Skip to main content
SpringerLink
Log in

Homocysteine and Asymmetrical Dimethylarginine in Diabetic Rats Treated with Docosahexaenoic Acid–Loaded Zinc Oxide Nanoparticles

  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

Hyperglycemia, the hallmark of diabetes mellitus, is considered one of the endothelial dysfunction risk factors, the main reason of vascular complication. In this study, we aimed to evaluate homocysteine (Hcy) and asymmetrical dimethylarginine (ADMA) levels in diabetic rats and the possibility to attenuate the elevation of these two parameters by supplementation of docosahexaenoic acid (DHA) alone or loaded zinc oxide nanoparticles (ZnONPs) to improve endothelial dysfunction in streptozotocin (STZ)-induced diabetic rats. Forty male albino rats weighing 180–200 g were classified as control, diabetic, diabetic treated with DHA, and diabetic treated with DHA-loaded zinc oxide nanoparticles (DHA/ZnONPs) groups. Fasting blood glucose, insulin, ADMA, Hcy, and nitric oxide (NO) were estimated. Fatty acids (linoleic acid (LA), arachidonic acid (AA), DHA, α-linolenic acid (ALA), and oleic acid (OA)) were also evaluated by reversed phase HPLC using a UV detector. The results showed that fasting blood sugar, insulin resistance, LA, AA, OA, ADMA, and Hcy increased significantly in diabetic rats compared with control while fasting insulin, DHA, ALA, and NO decreased significantly in diabetic rats. In both treated groups, fasting blood sugar, insulin resistance, LA, AA, OA, ADMA, and Hcy significantly decreased as compared with the diabetic group while fasting insulin, DHA, ALA, and NO were significantly increased. In conclusion, DHA and DHA/ZnONP supplementation protect against diabetic complications and improve endothelial dysfunction as well as hyperhomocysteinemia in diabetes. DHA/ZnONP-treated group appeared more efficient than DHA alone.

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

Similar content being viewed by others

References

  1. Nesto, R. W. (2004). Correlation between cardiovascular disease and diabetes mellitus: current concepts. The American Journal of Medicine, 116, 11S–22S.

    PubMed  Google Scholar 

  2. Sena, C. M., Pereira, A. M., & Seiça, R. (2013). Endothelial dysfunction - a major mediator of diabetic vascular disease. Biochimica et Biophysica Acta, 1832(12), 2216–2231.

    CAS  PubMed  Google Scholar 

  3. Hagiwara, H., Nishiyama, Y., & Katayama, Y. (2011). Effects of eicosapentaenoic acid on asymmetric dimethylarginine in patients in the chronic phase of cerebral infarction: a preliminary study. Journal of Stroke and Cerebrovascular Diseases, 20(5), 474–478.

    PubMed  Google Scholar 

  4. Korandjia, C., Zeller, M., & Guillanda, J. C. (2011). Time course of asymmetric dimethylarginine (ADMA) and oxidative stress in fructose-hypertensive rats: a model related to metabolic syndrome. Atherosclerosis, 214, 310–315.

    Google Scholar 

  5. Selhub, J. (1999). Homocysteine metabolism. Annual Review of Medicine, 19, 217–246.

    CAS  Google Scholar 

  6. Stirban, A., Nandrean, S., Gotting, C., Tamler, R., Pop, A., Negrean, M., et al. (2010). Effects of n-3 fatty acids on macro- and microvascular function in subjects with type 2 diabetes mellitus. The American Journal of Clinical Nutrition, 91(3), 808–813.

    CAS  PubMed  Google Scholar 

  7. Cavieres, V., Valdes, K., Moreno, B., Moore-Carrasco, R., & Gonzalez, D. R. (2014). Vascular hypercontractility and endothelial dysfunction before development of atherosclerosis in moderate dyslipidemia: role for nitric oxide and interleukin-6. American Journal of Cardiovascular Disease, 4(3), 114–122.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Alkaladi, A., Abdelazim, A. M., & Afifi, M. (2014). Antidiabetic activity of zinc oxide and silver nanoparticles on streptozotocin-induced diabetic rats. International Journal of Molecular Sciences, 15(2), 2015–2023.

    PubMed  PubMed Central  Google Scholar 

  9. Yih, T. C., & Al-Fandi, M. (2006). Engineered nanoparticles as precise drug delivery system. Journal of Cellular Biochemistry, 97(6), 1184–1190.

    CAS  PubMed  Google Scholar 

  10. Hirst, S. M., Karakoti, A. S., Tyle, R. R. D., Sriranganathan, N., Seal, S., & Reilly, C. M. (2009). Anti-inflammatory properties of cerium oxide nanoparticles. Small, 5(24), 2848–2856.

    CAS  PubMed  Google Scholar 

  11. Hussein, J., El-Bannaa, M., Abdel Razikb, T., & El-Naggar, M. E. (2018a). Biocompatible zinc oxide nanocrystals stabilized via hydroxyethyl cellulose for mitigation of diabetic complications. International Journal of Biological Macromolecules, 107, 748–754.

    CAS  PubMed  Google Scholar 

  12. Hussein, J., El-Naggar, M. E., Abdel Latif, Y., Medhat, D., El Bana, M., Refaat, E., & Morsy, S. (2018b). Solvent-free and one-pot synthesis of silver and zinc oxide nanoparticles: activity toward cell membrane component and insulin signaling pathway in experimental diabetes. Colloids and Surfaces B: Biointerfaces, 170, 76–84.

    CAS  PubMed  Google Scholar 

  13. Mathews, D. R., Hoker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F., & Turner, R. C. (1985). Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28, 412–419.

    Google Scholar 

  14. Sun, Q., van Dam, R. M., Willett, W. C., & Hu, F. B. (2009). Prospective study of zinc intake and risk of type 2 diabetes in women. Diabetes Care, 32(4), 629–634.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Uchiyama, S., & Yamaguchi, M. (2003). Alteration in serum and bone component findings induced in streptozotocin-diabetic rats is restored by zinc acexamate. International Journal of Molecular Medicine, 12, 949–954.

    CAS  PubMed  Google Scholar 

  16. Hussein, J., Attia, M. F., El Bana, M., El-Daly, S. M., Mohamed, N., El-Khayat, Z., & El-Naggar, M. (2019a). Solid state synthesis of docosahexaenoic acid-loaded zinc oxide nanoparticles as a potential antidiabetic agent in rats. International Journal of Biological Macromolecules, 140, 1305–1314.

    CAS  PubMed  Google Scholar 

  17. Trinder, P. (1969). Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Annals of Clinical Biochemistry, 6, 24–27.

    CAS  Google Scholar 

  18. Yalow, R., & Bauman, W. A. (1983). Insulin in health and disease. In M. Ellenberg & H. Rifkin (Eds.), Diabetes mellitus: theory and practice (pp. 119–150). New York: Excerpta Medica.

    Google Scholar 

  19. Moshage, H., Kok, B., & Huizenga, J. R. (1995). Nitrite and nitrate determination in plasma: a critical evaluation. Clinical Chemistry, 41, 892–896.

    CAS  PubMed  Google Scholar 

  20. El-Khayat, Z., Abo El-Matty, D., Rasheed, W., Hussein, J., Shaker, O., & Raafat, J. (2013). Role of cell membrane fatty acids in insulin sensitivity in diabetic rats treated with flaxseed oil. International Journal of Pharmacy and Pharmaceutical Sciences, 5(2), 146–151.

    Google Scholar 

  21. Hussein, J., El-Khayat, Z., Morsy, S., Oraby, F., & Singer, G. (2014). The effect of fish oil on oxidant/antioxidant status in diabetic rats through the reduction of arachidonic acid in the cell membrane. International Journal of Pharmacy and Pharmaceutical Sciences, 6(2), 196–199.

    Google Scholar 

  22. Hussein, J. S., Rasheed, W., Ramzy, T., Nabeeh, M., Harvy, M., El-Toukhy, S., Ali, O., Raafat, J., & El-Naggar, M. (2019b). Synthesis of docosahexaenoic acid–loaded silver nanoparticles for improving endothelial dysfunctions in experimental diabetes. Human and Experimental Toxicology, 38(8), 962–973.

    CAS  PubMed  Google Scholar 

  23. Hussein, J., El-Khayat, Z., Abdel Latif, Y., & Khateeb, S. (2016). Quercetin ameliorates endothelial dysfunction and prevents elevation of asymmetrical dimethylarginine in experimental diabetes. Der Pharma Chemica, 8(13), 247–252.

    CAS  Google Scholar 

  24. Hussein, J., El-Bana, M., Refaat, E., & El-Naggar, M. E. (2017). Synthesis of carvacrol-based nanoemulsion for treating neurodegenerative disorders in experimental diabetes. Journal of Functional Foods, 37, 441–448.

    CAS  Google Scholar 

  25. Shah, P., Zhu, X., Zhang, X., He, J., & Li, C. (2016). Microelectromechanical system-based sensing arrays for comparative in vitro nanotoxicity assessment at single cell and small cell-population using electrochemical impedance spectroscopy. ACS Applied Materials & Interfaces, 8, 5804–5812.

    CAS  Google Scholar 

  26. Krishna, D., Rao, S., & Satyanarayana, M. L. (2012). Serum insulin levels and lipid profiles of streptozotocin induced diabetic Wistar rats. Journal Indian Veterinary Association, 10, 22–26.

    Google Scholar 

  27. Kou, L., Du, M., Liu, P., Zhang, B., Zhang, Y., Yang, P., Shang, M., & Wang, X. (2019). Anti-diabetic and anti-nephritic activities of Grifola frondosa mycelium polysaccharides in diet-streptozotocin-induced diabetic rats via modulation on oxidative stress. Applied Biochemistry and Biotechnology, 187, 310–322.

    CAS  PubMed  Google Scholar 

  28. Argacha, J. F., Adamopoulos, D., Gujic, M., Fontaine, D., Amyai, N., Berkenboom, G., & van de Borne, P. (2008). Acute effects of passive smoking on peripheral vascular function. Hypertension, 51(6), 1506–1511.

    CAS  PubMed  Google Scholar 

  29. Sydow, K., Schwedhelm, E., Arakawa, N., Bode-Böger, S. M., Tsikas, D., Hornig, B., Frölich, J. C., & Böger, R. H. (2003). ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocysteinemia: effects of l-arginine and B vitamins. Cardiovascular Research, 57(1), 244–252.

    CAS  PubMed  Google Scholar 

  30. Aly, O., Elias, T. R., Agaiby, M. H., Rasheed, W. I., Ashour, M. N., & Hussein, J. S. (2017). Role of a combination of myrtle extract and fish oil supplementation in improving endothelial dysfunction in streptozotocin-induced diabetic rats. Journal of The Arab Society for Medical, 12, 86–91.

    Google Scholar 

  31. Agullo-Ortuno, M. T., Albaladejo, M. D., Parra, S., Rodriguez-Manotas, M., Fenollar, M., Ruíz-Espejo, F., Teba, J., & Martínez, P. (2002). Plasmatic homocysteine concentration and its relationship with complications associated to diabetes mellitus. Clinica Chimica Acta, 326(1–2), 105–112.

    CAS  Google Scholar 

  32. Emoto, M., Kanda, H., Shoji, T., Kawagishi, T., Komatsu, M., Mori, K., Tahara, H., Ishimura, E., Inaba, M., Okuno, Y., & Nishizawa, Y. (2001). Impact of insulin resistance and nephropathy on homocysteine in type 2 diabetes. Diabetes Care, 24(3), 533–538.

    CAS  PubMed  Google Scholar 

  33. Tarkun, I., Arslan, B. C., Cantürk, Z., Tarkun, P., Kozdağ, G., & Topsever, P. (2003). Homocysteine concentrations in type 2 diabetes mellitus patients without cardiovascular disease: relationship to metabolic parameters and diabetic complications. Turkish Journal of Endocrinology and Metabolism, 1, 11–17.

    Google Scholar 

  34. Jakubowski, H., Zhang, L., Bardeguez, A., & Aviv, A. (2000). Homocysteine thiolactone and protein homocysteinylation in human endothelial cells. Circulation Research, 87, 45–51.

    CAS  PubMed  Google Scholar 

  35. Akbariana, M., Ghasemib, Y., Vladimir, N., Verskyc, D., & Yousefia, R. (2018). Chemical modifications of insulin: finding a compromise between stability and pharmaceutical performance. International Journal of Pharmaceutics, 547, 450–468.

    Google Scholar 

  36. Dayal, S., & Lentz, S. R. (2005). ADMA and hyperhomocysteinemia. Vascular Medicine, 10, S27–S33.

    PubMed  Google Scholar 

  37. Fruchart, J. C. (2009). Peroxisome proliferator-activated receptor-alpha(PPARα): at the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis, 205(1), 1–8.

    CAS  PubMed  Google Scholar 

  38. Guerre-Millo, M., Gervois, P., Raspe, E., Madsen, L., Poulain, P., Derudas, B., Herbert, J. M., Winegar, D. A., Willson, T. M., Fruchart, J. C., Berge, R. K., & Staels, B. (2000). Peroxisome proliferator-activated receptor α activators improve insulin sensitivity and reduce adiposity. The Journal of Biological Chemistry, 275(22), 16638–16642.

    CAS  PubMed  Google Scholar 

  39. Serhan, C. N., Arita, M., Hong, S., & Gotlinger, K. (2004). Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their endogenous aspirin triggered epimers. Lipids, 39(11), 1125–1132.

    CAS  PubMed  Google Scholar 

  40. Mozaffarian, D., & Wu, J. H. (2011). Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. Journal of the American College of Cardiology, 58(20), 2047–2067.

    CAS  PubMed  Google Scholar 

  41. Huang, T., Wahlqvist, M. L., & Li, D. (2010). Docosahexaenoic acid decreases plasma homocysteine via regulating enzyme activity and mRNA expression involved in methionine metabolism. Nutrition, 26(1), 112–119.

    CAS  PubMed  Google Scholar 

  42. Shaheen, T., El-Naggar, M. E., Hussein, J. S., El-Bana, M., Emara, E., El-Khayat, Z., Moustafa, M. G., Hossam, F. E., & Hebeisha, A. (2016). Antidiabetic assessment; in vivo study of gold and core-shell silver-gold nanoparticles on streptozotocin-induced diabetic rats. Biomedicine & Pharmacotherapy, 83, 865–875.

    CAS  Google Scholar 

  43. Hussein, J., El-Banna, M., Mahmoud, K. F., Morsy, S., Abdel Latif, Y., Medhat, D., Refaat, E., Farrag, A. H., & El-Daly, S. M. (2017). The therapeutic effect of nano-encapsulated and nano-emulsion forms of carvacrol on experimental liver fibrosis. Biomedicine & Pharmacotherapy, 90, 880–887.

    CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful to the National Research Centre, Giza, Egypt, for funding this work (internal project no. 11010130).

Author information

Authors and Affiliations

  1. Medical Biochemistry Department, National Research Centre, Dokki, Giza, Egypt

    Jihan Hussein, Ehsan Badawy, Nabila El-laithy, Maha El-Waseef, Hanan Hassan & Yasmin Abdel-Latif

  2. Textile Research Division, National Research Centre, Dokki, Giza, Egypt

    Mehrez El-Naggar

Authors
  1. Jihan Hussein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mehrez El-Naggar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ehsan Badawy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nabila El-laithy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maha El-Waseef
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hanan Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasmin Abdel-Latif
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jihan Hussein.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

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

Hussein, J., El-Naggar, M., Badawy, E. et al. Homocysteine and Asymmetrical Dimethylarginine in Diabetic Rats Treated with Docosahexaenoic Acid–Loaded Zinc Oxide Nanoparticles. Appl Biochem Biotechnol 191, 1127–1139 (2020). https://doi.org/10.1007/s12010-020-03230-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12010-020-03230-z

Keywords

Search

Navigation