Abstract

Background: This study aimed to evaluate the possible role of selenium in mitigating the toxic effect of cyclophosphamide on the oxidative parameters as well as the histology of submandibular salivary glands’ tissues of albino male rats.
Methods: Twenty male albino rats (aged 3-4 months, 300-400 grams) were divided into four groups (n=5): the first group was administered with distilled water orally, the second group was administered with selenium (0.2 mg/kg) orally for 14 days, the third group was given (150 mg/kg) cyclophosphamide by i.p. injection on day eight, and the fourth group was given selenium (0.2 mg/kg) and cyclophosphamide (150 mg/kg) by i.p. injection on day eight. On day 15, all rats were anesthetized, blood samples were collected for total antioxidant capacity (TAC) and malondialdehyde (MDA) analysis, all rats were euthanized, and the submandibular salivary glands were collected.
Results: The biochemical analysis of serum TAC values and MDA levels revealed a significant reduction in the TAC levels and an elevation in MDA levels in the cyclophosphamide (CY) group in comparison with other groups, whereas, the cyclophosphamide with selenium (CY+Se) group showed an elevation in TAC values and a reduction in MDA levels in comparison with the CY group. The histopathological study revealed mucous acini necrosis, atrophy, vacuoles in the serous acini, with edema surrounding the striated ducts, degeneration signs in granular convoluted tubules, as well as an increase in fibrous tissue surrounding the interlobular ducts, while the CY+Se group showed an improvement in the histological architectures.
Conclusion: Cyclophosphamide caused oxidative stress, represented by a reduction in the antioxidant marker level, an elevation in the oxidative marker level, and structural alterations in the submandibular salivary glands of rats and selenium mitigated these effects, as seen by the biochemical analysis and histological investigation.

Keywords: Oxidative stress Salivary gland Cyclophosphamide Selenium References

1. Suryadinata RV, Adriani M, Martini S, Sumarmi S, Wirjatmadi B. The role of selenium micronutrients as antioxidants in exposure to e-cigarette smoke. Asian Journal Pharmaceutical and Clinical Research (AJPCR). 2019;12(8):265-8.
2. Nakao A, Matsunaga Y, Hayashida K, Takahashi N. Role of oxidative stress and Ca2+ signalling in psychiatric disorders. Frontiers in Cell and Developmental Biology. 2021 Feb 11;9:615569.
3. Forman HJ, Zhang H. Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy. Nature Reviews Drug Discovery. 2021 Sep;20(9):689-709.
4. Hasan HF, Abdel-Hamid GR, Ebrahim SI. Antioxidant and anti-inflammatory effects of diallyl disulfide on hepatotoxicity induced by cyclophosphamide in rats. Natural Product Communications. 2020 Oct;15(10):1934578X20969083.
5. Singh C, Prakash C, Tiwari KN, Mishra SK, Kumar V. Premna integrifolia ameliorates cyclophosphamide-induced hepatotoxicity by modulation of oxidative stress and apoptosis. Biomedicine & Pharmacotherapy. 2018 Nov 1;107:634-43.
6. Tong J, Mo QG, Ma BX, Ge LL, Zhou G, Wang YW. The protective effects of Cichorium glandulosum seed and cynarin against cyclophosphamide and its metabolite acrolein-induced hepatotoxicity in vivo and in vitro. Food & function. 2017;8(1):209-19.
7. Al-Allaf LI, Attarbashee RK, Mammdoh JK. The effect of cyclophosphamide on hippocampal structure of adult male rats (role of rosuvastatin). Mil. Med. Sci. Lett. (Voj. Zdrav. Listy) 2022, 91, 1-9.[Inpress]
8. Roblegg E, Coughran A, Sirjani D. Saliva: An all-rounder of our body. European Journal of Pharmaceutics and Biopharmaceutics. 2019 Sep 1;142:133-41.
9. Smith TA, Petty DJ, Pantano C. A Roe-like numerical method for weakly hyperbolic systems of equations in conservation and non-conservation form. Journal of Computational Physics. 2016 Jul 1;316:117-38.
10. Germoush MO, Mahmoud AM. Berberine mitigates cyclophosphamide-induced hepatotoxicity by modulating antioxidant status and inflammatory cytokines. Journal of cancer research and clinical oncology. 2014 Jul;140(7):1103-9.
11. Younis HY, Thanoon IA, Fadhil NN, Merkhan MM. Effect of Zinc as an Add-On to Metformin Therapy on Glycemic control, Serum Insulin, and C-peptide Levels and Insulin Resistance in Type 2 Diabetes Mellitus Patient. Research Journal of Pharmacy and Technology. 2022 Mar 24;15(3):1184-8.
12. Althanoon ZA, Merkhan MM. Effects of zinc supplementation on metabolic status in patients with metabolic syndrome. Acta Poloniae Pharmaceutica. 2021 Jul 1;78(4):521-6.
13. Younis HY, Imad A. Effect of zinc as an add on to metformin therapy on serum lipid profile and uric acid in type 2 diabetes mellitus patients. Curr topics in Pharmacology. 2021;25.
14. Kieliszek M, Błażejak S. Current knowledge on the importance of selenium in food for living organisms: a review. Molecules. 2016 May 10;21(5):609.
15. Kuršvietienė L, Mongirdienė A, Bernatonienė J, Šulinskienė J, Stanevičienė I. Selenium anticancer properties and impact on cellular redox status. Antioxidants. 2020 Jan 17;9(1):80.
16. Yang R, Liu Y, Zhou Z. Selenium and selenoproteins, from structure, function to food resource and nutrition. Food Science and Technology Research. 2017;23(3):363-73.
17. Zhang Y, Roh YJ, Han SJ, Park I, Lee HM, Ok YS, Lee BC, Lee SR. Role of selenoproteins in redox regulation of signaling and the antioxidant system: A review. Antioxidants. 2020 May 5;9(5):383.
18. Abdulmaguid RF, Elsayed HH. Assessment of gingival and total anti-oxidant capacity in smokers and nonsmoker’s chronic periodontitis patients following non-surgical periodontal therapy. Egyptian Dental Journal. 2017 Apr 1;63(2-April (Oral Medicine, X-Ray, Oral Biology & Oral Pathology)):1591-9.
19. Savran M, Cicek E, Doguc DK, Asci H, Yesilot S, Candan IA, Dagdeviren B, Cankara FN, Oncu M, Uğuz AC, Ozer MK. Vitamin C attenuates methotrexate-induced oxidative stress in kidney and liver of rats. Physiology international. 2017 Jun;104(2):139-49.
20. Adwas AA, Elsayed A, Azab AE, Quwaydir FA. Oxidative stress and antioxidant mechanisms in human body. J. Appl. Biotechnol. Bioeng. 2019 Feb 21;6(1):43-7.
21. Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. World allergy organization journal. 2012 Dec;5(1):9-19.
22. Czerska M, Mikołajewska K, Zieliński M, Gromadzińska J, Wąsowicz W. Today’s oxidative stress markers. Medycyna pracy. 2015;66(3).
23. Conklin KA. Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integrative cancer therapies. 2004 Dec;3(4):294-300.
24. Elsaied HA. Histological and immunohistochemical study of selenium regenerative effect on submandibular and sublingual glands of aging rats. Egyptian Dental Journal. 2019 Oct 1;65(4-October (Oral Medicine, X-Ray, Oral Biology & Oral Pathology)):3413-26.
25. Zhang Z, Pan T, Liu C, Shan X, Xu Z, Hong H, Lin H, Chen J, Sun H. Cyclophosphamide induced physiological and biochemical changes in mice with an emphasis on sensitivity analysis. Ecotoxicology and Environmental Safety. 2021 Mar 15;211:111889.
26. Hasan HF, Abdel-Hamid GR, Ebrahim SI. Antioxidant and anti-inflammatory effects of diallyl disulfide on hepatotoxicity induced by cyclophosphamide in rats. Natural Product Communications. 2020 Oct;15(10):1934578X20969083.
27. Zanchi MM, Manfredini V, dos Santos Brum D, Vargas LM, Spiazzi CC, Soares MB, Izaguirry AP, Santos FW. Green tea infusion improves cyclophosphamide-induced damage on male mice reproductive system. Toxicology reports. 2015 Jan 1;2:252-60.
28. Al-Refai AS, Khaleel AK, Ali S. The effect of green tea extract on submandibular salivary gland of methotrexate treated albino rats: immunohistochemical study. Journal of Cytology & Histology. 2014 Feb 15;5(2):1.
29. Fernández-Lázaro D, Fernandez-Lazaro CI, Mielgo-Ayuso J, Navascués LJ, Córdova Martínez A, Seco-Calvo J. The role of selenium mineral trace element in exercise: Antioxidant defense system, muscle performance, hormone response, and athletic performance. A systematic review. Nutrients. 2020 Jun;12(6):1790.
30. Talas ZS, Ozdemir I, Ates B, Gok Y, Yilmaz I. Modulating effects of selenium in adrenal medulla of rats exposed to 7, 12-dimethylbenz [a] anthracene. Toxicology and Industrial Health. 2013 Apr;29(3):286-92.
31. Barchielli G, Capperucci A, Tanini D. The role of selenium in pathologies: an updated review. Antioxidants. 2022 Jan 27;11(2):251.
32. Zhang X, Wang Q, Zhang J, Song M, Shao B, Han Y, Yang X, Li Y. The protective effect of selenium on T-2-induced nephrotoxicity is related to the inhibition of ROS-mediated apoptosis in mice kidney. Biological Trace Element Research. 2022 Jan;200(1):206-16.
33. Ayhanci A, Heybeli N, Sahin İK, Cengiz M. Myelosuppression and oxidative stress induced by cyclophosphamide in rats: The protective role of selenium. Adıyaman University Journal of Science. 2019;9(2):252-65.
34. El-Sebaey AM, Abdelhamid FM, Abdalla OA. Protective effects of garlic extract against hematological alterations, immunosuppression, hepatic oxidative stress, and renal damage induced by cyclophosphamide in rats. Environmental Science and Pollution Research. 2019 May;26(15):15559-72.
35. Duggina P, Kalla CM, Varikasuvu SR, Bukke S, Tartte V. Protective effect of centella triterpene saponins against cyclophosphamide-induced immune and hepatic system dysfunction in rats: Its possible mechanisms of action. Journal of physiology and biochemistry. 2015 Sep;71(3):435-54.
36. Cengiz M, Kutlu HM, Peker Cengiz B, Ayhancı A. Escin attenuates oxidative damage, apoptosis and lipid peroxidation in a model of cyclophosphamide-induced liver damage. Drug and Chemical Toxicology. 2022 May 4;45(3):1180-7.
37. Bahmani F, Kia M, Soleimani A, Mohammadi AA, Asemi Z. The effects of selenium supplementation on biomarkers of inflammation and oxidative stress in patients with diabetic nephropathy: a randomised, double-blind, placebo-controlled trial. British journal of nutrition. 2016 Oct;116(7):1222-8.
38. Mesdaghinia E, Rahavi A, Bahmani F, Sharifi N, Asemi Z. Clinical and metabolic response to selenium supplementation in pregnant women at risk for intrauterine growth restriction: randomized, double-blind, placebo-controlled trial. Biological Trace Element Research. 2017 Jul;178(1):14-21.
39. Chakrabarti SK, Ghosh S, Banerjee S, Mukherjee S, Chowdhury S. Oxidative stress in hypothyroid patients and the role of antioxidant supplementation. Indian journal of endocrinology and metabolism. 2016 Sep;20(5):674.
40. Hasani M, Djalalinia S, Khazdooz M, Asayesh H, Zarei M, Gorabi AM, Ansari H, Qorbani M, Heshmat R. Effect of selenium supplementation on antioxidant markers: a systematic review and meta-analysis of randomized controlled trials. Hormones. 2019 Dec;18(4):451-62.
41. Ghosh P, Bhattacharjee A, Basu A, Singha Roy S, Bhattacharya S. Attenuation of cyclophosphamide-induced pulmonary toxicity in Swiss albino mice by naphthalimide-based organoselenium compound 2-(5-selenocyanatopentyl)-benzo [de] isoquinoline 1, 3-dione. Pharmaceutical biology. 2015 Apr 3;53(4):524-32.
42. Wang Y, Zhao H, Shao Y, Liu J, Li J, Luo L, Xing M. Copper (II) and/or arsenite-induced oxidative stress cascades apoptosis and autophagy in the skeletal muscles of chicken. Chemosphere. 2018 Sep 1;206:597-605.
43. Gunes S, Ayhanci A, Sahinturk V, Altay DU, Uyar R. Carvacrol attenuates cyclophosphamide-induced oxidative stress in rat kidney. Canadian journal of physiology and pharmacology. 2017;95(7):844-9.
44. Moawad AA, Elhindawy M. The possible protective effect of Graviola extract on salivary gland against cytotoxicity during cisplatin treatment (Histological, Biochemical and Immuno-histochemical Study). Egyptian Journal of Histology. 2022 Jul 1;45(2):588-96.
45. Amin LE, Fathy H. Role of Ghrelin on cisplatin induced morphological changes on submandibular salivary glands. Egyptian Dental Journal. 2017 Oct 1;63(4-October (Oral Medicine, X-Ray, Oral Biology & Oral Pathology)):3225-33.
46. Yahyazadeh A. Effect of curcumin on rat sublingual gland exposed to cyclophosphamide. Cukurova Medical Journal. 2021;46(3):897-903.
47. Elsaied HA. Histological and immunohistochemical study of selenium regenerative effect on submandibular and sublingual glands of aging rats. Egyptian Dental Journal. 2019 Oct 1;65(4-October (Oral Medicine, X-Ray, Oral Biology & Oral Pathology)):3413-26.
48. Alghamdi SA, Mugri MH, Elamin NM, Kamil MA, Osman H, Eid BG, Shaik RA, Shaker SS, Alrafiah A. A Possible Novel Protective Effect of Piceatannol against Isoproterenol (ISO)-Induced Histopathological, Histochemical, and Immunohistochemical Changes in Male Wistar Rats. Current Issues in Molecular Biology. 2022 May 27;44(6):2505-28.
49. Samah K, Aya A, Nafisa A, Reda H. Histological and Immunohistochemical Study of the Effect of Alendronate on the Submandibular Salivary Gland of Adult Male Albino Rat and the Possible Protective Effect of Propolis. The Medical Journal of Cairo University. 2018 Sep 1;86(September):3119-32.
50. Li B, Li W, Tian Y, Guo S, Qian L, Xu D, Cao N. Selenium-alleviated hepatocyte necrosis and DNA damage in cyclophosphamide-treated geese by mitigating oxidative stress. Biological trace element research. 2020 Feb;193(2):508-16.
51. Sengul E, Gelen V, Yildirim S, Tekin S, Dag Y. The effects of selenium in acrylamide-induced nephrotoxicity in rats: roles of oxidative stress, inflammation, apoptosis, and DNA damage. Biological Trace Element Research. 2021 Jan;199(1):173-84.
52. Ayhanci A, Günes S, Sahinturk V, Appak S, Uyar R, Cengiz M, Altuner Y, Yaman S. Seleno L-methionine acts on cyclophosphamide-induced kidney toxicity. Biological trace element research. 2010 Aug;136(2):171-9.
53. Bhattacharjee A, Basu A, Biswas J, Sen T, Bhattacharya S. Chemoprotective and chemosensitizing properties of selenium nanoparticle (Nano-Se) during adjuvant therapy with cyclophosphamide in tumor-bearing mice. Molecular and cellular biochemistry. 2017 Jan;424(1):13-33.
54. Elshater AE, Haridy MA, Salman MM, Fayyad AS, Hammad S. Fullerene C60 nanoparticles ameliorated cyclophosphamide-induced acute hepatotoxicity in rats. Biomedicine & Pharmacotherapy. 2018 Jan 1;97:53-9.