Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Diallyl Disulfide Prevents Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats through the Inhibition of Oxidative Damage, MAPKs, and NF-κB Pathways

  • Kim, Sung Hwan (College of Veterinary Medicine, Chonnam National University) ;
  • Lee, In Chul (College of Veterinary Medicine, Chonnam National University) ;
  • Ko, Je Won (College of Veterinary Medicine, Chonnam National University) ;
  • Moon, Changjong (College of Veterinary Medicine, Chonnam National University) ;
  • Kim, Sung Ho (College of Veterinary Medicine, Chonnam National University) ;
  • Shin, In Sik (College of Veterinary Medicine, Chonnam National University) ;
  • Seo, Young Won (Biomedical Mouse Resource Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Hyoung Chin (Biomedical Mouse Resource Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Jong Choon (College of Veterinary Medicine, Chonnam National University)
  • Received : 2014.11.13
  • Accepted : 2015.01.12
  • Published : 2015.03.01
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Abstract

This study investigated the possible effects and molecular mechanisms of diallyl disulfide (DADS) against cyclophosphamide (CP)-induced hemorrhagic cystitis (HC) in rats. Inflammation response was assessed by histopathology and serum cytokines levels. We determined the protein expressions of nuclear transcription factor kappa-B (NF-${\kappa}B$), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$), oxidative stress, urinary nitrite-nitrate, malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Finally, we studied the involvement of mitogen-activated protein kinases (MAPKs) signaling in the protective effects of DADS against CP-induced HC. CP treatment caused a HC which was evidenced by an increase in histopathological changes, proinflammatory cytokines levels, urinary nitrite-nitrate level, and the protein expression of NF-${\kappa}B$, COX-2, iNOS, TNF-${\alpha}$, p-c-Jun N-terminal kinase (JNK), and p-extracellular signal regulated kinase (ERK). The significant decreases in glutathione content and glutathione-S-transferase and glutathione reductase activities, and the significant increase in MDA content and urinary MDA and 8-OHdG levels indicated that CP-induced bladder injury was mediated through oxidative DNA damage. In contrast, DADS pretreatment attenuated CP-induced HC, including histopathological lesion, serum cytokines levels, oxidative damage, and urinary oxidative DNA damage. DADS also caused significantly decreased the protein expressions of NF-${\kappa}B$, COX-2, iNOS, TNF-${\alpha}$, p-JNK, and p-ERK. These results indicate that DADS prevents CP-induced HC and that the protective effects of DADS may be due to its ability to regulate proinflammatory cytokines production by inhibition of NF-${\kappa}B$ and MAPKs expressions, and its potent anti-oxidative capability through reduction of oxidative DNA damage in the bladder.

Keywords

References

  1. Beckman, K. B. and Ames, B. N. (1997) Oxidative decay of DNA. J. Biol. Chem. 272, 19633-19666. https://doi.org/10.1074/jbc.272.32.19633
  2. Berton, T. R., Conti, C. J., Mitchell, D. L., Aldaz, C. M., Lubet, R. A. and Fischer, S. M. (1998) The effect of vitamin E acetate on ultravioletinduced mouse skin carcinogenesis. Mol. Carcinog. 23, 175-184. https://doi.org/10.1002/(SICI)1098-2744(199811)23:3<175::AID-MC6>3.0.CO;2-B
  3. Bhatia, K., Kaur, M., Atif, F., Ali, M., Rehman, H., Rahman, S. and Raisuddin, S. (2006) Aqueous extract of Trigonella foenum-graecum L. ameliorates additive urotoxicity of buthionine sulfoximine and cyclophosphamide in mice. Food Chem. Toxicol. 44, 1744-1750. https://doi.org/10.1016/j.fct.2006.05.013
  4. Bradford, M. M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248-254. https://doi.org/10.1016/0003-2697(76)90527-3
  5. Carlberg, I. and Mannervik, B. (1986) Reduction of 2,4,6-trinitrobenzenesulfonate by glutathione reductase and the effect of NADP+ on the electron transfer. J. Biol. Chem. 261, 1629-1635.
  6. Checker, R., Sharma, D., Sandur, S. K., Khanam, S. and Poduval, T. B. (2009) Anti-inflammatory effects of plumbagin are mediated by inhibition of NF-kappaB activation in lymphocytes. Int. Immunopharmacol. 9, 949-958. https://doi.org/10.1016/j.intimp.2009.03.022
  7. Chiang, Y. H., Jen, L. N., Su, H. Y., Lii, C. K., Sheen, L. Y. and Liu, C. T. (2006) Effects of garlic oil and two of its major organosulfur compounds, diallyl disulfide and diallyl trisulfide, on intestinal damage in rats injected with endotoxin. Toxicol. Appl. Pharmacol. 213, 46-54. https://doi.org/10.1016/j.taap.2005.08.008
  8. Chung, C. W., Zhang, Q. L. and Qiao, L. Y. (2010) Endogenous nerve growth factor regulates collagen expression and bladder hypertrophy through Akt and MAPK pathways during cystitis. J. Biol. Chem. 285, 4206-4212. https://doi.org/10.1074/jbc.M109.040444
  9. Corrow, K. A. and Vizzard, M. A. (2007) Phosphorylation of extracellular signal-regulated kinases in urinary bladder in rats with cyclophosphamide-induced cystitis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R125-134. https://doi.org/10.1152/ajpregu.00857.2006
  10. Cuesta, S., Kireev, R., Forman, K., Garcí, C., Escames, G., Ariznavarreta, C., Vara, E. and Tresguerres, J. A. (2010) Melatonin improves inflammation processes in liver of senescence-accelerated prone male mice (SAMP8). Exp. Gerontol. 45, 950-956. https://doi.org/10.1016/j.exger.2010.08.016
  11. Dantas, A. C., Batista-Júior, F. F., Macedo, L. F., Mendes, M. N., Azevedo, I. M. and Medeiros, A. C. (2010) Protective effect of simvastatin in the cyclophosphamide-induced hemorrhagic cystitis in rats. Acta Cir. Bras. 25, 43-46. https://doi.org/10.1590/S0102-86502010000100011
  12. Fukao, T., Hosono, T., Misawa, S., Seki, T. and Ariga, T. (2004) The effects of allyl sulfides on the induction of phase II detoxification enzymes and liver injury by carbon tetrachloride. Food Chem. Toxicol. 42, 743-749. https://doi.org/10.1016/j.fct.2003.12.010
  13. Guyonnet, D., Belloir, C., Suschetet, M., Siess, M. H. and Le Bon, A. M. (2002) Mechanisms of protection against aflatoxin B1 genotoxicity in rats treated by organosulfur compounds from garlic. Carcinogenesis 23, 1335-1341. https://doi.org/10.1093/carcin/23.8.1335
  14. Habig, W. H., Jakoby, W. B., Guthenberg, C., Mannervik, B. and Vander Jagt, D. L. (1984) 2-Propylthiouracil does not replace glutathione for the glutathione transferases. J. Biol. Chem. 259, 7409-7410.
  15. Hamada, Y., Miyata, S., Nii-Kono, T., Kitazawa, R., Kitazawa, S., Higo, S., Fukunaga, M., Ueyama, S., Nakamura, H., Yodoi, J., Fukagawa, M. and Kasuga, M. (2007) Overexpression of thioredoxin1 in transgenic mice suppresses development of diabetic nephropathy. Nephrol. Dial. Transplant. 22, 1547-1557. https://doi.org/10.1093/ndt/gfm099
  16. Hamsa, T. P. and Kuttan, G. (2012) Tinospora cordifolia ameliorates urotoxic effect of cyclophosphamide by modulating GSH and cytokine levels. Exp. Toxicol. Pathol. 64, 307-314. https://doi.org/10.1016/j.etp.2010.09.003
  17. Hommes, D. W., Peppelenbosch, M. P. and van Deventer, S. J. (2003) Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti-inflammatory targets. Gut 52, 144-151. https://doi.org/10.1136/gut.52.1.144
  18. Huang, Y., Jin, M., Pi, R., Zhang, J., Chen, M., Ouyang, Y., Liu, A., Chao, X., Liu, P., Liu, J., Ramassamy, C. and Qin, J. (2013) Protective effects of caffeic acid and caffeic acid phenethyl ester against acrolein-induced neurotoxicity in HT22 mouse hippocampal cells. Neurosci. Lett. 535, 146-151. https://doi.org/10.1016/j.neulet.2012.12.051
  19. Inano, H. and Onoda, M. (2002) Radioprotective action of curcumin extracted from Curcuma longa LINN: inhibitory effect on formation of urinary 8-hydroxy-2'-deoxyguanosine, tumorigenesis, but not mortality, induced by gamma-ray irradiation. Int. J. Radiat. Oncol. Biol. Phys. 53, 735-743. https://doi.org/10.1016/S0360-3016(02)02794-3
  20. Jurado, J. M., Sechez, A., Pajares, B., Peez, E., Alonso, L. and Alba, E. (2008) Combined oral cyclophosphamide and bevacizumab in heavily pre-treated ovarian cancer. Clin. Transl. Oncol. 10, 583-586. https://doi.org/10.1007/s12094-008-0254-7
  21. Kang, S., Kim, S., Park, J., Kim, H.J., Lee, J., Choi, G., Choi, S., Kim, S., Kim, S. Y., Moon, H. B., Kim, S., Kho, Y. L. and Choi, K. (2013) Urinary paraben concentrations among pregnant women and their matching newborn infants of Korea, and the association with oxidative stress biomarkers. Sci. Total Environ. 461-2, 214-221. https://doi.org/10.1016/j.scitotenv.2013.04.097
  22. Keiss, H. P., Dirsch, V. M., Hartung, T., Haffner, T., Trueman, L., Auger, J., Kahane, R. and Vollmar, A. M. (2003) Garlic (Allium sativum L.) modulates cytokine expression in lipopolysaccharide-activated human blood thereby inhibiting NF-kappaB activity. J. Nutr. 133, 2171-2175.
  23. Kim, H. G., Yoon, D. H., Lee, W. H., Han, S. K., Shrestha, B., Kim, C. H., Lim, M. H., Chang, W., Lim, S., Choi, S., Song, W. O., Sung, J. M., Hwang, K. C. and Kim, T. W. (2007) Phellinus linteus inhibits inflammatory mediators by suppressing redox-based NF-kappaB and MAPKs activation in lipopolysaccharide-induced RAW 264.7 macrophage. J. Ethnopharmacol. 114, 307-315. https://doi.org/10.1016/j.jep.2007.08.011
  24. Kim, S. H., Lee, I. C., Baek, H. S., Shin, I. S., Moon, C., Bae, C. S., Kim, S. H., Kim, J. C. and Kim, H. C. (2014) Mechanism for the protective effect of diallyl disulfide against cyclophosphamide acute urotoxicity in rats. Food Chem. Toxicol. 64, 110-118. https://doi.org/10.1016/j.fct.2013.11.023
  25. Kiuchi, H., Takao, T., Yamamoto, K., Nakayama, J., Miyagawa, Y., Tsujimura, A., Nonomura, N. and Okuyama, A. (2009) Sesquiterpene lactone parthenolide ameliorates bladder inflammation and bladder overactivity in cyclophosphamide induced rat cystitis model by inhibiting nuclear factor-kappaB phosphorylation. J. Urol. 18, 2339-2348.
  26. Koranteng, R. D., Swindle, E. J., Davis, B. J., Dearman, R. J., Kimber, I., Flanagan, B. F. and Coleman, J. W. (2004) Differential regulation of mast cell cytokines by both dexamethasone and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. Clin. Exp. Immunol. 137, 81-87. https://doi.org/10.1111/j.1365-2249.2004.02510.x
  27. Korhonen, R., Lahti, A., Kankaanranta, H. and Moilanen, E. (2005) Nitric oxide production and signaling in inflammation. Curr. Drug Targets Inflamm. Allergy 4, 471-479. https://doi.org/10.2174/1568010054526359
  28. Korkmaz, A., Oter, S., Deveci, S., Ozgurtas, T., Topal, T., Sadir, S. and Bilgic, H. (2003) Involvement of nitric oxide and hyperbaric oxygen in the pathogenesis of cyclophosphamide induced hemorrhagic cystitis in rats. J. Urol. 170, 2498-2502. https://doi.org/10.1097/01.ju.0000085593.31396.d8
  29. Kurowski, V. and Wagner, T. (1997) Urinary excretion of ifosfamide, 4-hydroxyifosfamide, 3- and 2-dechloroethylifosfamide, mesna, and dimesna in patients on fractionated intravenous ifosfamide and concomitant mesna therapy. Cancer Chemother. Pharmacol. 39, 431-439. https://doi.org/10.1007/s002800050594
  30. Lee, I. C., Kim, S. H., Baek, H. S., Moon, C., Kang, S. S., Kim, S. H., Kim, Y. B., Shin, I. S. and Kim, J. C. (2014) The involvement of Nrf2 in the protective effects of diallyl disulfide on carbon tetrachlorideinduced hepatic oxidative damage and inflammatory response in rats. Food Chem. Toxicol. 63, 174-185. https://doi.org/10.1016/j.fct.2013.11.006
  31. Manesh, C. and Kuttan, G. (2002) Alleviation of cyclophosphamideinduced urotoxicity by naturally occurring sulphur compounds. J. Exp. Clin. Cancer Res. 21, 509-517.
  32. Martíez-Ruiz, A., Cadenas, S. and Lamas, S. (2011) Nitric oxide signaling: classical, less classical, and nonclassical mechanisms. Free Radic. Biol. Med. 51, 17-29. https://doi.org/10.1016/j.freeradbiomed.2011.04.010
  33. Moron, M. S., Depierre, J. W. and Mannervik, B. (1979) Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim. Biophys. Acta 582, 67-78. https://doi.org/10.1016/0304-4165(79)90289-7
  34. Nakagawa, H., Tsuta, K., Kiuchi, K., Senzaki, H., Tanaka, K., Hioki, K. and Tsubura, A. (2001) Growth inhibitory effects of diallyl disulfide on human breast cancer cell lines. Carcinogenesis 22, 891-897. https://doi.org/10.1093/carcin/22.6.891
  35. Oter, S., Korkmaz, A., Oztas, E., Yildirim, I., Topal, T. and Bilgic, H. (2004) Inducible nitric oxide synthase inhibition in cyclophosphamide induced hemorrhagic cystitis in rats. Urol. Res. 32, 185-189.
  36. Pang, L. and Hoult, J. R. (1997) Repression of inducible nitric oxide synthase and cyclooxygenase-2 by prostaglandin E2 and other cyclic AMP stimulants in J774 macrophages. Biochem. Pharmacol. 53, 493-500. https://doi.org/10.1016/S0006-2952(96)00737-X
  37. Park, H. Y., Kim, N. D., Kim, G. Y., Hwang, H. J., Kim, B. W., Kim, W. J. and Choi, Y. H. (2012) Inhibitory effects of diallyl disulfide on the production of inflammatory mediators and cytokines in lipopolysaccharide-activated BV2 microglia. Toxicol. Appl. Pharmacol. 262, 177-184. https://doi.org/10.1016/j.taap.2012.04.034
  38. Pedraza-Chaverri J., Gonzaez-Orozco, A. E., Maldonado, P. D., Barrera, D., Medina-Campos, O. N. and Hernadez-Pando, R. (2003) Diallyl disulfide ameliorates gentamicin-induced oxidative stress and nephropathy in rats. Eur. J. Pharmacol. 473, 71-78. https://doi.org/10.1016/S0014-2999(03)01948-4
  39. Posadas, I., Terencio, M. C., Guille, I., Ferradiz, M. L., Coloma, J., Paya M. and Alcaraz, M. J. (2000) Co-regulation between cyclooxygenase- 2 and iaducible nitric oxide synthase expression in the time-course of murine inflammation. Naunyn Schmiedebergs Arch. Pharmacol. 361, 98-106. https://doi.org/10.1007/s002109900150
  40. Ray, P. D., Huang, B. W. and Tsuji, Y. (2012) Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal. 24, 981-990. https://doi.org/10.1016/j.cellsig.2012.01.008
  41. Shen, J., Deininger, P., Hunt, J. D. and Zhao, H. (2007) 8-Hydroxy-2'-deoxyguanosine (8-OH-dG) as a potential survival biomarker in patients with nonsmall-cell lung cancer. Cancer 109, 574-580. https://doi.org/10.1002/cncr.22417
  42. Song, J., Liu, L., Li, L., Liu, J., Song, E. and Song, Y. (2014) Protective effects of lipoic acid and mesna on cyclophosphamide-induced haemorrhagic cystitis in mice. Cell Biochem. Funct. 32, 125-132. https://doi.org/10.1002/cbf.2978
  43. Spelman, K., Burns, J., Nichols, D., Winters, N., Ottersberg, S. and Tenborg, M. (2006) Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators. Altern. Med. Rev. 11, 128-150.
  44. Surh, Y. J. (2008) NF-kappa B and Nrf2 as potential chemopreventive targets of some anti-inflammatory and antioxidative phytonutrients with anti-inflammatory and antioxidative activities. Asia Pac. J. Clin. Nutr. 17 (S1), 269-272.
  45. Szabo C. and Billiar, T. R. (1999) Novel roles of nitric oxide in hemorrhagic shock. Shock 12, 1-9.
  46. Tanel, A., Averill-Bates, D. A. (2007) P38 and ERK mitogen-activated protein kinases mediate acrolein-induced apoptosis in Chinese hamster ovary cells. Cell. Signal. 19, 968-977. https://doi.org/10.1016/j.cellsig.2006.10.014
  47. Tripathi, D. N. and Jena, G. B. (2010) Effect of melatonin on the expression of Nrf2 and NF-kappaB during cyclophosphamide-induced urinary bladder injury in rat. J. Pineal Res. 48, 324-331. https://doi.org/10.1111/j.1600-079X.2010.00756.x
  48. You, S., Nakanishi, E., Kuwata, H., Chen, J., Nakasone, Y., He, X., He, J., Liu, X., Zhang, S., Zhang, B. and Hou, D. X. (2013) Inhibitory effects and molecular mechanisms of garlic organosulfur compounds on the production of inflammatory mediators. Mol. Nutr. Food Res. 57, 2049-2060. https://doi.org/10.1002/mnfr.201200843
  49. Zhang, Y. and Dong, C. (2007) Regulatory mechanisms of mitogenactivated kinase signaling. Cell. Mol. Life Sci. 64, 2771-2789. https://doi.org/10.1007/s00018-007-7012-3
  50. Zhou, H. Y., Shin, E. M., Guo, L. Y., Youn, U. J., Bae, K., Kang, S. S., Zou, L. B. and Kim, Y. S. (2008) Anti-inflammatory activity of 4-methoxyhonokiol is a function of the inhibition of iNOS and COX-2 expression in RAW 264.7 macrophages via NF-kappaB, JNK and p38 MAPK inactivation. Eur. J. Pharmacol. 586, 340-349. https://doi.org/10.1016/j.ejphar.2008.02.044

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