Sisplatin ile Karaciğer Toksisitesi Geliştirilen Ratlarda Zingeron’un Bazı Biyokimyasal Parametreler Üzerine Etkisinin Araştırılması

Öz

Bu çalışmada, ratlarda sisplatin (SP) kaynaklı hepatotoksisite üzerine zingeron’ un (ZO) etkilerinin araştırılması amaçlandı. Çalışmada 35 adet Sprague Dawley erkek rat kullanıldı. Hayvanlar, her grupta 7 rat olacak şekilde 5 gruba ayrıldı. 1.Grup (Kontrol): Sadece oral serum fizyolojik (SF, 7 gün) verildi. 2. Grup (SP): Tek doz 7 mg/kg SP periton içi (i.p.) uygulandı. 3.Grup (ZO): ZO 7 gün boyunca 50 mg/kg/gün dozunda oral verildi. 4. Grup (SP+ZO 25): Tek doz SP uygulamasından 30 dk sonra 25 mg/kg/gün dozunda ZO verilmeye başlandı ve 7 gün devam etti. 5.Grup (SP+ZO 50): Tek doz SP uygulamasından 30 dk sonra 50 mg/kg/gün dozunda ZO verildi ve 7 gün devam etti. Alanin transaminaz (ALT), aspartat transaminaz (AST) ve alkalen fosfataz (ALP) aktivitelerinin SP uygulaması ile arttığı, antioksidan enzimlerden süperoksit dismutaz (SOD), glutatyon peroksidaz (GPx), katalaz (KAT) aktiviteleri ile non-enzimatik antioksidan olan redükte glutatyon (GSH) seviyelerinin SP grubunda düştüğü, malondialdehit (MDA) düzeyinin arttığı görülmüş, ZO’ un ise antioksidan sistemi desteklediği ve MDA düzeylerini azalttığı gözlenmiştir. SP uygulamasının arginaz aktivitesini düşürürken nitrik oksit (NO), 8-hidroksi-2'-deoksiguanozin (8-OHdG), sistein aspartat spesifik proteaz-3 (kaspaz-3), tümör nekroz faktör-alfa (TNF-α), nükleer faktör kappa B (NF-ĸB) ve B-hücreli lenfoma-3 (Bcl-3) seviyelerini artırdığı, ZO’ un bu parametrelerde iyileşme sağladığı saptandı.

Anahtar Kelimeler

• Hepatotoksisite
• İnflamasyon
• Oksidatif stres
• Sisplatin
• Zingeron

Investigation of the Effect of Zingerone on Some Biochemical Parameters on Cisplatin-Induced Liver Toxicity in Rats

Abstract

This study was aimed to investigate the protective effects of zingerone (ZO) on cisplatin (CP)-induced hepatotoxicity in rats. Thirty-five (35) Sprague Dawley male rats were used in the study; the animals were divided into 5 groups of 7 rats in each group. Group 1 (Control): received only oral serum physiologic (SP, for 7 days). Group 2 (CP): received a single dose of 7 mg/kg intraperitoneal (i.p.) of CP. Group 3 (ZO): Received daily oral doses of ZO at 50 mg/kg/day for 7 days. Group 4 (CP+ZO 25): Oral administration of ZO at 25 mg/kg/day was started 30 minutes after a single dose CP application and continued for 7 days. Group 5 (CP+ZO 50): Oral administration of ZO at 50 mg/kg/day was started 30 minutes after a single dose CP application and continued for 7 days. Alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities increased due to CP administration. Also, enzymatic antioxidants; superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and glutathione (GSH) level were shown to had decreased upon CP administration. After ZO was supported by antioxidant system and decreased malondialdehyde (MDA) levels. It was determined that CP administration increased nitric oxide (NO), 8-hydroxy-2'- deoxyguanosine (8-OHdG), cysteine aspartate specific protease-3 (caspase-3), tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB) and B-cell lymphoma-3 (Bcl-3) levels while arginase activity reduced, ZO administrations could have been the main cause of the improved effects on the parameters.

Keywords

• Cisplatin
• Hepatotoxicity
• Inflammation
• Oxidative stress
• Zingerone.

References

1. Aerbi H, Catalase BH, GraBI M. Methods of Enzymatic Analysis. Angew Chem Int Ed Engl. 1983; 3: 273-286.
2. Aksu EH, Kandemir FM, Altun S, Kucukler S, Comaklı S, Omur AD. Ameliorative effect of carvacrol on cisplatin-induced reproductive damage in male rats. J Biochem Mol Toxicol. 2016b; 30(10): 513-520.
3. Aksu EH, Kandemir FM, Kılıç K, Akman O, Ömür AD, Uçar Ö. Arginase activity of ovarian structures in cows of Brown Swiss and its cross-breeds. Vet. Arhiv. 2015; 85, 261-271.
4. Aksu EH, Özkaraca M, Kandemir FM, Ömür AD, Eldutar E, Küçükler S. Mitigation of paracetamol‐induced reproductive damage by chrysin in male rats via reducing oxidative stress. Andrologia. 2016a; 48: 1145-1154.
5. Alam MF. Neuroprotective effects of Zingerone against carbon tetrachloride (CCl4) induced brain mitochondrial toxicity in Swiss albino mice. J Appl Nat Sci. 2018; 10(2): 548 -552.
6. Almaghrabi OA. Molecular and biochemical investigations on the effect of quercetin on oxidative stress induced by cisplatin in rat kidney. Saudi J Biol Sci. 2015; 22: 227-231.
7. Al-malik A, Sayed AAR. Thymoquinone attenuates cisplatin-induced hepatotoxicity via nuclear factor kappa- β. BMC Complement Altern Med. 2014; 14: 282-289.
8. Atessahin A, Yilmaz S, Karahan I, Ceribasi AO, Karaoglu A. Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats. Toxicology. 2005; 212: 116–123.

9. Auger C, Alhasawi A, Contavadoo M, Appanna VD. Dysfunctional mitochondrial bioenergetics and the pathogenesis of hepatic disorders. Front Cell Dev Biol. 2015; 3: 65-83.
10. Baeuerle PA, Henkel T. Function and activation of NF-κB in the immune system. Annu Rev Immunol. 1994; 12: 141-179.
11. Bantel H, Lügering A, Heideman J, Volkmann X, Poremba C, Strassburg C, Manns MP, Schulze-Osthoff K. Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury. Hepatology. 2004; 40(5): 1078-1087.
12. Barry GG, John EH. Individual differences in perception of bitterness from capsaicin, piperine and zingerone. Chem Senses. 2004; 29: 53-60.
13. Bilal A, Muneeb UR, Insha A, Ahmad A, Saiema R, Showkat AB, Insha A, Ishraq H, Sheikh B, Manzoorur RM. A Review on Pharmacological Properties of Zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butanone] Scientific World Journal. 2015; 6: 101-155.
14. Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S. Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy. Environ Sci Pollut Res Int. 2018; 25(21): 20968-20984
15. Casa CL, Villegas I, Alarcon, de la Lastra C, Motilva V, Calero MJ. Evidence for protective and antioxidant properties of rutin, a natural flavone, against ethanol induced gastric lesions. J Ethnopharmacol. 2000; 71: 45-53.
16. Casas-Grajales S, Muriel P. Antioxidants in liver health. World J Gastrointest Pharmacol Ther. 2015; 6(3): 59-72.
17. Cayin YF, Erdogan MA, Sahin N, Parlakpinar H, Atayan Y, Polat A, Vardi N, Yildiz A, Tanbek K. Protective effects of apocynin on cisplatin-induced hepatotoxicity in rats. Arch Med Res. 2015; 46( 7): 517-526.
18. Cayir K, Karadeniz A, Simsek N, Yildirim S, Karakus E, Kara A, Turan AH, Sengul E. Pomegranate seed extract attenuates chemotherapy-ınduced acute nephrotoxicity and hepatotoxicity in rats. J Med Food. 2011; 14(10): 1254-1262.
19. Cheng T, Hsu Y, Lu F, Chen Y, Tsai N, Chen W, Tsai C. Nephroprotective effect of electrolyzed reduced water against cisplatin-induced kidney toxicity and oxidative damage in mice. J Chin Med Assoc. 2018; 81: 119-126.
20. Cheong KO, Shin D, Bak J, Lee C, Kyung KW, Je NK, Chung HY, Moon SY. Hepatoprotective effects of zingerone on carbon tetrachloride and dimethylnitrosamine-induced liver injuries in rats. Arch Pharm Res. 2016; 39(2): 279-291.
21. Chirino YI, Pedraza-Chaverri J. Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Exp Toxicol Pathol. 2009; 61: 223-242.
22. Cui Y, Shi Y, Bao Y, Wang S, Hua WQ, Liu Y. Zingerone attenuates diabetic nephropathy through inhibition of nicotinamide adenine dinucleotide phosphate oxidase. Biomed Pharmacother. 2018; 99: 422-430.
23. Cure MC, Cure E, Kalkan Y, Kirbas A, Tumkaya L, Yilmaz A, Turkyilmaz AK, Sehitoglu I, Yuce S. Infliximab modulates cisplatin-induced hepatotoxicity in rats. Balkan Med J. 2016; 33(5): 504-511.
24. Çoşkun P, Benzer F, Kandemir FM, Yıldırım S, Küçükler S. Ratlarda Kurşun Asetat Kaynaklı Karaciğer Hasarı Üzerine Chrysin’ in Etkilerinin Araştırılması. Türk Tarım ve Doğa Bilimleri Dergisi. 2021; 8(2): 250-261.
25. Dhar BS, Kumar JM, Sistla R. Baicalein, a bioflavonoid, prevents cisplatin-ınduced acute kidney ınjury by up-regulating antioxidant defenses and down-regulating the mapks and NF-κB pathways. Nature. 2015; 10: 39-52.
26. Eldutar E, Kandemir FM, Kucukler S, Caglayan C. 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. 2017; 31: 1-6.
27. Eldutar E. Ratlarda parasetamol ile oluşturulan karaciğer hasarı üzerine chrysinin etkilerinin araştırılması. Yüksek Lisans Tezi, Atatürk Üniversitesi Sağlık Bilimleri Enstitütüsü, Erzurum, 2015.
28. Eugene AK, Kennedy MC, Kalyanaraman B. Cell-permeable superoxide dismutase and glutathione peroxidase mimetics afford superior protection against doxorubicin-induced cardiotoxicity: The role of reactive oxygen and nitrogen intermediates. Arch Biochem Biophys. 1999; 368(2): 421-428.
29. Evans MD, Dizdaroglu M, Cooke MS. Oxidative DNA damage and disease: in-duction, repair and significance. Mutat Res. 2004; 567:1-67.
30. Geyer JW, Dabich D. Rapid method for determination of arginase activity in tissue homogenates. Anal Biochem. 1971; 39: 412-417.
31. Giuseppe G, Majid YM, Tom SC, Peter JB. Peroxidative metabolism of apigenin and naringenin versus luteolin and quercetin: glutathione oxidation and conjugation. Free Radic Biol Med. 2001; 30: 370-382.
32. Gordon, JB, Ganz P, Nabel EG, Fish RD, Zebede J, Mudge GH, Alexander RW, Selwyn AP. Atherosclerosis influences the vasomotor response of epicardial coronary arteries to exercise. J Clin Invest. 1989; 83: 1946-1952.
33. Grover JK, Yadav S, Vats V. Medicinal plants of India with anti-diabetic potential. J Ethnopharmacol. 2002; 81(1): 81-100.
34. Gür C, Kandemir FM, Genç A. Bortezomib ile Kalp Hasarı Oluşturulan Ratlarda Berberinin Oksidatif ve Nitrozatif Stres Üzerine Etkisi. Türk Doğa ve Fen Dergisi. 2020; 9(2): 118-126.
35. Hanedan B, Kirbas A, FM Kandemir, Aktas MS, Yildiz A. Evaluation of arginase activity, nitric oxide and oxidative stress status in sheep with contagious agalactia. Acta Vet Hung. 2017; 65: 394-401.
36. Hanedan B, Ozkaraca M, Kirbas A, Kandemir FM, Aktas MS, Kilic K, Comakli S, Kucukler S. Bilgili A. Investigation of the effects of hesperidin and chrysin on renal injury induced by colistin in rats. Biomedicine & Pharmacotherapy. 2018; 10(1): 1607-1616.
37. Heeba GH, Mahmoud ME. Dual effects of quercetin in doxorubicin-induced nephrotoxicity in rats and its modulation of the cytotoxic activity of doxorubicin on human carcinoma cells. Environ Toxico. 2016; 31(5): 624-636.
38. Hemalatha KL, Prince PSM. Anti-inflammatory and anti-thrombotic effects of zingerone in a rat model of myocardial infarction. Eur J Pharmacol. 2016; 791: 595-602.
39. Ileritürk M, Benzer F, Aksu EH, Yildirim S, Kandemir FM, Dogan T, Genc A. Chrysin protects against testicular toxicity caused by lead acetate in rats with its antioxidant, anti-inflammatory, and antiapoptotic properties. Journal of Food Biochemistry. 2020; 45(2): e13593.
40. Ince S, Keles H, Erdogan M, Hazman O, Kucukkurt I. Protective effect of boric acid against carbon tetrachloride-induced hepatotoxicity in mice. Drug Chem Toxicol. 2012; 35: 285-292.
41. Kabuto H, Nishizawa M, Tada M, Higashio C, Shishibori T, Kohno M. Zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butanone] prevents 6-hydroxydopamine-induced dopamine depression in mouse striatum and increases superoxide scavenging activity in serum. Neurochem Res. 2005; 30(3): 325-332.
42. Kandemir F, Yüksel M, Benzer F, Özdemir N. Sağlıklı ve piyometralı ineklerde eritrosit arginaz aktivitesi ve plazma nitrik oksit düzeyi. Atatürk Üniversitesi Veteriner Bilimleri Dergisi. 2010; 5(3): 107-112.
43. Kandemir FM, Küçükler S, Çağlayan C. Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri. Atatürk Üniversitesi Vet Bil Derg. 2017a; 12 (2): 167-177.
44. Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Mahamadu A, Dortbudak MB. Therapeutic efficacy of zingerone against vancomycin-induced oxidative stress, inflammation, apoptosis and aquaporin 1 permeability in rat kidney. Biomed Pharmacothe. 2018a; 105: 981-991.
45. Kandemir FM, Benzer E, Ozkaraca M, Ceribasi S, Yildirim NC, Ozdemir N. Protective antioxidantk effects of grape seed extract in a cisplatin-induced hepatotoxicity model in rabbits. Rev Med Vet-Toulouse. 2012; 163(11): 539-545.
46. Kandemir FM, Caglayan C, Darendelioglu E, Kucukler S, Izol E, Kandemir O. Modulatory effects of carvacrol against cadmium-induced hepatotoxicity and nephrotoxicity by molecular targeting regulation. Life Sciences. Volume 277.
47. Kandemir FM, Kucukler S, Caglayan C, Gur C, Batil AA, Gülçin I. Therapeutic effects of silymarin and naringin on methotrexate‐induced nephrotoxicity in rats: Biochemical evaluation of anti‐inflammatory, antiapoptotic, and antiautophagic properties. J Food Biochem. 2017b; 41: 69-76.
48. Kandemir FM, Kucukler S, Eldutar E, Caglayan C, Gülçin İ. Chrysin protects rat kidney from paracetamol-ınduced oxidative stress, ınflammation, apoptosis, and autophagy: A Multi-Biomarker Approach. Sci Pharm. 2017c; 85 (1): 4.
49. Kandemir FM, Küçükler S, Çağlayan C. Beneficial effects of silymarin and naringin against methotrexate-induced hepatotoxicity in rats. Atatürk Üniversitesi Veteriner Bilimleri Dergisi. 2017e; 12(2): 167-177.
50. Kandemir FM, Ozkaraca M, Kuçukler S, Caglayan C, Hanedan B. Preventive effects of hesperidin on diabetic nephropathy induced by streptozotocin via modulating TGF-β1 and oxidative DNA damage. Toxin Rev. 2017d; 10: 1080.
51. Kandemir FM, Ozkaraca M, Yildirim AB, Hanedan B, Kirbas A, Kilic K. Rutin attenuates gentamicin-induced renal damage by reducing oxidative stress, inflammation, apoptosis, and autophagy in rats. Ren Fail. 2015; 37(3): 518-525.
52. Kandemir FM, Özdemir N. Koyun dalak doku arginazının bazı kinetik özellikleri. Kafkas Üniv Vet Fak Derg. 2009; 15: 553-559.
53. Kandemir FM, Özdemir N. L-Lizin ve L-ornitinin sığır böbrek doku arginaz aktivitesi üzerine inhibisyon etkisi. Fırat Üniv. Sağlık Bilimleri Derg. 2008; 22(1): 1-4.
54. Kandemir FM, Yuksel M, Ozdemir N, Deveci H. A different approach to diagnosis of subclinical mastitis: Milk arginase activity. Vet. Arhiv. 2013; 83: 603-610.
55. Kart A, Cigremiş Y, Karaman M, Özen H. Caffeic acid phenethyl ester (CAPE) ameliorates cisplatin-induced hepatotoxicity in rabbit. Exp Toxicol Pathol, 2010, 62(1): 45-52.
56. Kaygusuzoglu E, Caglayan C, Kandemir FM, Yildirim S, Kucukler S, Akif MK, Saglam YS. Zingerone ameliorates cisplatin‐induced ovarian and uterine toxicity via suppression of sex hormone imbalances, oxidative stress, inflammation and apoptosis in female wistar rats. Biomed Pharmacothe. 2018; 102: 517-530.
57. Kaymaz MB, Kandemir FM, Pamukçu E, Eröksüz Y, Özdemir N. Effects of Aqueous Artichoke (Cynara scolymus) Leaf Extract on Hepatic Damage Generated by Alpha-Amanitine. Kafkas Üniversitesi Veteriner Fakültesi Dergisi. 2017; 23(1): 155-160.
58. Kim MK, Chung SW, Kim DH, Kim JM, Lee EK, Kim JY, Haab YM. Modulation of age-related NF-κB activation by dietary zingerone via MAPK pathway. Exp Gerontol Rep. 2010; 45(6): 419-426
59. Ko JW, Lee IC, Park SH, Moon C, Kang SS, Kim SH, Kim JC. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats. Lab Anim Res. 2014; 30(4): 174-180.
60. Koc A, Duru M, Ciralik H, Akcan R, Sogut S. Protective agent, erdosteine, against cisplatin induced hepatic oxidant injury in rats. Mol Cell Biochem. 2015; 278: 79-84. Kopylchuk HP, Nykolaichuk IM, Zhuretska OM. Rat liver arginase system under acetaminophen-induced toxic injury and protein deprivation. Ukr Biochem J. 2017; 89(2): 92-98.
61. Kumar L, Chhibber S, Harjai K. Hepatoprotective effect of zingerone (4-(4-hydroxy-3-methoxyphenyl) butan-2-one) in lipopolysaccharide induced liver injury mouse model through down regulation of inflammatory mediators. Int J Pharmacogn and Phytochem Res. 2014; 6(2): 308-314.
62. Küçükler S. Ratlarda indometazin ile oluşturulan mide ülseri üzerine chrysin’in etkilerinin araştırılması. Doktora Tezi, Atatürk Üniversitesi Sağlık Bilimleri Enstitütüsü, Erzurum, 2018.
63. Leonetti C, Biroccio A, Gabellini C, Scarsella M, Maresca V, Flori E, Bove L, Pace A, Stoppacciaro A, Zupi G, Cognetti F, Picardo M. Alpha-tocopherol protects against cisplatin-induced toxicity without interfering with antitumor efficacy. Int J Cancer. 2003; 104: 243-50. Lockshin RA, Zakeri Z. Apoptosis, autophagy, and more. Int J Biochem Cell Bio. 2004; 36(12): 2405-2419.
64. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J. Biol. Chem. 1951; 193: 265-275.
65. Majumdar S, Lamothe B, Aggarwal BB. Thalidomide suppresses NF-kB activation induced by TNF and H2O2, but not that activated by ceramide, lipopolysaccharides, or phorbol ester. J Immunol. 2002; 168: 2644-51.
66. Mani V, Siddique AI, Arivalagan S, Thomas NS, Namasivayam N. Zingerone ameliorates hepatic and renal damage in alcohol-induced toxicity in experimental rats. Int J Nutr Pharmacol Neurol Dis. 2016; 6(3): 125.
67. Manjunatha JR, Bettadaiah BK, Negi PS, Srinivas P. Synthesis of quinoline derivatives of tetrahydrocurcumin and zingerone and evaluation of their antioxidant and antibacterial attributes. Food Chem. 2013; 136: 650-658.
68. Matkovics B, Szabo L, Varga IS. Determination of enzyme activities in lipid peroxidation and glutathione pathways. Labor diagnosztika. 1988; 15: 248-249.
69. Mercantepe F, Mercantepe T, Adnan T, Yilmaz A, Tumkaya L. Protective effects of amifostine, curcumin, and melatonin against cisplatin-induced acute kidney injury. Naunyn Schmiedebergs Arch Pharmacol. 2018; 6: 25-53.
70. Mokhtar IY, Hend MH. 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. 2015; 78: 15-25.
71. Nagi MN, Almakki HA. Thymoquinone supplementation induces quinone reductase and glutathione transferase in mice liver: possible role in protection against chemical carcinogenesis and toxicity. Phytother Res. 2009; 23: 1295-1298.
72. Naqshbandi A, Khan MW, Rizwan S, Yusufi A, Khan F. Studies on the protective effect of fish oil against cisplatin induced hepatotoxicity. Free Radic Biol Med. 2014; 3(2): 86-97.
73. Nemat A, Summya R, Sana N, Syed KH, Sarwat S. Beneficial effects of Chrysin against Methotrexate-induced hepatotoxicity via attenuation of oxidative stress and apoptosis. Mol Cell Biochem. 2014; 385: 215-223.
74. Nolan GP, Fujita T, Bhatia K, Huppi C, Liou HC, Scott ML, Baltimore D. The bcl-3 proto-oncogene encodes a nuclear I kappa B-like molecule that preferentially interacts with NF-kappa B p50 and p52 in a phosphorylation-dependent manner. Mol Cell Biol. 1993; 13: 3557-3566.
75. Ohno H, Takimoto G, McKeithan TW. The candidate proto-oncogene bcl-3 is related to genes implicated in cell lineage determination and cell cycle control. Cell. 1990; 60: 991-997.
76. Özçelik M, Kandemir FM, Özdemir N. Koyun böbrek doku arginazının etilen diamin tetra asetik asit (edta), para kloromerküri benzoik asit (p-cmba), n-etil maleimid (nem) tarafından inhibisyonu ve inhibisyon kinetiği. Fırat Üniv Sağ Bil Derg (Vet). 2010; 24: 23-27.
77. Pan HZ, Zhang L, Guo MY, Sui H, Li H, Wu WH, Qu NQ, Liang MH, Chang D. The oxidative stress status in diabetes mellitus and diabetic nephropathy. Acta Diabetol. 2010; 47: 71-76.
78. Penelope DS, Francisco JL, Montserrat D, Mart P, ElsaSanchez-Lopez J, Thomaleg M, Jos ML, Ana IM. Differential effect of quercetin on cisplatin-induced toxicity in kidney and tumor tissues. Food Chem Toxicol. 2017; 107: 226-236.
79. Persson T, Popescu BO, Cedazo-Minguez A. Oxidative stress in Alzheimer's disease: Why did antioxidant therapy fail. Oxid Med Cell Longev. 2014; 18: 42-73.
80. Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal. Biochem. 1966; 16: 359-364.
81. Poveda J, Sanz AB, Carrasco S, Ruiz-Ortega M, Cannata-Ortiz P, Sanchez-Nino MD, Ortiz A. Bcl3: a regulator of NF-κB inducible by TWEAK in acute kidney injury with anti-inflammatory and antiapoptotic properties in tubular cells. Exp Mol Med. 2017; 49: 352-369.
82. Purdy M, Kokki M, Anttila M. Does the rectus sheath block analgesia reduce the inflammatory response biomarkers’ IL-1ra, IL6, IL-8, IL-10 and IL-1beeta concentrations following surgery. A randomised clinical trial of patients with cancer and benign disease. Anticancer Res. 2016; 36: 3005-3111.
83. Saad SY, Najjar TA, Alashari M. Role of non-selective adenosine receptor blockade and phosphodiesterase inhibition in cisplatin-induced nephrogonadal toxicity in rats. Clin Exp Pharmacol Physiol. 2004; 31(12): 862-867.
84. Safhi MM. Nephroprotective Effect of Zingerone against CCl4-Induced Renal Toxicity in Swiss Albino Mice: Molecular Mechanism. 2018; Oxid Med Cell Longev, Samira A, Mahmoud R, Amin M, Somaye R, Loghman S. Aloe vera toxic effects: expression of inducible nitric oxide synthase (iNOS) in testis of Wistar rat. Iran J Basic Med Sci. 2001; 18(10): 967-973.
85. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydrl groups in tissue with Ellman’s reagent. Anal. Biochem. 1968; 25: 192-205.
86. Seong HK, Kyoung OH, Won-Yoon C, Jae KH, Kwang-Kyun P. Abrogation of cisplatin-induced hepatotoxicity in mice by xanthorrhizol is related to its effect on the regulation of gene transcription. Toxicol Appl Pharmacol. 2004; 196: 346-355.
87. Soliman AF, Anees LM, Ibrahim DM. Cardioprotective effect of zingerone against oxidative stress, inflammation, and apoptosis induced by cisplatin or gamma radiation in rat. Naunyn Schmiedebergs Arch Pharmacol. 2018; 391(8): 819-832.
88. Songa J, FanH, Li H, Ding H, Lv Q, Hou S. Zingerone ameliorates lipopolysaccharide-induced acute kidney injury by inhibiting Toll-like receptor 4 signaling pathway. Eur J Pharmacol. 2016; 772: 108-114.
89. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1988; 34: 497-500.
90. Thomson M, Al-Qattan KK, Al-Sawan SM, Alnaqeeb MA, Khan I, Ali M, Tori H. Ginger Zingiber officinale Roscoe: an overview of its safety and efficacy. BioScience. 2002; 67: 475-478.
91. Tian L, Shi MM, Forman HJ. Increased transcription of the regulatory subunit of gamma-glutamyl cysteine synthase in rat lung epithelial L2 cells exposed to oxidative stress or glutathione depletion. Arch Biochem Biophys. 1997; 342: 126-33.
92. Tikoo K, Tamta A, Ali IY, Gupta J, Gaikwad AB. Tannic acid prevents azidothymidine (AZT) induced hepatotoxicity and genotoxicity along with change in expression of PARG and histone H3 acetylation. Toxi Lett. 2008; 177: 90-96.
93. Vernet P, Aitken RJ, Drevet JR. Antioxidant strategies in the epididymis. Mol Cell Endocrinol. 2004; 216(1-2): 31-39.
94. Wandall JH. Etiology of chronic liver disease in ethiopia: a case control study with special reference to viral hepatitis and alcohol. EC Gastroenterol Dig Syst. 2018; 5: 120-128.
95. Wulczyn FG, Naumann M, Scheidereit C. Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-kappa B. Nature. 1992; 358: 597-599.
96. Yildirim NC, Kandemir FM, Benzer F. Beneficial effects of grape seed extract against cisplatın-induced testiculer damage in rabbits. Dig J Nanomat Biostruct. 2011; 6: 155-9.
97. Yildirim NC, Kandemir FM, Ceribasi S, Ozkaraca M, Benzer F. Pomegranate seed extract attenuates chemotherapy-induced liver damage in an experimental model of rabbits. Cellular and Molecular Biology. 2013; 59(2): 1842-47.
98. Yilmaz RH, Sogut S, Ozyurt B, Ozugurlu F, Sahin S, Isik B. The activities of liver adenosine deaminase, xanthine oxidase, catalase, superoxide dismutase enzymes and the levels of malondialdehyde and nitric oxide after cisplatin taoxicity in rats: protective effect of caffeic acid phenethyl ester. Toxicol Ind Health. 2005; 21: 1-2.
99. Yilmaz S, Atessahin A, Sahna E, Karahan I, Ozer S. Protective effect of lycopene on adriamycin-induced cardiotoxicity and nephrotoxicity. Toxicology. 2006; 218: 164-702.
100. Yilmaz S, Kandemir FM, Kaya E, Ozkaraca M. Chemoprotective Effects of Propolis on Aflatoxin B1-Induced Hepatotoxicity in Rats: Oxidative Damage and Hepatotoxicity by Modulating TP53, Oxidative Stress. Current Proteomics. 2020; 17(3): 191-199.
101. Yongke L, Arthur IC. Cisplatin-Induced Hepatotoxicity is enhanced by elevated expression of Cytochrome P450 2E1. Toxic Sci. 2006; 89: 515-523.
102. Young MM, Kester M, Wang HG. Sphingolipids: regulators of crosstalk between apoptosis and autophagy. J Lipid Res. 2012; 54: 5-19.
103. Young-Myeong K, Robert VT, Timothy RB. Nitric Oxide inhibits apoptosis by preventing increases in caspase-3-like Activity via two distinct mechanisms. J Biol Chem. 2017; 9: 254-289.