Sıçanlarda letrozolün indüklediği polikistik over sendromunda fisetinin etkileri
Year 2021,
, 508 - 515, 30.06.2021
Beradiye Çelikçi
,
Rüstem Anıl Uğan
,
Erdem Toktay
Abstract
Amaç: Bu çalışmanın amacı sıçanlarda letrozolle oluşturulmuş PKOS (polikistik over sendromu) üzerinde fisetinin antioksidan etkilerini değerlendirmektir.
Gereç ve Yöntem: Çalışmada 36 adet Albino Wistar dişi sıçan kullanıldı. Dişi sıçanlara, PKOS modelini indüklemek için 21 gün boyunca %1 karboksimetil selüloz (2 mL/kg) içinde çözülmüş 1 mg/kg dozunda letrozol oral yolla uygulanmıştır. PKOS oluşturulduktan sonra 7 gün boyunca metformin ve fisetin kendi gruplarına uygulandı. Hayvanların overleri alındı ve biyokimyasal, histolojik incelemeler için uygun koşullarda saklandı.
Bulgular: PKOS grubunda sağlıklı gruba göre glutatyon (GSH) seviyelerinde düşüş, malondialdehit (MDA) seviyelerinde artış görüldü. PKOS+MET+FIS25 (PKOS+20 mg/kg metformin+25 mg/kg fisetin) ve PKOS+MET+FIS50 (PKOS+20 mg/kg metformin+50 mg/kg fisetin) gruplarında doza bağlı olarak GSH seviyelerinin yükseldiği, MDA seviyelerinin düştüğü tespit edildi. Histolojik bulgularda PKOS grubunda kontrol grubuna göre çok sayıda kistik folikül içerdiği görüldü. PKOS+MET+FIS25 ve PKOS+MET+FIS50 gruplarında doza bağlı olarak kistik foliküllerin ve foliküllerin içerdiği apoptotik ve nekrotik hücrelerin azaldığı görüldü.
Sonuç: Sonuç olarak, fisetin metforminin ortadan kaldıramadığı oksidatif hasarı engelleyerek faydalı etkiler göstermiştir. Fisetin antioksidan aktivite göstererek yeni hücrelerin nekroza gitmesini engellemiş ve korumuştur. Bundan dolayı metformin tedavisine fisetin eklenmesi faydalı olacaktır.
Thanks
Bu çalışma, Beradiye ÇELİKÇİ’nin mezuniyet araştırma projesi tezi olarak savunulmuştur. Bu çalışma, Eczacılık Fakültesindeki deney hayvanları laboratuvarında (ATADEM) gerçekleştirilmiştir. Atatürk Üniversitesi Eczacılık Fakültesi Dekanlığına desteklerinden ötürü şükranlarımızı sunarız.
References
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- 3. Polson DW, Adams J, Wadsworth J, Franks S. Polycystic ovaries--a common finding in normal women. Lancet. 1988;1(8590):870-2.
- 4. Crosignani PG, Nicolosi AE. Polycystic ovarian disease: heritability and heterogeneity. Hum Reprod Update. 2001;7(1):3-7.
- 5. Hong Y, Yin Y, Tan Y, Hong K, Zhou H. The Flavanone, Naringenin, Modifies Antioxidant and Steroidogenic Enzyme Activity in a Rat Model of Letrozole-Induced Polycystic Ovary Syndrome. Med Sci Monit. 2019;25:395-401.
- 6. 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.
- 7. Zhang D, Luo WY, Liao H, Wang CF, Sun Y. [The effects of oxidative stress to PCOS]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2008;39(3):421-3.
- 8. Szafarowska M, Jerzak M. [Ovarian aging and infertility]. Ginekol Pol. 2013;84(4):298-304.
- 9. Meden-Vrtovec H. Ovarian aging and infertility. Clin Exp Obstet Gynecol. 2004;31(1):5-8.
- 10. Tola EN, Koroglu N, Ergin M, Oral HB, Turgut A, Erel O. The Role of Follicular Fluid Thiol/Disulphide Homeostasis in Polycystic Ovary Syndrome. Balkan Med J. 2018;35(4):306-10.
- 11. Agarwal A, Durairajanayagam D, du Plessis SS. Utility of antioxidants during assisted reproductive techniques: an evidence based review. Reprod Biol Endocrinol. 2014;12:112.
- 12. Atef MM, Abd-Ellatif RN, Emam MN, Abo El Gheit RE, Amer AI, Hafez YM. Therapeutic potential of sodium selenite in letrozole induced polycystic ovary syndrome rat model: Targeting mitochondrial approach (selenium in PCOS). Arch Biochem Biophys. 2019;671:245-54.
- 13. Basheer M, Rai S, Ghosh H, Ahmad Hajam Y. Therapeutic Efficacy of Melatonin Against Polycystic Ovary Syndrome (PCOS) Induced by Letrozole in Wistar Rat. Pak J Biol Sci. 2018;21(7):340-7.
- 14. Rajan RK, M SS, Balaji B. Soy isoflavones exert beneficial effects on letrozole-induced rat polycystic ovary syndrome (PCOS) model through anti-androgenic mechanism. Pharm Biol. 2017;55(1):242-51.
- 15. Marshall JC, Dunaif A. Should all women with PCOS be treated for insulin resistance? Fertility and sterility. 2012;97(1):18-22.
- 16. Mathur R, Alexander CJ, Yano J, Trivax B, Azziz R. Use of metformin in polycystic ovary syndrome. American journal of obstetrics and gynecology. 2008;199(6):596-609.
- 17. Amini L, Tehranian N, Movahedin M, Ramezani Tehrani F, Ziaee S. Antioxidants and management of polycystic ovary syndrome in Iran: A systematic review of clinical trials. Iranian journal of reproductive medicine. 2015;13(1):1-8.
- 18. Lashen H. Role of metformin in the management of polycystic ovary syndrome. Therapeutic advances in endocrinology and metabolism. 2010;1(3):117-28.
- 19. Melo AS, Ferriani RA, Navarro PA. Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice. Clinics. 2015;70(11):765-9.
- 20. Khan N, Syed DN, Ahmad N, Mukhtar H. Fisetin: a dietary antioxidant for health promotion. Antioxidants & redox signaling. 2013;19(2):151-62.
- 21. Sengupta B, Banerjee A, Sengupta PK. Investigations on the binding and antioxidant properties of the plant flavonoid fisetin in model biomembranes. FEBS letters. 2004;570(1-3):77-81.
- 22. Kashyap D, Garg VK, Tuli HS, Yerer MB, Sak K, Sharma AK, et al. Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential. Biomolecules. 2019;9(5).
- 23. Rengarajan T, Yaacob NS. The flavonoid fisetin as an anticancer agent targeting the growth signaling pathways. European journal of pharmacology. 2016;789:8-16.
- 24. Lall RK, Adhami VM, Mukhtar H. Dietary flavonoid fisetin for cancer prevention and treatment. Molecular nutrition & food research. 2016;60(6):1396-405.
- 25. Rajan RK, Balaji B. Soy isoflavones exert beneficial effects on letrozole-induced rat polycystic ovary syndrome (PCOS) model through anti-androgenic mechanism. Pharmaceutical biology. 2017;55(1):242-51.
- 26. Aksak Karamese S, Toktay E, Unal D, Selli J, Karamese M, Malkoc I. The protective effects of beta-carotene against ischemia/reperfusion injury in rat ovarian tissue. Acta Histochem. 2015;117(8):790-7.
- 27. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968;25(1):192-205.
- 28. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351-8.
- 29. Ugan RA, Un H, Kose D, Cadirci E, Tastan TB, Yayla M, et al. Can aprepitant used for nausea and vomiting be good gastrointestinal complaints? N-S Arch Pharmacol. 2020;393(12):2463-72.
- 30. Ugan RA, Un H, Gurbuz MA, Kaya G, Kahramanlar A, Aksakalli-Magden ZB, et al. Possible contribution of the neprilysin/ACE pathway to sepsis in mice. Life Sci. 2020;258.
- 31. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-75.
- 32. De Leo V, Musacchio MC, Cappelli V, Massaro MG, Morgante G, Petraglia F. Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol Endocrinol. 2016;14(1):38.
- 33. Mortensen M, Rosenfield RL, Littlejohn E. Functional significance of polycystic-size ovaries in healthy adolescents. J Clin Endocrinol Metab. 2006;91(10):3786-90.
- 34. Blank SK, Helm KD, McCartney CR, Marshall JC. Polycystic ovary syndrome in adolescence. Ann N Y Acad Sci. 2008;1135:76-84.
- 35. Papalou O, Victor VM, Diamanti-Kandarakis E. Oxidative Stress in Polycystic Ovary Syndrome. Curr Pharm Des. 2016;22(18):2709-22.
- 36. Zuo T, Zhu M, Xu W. Roles of Oxidative Stress in Polycystic Ovary Syndrome and Cancers. Oxid Med Cell Longev. 2016;2016:8589318.
- 37. Liu J, Zhang D. [The role of oxidative stress in the pathogenesis of polycystic ovary syndrome]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2012;43(2):187-90.
- 38. Kose SA, Naziroglu M. N-acetyl cysteine reduces oxidative toxicity, apoptosis, and calcium entry through TRPV1 channels in the neutrophils of patients with polycystic ovary syndrome. Free Radic Res. 2015;49(3):338-46.
- 39. Kose SA, Naziroglu M. Selenium reduces oxidative stress and calcium entry through TRPV1 channels in the neutrophils of patients with polycystic ovary syndrome. Biol Trace Elem Res. 2014;158(2):136-42.
- 40. Hossain MM, Cao M, Wang Q, Kim JY, Schellander K, Tesfaye D, et al. Altered expression of miRNAs in a dihydrotestosterone-induced rat PCOS model. J Ovarian Res. 2013;6(1):36.
- 41. Wilkinson M, Brown RE, Imran SA, Wilkinson DA. Letter to the Editor: Hypothalamic Kisspeptin in Female Rat Models of PCOS. Endocrinology. 2017;158(6):2011.
- 42. Lang Q, Yidong X, Xueguang Z, Sixian W, Wenming X, Tao Z. ETA-mediated anti-TNF-alpha therapy ameliorates the phenotype of PCOS model induced by letrozole. PLoS One. 2019;14(6):e0217495.
- 43. Li C, Chen L, Zhao Y, Chen S, Fu L, Jiang Y, et al. Altered expression of miRNAs in the uterus from a letrozole-induced rat PCOS model. Gene. 2017;598:20-6.
- 44. Wang F, Yu B, Yang W, Liu J, Lu J, Xia X. Polycystic ovary syndrome resembling histopathological alterations in ovaries from prenatal androgenized female rats. J Ovarian Res. 2012;5(1):15.
- 45. Gozukara I, Dokuyucu R, Ozgur T, Ozcan O, Pinar N, Kurt RK, et al. Histopathologic and metabolic effect of ursodeoxycholic acid treatment on PCOS rat model. Gynecol Endocrinol. 2016;32(6):492-7.
- 46. Tsilchorozidou T, Prelevic GM. The role of metformin in the management of polycystic ovary syndrome. Curr Opin Obstet Gynecol. 2003;15(6):483-8.
- 47. A Hussein S, A Ragab O, A El Senosi Y, A Abdel-Muttalib S. Biochemical Effect of Fisetinon Experimentally Induced Liver Damage in Rats. Benha Veterinary Medical Journal. 2018;34(3):98-107.
- 48. Adinehbeigi K, Razi Jalali MH, Shahriari A, Bahrami S. In vitro antileishmanial activity of fisetin flavonoid via inhibition of glutathione biosynthesis and arginase activity in Leishmania infantum. Pathogens and global health. 2017;111(4):176-85.
Effects of fisetin to letrozole-induced polycystic ovary syndrome in rats
Year 2021,
, 508 - 515, 30.06.2021
Beradiye Çelikçi
,
Rüstem Anıl Uğan
,
Erdem Toktay
Abstract
Purpose: The aim of this study is to evaluate the antioxidant effects of fisetin on letrozole induced PCOS (polycystic ovarian syndrome) in rats.
Materials and Methods: A total of 36 Albino Wistar female rats were used in the study. Letrozole at a dose of 1 mg/kg dissolved in 1% carboxymethyl cellulose (2ml/kg) was administered orally to rats for 21 days to induce the PCOS model. After 21 days, metformin and fisetin were administered to their groups for 7 days. The ovaries of the animals were removed and stored under suitable conditions for biochemical and histological examinations.
Results: The glutathione (GSH) levels decreased and the malondialdehyde (MDA) levels increased in the PCOS group compared to the healthy group. It was determined that GSH levels increased and MDA levels decreased in PCOS+MET+FIS25 (PCOS+metformin 20 mg/kg+fisetin 25 mg/kg) and PCOS+MET+FIS50 (PCOS+metformin 20 mg/kg+fisetin 50 mg/kg) groups in a dose dependent manner. Histological findings showed that the PCOS group contained more cystic follicles than the control group. It was observed that cystic follicles and the apoptotic and necrotic cells contained in follicles decreased in the PCOS+MET+FIS25 and PCOS+MET+FIS50 groups in a dose dependent manner.
Conclusion: As a result, fisetin showed beneficial effects in the treatment of PCOS by preventing the oxidative damage that metformin cannot eliminate. Fisetin prevented and protected new cells from going to necrosis by showing antioxidant activity. Therefore, it would be beneficial to add fisetin to the metformin treatment..
References
- 1. Hashemi S, Ramezani Tehrani F, Farahmand M, Bahri Khomami M. Polikistik over sendromu olan İranlı kadınlarda klinik bulguların cinsel fonksiyonla ilişkisi. J Sex Med. 2014.
- 2. Bagis HT, Hacıvelioğlu S, Haydardedeoğlu B, Şimşek E, Çok T, Parlakgümüş A, et al. Prevalance Of Insulın Resıstance, Impaired Glucose Tolerans Test And Diabetes Mellitus In Women With Polcystic Ovary Syndrome; Analysis Of 235 Patients.
- 3. Polson DW, Adams J, Wadsworth J, Franks S. Polycystic ovaries--a common finding in normal women. Lancet. 1988;1(8590):870-2.
- 4. Crosignani PG, Nicolosi AE. Polycystic ovarian disease: heritability and heterogeneity. Hum Reprod Update. 2001;7(1):3-7.
- 5. Hong Y, Yin Y, Tan Y, Hong K, Zhou H. The Flavanone, Naringenin, Modifies Antioxidant and Steroidogenic Enzyme Activity in a Rat Model of Letrozole-Induced Polycystic Ovary Syndrome. Med Sci Monit. 2019;25:395-401.
- 6. 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.
- 7. Zhang D, Luo WY, Liao H, Wang CF, Sun Y. [The effects of oxidative stress to PCOS]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2008;39(3):421-3.
- 8. Szafarowska M, Jerzak M. [Ovarian aging and infertility]. Ginekol Pol. 2013;84(4):298-304.
- 9. Meden-Vrtovec H. Ovarian aging and infertility. Clin Exp Obstet Gynecol. 2004;31(1):5-8.
- 10. Tola EN, Koroglu N, Ergin M, Oral HB, Turgut A, Erel O. The Role of Follicular Fluid Thiol/Disulphide Homeostasis in Polycystic Ovary Syndrome. Balkan Med J. 2018;35(4):306-10.
- 11. Agarwal A, Durairajanayagam D, du Plessis SS. Utility of antioxidants during assisted reproductive techniques: an evidence based review. Reprod Biol Endocrinol. 2014;12:112.
- 12. Atef MM, Abd-Ellatif RN, Emam MN, Abo El Gheit RE, Amer AI, Hafez YM. Therapeutic potential of sodium selenite in letrozole induced polycystic ovary syndrome rat model: Targeting mitochondrial approach (selenium in PCOS). Arch Biochem Biophys. 2019;671:245-54.
- 13. Basheer M, Rai S, Ghosh H, Ahmad Hajam Y. Therapeutic Efficacy of Melatonin Against Polycystic Ovary Syndrome (PCOS) Induced by Letrozole in Wistar Rat. Pak J Biol Sci. 2018;21(7):340-7.
- 14. Rajan RK, M SS, Balaji B. Soy isoflavones exert beneficial effects on letrozole-induced rat polycystic ovary syndrome (PCOS) model through anti-androgenic mechanism. Pharm Biol. 2017;55(1):242-51.
- 15. Marshall JC, Dunaif A. Should all women with PCOS be treated for insulin resistance? Fertility and sterility. 2012;97(1):18-22.
- 16. Mathur R, Alexander CJ, Yano J, Trivax B, Azziz R. Use of metformin in polycystic ovary syndrome. American journal of obstetrics and gynecology. 2008;199(6):596-609.
- 17. Amini L, Tehranian N, Movahedin M, Ramezani Tehrani F, Ziaee S. Antioxidants and management of polycystic ovary syndrome in Iran: A systematic review of clinical trials. Iranian journal of reproductive medicine. 2015;13(1):1-8.
- 18. Lashen H. Role of metformin in the management of polycystic ovary syndrome. Therapeutic advances in endocrinology and metabolism. 2010;1(3):117-28.
- 19. Melo AS, Ferriani RA, Navarro PA. Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice. Clinics. 2015;70(11):765-9.
- 20. Khan N, Syed DN, Ahmad N, Mukhtar H. Fisetin: a dietary antioxidant for health promotion. Antioxidants & redox signaling. 2013;19(2):151-62.
- 21. Sengupta B, Banerjee A, Sengupta PK. Investigations on the binding and antioxidant properties of the plant flavonoid fisetin in model biomembranes. FEBS letters. 2004;570(1-3):77-81.
- 22. Kashyap D, Garg VK, Tuli HS, Yerer MB, Sak K, Sharma AK, et al. Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential. Biomolecules. 2019;9(5).
- 23. Rengarajan T, Yaacob NS. The flavonoid fisetin as an anticancer agent targeting the growth signaling pathways. European journal of pharmacology. 2016;789:8-16.
- 24. Lall RK, Adhami VM, Mukhtar H. Dietary flavonoid fisetin for cancer prevention and treatment. Molecular nutrition & food research. 2016;60(6):1396-405.
- 25. Rajan RK, Balaji B. Soy isoflavones exert beneficial effects on letrozole-induced rat polycystic ovary syndrome (PCOS) model through anti-androgenic mechanism. Pharmaceutical biology. 2017;55(1):242-51.
- 26. Aksak Karamese S, Toktay E, Unal D, Selli J, Karamese M, Malkoc I. The protective effects of beta-carotene against ischemia/reperfusion injury in rat ovarian tissue. Acta Histochem. 2015;117(8):790-7.
- 27. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968;25(1):192-205.
- 28. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351-8.
- 29. Ugan RA, Un H, Kose D, Cadirci E, Tastan TB, Yayla M, et al. Can aprepitant used for nausea and vomiting be good gastrointestinal complaints? N-S Arch Pharmacol. 2020;393(12):2463-72.
- 30. Ugan RA, Un H, Gurbuz MA, Kaya G, Kahramanlar A, Aksakalli-Magden ZB, et al. Possible contribution of the neprilysin/ACE pathway to sepsis in mice. Life Sci. 2020;258.
- 31. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-75.
- 32. De Leo V, Musacchio MC, Cappelli V, Massaro MG, Morgante G, Petraglia F. Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol Endocrinol. 2016;14(1):38.
- 33. Mortensen M, Rosenfield RL, Littlejohn E. Functional significance of polycystic-size ovaries in healthy adolescents. J Clin Endocrinol Metab. 2006;91(10):3786-90.
- 34. Blank SK, Helm KD, McCartney CR, Marshall JC. Polycystic ovary syndrome in adolescence. Ann N Y Acad Sci. 2008;1135:76-84.
- 35. Papalou O, Victor VM, Diamanti-Kandarakis E. Oxidative Stress in Polycystic Ovary Syndrome. Curr Pharm Des. 2016;22(18):2709-22.
- 36. Zuo T, Zhu M, Xu W. Roles of Oxidative Stress in Polycystic Ovary Syndrome and Cancers. Oxid Med Cell Longev. 2016;2016:8589318.
- 37. Liu J, Zhang D. [The role of oxidative stress in the pathogenesis of polycystic ovary syndrome]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2012;43(2):187-90.
- 38. Kose SA, Naziroglu M. N-acetyl cysteine reduces oxidative toxicity, apoptosis, and calcium entry through TRPV1 channels in the neutrophils of patients with polycystic ovary syndrome. Free Radic Res. 2015;49(3):338-46.
- 39. Kose SA, Naziroglu M. Selenium reduces oxidative stress and calcium entry through TRPV1 channels in the neutrophils of patients with polycystic ovary syndrome. Biol Trace Elem Res. 2014;158(2):136-42.
- 40. Hossain MM, Cao M, Wang Q, Kim JY, Schellander K, Tesfaye D, et al. Altered expression of miRNAs in a dihydrotestosterone-induced rat PCOS model. J Ovarian Res. 2013;6(1):36.
- 41. Wilkinson M, Brown RE, Imran SA, Wilkinson DA. Letter to the Editor: Hypothalamic Kisspeptin in Female Rat Models of PCOS. Endocrinology. 2017;158(6):2011.
- 42. Lang Q, Yidong X, Xueguang Z, Sixian W, Wenming X, Tao Z. ETA-mediated anti-TNF-alpha therapy ameliorates the phenotype of PCOS model induced by letrozole. PLoS One. 2019;14(6):e0217495.
- 43. Li C, Chen L, Zhao Y, Chen S, Fu L, Jiang Y, et al. Altered expression of miRNAs in the uterus from a letrozole-induced rat PCOS model. Gene. 2017;598:20-6.
- 44. Wang F, Yu B, Yang W, Liu J, Lu J, Xia X. Polycystic ovary syndrome resembling histopathological alterations in ovaries from prenatal androgenized female rats. J Ovarian Res. 2012;5(1):15.
- 45. Gozukara I, Dokuyucu R, Ozgur T, Ozcan O, Pinar N, Kurt RK, et al. Histopathologic and metabolic effect of ursodeoxycholic acid treatment on PCOS rat model. Gynecol Endocrinol. 2016;32(6):492-7.
- 46. Tsilchorozidou T, Prelevic GM. The role of metformin in the management of polycystic ovary syndrome. Curr Opin Obstet Gynecol. 2003;15(6):483-8.
- 47. A Hussein S, A Ragab O, A El Senosi Y, A Abdel-Muttalib S. Biochemical Effect of Fisetinon Experimentally Induced Liver Damage in Rats. Benha Veterinary Medical Journal. 2018;34(3):98-107.
- 48. Adinehbeigi K, Razi Jalali MH, Shahriari A, Bahrami S. In vitro antileishmanial activity of fisetin flavonoid via inhibition of glutathione biosynthesis and arginase activity in Leishmania infantum. Pathogens and global health. 2017;111(4):176-85.