombotic effects of zingerone in a rat model of myocardial infarction. Eur J Pharmacol 791:595–602
Hemalatha KL, Prince PSM (2016b) Preventive effects of zingerone on cardiac mitochondrial oxidative stress, calcium ion overload and adenosine triphosphate depletion in isoproterenol induced myocardial infarcted rats. RSC Adv 6:112332–112339
Jeong J-J, Park N, Kwon Y-J, Ye D-J, Moon A, Chun Y-J (2014) Role of Annexin A5 in cisplatin-induced toxicity in renal cells molecular mechanism of apoptosis. J Biol Chem 289:2469–2481
Kamel KM, Abd El-Raouf OM, Metwally SA, Abd El-Latif HA, El-sayed ME (2014) Hesperidin and rutin, antioxidant citrus flavonoids, attenuate cisplatin-induced nephrotoxicity in rats. J Biochem Mol Toxicol 28:312–319
Kandemir FM, Kucukler S, Caglayan C, Gur C, Batil AA, Gülçin İ (2017a) Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties. J Food Biochem 41:e12398
Kandemir FM, Kucukler S, Eldutar E, Caglayan C, Gülçin I (2017b) Chrysin protects rat kidney from paracetamol-induced oxidative stress, inflammation, apoptosis, and autophagy: a multi-biomarker approach. Sci Pharm 85:4
Kandemir FM, Ozkaraca M, Küçükler S, Caglayan C, Hanedan B (2018a) Preventive effects of hesperidin on diabetic nephropathy induced by streptozotocin via modulating TGF-β1 and oxidative DNA damage. Toxin Rev 37:287–293
Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Mahamadu A, Dortbudak MB (2018b) Therapeutic efficacy of zingerone against vancomycin-induced oxidative stress, inflammation, apoptosis and aquaporin 1 permeability in rat kidney. Biomed Pharmacother 105:981–991
Kang KP, Kim DH, Jung YJ, Lee AS, Lee S, Lee SY, Jang KY, Sung MJ, Park SK, Kim W (2009) Alpha-lipoic acid attenuates cisplatin-induced acute kidney injury in mice by suppressing renal inflammation. Nephrol Dial Transplant 24:3012–3020
Khan R, Rehman MU, Khan AQ, Tahir M, Sultana S (2018) Glycyrrhizic acid suppresses 1, 2-dimethylhydrazine-induced colon tumorigenesis in Wistar rats: alleviation of inflammatory, proliferation, angiogenic, and apoptotic markers. EnTox 33:1272–1283
Kilic U, Kilic E, Tuzcu Z, Tuzcu M, Ozercan IH, Yilmaz O, Sahin F, Sahin K (2013) Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway. Nutr Metab (Lond) 10:7
Kim S-W, Lee J-U, Nah M-Y, Kang D-G, Ahn K-Y, Lee H-S, Choi K-C (2001) Cisplatin decreases the abundance of aquaporin water channels in rat kidney. J Am Soc Nephrol 12:875–882
Lawrence RA, Burk RF (1976) Glutathione peroxidase activity in selenium-deficient rat liver. BBRC 71:952–958
Lee KW, Jeong JY, Lim BJ, Chang Y-K, Lee S-J, Na K-R, Shin Y-T, Choi DE (2009) Sildenafil attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity. Toxicology 257:137–143
Li W, Yan M-H, Liu Y, Liu Z, Wang Z, Chen C, Zhang J, Sun Y-S (2016) Ginsenoside Rg5 ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of inflammation, oxidative stress, and apoptosis. Nutrients 8:566
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Ma P, **ao H, Yu C, Liu J, Cheng Z, Song H, Zhang X, Li C, Wang J, Gu Z (2017) Enhanced cisplatin chemotherapy by iron oxide nanocarrier-mediated generation of highly toxic reactive oxygen species. Nano Lett 17:928–937
Malik S, Suchal K, Gamad N, Dinda AK, Arya DS, Bhatia J (2015) Telmisartan ameliorates cisplatin-induced nephrotoxicity by inhibiting MAPK mediated inflammation and apoptosis. Eur J Pharmacol 748:54–60
Miller RP, Tadagavadi RK, Ramesh G, Reeves WB (2010) Mechanisms of cisplatin nephrotoxicity. Toxins (Basel) 2:2490–2518
Nakazawa H, Chang K, Shinozaki S, Yasukawa T, Ishimaru K, Yasuhara S, Yu Y-M, Martyn JJ, Tompkins RG, Shimokado K (2017) iNOS as a driver of inflammation and apoptosis in mouse skeletal muscle after burn injury: possible involvement of Sirt1 S-nitrosylation-mediated acetylation of p65 NF-κB and p53. PLoS One 12:e0170391
Pani SR, Mishra S, Sahoo S, Panda PK (2011) Nephroprotective effect of Bauhinia variegata (Linn.) whole stem extract against cisplatin-induced nephropathy in rats. Indian J Pharm 43:200
Placer ZA, Cushman LL, Johnson BC (1966) Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. AnBio 16:359–364
Rehman MU, Ahmad B, Arif A, Rasool S, Farooq A, Razzaq R, Bhat SA, Bashir S, Shabir O, Amin I (2015) Zingerone protects against cisplatin-induced oxidative damage in the jejunum of Wistar rats. Orient Pharm Exp Med 15:199–206
Saad AA, Youssef MI, El-Shennawy LK (2009) Cisplatin induced damage in kidney genomic DNA and nephrotoxicity in male rats: the protective effect of grape seed proanthocyanidin extract. Food Chem Toxicol 47:1499–1506
Sabolic I, Valenti G, Verbavatz J-M, Van Hoek AN, Verkman A, Ausiello DA, Brown D (1992) Localization of the CHIP28 water channel in rat kidney. Am J Phys Cell Phys 263:C1225–C1233
Sahin K, Tuzcu M, Gencoglu H, Dogukan A, Timurkan M, Sahin N, Aslan A, Kucuk O (2010a) Epigallocatechin-3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats. Life Sci 87:240–245
Sahin K, Tuzcu M, Sahin N, Ali S, Kucuk O (2010b) Nrf2/HO-1 signaling pathway may be the prime target for chemoprevention of cisplatin-induced nephrotoxicity by lycopene. Food Chem Toxicol 48:2670–2674
Sahu BD, Kuncha M, Sindhura GJ, Sistla R (2013) Hesperidin attenuates cisplatin-induced acute renal injury by decreasing oxidative stress, inflammation and DNA damage. Phytomedicine 20:453–460
Sahu BD, Kalvala AK, Koneru M, Kumar JM, Kuncha M, Rachamalla SS, Sistla R (2014) Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-κB activation and antioxidant defence. PLoS One 9:e105070
Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. AnBio 25:192–205
Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34:497–500
Taslimi P, Caglayan C, Gulcin İ (2017) The impact of some natural phenolic compounds on carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and α-glycosidase enzymes: an antidiabetic, anticholinergic, and antiepileptic study. J Biochem Mol Toxicol 31:e21995
Turk E, Kandemir FM, Yildirim S, Caglayan C, Kucukler S, Kuzu M (2018) Protective effect of hesperidin on sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats. Biol Trace Elem Res:1–14
Wang H, Jia Z, Sun J, Xu L, Zhao B, Yu K, Yang M, Yang T, Wang R (2015): Nitrooleic acid protects against cisplatin nephropathy: role of COX-2/mPGES-1/PGE2 cascade. Mediat Inflamm 2015
Wu D, Liu B, Yin J, Xu T, Zhao S, Xu Q, Chen X, Wang H (2017) Detection of 8-hydroxydeoxyguanosine (8-OHdG) as a biomarker of oxidative damage in peripheral leukocyte DNA by UHPLC–MS/MS. J Chromatogr B 1064:1–6
Yousef MI, Hussien HM (2015) Cisplatin-induced renal toxicity via tumor necrosis factor-α, interleukin 6, tumor suppressor P53, DNA damage, xanthine oxidase, histological changes, oxidative stress and nitric oxide in rats: protective effect of ginseng. Food Chem Toxicol 78:17–25
Yu X, Yang Y, Yuan H, Wu M, Li S, Gong W, Yu J, **a W, Zhang Y, Ding G (2017) Inhibition of COX-2/PGE2 cascade ameliorates cisplatin-induced mesangial cell apoptosis. Am J Transl Res 9:1222
Zhu S, Pabla N, Tang C, He L, Dong Z (2015) DNA damage response in cisplatin-induced nephrotoxicity. Arch Toxicol 89:2197–2205
Zirak MR, Rahimian R, Ghazi-Khansari M, Abbasi A, Razmi A, Mehr SE, Mousavizadeh K, Dehpour AR (2014) Tropisetron attenuates cisplatin-induced nephrotoxicity in mice. Eur J Pharmacol 738:222–229
Acknowledgments
We are indebted to Prof. Dr. Erdal Kaygusuzoglu at the Department of Obstetrics and Gynecology, Faculty of Veterinary Medicine, Bingol University for his contribution to this study.
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This work was supported by Bingol University, Foundation of Scientific Researches Projects (Project number: BAP-VF.2016.00.001).
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The committee of Animal Experimentation Ethics, Bingol University, approved the design of the experiments, and the protocol conforms to the guidelines of the National Institutes of Health (NIH) (ethic code number: 2018-9/03).
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Kandemir, F.M., Yildirim, S., Caglayan, C. et al. Protective effects of zingerone on cisplatin-induced nephrotoxicity in female rats. Environ Sci Pollut Res 26, 22562–22574 (2019). https://doi.org/10.1007/s11356-019-05505-3
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DOI: https://doi.org/10.1007/s11356-019-05505-3