Anatomy and Cell Biology

Korean Association of Anatomists (대한해부학회)
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Effect of Sofosbuvir on rats' ovaries and the possible protective role of vitamin E: biochemical and immunohistochemical study

  • Neven A. Ebrahim (Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University) ;
  • Hussein Abdelaziz Abdalla (Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University) ;
  • Neimat Abd Elhakam Yassin (Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University) ;
  • Aya Elsayed Maghrabia (Veterinary in Medical Experimental Research Center, Faculty of Medicine, Mansoura University) ;
  • Amira Ibrahim Morsy (Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University)
  • Received : 2023.03.21
  • Accepted : 2023.06.22
  • Published : 2023.12.31
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Abstract

Hepatitis C virus (HCV) infection is a major health problem worldwide and its eradication is mandatory. Direct acting HCV polymerase inhibitors, such as Sofosbuvir (SOF), is an effective regimen. However, it has some side effects like mutagenesis, carcinogenesis, and the impairment of testicular function. It is important to evaluate the safety of SOF on the ovary, as there are no studies yet. Increasing the production of Reactive Oxygen Species (ROS), causes oxidative stress, which affects ovulation process, female reproduction, and fertility. Accumulation of SOF in the cells was demonstrated to promote ROS generation. Vitamin E (Vit E) is an antioxidant agent that has an essential role in the female reproductive system, its deficiency can cause infertility. We explored the effect of SOF treatment alone and co-treated with Vit E on ovarian ROS level and ovarian morphology experimentally using biochemical and immunohistochemical studies. Significant changes in oxidative stress markers; nitric oxide and malondialdehyde lipid peroxidation, antioxidant enzymes; catalase, super oxide dismutase, and reduced glutathione, proliferating markers; proliferation cell nuclear antigen and Ki-67 antigen and caspase 3 apoptotic marker were demonstrated. It was shown that where SOF induced oxidative stress, it also aggravated ovarian dysfunction. The essential role of Vit E as an antioxidant agent in protecting the ovarian tissue from the effect of oxidative stress markers and preserving its function was also displayed. This could be guidance to add Vit E supplements to SOF regimens to limit its injurious effect on ovarian function.

Keywords

Acknowledgement

The authors are thankful to the Medical Experimental Research Center (MERC) Staff, Mansoura University, for their advice and support. They also extend gratitude to Jana Hassanein for her help with language editing.

References

  1. Abdel-Ghaffar TY, Sira MM, El Naghi S. Hepatitis C genotype 4: the past, present, and future. World J Hepatol 2015;7:2792-810. 
  2. Welsch C, Jesudian A, Zeuzem S, Jacobson I. New direct-acting antiviral agents for the treatment of hepatitis C virus infection and perspectives. Gut 2012;61 Suppl 1:i36-46. Erratum in: Gut 2012;61:1145. 
  3. Younossi ZM, Stepanova M, Henry L, Gane E, Jacobson IM, Lawitz E, Nelson D, Gerber L, Nader F, Hunt S. Effects of sofosbuvir-based treatment, with and without interferon, on outcome and productivity of patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2014;12:1349-59.e13. 
  4. El-Kholy WB, Faried MA, Salama RM, El-Fiky MM, El-Garawani I. Evaluation of testicular cytotoxicity and genotoxicity of sofosbuvir and sofosbuvir - ribavirin in the adult male albino rats. Eur J Anat 2019;23:393-403. 
  5. Mahmood SAF, Amin K, Rahman HS, Othman HH. The pathophysiological effects of acrylamide in albino wister rats. Int J Med Res Health Sci 2016;5:42-8. 
  6. Midan MF, Eid SM, El-Latif MA. The effect of hepatitis C virus treatment on ovarian reserve. Int J Reprod Contracept Obstet Gynecol 2016;5:715-24. 
  7. Zhang H, Jiang X, Zhang Y, Xu B, Hua J, Ma T, Zheng W, Sun R, Shen W, Cooke HJ, Hao Q, Qiao J, Shi Q. microRNA 376a regulates follicle assembly by targeting Pcna in fetal and neonatal mouse ovaries. Reproduction 2014;148:43-54. 
  8. Unek G, Ozmen A, Kipmen-Korgun D, Korgun ET. Immunolocalization of PCNA, Ki67, p27 and p57 in normal and dexamethasone-induced intrauterine growth restriction placental development in rat. Acta Histochem 2012;114:31-40. 
  9. Haggag YN, Nossair MA, Elaadli H, Mackey Z. Selective inhibition of T2AA for human PCNA over PCNA homolog in Trypanosoma brucei. Alex J Vet Sci 2018;56:81-7. 
  10. Apte SS. Expression of the cell proliferation-associated nuclear antigen reactive with the Ki-67 monoclonal antibody by cells of the skeletal system in humans and other species. Bone Miner 1990;10:37-50. 
  11. Muskhelishvili L, Latendresse JR, Kodell RL, Henderson EB. Evaluation of cell proliferation in rat tissues with BrdU, PCNA, Ki-67(MIB-5) immunohistochemistry and in situ hybridization for histone mRNA. J Histochem Cytochem 2003;51:1681-8. 
  12. Sargazi Z, Reza Nikravesh M, Jalali M, Reza Sadeghnia H, Rahimi Anbarkeh F. The protective effect of vitamin E on rats' ovarian follicles following an administration of diazinon: an experimental study. Int J Reprod Biomed 2019;17:79-88. 
  13. Abali R, Yuksel MA, Aktas C, Celik C, Guzel S, Erfan G, Sahin O. Decreased ovarian reserve in female Sprague-Dawley rats induced by isotretinoin (retinoic acid) exposure. Reprod Biomed Online 2013;27:184-91. 
  14. Jedrych M, Wawryk-Gawda E, Jodlowska-Jedrych B, Chylinska-Wrzos P, Jasinski L. Immunohistochemical evaluation of cell proliferation and apoptosis markers in ovarian surface epithelial cells of cladribine-treated rats. Protoplasma 2013;250:1025-34. 
  15. Asadi M, Taghizadeh S, Kaviani E, Vakili O, Taheri-Anganeh M, Tahamtan M, Savardashtaki A. Caspase-3: structure, function, and biotechnological aspects. Biotechnol Appl Biochem 2022;69:1633-45. 
  16. Abdel-Aziz AM, Mohamed ASM, Abdelazem O, Okasha AMM, Kamel MY. Cilostazol protects against cyclophosphamide-induced ovarian toxicity in female rats: role of cAMP and HO-1. Toxicol Mech Methods 2020;30:526-35. 
  17. Cui L, Zhao Y, Pan Y, Zheng X, Shao D, Jia Y, He K, Li K, Chen L. Chemotherapy induces ovarian cancer cell repopulation through the caspase 3-mediated arachidonic acid metabolic pathway. Onco Targets Ther 2017;10:5817-26. Erratum in: Onco Targets Ther 2022;15:1503-4. 
  18. Hanukoglu I. Antioxidant protective mechanisms against reactive oxygen species (ROS) generated by mitochondrial P450 systems in steroidogenic cells. Drug Metab Rev 2006;38:171-96. 
  19. Devine PJ, Perreault SD, Luderer U. Roles of reactive oxygen species and antioxidants in ovarian toxicity. Biol Reprod 2012;86:27. 
  20. Roede JR, Jones DP. Reactive species and mitochondrial dysfunction: mechanistic significance of 4-hydroxynonenal. Environ Mol Mutagen 2010;51:380-90. 
  21. Kowaltowski AJ, Vercesi AE. Mitochondrial damage induced by conditions of oxidative stress. Free Radic Biol Med 1999;26:463-71. 
  22. Behrman HR, Kodaman PH, Preston SL, Gao S. Oxidative stress and the ovary. J Soc Gynecol Investig 2001;8(1 Suppl Proceedings):S40-2. 
  23. Tatemoto H, Sakurai N, Muto N. Protection of porcine oocytes against apoptotic cell death caused by oxidative stress during In vitro maturation: role of cumulus cells. Biol Reprod 2000;63:805-10. 
  24. Oborna I, Wojewodka G, De Sanctis JB, Fingerova H, Svobodova M, Brezinova J, Hajduch M, Novotny J, Radova L, Radzioch D. Increased lipid peroxidation and abnormal fatty acid profiles in seminal and blood plasma of normozoospermic males from infertile couples. Hum Reprod 2010;25:308-16. 
  25. Robbins RA, Grisham MB. Nitric oxide. Int J Biochem Cell Biol 1997;29:857-60. 
  26. Basini G, Baratta M, Ponderato N, Bussolati S, Tamanini C. Is nitric oxide an autocrine modulator of bovine granulosa cell function? Reprod Fertil Dev 1998;10:471-8. 
  27. Anteby EY, Hurwitz A, Korach O, Revel A, Simon A, Finci-Yeheskel Z, Mayer M, Laufer N. Human follicular nitric oxide pathway: relationship to follicular size, oestradiol concentrations and ovarian blood flow. Hum Reprod 1996;11:1947-51. 
  28. Tao M, Kodama H, Kagabu S, Fukuda J, Murata M, Shimizu Y, Hirano H, Tanaka T. Possible contribution of follicular interleukin-1beta to nitric oxide generation in human pre-ovulatory follicles. Hum Reprod 1997;12:2220-5. 
  29. Goud AP, Goud PT, Diamond MP, Gonik B, Abu-Soud HM. Reactive oxygen species and oocyte aging: role of superoxide, hydrogen peroxide, and hypochlorous acid. Free Radic Biol Med 2008;44:1295-304. 
  30. Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol 2012;10:49. 
  31. Uzun FG, Kalender S, Durak D, Demir F, Kalender Y. Malathion-induced testicular toxicity in male rats and the protective effect of vitamins C and E. Food Chem Toxicol 2009;47:1903-8. 
  32. Ruder EH, Hartman TJ, Goldman MB. Impact of oxidative stress on female fertility. Curr Opin Obstet Gynecol 2009;21:219-22. 
  33. Dosuky MA, Ouies SM, Fouda NAR. Effect of acrylamide on ovaries of female albino rats and possible protective role of vitamin E. Med J Cairo Univ 2020;88:2177-82. 
  34. Bhatia HK, Singh H, Grewal N, Natt NK. Sofosbuvir: a novel treatment option for chronic hepatitis C infection. J Pharmacol Pharmacother 2014;5:278-84. 
  35. Gharabawy G, Abdallah E, Kaabo H, Aleem A. Histological effects of sofosbuvir on the kidney of male albino rats and the possible protective role of vitamin C. Egypt J Hosp Med 2019;76:3335-54. 
  36. Abdeen AM, Essawy T, Mohammed SS. Effect of sofosbuvir administration and its withdrawal on the submandibular salivary gland of adult male albino rats: a histological and ultrastructural study. Open Access Maced J Med Sci 2019;7:4101-9. 
  37. Wang H, Wei W, Wang NP, Gui SY, Wu L, Sun WY, Xu SY. Melatonin ameliorates carbon tetrachloride-induced hepatic fibrogenesis in rats via inhibition of oxidative stress. Life Sci 2005;77:1902-15. 
  38. Bryan NS, Grisham MB. Methods to detect nitric oxide and its metabolites in biological samples. Free Radic Biol Med 2007;43:645-57. 
  39. Ebrahim NA, Leach L. Transendothelial migration of human umbilical mesenchymal stem cells across uterine endothelial monolayers: junctional dynamics and putative mechanisms. Placenta 2016;48:87-98. 
  40. Mahran HA, Okdah YA, Zaky AA, Arisha SM. The possible ameliorative role of Moringa oleifera seed oil on sofosbuvir-induced nephrotoxicity in albino rats; histopathological, immunohistochemical and biochemical studies. J Basic Appl Zool 2022;83:16. 
  41. Elseady WS, Keshk WA, Negm WA, Elkhalawany W, Elhanafy H, Ibrahim MAA, Radwan DA. Saffron extract attenuates sofosbuvir-induced retinal neurodegeneration in albino rat. Anat Rec (Hoboken) 2023;306:422-36. 
  42. Tilly JL, Tilly KI. Inhibitors of oxidative stress mimic the ability of follicle-stimulating hormone to suppress apoptosis in cultured rat ovarian follicles. Endocrinology 1995;136:242-52. 
  43. Khalaf HA, Elmorsy E, Mahmoud EM, Aggour AM, Amer SA. The role of oxidative stress in ovarian toxicity induced by haloperidol and clozapine-a histological and biochemical study in albino rats. Cell Tissue Res 2019;378:371-83. 
  44. Patil S, Patil S, Bhaktaraj B, Patil SB. Effect of graded doses of nicotine on ovarian and uterine activities in albino rats. Indian J Exp Biol 1999;37:184-6. 
  45. Prasad N, Patel MR, Pandey A, Jaiswal A, Bhadauria D, Kaul A, Sharma RK, Mohindra S, Pandey G, Goel A, Gupta A. Directacting antiviral agents in hepatitis C virus-infected renal allograft recipients: treatment and outcome experience from single center. Indian J Nephrol 2018;28:220-5. Erratum in: Indian J Nephrol 2018;28:333. 
  46. Moustafa AH, Pasha HF, Abas MA, Aboregela AM. The ameliorating role of sofosbuvir and daclatasvir on thioacetamide-induced kidney injury in adult albino rats. Anat Cell Biol 2023;56:109-21. 
  47. Helal EGE, Taha NM, Mohamed AM, Abu-Taleb HM. Ameliorative effect of vitamin E on oxidative stress induced by bisphenol A in female albino rats. Egypt J Hosp Med 2016;65:474-8. 
  48. Al-Serwi RH, Ghoneim FM. The impact of vitamin E against acrylamide induced toxicity on skeletal muscles of adult male albino rat tongue: light and electron microscopic study. J Microsc Ultrastruct 2015;3:137-47. Erratum in: J Microsc Ultrastruct 2015;3:220. 
  49. Tomanek M, Chronowska E. Immunohistochemical localization of proliferating cell nuclear antigen (PCNA) in the pig ovary. Folia Histochem Cytobiol 2006;44:269-74. 
  50. Bullwinkel J, Baron-Luhr B, Ludemann A, Wohlenberg C, Gerdes J, Scholzen T. Ki-67 protein is associated with ribosomal RNA transcription in quiescent and proliferating cells. J Cell Physiol 2006;206:624-35. 
  51. Carrasco-Torres G, Baltierrez-Hoyos R, Andrade-Jorge E, Villa-Trevino S, Trujillo-Ferrara JG, Vasquez-Garzon VR. Cytotoxicity, oxidative stress, cell cycle arrest, and mitochondrial apoptosis after combined treatment of hepatocarcinoma cells with maleic anhydride derivatives and quercetin. Oxid Med Cell Longev 2017;2017:2734976. 
  52. Eldutar E, Kandemir FM, Kucukler S, Caglayan C. Restorative effects of Chrysin pretreatment on oxidant-antioxidant status, inflammatory cytokine production, and apoptotic and autophagic markers in acute paracetamol-induced hepatotoxicity in rats: an experimental and biochemical study. J Biochem Mol Toxicol 2017;31:e21960. 
  53. Nicholson DW, Thornberry NA. Apoptosis. Life and death decisions. Science 2003;299:214-5. 
  54. Packer L, Weber SU, Rimbach G. Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. J Nutr 2001;131:369S-73S.