Biomol Ther.  2015 Mar;23(2):180-188. 10.4062/biomolther.2014.126.

Diallyl Disulfide Prevents Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats through the Inhibition of Oxidative Damage, MAPKs, and NF-kappaB Pathways

Affiliations
  • 1College of Veterinary Medicine, Chonnam National University, Gwangju 500-757. toxkim@jnu.ac.kr
  • 2Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, Jeonbuk 580-185.
  • 3Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883.
  • 4Biomedical Mouse Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea. hckim@kribb.re.kr

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-kappaB), 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-kappaB, 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-kappaB, 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-kappaB and MAPKs expressions, and its potent anti-oxidative capability through reduction of oxidative DNA damage in the bladder.

Keyword

Cyclophosphamide; Hemorrhagic cystitis; Diallyl disulfide; Oxidative damage; MAPKs; NF-kappaB

MeSH Terms

Animals
Cyclooxygenase 2
Cyclophosphamide
Cystitis*
Cytokines
DNA Damage
Glutathione
Glutathione Reductase
Inflammation
Malondialdehyde
Mitogen-Activated Protein Kinases
NF-kappa B*
Nitric Oxide Synthase Type II
Oxidative Stress
Phosphotransferases
Rats*
Transcription Factors
Tumor Necrosis Factor-alpha
Urinary Bladder
Cyclooxygenase 2
Cyclophosphamide
Cytokines
Glutathione
Glutathione Reductase
Malondialdehyde
Mitogen-Activated Protein Kinases
NF-kappa B
Nitric Oxide Synthase Type II
Phosphotransferases
Transcription Factors
Tumor Necrosis Factor-alpha
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