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Diacerein ameliorates induced polycystic ovary in female rats via modulation of inflammasome/caspase1/IL1β and Bax/Bcl2 pathways

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Abstract

Polycystic ovary syndrome (PCOS) is a very common gynecological disease during childbearing period and markedly affects female fertility. Until now, there are no studies evaluating the possible curative effect of diacerein (DIA) in induced PCOS. For the first time, we aimed in current model to study the effect of DIA (50 mg/kg/day) orally for 3 weeks on experimentally induced PCOS by letrozole (1 mg/kg/day) for 3 weeks. We measured rats’ body weight changes, levels of serum insulin, anti-Müllerian hormone (AMH), testosterone, inflammasome, caspase1, and total anti-oxidant capacity (TAC). Moreover, we measured ovarian tissue parameters as malondialdehyde (MDA), interleukin 1β (IL1β), real-time polymerase chain reaction (rt-PCR) of Bcl2-associated X protein (Bax), and interleukin 10 (IL10) gene expression changes. Furthermore, histopathological features and anti-apoptotic marker B cell lymphoma 2 (Bcl2) immunoexpression changes were evaluated. Our results showed that letrozole markedly induced PCOS as manifested by significant increase in serum testosterone, insulin, AMH, rats’ body weights, ovarian tissue MDA, IL1β, inflammasome, and caspase1 but decrease of serum TAC. In addition, gene expression of Bax increased but IL10 gene expression decreased. Ovaries showed the typical histopathological changes of PCOS with no immunoexpression of Bcl2. DIA was greatly able to ameliorate letrozole-induced PCOS changes in rats mainly via prevention of IL1β, and improving metabolic disturbances, and its anti-apoptotic, anti-oxidant, and anti-inflammatory effects with further regulation of inflammasome/caspase1/IL1β and Bax/Bcl2 pathways.

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References

  • Almezgagia M, Zhangb Y, Hezame K, Shamsan E, Gamaha M, Al-shaebic F, Abbas A, Shoaibb M, Saifd B, Hana Y, Jiaa R, Zhanga W (2020) Diacerein: recent insight into pharmacological activities and molecular pathways. Biomed Pharmacother 131:11059

    Google Scholar 

  • Alves ED, Bonfá ALO, Pigatto GR, Anselmo-Franci JA, Achcar JA, Parizotto NA, Montrezor LH (2019) Photobiomodulation can improve ovarian activity in polycystic ovary syndrome-induced rats. J Photochem Photobiol B 194:6–13

    Article  CAS  Google Scholar 

  • Barrett ES, Sobolewski M (2014) Polycystic ovary syndrome: do endocrine-disrupting chemicals play a role? Semin Reprod Med 32(3):166–176

    Article  Google Scholar 

  • Bas D, Abramovich D, Hernandez F, Tesone M (2011) Altered expression of Bcl-2 and Bax in follicles within dehydroepiandrosterone-induced polycystic ovaries in rats. Cell Biol Int 35(5):423–429

    Article  CAS  Google Scholar 

  • Cabus U, Kabukcu C, Fenkci S, Caner V, Oztekin O, Fenkci V, Enli Y (2020) Serum caspase-1 levels in women with polycystic ovary syndrome. Taiwan J Obstet Gynecol 59(2):207–210

    Article  Google Scholar 

  • Corbin C, Trant J, Walters K, Conley AJ (1999) Changes in testosterone metabolism associated with the evolution of placental and gonadal isozymes of porcine aromatase cytochrome P450. Endocrinology 140(11):5202–5210

    Article  CAS  Google Scholar 

  • Daneshian Z, Ramezani Tehrani F, Zarkesh M, Norooz Zadeh M, Mahdian R, ZadehVakili A (2015) Antimullerian hormone and its receptor gene expression in prenatally androgenized female rats. Int J Endocrinol Metab 13(1):e19511

    PubMed  PubMed Central  Google Scholar 

  • Ding T, Hardiman PJ, Petersen I, Wang F, Qu F, Baio G (2017) The prevalence of polycystic ovary syndrome in reproductive-aged women of different ethnicity: a systematic review and meta-analysis. Oncotarget Actions 8(56):96351–96358

    Article  Google Scholar 

  • Dunaif A (1997) Insulin resistance and the oily cystic ovary syndrome: mechanism and implications for pathogenesis. Endocrinol.Rev. 18:774–800

    CAS  Google Scholar 

  • Figueroa F, Motta A, Acosta M, Mohamed F, Oliveros L, Forneris M (2015) Role of macrophage secretions on rat polycystic ovary: its effect on apoptosis. Reproduction. 150(5):437–448

    Article  CAS  Google Scholar 

  • Fouad AA, Abdel-Aziz AM, Hamouda AAH (2020) Diacerein downregulates NLRP3/caspase-1/IL-1β and IL-6/STAT3 pathways of inflammation and apoptosis in a rat model of cadmium testicular toxicity. Biol Trace Elem Res 195(2):499–505

    Article  CAS  Google Scholar 

  • Ghowsi M, Khazali H, Sisakhtnezhad S (2018) The effect of resveratrol on oxidative stress in the liver and serum of a rat model of polycystic ovary syndrome: an experimental study. Int J Reprod Biomed 16(3):149–158

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gonzalez-Moles MA, Bascones-Ilundain C, Gil Montoya JA et al (2006) Cell cycle regulating mechanisms in oral lichen planus: molecular bases in epithelium predisposed to malignant transformation. Arch Oral Biol 51:1093–1103

    Article  CAS  Google Scholar 

  • Jahan S, Munir F, Razak S, Mehboob A, UlAin Q, Ullah H, Afsar T, Shaheen G, Almajwal A (2016) Ameliorative effects of rutin against metabolic, biochemical and hormonal disturbances in polycystic ovary syndrome in rats. J Ovarian Res 9:86

    Article  Google Scholar 

  • Johansson J, Stener-Victorin E (2013) Polycystic ovary syndrome: effect and mechanisms of acupuncture for ovulation induction. Evid Based Complement Alternat Med 2013:762615

    Article  Google Scholar 

  • Karadeniz M, Erdogan M, Zengi A, Tamsel S, Berdeli A, Saygili F, Yilmaz C (2008) Polymorphism of the interleukin-10 gene in polycystic ovary syndrome. Int J Immunogenet 35:119–123

    Article  CAS  Google Scholar 

  • Longo MC et al (1990) Use of uracil DNA glycosylase to control carry over contamination in under the foregoing patent claims for using only this amount of product in a passive reference method for polymerase chain reactions. Gene. 93:125–128

    Article  CAS  Google Scholar 

  • Lutz A, Sanwald J, Thomas M, Feuer R, Sawodny O, Ederer M, Borner C, Humar M, Merfort I (2014) Interleukin-1β enhances FasL-induced caspase-3/-7 activity without increasing apoptosis in primary mouse hepatocytes. PLoS One 9(12):e115603

    Article  Google Scholar 

  • Mihara M, Uchiyama M (1983) Properties of thiobarbituric acid-reactive materials obtained from lipid peroxide and tissue homogenate. Chem Pharm Bull 31(2):605–611

    Article  CAS  Google Scholar 

  • Noroozzadeh M, Behboudi-Gandevani S, Zadeh-Vakili A, Ramezani Tehrani F (2017) Hormone-induced rat model of polycystic ovary syndrome: a systematic review. Life Sci 191:259–272

    Article  CAS  Google Scholar 

  • Pandey V, Singh A, Singh A, Krishna A, Pandey U, Tripathi YB (2016) Role of oxidative stress and low-grade inflammation in letrozole-induced polycystic ovary syndrome in the rat. Reprod Biol 16(1):70–77

    Article  Google Scholar 

  • Ragy MM, Abdel-Hamid HA, Toni NDM (2019) Pathophysiological changes in experimental polycystic ovary syndrome in female albino rats: using either hemin or L-arginine. J Cell Physiol 234(6):8426–8435

    Article  CAS  Google Scholar 

  • Refaie MMM, El-Hussieny M (2017) The role of interleukin-1b and its antagonist (diacerein) in estradiol benzoate-induced endometrial hyperplasia and atypia in female rats. Fundam Clin Pharmacol 31(4):438–446

    Article  CAS  Google Scholar 

  • Rencber FS, Ozbek KS, Eraldemır C, Sezer Z, Kum T, Ceylan S, Guzel E (2018) Effect of resveratrol and metformin on ovarian reserve and ultrastructure in PCOS: an experimental study. J Ovarian Res 11(1):55

    Article  Google Scholar 

  • Rezvanfar MA, Shojaei Saadi HA, Gooshe M, Abdolghaffari AH, Baeeri M, Abdollahi M (2014) Ovarian aging-like phenotype in the hyperandrogenism-induced murine model of polycystic ovary. Oxid Med Cell Longev 2014:948951

    Article  Google Scholar 

  • Rostamtabar M, Esmaeilzadeh S, Tourani M, Rahmani A, Baee M, Shirafkan F, Saleki K, Mirzababayi SS, Ebrahimpour S, Nouri HR (2021) Pathophysiological roles of chronic low-grade inflammation mediators in polycystic ovary syndrome. J Cell Physiol 236(2):824–838

    Article  CAS  Google Scholar 

  • Salvetti NR, Panzani CG, Gimeno EJ, Neme LG, Alfaro NS, Ortega HH (2009) An imbalance between apoptosis and proliferation contributes to follicular persistence in polycystic ovaries in rats. Reprod Biol Endocrinol 7:68

    Article  Google Scholar 

  • Sathyapalan T, Atkin SL (2010) Mediators of inflammation in polycystic ovary syndrome in relation to adiposity. Mediat Inflamm 2010:758656 5 pages

    Article  Google Scholar 

  • Sun Y, Ma J, Li D, Li P, Zhou X, Yu L, He Z, Qin L, Liang L, Luo X (2019) Interleukin-10 inhibits interleukin-1β production and inflammasome activation of microglia in epileptic seizures. J Neuroinflammation 16:66

    Article  Google Scholar 

  • Van Guilder HD, Vrana KE, Freeman WM (2008) Twenty-five years of quantitative PCR for gene expression analysis. Biotechniques. 44(5):619–626

    Article  Google Scholar 

  • Wang C, Wang MW, Tashiro S, Onodera S, Ikejima T (2005) IL-1beta acts in synergy with endogenous IL-1beta in A375-S2 human melanoma cell apoptosis through mitochondrial pathway. J Korean Med Sci 20(4):555–561. https://doi.org/10.3346/jkms.2005.20.4.555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Y, Li P, Zhang D, Sun Y (2018) Metformin and pioglitazone combination therapy ameliorate polycystic ovary syndrome through AMPK/PI3K/JNK pathway. ExpTher Med 15(2):2120–2127

    CAS  Google Scholar 

  • Xu Y, Zhang H, Li Q, Lao K, Wang Y (2017) The role of nesfatin-1 expression in letrozole-induced polycystic ovaries in the rat. Gynecol Endocrinol 33(6):438–441

    Article  Google Scholar 

  • Xu G, Zhang A, Liu J, Wang X, Feng J, Chen Y (2020) Effects of electroacupuncture on ovarian expression of the androgen receptor and connexin 43 in rats with letrozole-induced polycystic ovaries. Evid Based Complement Alternat Med 2020:3608062

    PubMed  PubMed Central  Google Scholar 

  • Yang Y, Yang L, Qi C, Hu G, Wang L, Sun Z, Ni X (2020) Cryptotanshinone alleviates polycystic ovary syndrome in rats by regulating the HMGB1/TLR4/NF-kappaB signaling pathway. Mol Med Rep 22(5):3851–3861

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang N, Liu X, Zhuang L, Liu X, Zhao H, Shan Y, Liu Z, Li F, Wang Y, Fang J (2020) Berberine decreases insulin resistance in a PCOS rats by improving GLUT4: dual regulation of the PI3K/AKT and MAPK pathways. Regul Toxicol Pharmacol 110:104544

    Article  CAS  Google Scholar 

  • Zhao H, Zhou D, Chen Y, Liu D, Chu S, Zhang S (2017) Beneficial effects of Heqi san on rat model of polycystic ovary syndrome through the PI3K/AKT pathway. DARU J Pharm Sci 25(1):21

    Article  Google Scholar 

  • Zhao DM, Shan YH, Li FH, Jiang L, Qu QL (2019) Correlation between endometrial receptivity with expressions of IL-1 and VEGF in rats with polycystic ovary syndrome. Eur Rev Med Pharmacol Sci 23(13):5575–5580

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt

    Marwa M. M. Refaie

  2. Department of Pathology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt

    Maram El-Hussieny

  3. Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt

    Wedad M. Abdelraheem

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  1. Marwa M. M. Refaie
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  2. Maram El-Hussieny
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  3. Wedad M. Abdelraheem
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Contributions

MR selected the point, performed the experimental part, and wrote and sent the manuscript. MH performed and wrote the histopathology and immunohistochemical part and revised the manuscript as a whole. WA performed and wrote the rt-PCR part and revised the manuscript as a whole. All authors read and approved the manuscript and all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Marwa M. M. Refaie.

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This work was conducted in the Pharmacology Department, Faculty of Medicine, Minia University, Minia, Egypt, and the animal experimental protocol was approved by the faculty board.

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Refaie, M.M.M., El-Hussieny, M. & Abdelraheem, W.M. Diacerein ameliorates induced polycystic ovary in female rats via modulation of inflammasome/caspase1/IL1β and Bax/Bcl2 pathways. Naunyn-Schmiedeberg's Arch Pharmacol 395, 295–304 (2022). https://doi.org/10.1007/s00210-021-02175-2

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  • DOI: https://doi.org/10.1007/s00210-021-02175-2

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