Assessment of Resveratrol's effects comparatively with zinc in experimental rat testicular damage induced by Cyclophosphamide

Cansın Şirin; Canberk Tomruk; Elif Karadadaş; Burcu Denizlioğlu; Gülinnaz Ercan; Aslı Suner; Özlem Yılmaz

doi:10.19161/etd.1239707

Research Article

Assessment of Resveratrol's effects comparatively with zinc in experimental rat testicular damage induced by Cyclophosphamide

Year 2023, Volume: 62 Issue: 1, 18 - 29, 15.03.2023

Cansın Şirin Canberk Tomruk Elif Karadadaş Burcu Denizlioğlu Gülinnaz Ercan Aslı Suner Özlem Yılmaz

Abstract

Aim: To investigate protective effects of Resveratrol in combination or comparison with zinc in
experimental testicular injury induced by Cyclophosphamide is studied for the first time in literature.
Materials and Methods: Rats (n=63) were randomly divided into 9 groups. After 21 days of drug
administration biochemical and histological analysis were performed. Daily water consumption, body
weights and weight of testes were measured. Johnsen’s testicular scoring and sperm morphology were
evaluated. Hematoxylin&Eosin, Periodic Acid-Schiff and Masson's Trichrome stainings and iNOS,
eNOS and CD34 antibodies were applied histologically. To determine oxidative stress, MDA and CAT
values were determined. Statistically, one-way ANOVA with post hoc Tukey HSD test for multiple
comparisons was performed via IBM SPSS Version 25.0.
Results: Cyclophosphamide caused an increase in testicular MDA levels due to elevated oxidant stress.
Testicular MDA levels significantly decreased in zinc and Resveratrol groups which revealed protective
effects related to Cyclophosphamide treatment, while no significant improvement was observed for
control and saline groups. However, the most significant decrease was observed in MDA for
Cyclophosphamide+zinc+Resveratrol group in comparison to Cyclophosphamide. Telocytes, which are
lately defined novel cells, were detected in the interstitium encircling seminiferous tubules as a sheath
immunohistochemically.
Conclusion: Not only Resveratrol and zinc, but also their optimum administration separately protects
testes in Cyclophosphamide treatment groups. Clinical adaptations of this in vivo model may lead to
novel futuristic ideas in preventing infertility due to cancer chemotherapy.

Keywords

Cyclophosphamide, Resveratrol, zinc, testis

References

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Siklofosfamid’in neden olduğu deneysel sıçan testis hasarında Resveratrol’ün etkilerinin çinko ile karşılaştırmalı olarak değerlendirilmesi

Year 2023, Volume: 62 Issue: 1, 18 - 29, 15.03.2023

Cansın Şirin Canberk Tomruk Elif Karadadaş Burcu Denizlioğlu Gülinnaz Ercan Aslı Suner Özlem Yılmaz

Abstract

Amaç: Siklofosfamid'in neden olduğu deneysel testis hasarında Resveratrol’ün olası koruyucu etkilerini
çinko ile kombine ya da kıyaslamalı olarak araştırılması amaçlanmıştır.
Gereç ve Yöntem: Sıçanlar (n=63) rastgele 9 gruba ayrıldı. 21 günlük ilaç uygulaması sonunda; tüm
gruplar biyokimyasal ve histolojik olarak incelendi. Günlük su tüketimleri ile deneklerin vücut ağırlıkları
ve testis ağırlıkları ölçüldü. Johnsen'in testis skorlaması ve sperm morfolojileri değerlendirildi. Histolojik
olarak Hematoksilen&Eozin, Periyodik Asit-Schiff ve Masson'un Trikrom boyaları ve iNOS, eNOS ve
CD34 antikorları uygulandı. Doku oksidatif stres düzeyleri için MDA ve CAT değerleri biyokimyasal
olarak saptandı. İstatistiksel değerlendirmelerde çoklu karşılaştırmalar için post hoc Tukey HSD testi ile
tek yönlü ANOVA, IBM SPSS Sürüm 25.0 kullanıldı.
Bulgular: Siklofosfamid, yüksek oksidan stres nedeniyle testis MDA düzeylerini arttırdı. Siklofosfamid
tedavisine bağlı koruyucu etkiler ortaya çıkaran çinko ve Resveratrol gruplarında testis MDA
seviyelerinde anlamlı düşüşe karşılık, kontrol ve salin gruplarında anlamlı bir iyileşme gözlenmedi.
Ancak MDA'da en belirgin azalma Siklofosfamid’e göre Siklofosfamid+çinko+Resveratrol grubunda
saptandı. Son zamanlarda yeni tanımlanan hücreler olan telositlerin interstisyumda kılıf şeklinde
seminifer tübülleri çevreledikleri immünohistokimyasal olarak gösterildi.
Sonuç: Siklofosfamid tedavisi altında testis dokularını korumada sadece Resveratrol ve çinkonun
kombine kullanımı değil, optimum dozlarda ayrı ayrı uygulamaları da değerlidir. Bu in vivo modelin klinik
uyarlamaları, kanser tedavisine bağlı potansiyel infertilitenin önlenmesinde yeni fikirlerin gelişmesine
gelecekte öncülük edebilir.

Keywords

Siklofosfamid, Resveratrol, çinko, testis, Cyclophosphamide, zinc

References

Abraham DJ, Rotella DP, Burger A. Burger’s medicinal chemistry, drug discovery and development. Volume:5 C. Abraham DJ, editor. Wiley-interscience; 2010.
Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S. Naringin protects against cyclophosphamideinduced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environmental Science and Pollution Research. 2018;25(21):20968–84.
Nafees S, Rashid S, Ali N, Hasan SK, Sultana S. Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: Role of NFκB/MAPK pathway. Chem Biol Interact. 2015;231:98–107.
Oyagbemi AA, Omobowale TO, Saba AB, Adedara IA, Olowu ER, Akinrinde AS, et al. Gallic acid protects against cyclophosphamide-induced toxicity in testis and epididymis of rats. Andrologia. 2016 May 1;48(4):393–401.
Garolla A, Pizzato C, Ferlin A, Carli MO, Selice R, Foresta C. Progress in the development of childhood cancer therapy. Reproductive Toxicology. 2006;22(2):126–32.
Kenney LB, Laufer MR, Grant FD, Grier H, Diller L. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer. 2001;91(3):613–21.
Benzer F, Kandemir FM, Ozkaraca M, Kucukler S, Caglayan C. Curcumin ameliorates doxorubicin-induced cardiotoxicity by abrogation of inflammation, apoptosis, oxidative DNA damage, and protein oxidation in rats. J Biochem Mol Toxicol. 2018;32(2).
Kandemir FM, Kucukler S, Caglayan C, Gur C, Batil AA, Gülçin İ. Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: Biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties. J Food Biochem. 2017;41(5).
Kaygusuzoglu E, Caglayan C, Kandemir FM, Yıldırım S, Kucukler S, Kılınc MA, et al. Zingerone ameliorates cisplatin‐induced ovarian and uterine toxicity via suppression of sex hormone imbalances, oxidative stress, inflammation and apoptosis in female wistar rats. Biomedicine & Pharmacotherapy. 2018; 102:517–30.
Kuzu M, Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Turk E. Morin attenuates doxorubicin-induced heart and brain damage by reducing oxidative stress, inflammation and apoptosis. Biomedicine and Pharmacotherapy. 2018;106(June):443–53.
Burns J, Yokota T, Ashihara H, Lean MEJ, Crozier A. Plant foods and herbal sources of resveratrol. J Agric Food Chem. 2002;50(11):3337–40.
Levenson AS, Svoboda KM, Pease KM, Kaiser SA, Chen B, Simons LA, et al. Cancer Research. Cancer Res. 2002 Aug 1;58(20):4519–24.
Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, et al. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J Neuroinflammation. 2017;14(1):1–10.
Narayanan BA, Narayanan NK, Re GG, Nixon DW. Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204–12.
Shi T, Liou LS, Sadhukhan P, Duan ZH, Novick AC, Hissong JG, et al. Effects of resveratrol on gene expression in renal cell carcinoma. Cancer Biol Ther. 2004 Sep;3(9):882–8.
Yang S, Kim J, Oh T, Kim M, Lee S, Woo S, et al. Genome-scale analysis of resveratrol-induced gene expression profile in human ovarian cancer cells using a cDNA microarray. Int J Oncol. 2003 Apr 1;22(4):741–50.
Halliwell B. Dietary polyphenols: Good, bad, or indifferent for your health? Cardiovasc Res. 2007;73(2):341–7.
Eleawa SM, Alkhateeb MA, Alhashem FH, Bın-Jalıah I, Sakr HF, Elrefaey HM, et al. Resveratrol Reverses Cadmium Chloride-induced Testicular Damage and Subfertility by Downregulating p53 and Bax and Upregulating Gonadotropins and Bcl-2 gene Expression. Journal of Reproduction and Development. 2014;60(2):115–27.
Juan ME, González-Pons E, Munuera T, Ballester J, Rodríguez-Gil JE, Planas JM. trans-Resveratrol, a natural antioxidant from grapes, increases sperm output in healthy rats. J Nutr. 2005;135(4):757–60.
Shin S, Jeon JH, Park D, Jang MJ, Choi JH, Choi BH, et al. Trans-Resveratrol Relaxes the Corpus Cavernosum Ex Vivo and Enhances Testosterone Levels and Sperm Quality in Vivo. Arch Pharm Res. 2008;31(1):83–7.
Uguralp S, Usta U, Mizrak B. Resveratrol may reduce apoptosis of rat testicular germ cells after experimental testicular torsion. European Journal of Pediatric Surgery. 2005;15(5):333–6.
Yong-guang Jiang, Tao Peng, Yong Luo, Ming-chuan Li, Yun-hua Lin. Resveratrol reestablishes spermatogenesis after testicular injury in rats caused by 2, 5-hexanedione. Chin Med J (Engl). 2008 Jul 1;121(13):1204–9.
Li H, Xia N, Förstermann U. Cardiovascular effects and molecular targets of resveratrol. Vol. 26, Nitric Oxide - Biology and Chemistry. 2012. p. 102–10.
MacDiarmid CW, Taggart J, Jeong J, Kerdsomboon K, Eide DJ. Activation of the Yeast UBI4 Polyubiquitin Gene by Zap1 Transcription Factor via an Intragenic Promoter Is Critical for Zinc-deficient Growth. J Biol Chem. 2016;291(36):18880–96.
Rice JM, Zweifach A, Lynes MA. Metallothionein regulates intracellular zinc signaling during CD4+ T cell activation. BMC Immunol. 2016 Dec 2;17(1):13.
Kambe T, Tsuji T, Hashimoto A, Itsumura N. The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism. Physiol Rev. 2015 Jul;95(3):749–84.
Cheah Y, Yang W. Functions of essential nutrition for high quality spermatogenesis. Advances in Bioscience and Biotechnology. 2011;02(04):182–97.
Saïd L, Banni M, Kerkeni A, Saïd K, Messaoudi I. Influence of combined treatment with zinc and selenium on cadmium induced testicular pathophysiology in rat. Food and Chemical Toxicology. 2010 Oct;48(10):2759–65.
Pellegrini MSF, Popescu LM. Telocytes. Biomol Concepts. 2011 Jan 1;2(6):481–9.
Hinescu ME, Popescu LM, Gherghiceanu M, Faussone-Pellegrini MS. Interstitial Cajal-like cells in rat mesentery: an ultrastructural and immunohistochemical approach. J Cell Mol Med. 2008;12(1):260–70.
Creţoiu SM, Creţoiu D, Popescu LM. Human myometrium - the ultrastructural 3D network of telocytes. J Cell Mol Med. 2012 Nov;16(11):2844–9.
Lowry OH, Rosebrough NJ, Farr LA, Randall RJ. Protein measurement with the Folin phenol reagent - Journal of Biological Chemistry. 1951;193(1):265–75.
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979 Jun 1;95(2):351–8.
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Primary Language	English
Subjects	Health Care Administration
Journal Section	Research Articles
Authors	Cansın Şirin Canberk Tomruk Elif Karadadaş Burcu Denizlioğlu Gülinnaz Ercan Aslı Suner Özlem Yılmaz
Publication Date	March 15, 2023
Submission Date	November 9, 2022
Published in Issue	Year 2023Volume: 62 Issue: 1

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Vancouver	Şirin C, Tomruk C, Karadadaş E, Denizlioğlu B, Ercan G, Suner A, Yılmaz Ö. Assessment of Resveratrol’s effects comparatively with zinc in experimental rat testicular damage induced by Cyclophosphamide. EJM. 2023;62(1):18-29.

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