title: Protective Effect of Thymoquinone against Cyclophosphamide-Induced Hemorrhagic Cystitis through Inhibiting DNA Damage and Upregulation of Nrf2 Expression.
abstract: Cyclophosphamide (CYP) induced hemorrhagic cystitis is a dose-limiting side effect involving increased oxidative stress, inflammatory cytokines and suppressed activity of nuclear factor related erythroid 2-related factor (Nrf2). Thymoquinone (TQ), an active constituent of Nigella sativa seeds, is reported to increase the expression of Nrf2, exert antioxidant action, and anti-inflammatory effects in the experimental animals. The present study was designed to explore the effects of TQ on CYP-induced hemorrhagic cystitis in Balb/c mice. Cystitis was induced by a single intraperitoneal injection of CYP (200 mg/kg). TQ was administered intraperitoneally at 5, 10 and 20 mg/kg doses twice a day, for three days before and three days after the CYP administration. The efficacy of TQ was determined in terms of the protection against the CYP-induced histological perturbations in the bladder tissue, reduction in the oxidative stress, and inhibition of the DNA fragmentation. Immunohistochemistry was performed to examine the expression of Nrf2. TQ protected against CYP-induced oxidative stress was evident from significant reduction in the lipid peroxidation, restoration of the levels of reduced glutathione, catalase and superoxide dismutase activities. TQ treatment significantly reduced the DNA damage evident as reduced DNA fragmentation. A significant decrease in the cellular infiltration, edema, epithelial denudation and hemorrhage were observed in the histological observations. There was restoration and rise in the Nrf2 expression in the bladder tissues of mice treated with TQ. These results confirm that, TQ ameliorates the CYP-induced hemorrhagic cystitis in mice through reduction in the oxidative stress, inhibition of the DNA damage and through increased expression of Nrf2 in the bladder tissues.
authors.affiliation: 1. Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District-Dhule, Maharashtra, 425405, India.
authors.forename: Prashant R
authors.initials: PR
authors.lastname: Gore
authors.affiliation: 1. Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District-Dhule, Maharashtra, 425405, India.
authors.forename: Chaitali P
authors.initials: CP
authors.lastname: Prajapati
authors.affiliation: 1. Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District-Dhule, Maharashtra, 425405, India.
authors.forename: Umesh B
authors.initials: UB
authors.lastname: Mahajan
authors.affiliation: 1. Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District-Dhule, Maharashtra, 425405, India.
authors.forename: Sameer N
authors.initials: SN
authors.lastname: Goyal
authors.affiliation: 2. School of Pharmacy and Technology Management, SVKM's NMIMS, MPTP, Shirpur, District- Dhule, Maharashtra, 425405, India.
authors.forename: Sateesh
authors.initials: S
authors.lastname: Belemkar
authors.affiliation: 3. Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates, University, Al Ain, Abu Dhabi 17666, United Arab Emirates.
authors.forename: Shreesh
authors.initials: S
authors.lastname: Ojha
authors.affiliation: 1. Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District-Dhule, Maharashtra, 425405, India.
authors.forename: Chandragouda R
authors.initials: CR
authors.lastname: Patil
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000633:toxicity*; D003556:Cystitis / Q000139:chemically induced* / Q000188:drug therapy*; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D053938:DNA Fragmentation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006470:Hemorrhage / Q000139:chemically induced* / Q000188:drug therapy*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D016227:Benzoquinones; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D003520:Cyclophosphamide; D013482:Superoxide Dismutase; D005978:Glutathione; C003466:thymoquinone
keywords: DNA damage; Nrf2; Thymoquinone; comet assay; cyclophosphamide; cytokines