Diacerein Downregulates NLRP3/Caspase-1/IL-1β and IL-6/STAT3 Pathways of Inflammation and Apoptosis in a Rat Model of Cadmium Testicular Toxicity


The potential gonadal protective effect of diacerein (DCN) and its underlying mechanisms were studied in a rat model of cadmium-induced testicular toxicity. The rats received DCN (50 mg/kg/day, p.o.) for 10 days and one injection of CdCl2 (2 mg/kg, i.p.) on day 9. Cadmium significantly declined serum testosterone and significantly raised interleukin-1β, interleukin-6, interleukin-18, tumor necrosis factor-α, caspase-1, phosphorylated signal transducer and activator of transcription-3 (pSTAT3), nuclear factor-κB p65, Bax, and caspase-3 in rat testes. DCN significantly ameliorated the changes in the biochemical measurements observed with CdCl2 insult. Additionally, DCN preserved the normal testicular architecture, maintained spermatogenesis, and lowered the expression of NOD-like receptor family protein 3 (NLRP3) inflammasome in testes of rats that received CdCl2. It was concluded that DCN significantly protected the gonads of male rats exposed to cadmium toxicity through modulation of NLRP3/caspase-1/IL-1β and IL-6/STAT3 pathways of inflammation and apoptosis.

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  1. 1.

    Satarug S (2019) Cadmium sources and toxicity. Toxics 7

  2. 2.

    Zhang H, Reynolds M (2019) Cadmium exposure in living organisms: a short review. Sci Total Environ 678:761–767

    CAS  Article  Google Scholar 

  3. 3.

    World Health Organization (2007) Health risks of heavy metals from long range trans-boundary air pollution. Copenhagen. Available at: http://www.euro.who.int/document/E91044.pdf

  4. 4.

    World Health Organization (2010) Exposure to cadmium: a major public health concern. Geneva, Switzerland. Available at: http://www.who.int/ipcs/features/cadmium

  5. 5.

    de Angelis C, Galdiero M, Pivonello C, Salzano C, Gianfrilli D, Piscitelli P, Lenzi A, Colao A, Pivonello R (2017) The environment and male reproduction: the effect of cadmium exposure on reproductive function and its implication in fertility. Reprod Toxicol 73:105–127

    Article  Google Scholar 

  6. 6.

    Chen H, Lu Y, Cao Z, Ma Q, Pi H, Fang Y, Yu Z, Hu H, Zhou Z (2016) Cadmium induces NLRP3 inflammasome-dependent pyroptosis in vascular endothelial cells. Toxicol Lett 246:7–16

    CAS  Article  Google Scholar 

  7. 7.

    Fouad AA, Jresat I (2015) Thymoquinone therapy abrogates toxic effect of cadmium on rat testes. Andrologia 47:417–426

    CAS  Article  Google Scholar 

  8. 8.

    Wang H, Zhang R, Song Y, Li T, Ge M (2019) Protective effect of Ganoderma triterpenoids on cadmium-induced testicular toxicity in chickens. Biol Trace Elem Res 187:281–290

    CAS  Article  Google Scholar 

  9. 9.

    Fan R, Hu PC, Wang Y, Lin HY, Su K, Feng XS, Wei L, Yang F (2018) Betulinic acid protects mice from cadmium chloride-induced toxicity by inhibiting cadmium-induced apoptosis in kidney and liver. Toxicol Lett 299:56–66

    CAS  Article  Google Scholar 

  10. 10.

    Bashir N, Shagirtha K, Manoharan V, Miltonprabu S (2019) The molecular and biochemical insight view of grape seed proanthocyanidins in ameliorating cadmium-induced testes-toxicity in rat model: implication of PI3K/Akt/Nrf-2 signaling. Biosci Rep 39:BSR20180515

    Article  Google Scholar 

  11. 11.

    Li R, Luo X, Li L, Peng Q, Yang Y, Zhao L, Ma M, Hou Z (2016) The protective effects of melatonin against oxidative stress and inflammation induced by acute cadmium exposure in mice testis. Biol Trace Elem Res 170:152–164

    CAS  Article  Google Scholar 

  12. 12.

    Mitra S, Bhattacharyya S, Ray S, Saha R, Ghosh P, Rauth S, Mandal S, Banerjee S, Murmu N (2016) Resveratrol alleviates cadmium-induced damage and overexpression of epidermal growth factor receptor and its downstream signaling proteins in the reproductive system of male Swiss albino mice. J Environ Pathol Toxicol Oncol 35:73–90

    Article  Google Scholar 

  13. 13.

    da Silva KLC, Camacho AP, Mittestainer FC, Carvalho BM, Santos A, Guadagnini D, Oliveira AG, Saad MJA (2018) Atorvastatin and diacerein reduce insulin resistance and increase disease tolerance in rats with sepsis. J Inflamm (Lond) 15:8

    Article  Google Scholar 

  14. 14.

    Tres GS, Fuchs SC, Piovesan F, Koehler-Santos P, Pereira FDS, Camey S, Lisboa HK, Moreira LB (2018) Effect of diacerein on metabolic control and inflammatory markers in patients with type 2 diabetes using antidiabetic agents: a randomized controlled trial. J Diabetes Res 2018:4246521

    Article  Google Scholar 

  15. 15.

    Abd-Ellatif RN, Hegab II, Atef MM, Sadek MT, Hafez YM (2019) Diacerein protects against glycerol-induced acute kidney injury: modulating oxidative stress, inflammation, apoptosis and necroptosis. Chem Biol Interact 306:47–53

    CAS  Article  Google Scholar 

  16. 16.

    Leite NC, Viegas BB, Villela-Nogueira CA, Carlos FO, Cardoso CRL, Salles GF (2019) Efficacy of diacerein in reducing liver steatosis and fibrosis in patients with type 2 diabetes and non-alcoholic fatty liver disease: a randomized, placebo-controlled trial. Diabetes Obes Metab 21:1266–1270

    CAS  Article  Google Scholar 

  17. 17.

    Abdel-Gaber SA, Mohammed RK, Refaie MMM (2018) Mechanism mediating the protective effect of diacerein in ischemia-reperfusion-induced testicular injury in rats. Life Sci 209:57–62

    CAS  Article  Google Scholar 

  18. 18.

    Martel-Pelletier J, Pelletier JP (2010) Effects of diacerein at the molecular level in the osteoarthritis disease process. Ther Adv Musculoskelet Dis 2:95–104

    CAS  Article  Google Scholar 

  19. 19.

    Gupta RS, Gupta ES, Dhakal BK, Thakur AR, Ahnn J (2004) Vitamin C and vitamin E protect the rat testes from cadmium-induced reactive oxygen species. Mol Cells 17:132–139

    PubMed  Google Scholar 

  20. 20.

    Refaie MM, Amin EF, El-Tahawy NF, Abdelrahman AM (2016) Possible protective effect of diacerein on doxorubicin-induced nephrotoxicity in rats. J Toxicol 2016:9507563

    Article  Google Scholar 

  21. 21.

    Johnsen SG (1970) Testicular biopsy score count – a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. Hormones 1:2–25

    CAS  PubMed  Google Scholar 

  22. 22.

    Rasmussen OF (2009) Controls. In: Kumar GL, Rudbeck L (Eds.) Immunohistochemical staining methods. Dako North America, Carpinteria, CA, p. 127

  23. 23.

    Leng B, Zhang Y, Liu X, Zhang Z, Liu Y, Wang H, Lu M (2019) Astragaloside IV suppresses high glucose-induced NLRP3 inflammasome activation by inhibiting TLR4/NF-κB and CaSR. Mediat Inflamm 2019:1082497

    Article  Google Scholar 

  24. 24.

    Chou X, Ding F, Zhang X, Ding X, Gao H, Wu Q (2019) Sirtuin-1 ameliorates cadmium-induced endoplasmic reticulum stress and pyroptosis through XBP-1s deacetylation in human renal tubular epithelial cells. Arch Toxicol 93:965–986

    Article  Google Scholar 

  25. 25.

    Huang G, Yuan M, Zhang J, Li J, Gong D, Li Y, Zhang J, Lin P, Huang L (2016) IL-6 mediates differentiation disorder during spermatogenesis in obesity-associated inflammation by affecting the expression of Zfp637 through the SOCS3/STAT3 pathway. Sci Rep 6:28012

    CAS  Article  Google Scholar 

  26. 26.

    Zhu L, Gu P, Shen H (2019) Protective effects of berberine hydrochloride on DSS-induced ulcerative colitis in rats. Int Immunopharmacol 68:242–251

    CAS  Article  Google Scholar 

  27. 27.

    Kundu S, Sengupta S, Chatterjee S, Mitra S, Bhattacharyya A (2009) Cadmium induces lung inflammation independent of lung cell proliferation: a molecular approach. J Inflamm (Lond) 6:19

    Article  Google Scholar 

  28. 28.

    Souza V, Escobar Mdel C, Bucio L, Hernandez E, Gomez-Quiroz LE, Gutierrez Ruiz MC (2009) NADPH oxidase and ERK1/2 are involved in cadmium induced-STAT3 activation in HepG2 cells. Toxicol Lett 187:180–186

    CAS  Article  Google Scholar 

  29. 29.

    Ansari MA, Raish M, Ahmad A, Alkharfy KM, Ahmad SF, Attia SM, Alsaad AMS, Bakheet SA (2017) Sinapic acid ameliorate cadmium-induced nephrotoxicity: in vivo possible involvement of oxidative stress, apoptosis, and inflammation via NF-κB downregulation. Environ Toxicol Pharmacol 51:100–107

    CAS  Article  Google Scholar 

  30. 30.

    Almeer RS, Soliman D, Kassab RB, AlBasher GI, Alarifi S, Alkahtani S, Ali D, Metwally D, Abdel Moneim AE (2018) Royal jelly abrogates cadmium-induced oxidative challenge in mouse testes: involvement of the Nrf2 pathway. Int J Mol Sci 19

  31. 31.

    Chang WC, Chu MT, Hsu CY, Wu YJ, Lee JY, Chen TJ, Chung WH, Chen DY, Hung SI (2019) Rhein, an anthraquinone drug, suppresses the NLRP3 inflammasome and macrophage activation in urate crystal-induced gouty inflammation. Am J Chin Med 47:135–151

    CAS  Article  Google Scholar 

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Corresponding author

Correspondence to Amr A. Fouad.

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The research was approved by the Research Ethics Committee, Faculty of Medicine, Minia University (approval number 143:12019). The international guidelines of use and care of laboratory animals were followed.

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Fouad, A.A., Abdel-Aziz, A.M. & Hamouda, A.A.H. 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, 499–505 (2020). https://doi.org/10.1007/s12011-019-01865-6

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  • Diacerein
  • CdCl2
  • NLRP3/caspase-1/IL-1β
  • IL-6/STAT3
  • Testes