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The effect of N-Acetyl cysteine on the expression of Fxr (Nr1h4), LXRα (Nr1h3) and Sirt1 genes, oxidative stress, and apoptosis in the liver of rats exposed to different doses of cadmium

Molecular Biology Reports volume 48, pages 2533–2542 (2021)Cite this article

Abstract

The aim of this study was to consider the expression of farnesoid X receptor (Fxr), liver X receptor (LXRα) and sirtuin 1 (Sirt1), oxidative stress, inflammation, apoptosis, and the protective role of N-acetylcysteine (NAC) in the liver of rats treated with cadmium (Cd). 30 Wistar rats were divided into 5 groups: G1 (control), G2 (single dose of Cd), G3 (continuous dose of Cd), G4 (single dose of Cd + continuous dose of NAC), and G5 (continuous dose of Cd + continuous dose of NAC). The apoptosis of hepatic cells was measured using the TUNEL assay. Levels of malondialdehyde (MDA), IL-10, TNF-α, and total antioxidant capacity (TAC) were measured by specific kits. The expression of Fxr, LXRα, and Sirt1 genes and ratio of Bax/Bcl2 was considered using RT-PCR. While NAC treatment improved TAC and IL-10 values, it decreased MDA and TNF-α levels in the liver of rats exposed to Cd (P < 0.001). NAC decreased Bax/Bcl2 in the liver of G4 and G5 groups (P < 0.001). Exposure to a continuous dose of Cd decreased Fxr, LXRα, and Sirt1 expression by 36.65- (P < 0.001), 12.52- (P < 0.001) and 11.34-fold (P < 0.001) compared to control, respectively. NAC increased Fxr, LXRα, and Sirt1 expression (P < 0.01) and decreased Cd concentrations in both serum and tissue samples in G4 and G5 groups. Our results suggested that NAC protects liver tissue against Cd toxicity by elevating antioxidant capacity, mitigating oxidative stress, inflammation, apoptosis and up-regulation of FXR, LXR, and SIRT1 genes.

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References

  1. García-Esquinas E et al (2014) Cadmium exposure and cancer mortality in a prospective cohort: the strong heart study. Environ Health Perspect 122:363–370

    Article  Google Scholar 

  2. Barbier O et al (2005) Effect of heavy metals on, and handling by, the kidney. Nephron Physiol 99:105–110

    Article  Google Scholar 

  3. Foulkes E (1985) Interactions between metals in rat jejunum: implications on the nature of cadmium uptake. Toxicology 37:117–125

    Article  CAS  Google Scholar 

  4. Genchi G, Sinicropi MS, Lauria G, Carocci A, Catalano A (2020) The effects of cadmium toxicity. Int J Environ Res Public Health 17(11):3782

    Article  CAS  Google Scholar 

  5. Hyder O, Chung M, Cosgrove D, Herman JM, Li Z, Firoozmand A, Gurakar A, Koteish A, Pawlik TM (2013) Cadmium exposure and liver disease among US adults. J Gastrointest Surg 17(7):1265–1273

    Article  Google Scholar 

  6. Vestena S (2011) Cadmium-induced oxidative stress and antioxidative enzyme response in water hyacinth and salvinia. Braz J Plant Physiol 23:1–12

    Article  Google Scholar 

  7. Liu T et al (2010) Roles of reactive oxygen species and mitochondria in cadmium-induced injury of liver cells. TIH 9:1–12

    Google Scholar 

  8. Liu J et al (2009) Role of oxidative stress in cadmium toxicity and carcinogenesis. Toxicol Appl Pharmacol 238:209–214

    Article  CAS  Google Scholar 

  9. Mahdavi LS et al (2017) Effects of intraperitoneal administration of cadmium on apoptotic Bcl-2 and Bax genes expression in rat hippocampal cells. Novin Genetic 12:81–89

    Google Scholar 

  10. Ilkhani M et al (1990) Core Ways on Cancer Patients. Ghazi Jahani Pub, Tehran

    Google Scholar 

  11. Kong B, Luyendyk P, Tawfik O, Guo GL (2009) Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet. J Pharmacol Exp Ther 328:116–122

    Article  CAS  Google Scholar 

  12. Colak Y, Ozturk O, Senates E, Tuncer I, Yorulmaz E, Adali G, Doganay L, Enc FY (2011) SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. Medical Sci Monit 17(5):5–9

    Article  Google Scholar 

  13. Kitada M, Koya D (2013) SIRT1 in Type 2 diabetes: mechanisms and therapeutic potential. Diabetes Metab J 37:315–325

    Article  Google Scholar 

  14. Yan T, Huang J, Nisar MF, Wan C, Huang W (2019) The Beneficial Roles of SIRT1 in drug-Induced Liver Injury. Oxid Med Cell Longev 2019:8506195. https://doi.org/10.1155/2019/8506195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Steffensen KR, Gustafsson JA (2004) Putative metabolic effects of the liver x receptor (LXR). Diabetes 53:S36–S42

    Article  CAS  Google Scholar 

  16. Ghafarizadeh A, Malmir M, Naderi Noreini S, Faraji T (2020) Antioxidant effects of N‐acetylcysteine on the male reproductive system: A systematic review. Andrologia:e13898

  17. Charron MJ, Williams L, Seki Y, Du XQ, Chaurasia B, Saghatelian A, Summers SA, Katz EB, Vuguin PM, Reznik SE (2020) Antioxidant effects of N-acetylcysteine prevent programmed metabolic disease in mice. Diabetes

  18. Turkmen R, Birdane YO, Demirel HH, Yavuz H, Kabu M, Ince S (2019) Antioxidant and cytoprotective effects of N-acetylcysteine against subchronic oral glyphosate-based herbicide-induced oxidative stress in rats. Environ Sci Pollut Res 26(11):11427–11437

    Article  CAS  Google Scholar 

  19. Nna VU, Ujah GA, Mohamed M, Etim KB, Igba BO, Augustine ER, Osim EE (2017) Cadmium chloride–induced testicular toxicity in male wistar rats; prophylactic effect of quercetin, and assessment of testicular recovery following cadmium chloride withdrawal. Biomed Pharmacother 94:109–123. https://doi.org/10.1016/j.biopha.2017.07.087

    Article  CAS  PubMed  Google Scholar 

  20. Patel Manali B, Deshpande S, Shah G (2011) Evaluation of efficacy of vitamin E and N-acetyl cysteine in gentamicin-induced nephrotoxicity in rats. Ren Fail 33(3):341–347. https://doi.org/10.3109/0886022X.2011.560987

    Article  CAS  PubMed  Google Scholar 

  21. Dickey DT, Muldoon LL, Doolittle ND, Peterson DR, Kraemer DF, Neuwelt EA (2008) Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models. Cancer Chemother Pharmacol 62(2):235–241. https://doi.org/10.1007/s00280-007-0597-2

    Article  CAS  PubMed  Google Scholar 

  22. Harvey BH, Joubert C, du Preez JL, Berk M (2008) Effect of chronic N-acetyl cysteine administration on oxidative status in the presence and absence of induced oxidative stress in rat striatum. Neurochem Res 33(3):508–517. https://doi.org/10.1007/s11064-007-9466-y

    Article  CAS  PubMed  Google Scholar 

  23. Liu Q, Zhang R, Wang X, Shen X, Wang P, Sun N, Li X, Li X, Hai C (2019) Effects of sub-chronic, low-dose cadmium exposure on kidney damage and potential mechanisms. Ann Transl Med 7(8):177–177. https://doi.org/10.21037/atm.2019.03.66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Groten JP, Sinkeldam EJ, Luten JB, van Bladeren PJ (1991) Cadmium accumulation and metallothionein concentrations after 4-week dietary exposure to cadmium chloride or cadmium-metallothionein in rats. Toxicol Appl Pharmacol 111(3):504–513. https://doi.org/10.1016/0041-008X(91)90254-C

    Article  CAS  PubMed  Google Scholar 

  25. Shirinsokhan A, Koohpar ZK, Ranji N (2020) Effects of N-Acetyl Cysteine on the Expression of Matrix Metalloproteinases 2 and 9 in the Lung Tissue of Rats Exposed to Cadmium. Iranian Red Crescent Medical Journal 22 (11)

  26. Ma Z, Chu L, Liu H, Wang W, Li J, Yao W, Yi J, Gao Y (2017) Beneficial effects of paeoniflorin on non-alcoholic fatty liver disease induced by high-fat diet in rats. Sci Rep 7:44819. https://doi.org/10.1038/srep44819

    Article  PubMed  PubMed Central  Google Scholar 

  27. Benzie IF (1996) Lipid peroxidation: a review of causes, consequences, measurement and dietary influences. Int J Food Sci Nutr 47(3):233–261

    Article  CAS  Google Scholar 

  28. Benzie IF, Strain JJ (1996) The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 239(1):70–76

    Article  CAS  Google Scholar 

  29. Rao B, Soufir JC, Martin M, David G (1989) Lipid peroxidation in human spermatozoa as related to midpiece abnormalities and motility. Gamete Res 24(2):127–134. https://doi.org/10.1002/mrd.1120240202

    Article  CAS  PubMed  Google Scholar 

  30. Hajighasem A, Farzanegi P, Mazaheri Z, Naghizadeh M, Salehi G (2018) Effects of resveratrol, exercises and their combination on Farnesoid X receptor, Liver X receptor and Sirtuin 1 gene expression and apoptosis in the liver of elderly rats with nonalcoholic fatty liver. PeerJ 6:e5522

    Article  Google Scholar 

  31. Alizadeh B, Salehzadeh A, Ranji N, Arasteh A (2021) Effects of N-acetyl cysteine on genes expression of c-myc, and Ask-1, Histopathological, oxidative stress, inflammation, and apoptosis in the liver of male rats exposed to cadmium. Biol Trace Elem Res. https://doi.org/10.1007/s12011-021-02670-w

    Article  PubMed  Google Scholar 

  32. Nazimabashir MV, Miltonprabu S (2015) Cadmium induced cardiac oxidative stress in rats and its attenuation by GSP through the activation of Nrf2 signaling pathway. Chem Biol Interact 242:179–193

    Article  CAS  Google Scholar 

  33. Nazima B, Manoharan V, Miltonprabu S (2016) Oxidative stress induced by cadmium in the plasma, erythrocytes and lymphocytes of rats: Attenuation by grape seed proanthocyanidins. Hum Exp Toxicol 35:428–447

    Article  CAS  Google Scholar 

  34. Andjelkovic M, Djordjevic AB, Antonijevic E, Antonijevic B, Stanic M, Kotur-Stevuljevic J et al (2019) Toxic effect of acute cadmium and lead exposure in rat blood, liver, and kidney. Int J Environ Res Public Health 16:1–21

    Article  Google Scholar 

  35. Hart BA, Lee CH, Shukla GS, Shukla A, Osier M, Eneman JD, Chiu JF (1999) Characterization of cadmium-induced apoptosis in rat lung epithelial cells: evidence for the participation of oxidant stress. Toxicology 133:43–58

    Article  CAS  Google Scholar 

  36. Yuan Y, Jiang CY, Xu H, Sun Y, Hu F, Bian J et al (2013) Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway. PLoS ONE 8:e64330

    Article  CAS  Google Scholar 

  37. Yuan G, Dai S, Yin Z, Lu H, Jia R, Xu J et al (2014) Sub-chronic lead and cadmium co-induce apoptosis protein expression in liver and kidney of rats. Int J Clin Exp Pathol 7:2905–2914

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ma K, Saha PK, Chan L, Moore DD (2006) Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Investig 116:1102–1109

    Article  CAS  Google Scholar 

  39. Duran-Sandoval D, Mautino G, Martin G, Percevault F, Barbier O, Fruchart JC, Kuipers F, Staels B (2004) Glucose regulates the expression of the farnesoid X receptor in liver. Diabetes 53:890–898

    Article  CAS  Google Scholar 

  40. Nascimento AF, Ip BC, Luvizotto RA, Seitz HK, Wang XD (2013) Aggravation of nonalcoholic steatohepatitis by moderate alcohol consumption is associated with decreased SIRT1 activity in rats. Hepatobiliary Surg Nutri 2(5):252–259. https://doi.org/10.3978/j.issn.2304-3881.2013.07.05

    Article  Google Scholar 

  41. Hajighasem A, Farzanegi P, Mazaheri Z (2018) Effects of combined therapy with resveratrol, continuous and interval exercises on apoptosis, oxidative stress, and inflammatory biomarkers in the liver of old rats with non-alcoholic fatty liver disease. Arch Physiol Biochem 125:142–149

    Article  Google Scholar 

  42. Sevov M, Elfineh L, Cavelier LB (2006) Resveratrol regulates the expression of LXR-alpha in human macrophages. Biochem Biophys Res Commun 348(3):1047–1054. https://doi.org/10.1016/j.bbrc.2006.07.155

    Article  CAS  PubMed  Google Scholar 

  43. Wang J, Li M, Zhang W, Gu A, Dong J, Li J et al (2018) Protective effect of n-acetylcysteine against oxidative stress induced by zearalenone via mitochondrial apoptosis pathway in SIEC02 cells. Toxins (Basel) 10:407

    Article  CAS  Google Scholar 

  44. Shieh P, Jan CR, Liang WZ (2019) The protective effects of the antioxidant N-acetylcysteine (NAC) against oxidative stress-associated apoptosis evoked by the organophosphorus insecticide malathion in normal human astrocytes. Toxicology 417:1–14

    Article  CAS  Google Scholar 

  45. Al-Nahdi AMT, John A, Raza H (2018) Cytoprotective effects of n-acetylcysteine on streptozotocin- induced oxidative stress and apoptosis in RIN-5f pancreatic β-Cells. Cell Physiol Biochem 51:201–216

    Article  CAS  Google Scholar 

  46. Chen S, Ren Q, Zhang J, Ye Y, Zhang Z, Xu Y et al (2014) N-acetyl-L-cysteine protects against cadmium-induced neuronal apoptosis by inhibiting ROS-dependent activation of Akt/mTOR pathway in mouse brain. Neuropathol Appl Neurobiol 40:759–777

    Article  CAS  Google Scholar 

  47. Ji YL, Wang H, Zhang C, Zhang Y, Zhao M, Chen YH, DX. X, (2013) N-acetylcysteine protects against cadmium-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in testes. Asian J Androl 15:290–296

    Article  CAS  Google Scholar 

  48. Odewumi CO, Badisa VLD, Le UT, Latinwo LM, Ikediobi CO, Badisa RB et al (2011) Protective effects of N-acetylcysteine against cadmium-induced damage in cultured rat normal liver cells. Int J Mol Med 27:243–248

    Article  CAS  Google Scholar 

  49. Khanna S, Mitra S, Lakhera PC, Khandelwal S (2016) N-acetylcysteine effectively mitigates cadmium-induced oxidative damage and cell death in Leydig cells in vitro. Drug Chem Toxicol 39:74–80

    Article  CAS  Google Scholar 

  50. Rahmani Talatappeh N, Ranji N, Beigi Harchegani A (2021) The effect of N-acetyl cysteine on oxidative stress and apoptosis in the liver tissue of rats exposed to cadmium. Arch Environ Occup Health. https://doi.org/10.1080/19338244.2021.1887796

    Article  PubMed  Google Scholar 

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Acknowledgement

The authors are thankful to Dr. Sogol Meknatkhah (Institute of Biochemistry and Biophysics (IBB), University of Tehran), Dr. Ali Rahbari (Pathologist, Jam Hospital) and Dr. Armaghan Shirinsokhan (Rasht Branch, Islamic Azad University) for all of their helps and supports.

Funding

Hereby, we thank Islamic Azad University (Rasht Branch) (Grant No. 17/16/4/16035) for providing the project costs.

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Authors and Affiliations

  1. Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, P.O. Box, 3516-41335, Rasht, Iran

    Zahra Azarmehr, Najmeh Ranji & Hadi Habibollahi

  2. Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran

    Zeinab Khazaei Koohpar

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  1. Zahra Azarmehr
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  2. Najmeh Ranji
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  3. Zeinab Khazaei Koohpar
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  4. Hadi Habibollahi
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Contributions

ZA, NR and HH contributed to the conception and design of this article. ZA and NR contributed to analysis and interpretation. ZA, NR and ZKK were involved in statistical analysis. ZA, NR and HH contributed in writing and provided critical revision for this article. NR gave final approval for this article. All authors agree to be accountable for all aspects of the work.

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Correspondence to Najmeh Ranji.

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This experimental study was approved by the animal care and use committee at Islamic Azad University, Rasht branch, Iran (Approval ID: IR. IAU. RASHT. REC. 1399.008).

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Azarmehr, Z., Ranji, N., Khazaei Koohpar, Z. et al. The effect of N-Acetyl cysteine on the expression of Fxr (Nr1h4), LXRα (Nr1h3) and Sirt1 genes, oxidative stress, and apoptosis in the liver of rats exposed to different doses of cadmium. Mol Biol Rep 48, 2533–2542 (2021). https://doi.org/10.1007/s11033-021-06300-5

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