Skip to main content
SpringerLink
Log in

Nanoliposome-encapsulated ellagic acid prevents cyclophosphamide-induced rat liver damage

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

In this study, we aimed to evaluate whether the encapsulation of ellagic acid (EA) into nanoliposomes would improve its potential in preventing cyclophosphamide-induced liver damage. Stability and antioxidative potential of free and encapsulated EA were determined. Experimental study conducted in vivo included ten groups of rats treated with cyclophosphamide and ellagic acid in its free and encapsulated form during 5 days. The protective effect of EA in its free and encapsulated form was determined based on serum liver function, liver tissue antioxidative capacities, and oxidative tissue damage parameters. Also, tissue morphological changes following cyclophosphamide administration were studied using standard histopathological and immunohistochemical analyses. The encapsulation of EA significantly prevented its degradation and improved its antioxidant properties in in vitro conditions. In in vivo experiments in both forms of EA were found to prevent rat liver damage induced by cyclophosphamide estimated through the changes in serum liver-damage parameters and tissue antioxidant capacities, as well as based on oxidatively modified lipids and proteins. Also, changes in morphology of liver cells and the expressions of Bcl-2, HIF-1α, and CD15 molecules in livers of animals of different experimental groups are in accordance with the obtained biochemical parameters. Thus, the encapsulation process might be effective in preventing EA from different environmental influences and could significantly increase its hepatoprotective potential. The encapsulation could prevent ellagic acid degradation and might deliver this potent compound to its target tissue in significantly larger quantities than when it is administered in its free form.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Lawson M, Vasilaras A, De Vries A, Mactaggart P, Nicol D (2008) Urological implications of cyclophosphamide and ifosfamide. Scand J Urol Nephrol 42(4):309–317. https://doi.org/10.1080/00365590701570953

    Article  CAS  PubMed  Google Scholar 

  2. King PD, Perry MC (2001) Hepatotoxicity of chemotherapy. Oncologist 6(2):162–176

    Article  CAS  PubMed  Google Scholar 

  3. Adams JD Jr, Klaidman LK (1993) Acrolein-induced oxygen radical formation. Free Radic Biol Med 15(2):187–193

    Article  CAS  PubMed  Google Scholar 

  4. Mansour DF, Saleh DO, Mostafa RE (2017) Genistein ameliorates cyclophosphamide—induced hepatotoxicity by modulation of oxidative stress and inflammatory mediators. Open Access Maced J Med Sci 5(7):836–843. https://doi.org/10.3889/oamjms.2017.093

    Article  PubMed  PubMed Central  Google Scholar 

  5. García-Niño WR, Zazueta C (2015) Ellagic acid: pharmacological activities and molecular mechanisms involved in liver protection. Pharmacol Res 97:84–103. https://doi.org/10.1016/j.phrs.2015.04.008

    Article  CAS  PubMed  Google Scholar 

  6. Hadian Z (2016) A review of nanoliposomal delivery system for stabilization of bioactive omega-3 fatty acids. Electron Physician 8(1):1776–1785. https://doi.org/10.19082/1776

    Article  PubMed  PubMed Central  Google Scholar 

  7. Stojiljkovic N, Ilic S, Jakovljevic V, Stojanovic N, Stojnev S, Kocic H, Stojanovic M, Kocic G (2018) The encapsulation of lycopene in nanoliposomes enhances its protective potential in methotrexate-induced kidney injury model. Oxid Med Cell Longev 2018:2627917. https://doi.org/10.1155/2018/2627917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. TodorovicJ Jovanovic G, Todorovic A, Mitic A, Stojiljkovic N, Ilic S, Stojanovic N, Stojnev S (2017) Effects of coenzyme Q10 encapsulated in nanoliposomes on wound healing processes after tooth extraction. J Den Sci 13(2):103–108. https://doi.org/10.1016/j.jds.2017.10.004

    Article  Google Scholar 

  9. Kocic G, Tomovic K, Kocic H, Sokolovic D, Djordjevic B, Stojanovic S, Arsic I, Smelcerovic A (2017) Antioxidative, membrane protective and antiapoptotic effects of melatonin, in silico study of physico-chemical profile and efficiency of nanoliposome delivery compared to betaine. RSC Adv 7(3):1271–1281. https://doi.org/10.1039/C6RA24741E

    Article  CAS  Google Scholar 

  10. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

    CAS  Google Scholar 

  11. Góth L (1991) A simple method for determination of serum catalase activity and revision of reference range. Clin Chim Acta 196:143–151

    Article  PubMed  Google Scholar 

  12. Ellman G (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  CAS  Google Scholar 

  13. Sokolovic D, Djordjevic B, Kocic G, Stoimenov TJ, Stanojkovic Z, Sokolovic DM, Veljkovic A, Ristic G, Despotovic M, Milisavljevic D, Jankovic R, Binic I (2015) The effects of melatonin on oxidative stress parameters and DNA fragmentation in testicular tissue of rats exposed to microwave radiation. Adv Clin Exp Med 24:429–436. https://doi.org/10.17219/acem/43888

    Article  PubMed  Google Scholar 

  14. Gopalakrishnan L, Ramana LN, Sethuraman S, Krishnan UM (2014) Ellagic acid encapsulated chitosan nanoparticles as anti-hemorrhagic agent. Carbohydr Polym 111:215–221. https://doi.org/10.1016/j.carbpol.2014.03.093

    Article  CAS  PubMed  Google Scholar 

  15. Bala I, Bhardwaj V, Hariharan S, Kharade SV, Roy N, Ravi Kumar MN (2006) Sustained release nanoparticulate formulation containing antioxidant-ellagic acid as potential prophylaxis system for oral administration. J Drug Target 14(1):27–34. https://doi.org/10.1080/10611860600565987

    Article  CAS  PubMed  Google Scholar 

  16. Panichayupakaranant P, Itsuriya A, Sirikatitham A (2010) Preparation method and stability of ellagic acid-rich pomegranate fruit peel extract. Pharm Biol 48(2):201–205. https://doi.org/10.3109/13880200903078503

    Article  CAS  PubMed  Google Scholar 

  17. Przewloka SR, Shearer BJ (2005) Thefurther chemistry of ellagicacid II. Ellagicacid and water-soluble ellagates as metal precipitants. Holzforschung 56(1):13–19

    Article  Google Scholar 

  18. Arulmozhi V, Pandian K, Mirunalini S (2013) Ellagic acid encapsulated chitosan nanoparticles for drug delivery system in human oral cancer cell line (KB). Colloids Surf B 110:313–320. https://doi.org/10.1016/j.colsurfb.2013.03.039

    Article  CAS  Google Scholar 

  19. Sies H (1993) Strategies of antioxidant defense. Eur J Biochem 215:213–221

    Article  CAS  PubMed  Google Scholar 

  20. Hamzeh M, Hosseinimehr SJ, Khalatbary AR, Mohammadi HR, Dashti A, Amiri FT (2018) Atorvastatin mitigates cyclophosphamide-induced hepatotoxicity via suppression of oxidative stress and apoptosis in rat model. Res Pharm Sci 13(5):440–449. https://doi.org/10.4103/1735-5362.236837

    Article  PubMed  PubMed Central  Google Scholar 

  21. Girish C, Koner BC, Jayanthi S, Ramachandra Rao K, Rajesh B, Pradhan SC (2009) Hepatoprotective activity of picroliv, curcumin and ellagic acid compared to silymarin on paracetamol induced liver toxicity in mice. Fundam Clin Pharmacol 23:735–745. https://doi.org/10.1111/j.1472-8206.2009.00722.x

    Article  CAS  PubMed  Google Scholar 

  22. Girish C, Pradhan SC (2012) Hepatoprotective activities of picroliv, curcumin, and ellagic acid compared to silymarin on carbon-tetrachloride-induced liver toxicity in mice. J Pharmacol Pharmacother 3:149–155. https://doi.org/10.4103/0976-500X.95515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yüce A, Atessahin A, Ceribasi AO, Aksakal M (2007) Ellagic acid prevents cisplatin-induced oxidative stress in liver and heart tissue of rats. Basic Clin Pharmacol Toxicol 101:345–349. https://doi.org/10.1111/j.1742-7843.2007.00129.x

    Article  CAS  PubMed  Google Scholar 

  24. Souid AK, Tacka KA, Galvan KA, Penefsky HS (2003) Immediate effects of anticancer drugs on mitochondrial oxygen consumption. Biochem Pharmacol 66(6):977–987

    Article  CAS  PubMed  Google Scholar 

  25. Nugroho A, Rhim TJ, Choi MY, Choi JS, Kim YC, Kim MS, Park HJ (2014) Simultaneous analysis and peroxynitrite-scavenging activity of galloylated flavonoid glycosides and ellagic acid in Euphorbia supine. Arch Pharm Res 37:890–898. https://doi.org/10.1007/s12272-013-0307-z

    Article  CAS  PubMed  Google Scholar 

  26. Vijaya Padma V, KalaiSelvi P, Sravani S (2014) Protective effect of ellagic acid against TCDD-induced renal oxidative stress: modulation of CYP1A1 activity and antioxidant defense mechanisms. Mol Biol Rep 41:4223–4232. https://doi.org/10.1007/s11033-014-3292-5

    Article  CAS  PubMed  Google Scholar 

  27. Germoush MO (2016) Diosmin protects against cyclophosphamide-induced liver injury through attenuation of oxidative stress, inflammation and apoptosis. Int J Pharmacol 12(6):644–654. https://doi.org/10.3923/ijp.2016.644.654

    Article  CAS  Google Scholar 

  28. Aslan A, Gok O, Erman O, Kuloglu T (2018) Ellagic acid impedes carbon tetrachloride-induced liver damage in rats through suppression of NF-kB, Bcl-2 and regulating Nrf-2 and caspase pathway. Biomed Pharmacother 105:662–669. https://doi.org/10.1016/j.biopha.2018.06.020

    Article  CAS  PubMed  Google Scholar 

  29. Polce SA, Burke C, França LM, Kramer B, de Andrade Paes AM, Carrillo-Sepulveda MA (2018) Ellagic acid alleviates hepatic oxidative stress and insulin resistance in diabetic female rats. Nutrients. https://doi.org/10.3390/nu10050531

    Article  PubMed  PubMed Central  Google Scholar 

  30. Adeleke GE, Adedosu OT, Adaramoye OA, Olagunju AS, Teibo OJ, ArindeOO Afolabi OK (2016) Hepatoprotective effect of methanol extract of diospyros chloroxylon leaf in N-nitrosodimethylamine-induced hepatotoxicity in rats. Asian Pac J Health Sci 3(3):142–152

    Article  Google Scholar 

Download references

Acknowledgements

This work was funded by the Project of the Faculty of Medicine, University of Niš, Serbia (Project No. INT-MFN-13) and the Project of Ministry of Education and Science of the Republic of Serbia (number 175092).

Author information

Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, University of Nis, Bulevar Zorana Ðinđića 81, Niš, 18000, Serbia

    Nenad Stojiljković, Sonja Ilić & Milan Petković

  2. Faculty of Medicine, University of Nis, Bulevar Zorana Ðinđića 81, Niš, 18000, Serbia

    Nikola Stojanović & Marko Stojanović

  3. Department of Pathology, Faculty of Medicine, University of Nis, Bulevar Zorana Ðinđića 81, Niš, 18000, Serbia

    Ljubinka Janković-Veličković & Slavica Stojnev

  4. Department of Biochemistry, Faculty of Medicine, University of Nis, Bulevar Zorana Ðinđića 81, Niš, 18000, Serbia

    Gordana Kocić

  5. Department of Histology, Faculty of Medicine, University of Nis, Bulevar Zorana Ðinđića 81, Niš, 18000, Serbia

    Goran Radenković

  6. Department of Pharmacy, Faculty of Medicine, University of Nis, Bulevar Zorana Ðinđića 81, Niš, 18000, Serbia

    Ivana Arsić

Authors
  1. Nenad Stojiljković
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sonja Ilić
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nikola Stojanović
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ljubinka Janković-Veličković
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Slavica Stojnev
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gordana Kocić
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Goran Radenković
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ivana Arsić
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marko Stojanović
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Milan Petković
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nenad Stojiljković.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stojiljković, N., Ilić, S., Stojanović, N. et al. Nanoliposome-encapsulated ellagic acid prevents cyclophosphamide-induced rat liver damage. Mol Cell Biochem 458, 185–195 (2019). https://doi.org/10.1007/s11010-019-03541-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-019-03541-8

Keywords

Search

Navigation