ONCOLOGY / EXPERIMENTAL RESEARCH
Effect of thymoquinone on cyclophosphamide-induced injury in the rat urinary bladder
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1
Anatomy Department, Faculty of Medicine, Cairo University, Cairo, Egypt
2
Medical Physiology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
3
Fielding Graduate University, Student-Doctor of Clinical Psychology
4
California University of Science and Medicine, School of Medicine, San Bernardino, California, USA
5
Department of Medical Education, California University of Science and Medicine, School of Medicine, San Bernardino, California, USA
Submission date: 2019-10-25
Final revision date: 2020-04-23
Acceptance date: 2020-06-14
Online publication date: 2020-07-08
Publication date: 2026-02-28
Corresponding author
Sherif Sabry Hassan
Department of
Medical Education
California University
of Science and Medicine
School of Medicine
San Bernardino
92408 CA, USA
Phone: +1- 636-384-9499
Arch Med Sci 2026;22(1):515-526
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Cyclophosphamide (CP) is a chemotherapeutic agent used to treat neoplastic diseases, but its side effects include hemorrhagic cystitis. Thymoquinone (TQ) is an active ingredient of Nigella sativa with healing potential. This study examined the protective effect of TQ against CP-induced oxidative injury in rat urinary bladder.
Material and methods:
Sixty rats were divided into 6 equal groups: untreated control (group A), TQ-treated with 10 mg/kg/day TQ for 10 days (group B1), TQ-treated with 100 mg/kg/day TQ for 5 days (group B2), toxicity control where 100 mg/kg CP was administered for 2 days (group C), CP + TQ-treated with the same TQ treatment as group B1 and 100 mg/kg CP for 2 days (group D1), and CP + TQ-treated with the same TQ treatment as group B2 and 100 mg/kg CP for 2 days (group D2). Rat urinary bladders were assessed histopathologically via hematoxylin and eosin (H&E) and Masson’s trichrome stains and were evaluated for oxidative stress and cell death markers.
Results:
CP demonstrated significant reduction in glutathione reductase, and increased malondialdehyde levels and protein carbonylation (both p < 0.05). CP also induced cell death as measured by caspase-3 activation. Pretreatment with TQ (group D2) reduced CP-induced oxidative stress and apoptosis.
Conclusions:
TQ may ameliorate CP-induced oxidative injury in rat urinary bladder, via its antioxidant and antiapoptotic effects.
REFERENCES (41)
1.
Xu Z, Chang FR, Wang HK, et al. Anti-HIV agents 45(1) and antitumor agents 205.(2) two new sesquiterpenes, leitneridanins A and B, and the cytotoxic and anti-HIV principles from Leitneria floridana. J Nat Prod 2000; 63: 1712-5.
2.
Dollery C. Therapeutic Drugs. Churchill Livingstone; Edinburgh 1999; 349-53.
3.
Wrobel A, Doboszewska U, Rechberger E, et al. Rho kinase inhibition ameliorates cyclophosphamide-induced cystitis in rats. Naunyn Schmiedebergs Arch Pharmacol 2017; 390: 613-9.
4.
Esposito P, Domenech MV, Serpieri N, et al. Severe cyclophosphamide-related hyponatremia in a patient with acute glomerulonephritis. World J Nephrol 2017; 6: 217-20.
5.
Manikandan R, Kumar S, Dorairajan LN. Hemorrhagic cystitis: a challenge to the urologist. Indian J Urol 2010; 26: 159-66.
6.
Sobolev VE, Jenkins RO, Goncharov NV. Sulfated glycosaminoglycans in bladder tissue and urine of rats after acute exposure to paraoxon and cyclophosphamide. Exp Toxicol Pathol 2017; 69: 339-47.
7.
Zhang W, Deng X, Liu C, Wang X. Intravesical treatment for interstitial cystitis/painful bladder syndrome: a network meta-analysis. Int Urogynecol J 2017; 28: 515-25.
8.
Theoharides TC, Kempuraj D, Vakali S, Sant GR. Treatment of refractory interstitial cystitis/painful bladder syndrome with CystoProtek: an oral multi-agent natural supplement. Can J Urol 2008; 15: 4410-14.
9.
Crescenze IM, Tucky B, Li J, Moore C, Shoskes DA. Efficacy, side effects, and monitoring of oral cyclosporine in interstitial cystitis-bladder pain syndrome. Urology 2017; 107: 49-54.
10.
Ragheb A, Attia A, Eldin WS, Elbarbry F, Gazarin S, Shoker A. The protective effect of thymoquinone, an anti-oxidant and anti-inflammatory agent, against renal injury: a review. Saudi J Kidney Dis Transpl 2009; 20: 741-52.
11.
Woo CC, Kumar AP, Sethi G, Tan KH. Thymoquinone: potential cure for inflammatory disorders and cancer. Biochem Pharmacol 2012; 83: 443-51.
12.
El-Sheikh AA, Morsy MA, Abdalla AM, Hamouda AH, Alhaider IA. Mechanisms of thymoquinone hepatorenal protection in methotrexate-induced toxicity in rats. Mediators Inflamm 2015; 2015: 859383.
13.
Iskender B, Izgi K, Hizar E, et al. Inhibition of epithelial-mesenchymal transition in bladder cancer cells via modulation of mTOR signalling. Tumour Biol 2016; 37: 8281-91.
14.
Nagi MN, Mansour MA. Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity in rats: a possible mechanism of protection. Pharmacol Res 2000; 41: 283-9.
15.
Mansour MA, Nagi MN, El-Khatib AS, Al-Bekairi AM. Effects of thymoquinone on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase in different tissues of mice: a possible mechanism of action. Cell Biochem Funct 2002; 20: 143-51.
16.
Yildirim I, Korkmaz A, Oter S, Ozcan A, Oztas E. Contribution of antioxidants to preventive effect of mesna in cyclophosphamide-induced hemorrhagic cystitis in rats. Cancer Chemother Pharmacol 2004; 54: 469-73.
17.
Zhou Z, Kang YJ. Cellular and subcellular localization of catalase in the heart of transgenic mice. J Histochem Cytochem 2000; 48: 585-94.
18.
Begic A, Djuric A, Ninkovic M, et al. Disulfiram moderately restores impaired hepatic redox status of rats subchronically exposed to cadmium. J Enzyme Inhib Med Chem 2017; 32: 478-89.
19.
Yuksel Y, Guven M, Kaymaz B, et al. Effects of aloe vera on spinal cord ischemia-reperfusion injury of rats. J Invest Surg 2016; 29: 389-98.
20.
Stadtman ER, Oliver CN. Metal-catalyzed oxidation of proteins: physiological consequences. J Biol Chem 1991; 266: 2005-8.
21.
Jiang Z, Clemens PR. Cellular caspase-8-like inhibitory protein (cFLIP) prevents inhibition of muscle cell differentiation induced by cancer cells. FASEB J 2006; 20: 2570-2.
22.
Ozcan A, Korkmaz A, Oter S, Coskun O. Contribution of flavonoid antioxidants to the preventive effect of mesna in cyclophosphamide-induced cystitis in rats. Arch Toxicol 2005; 79: 461-5.
23.
Choi SH, Byun Y, Lee G. Expressions of uroplakins in the mouse urinary bladder with cyclophosphamide-induced cystitis. J Korean Med Sci 2009; 24: 684-9.
24.
Kim SH, Lee IC, Ko JW, et al. Diallyl disulfide prevents cyclophosphamide-induced hemorrhagic cystitis in rats through the inhibition of oxidative damage, MAPKs, and NF-kappaB pathways. Biomol Ther 2015; 23: 180-8.
25.
Zhang X, Gao S, Tanaka M, et al. Carbenoxolone inhibits TRPV4 channel-initiated oxidative urothelial injury and ameliorates cyclophosphamide-induced bladder dysfunction. J Cell Mol Med 2017; 21: 1791-802.
26.
Sedaghat Z, Kadkhodaee M, Seifi B, Salehi E. Inducible and endothelial nitric oxide synthase distribution and expression with hind limb per-conditioning of the rat kidney. Arch Med Sci 2019; 15: 1081-91.
27.
Ribeiro RA, Freitas HC, Campos MC, et al. Tumor necrosis factor-alpha and interleukin-1beta mediate the production of nitric oxide involved in the pathogenesis of ifosfamide induced hemorrhagic cystitis in mice. J Urol 2002; 167: 2229-34.
28.
Gore PR, Prajapati CP, Mahajan UB, et al. Protective effect of thymoquinone against cyclophosphamide-induced hemorrhagic cystitis through inhibiting DNA damage and upregulation of Nrf2 expression. Patil Int J Biol Sci 2016; 12: 944-53.
29.
Gao HB, Tong MH, Hu YQ, et al. Mechanisms of glucocorticoid-induced Leydig cell apoptosis. Mol Cell Endocrinol 2003; 199: 153-63.
30.
Cicero AFG, Ruscica M, Banach M. Resveratrol and cognitive decline: a clinician perspective. Arch Med Sci 2019; 15: 936-43.
31.
Kamisli S, Basaran C, Batcioglu K, et al. Neuroprotective effects of the new Na channel blocker rs100642 in global ischemic brain injury. Arch Med Sci 2019; 15: 467-74.
32.
Sagit M, Korkmaz F, Akcadag A, Somdas MA. Protective effect of thymoquinone against cisplatin-induced ototoxicity. Eur Arch Otorhinolaryngol 2013; 270: 2231-7.
33.
Badary OA, Al-Shabanah OA, Nagi MN, Al-bekairi AM, Elmazar M. Acute and subchronic toxicity of thymoquinone in mice. Drug Dev Res 1998; 44: 56-61.
34.
Klisic A, Kavaric N, Stanisic V, et al. Endocan and a novel score for dyslipidemia, oxidative stress and inflammation (DOI score) are independently correlated with glycated hemoglobin (HbA1c) in patients with prediabetes and type 2 diabetes. Arch Med Sci 2020; 16: 42-50.
35.
Kaczmarczyk-Sedlak I, Folwarczna J, Sedlak L. Effect of caffeine on biomarkers of oxidative stress in lenses of rats with streptozotocin-induced diabetes. Arch Med Sci 2019; 15: 1073-80.
36.
Attoub S, Sperandio O, Raza H, et al. Thymoquinone as an anticancer agent: evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo. Fundam Clin Pharmacol 2013; 27: 557-69.
37.
Virag L, Szabo E, Gergely P, Szabo C. Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. Toxicol Lett 2003; 140-141: 113-24.
38.
El-Ghany R, Sharaf N, Kassem L, Mahran L, Heikal O. Thymoquinone triggers anti-apoptotic signaling targeting death ligand and apoptotic regulators in a model of hepatic ischemia reperfusion injury. Drug Discov Ther 2009; 3: 296-306.
39.
Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 2013; 53: 401-26.
40.
Huang Y, Li W, Su Z, Kong A. The complexity of the Nrf2 pathway: beyond the antioxidant response. J Nutr Biochem 2015; 26: 1401-13.
41.
Helal GK. Thymoquinone supplementation ameliorates acute endotoxemia-induced liver dysfunction in rats. Pak J Pharm Sci 2010; 23: 131-7.