Biochemistry (Moscow)

, Volume 81, Issue 3, pp 289–295 | Cite as

Isoferulic acid action against glycation-induced changes in structural and functional attributes of human high-density lipoprotein

  • D. S. JairajpuriEmail author
  • Z. S. Jairajpuri


Glycation-induced high-density lipoprotein (HDL) modification by aldehydes can result in loss of its antiinflammatory/antioxidative properties, contributing to diabetes-associated cardiovascular diseases. Isoferulic acid, a major active ingredient of Cimicifuga heracleifolia, shows antiinflammatory, antiviral, antioxidant, and antidiabetic properties. Thus, this study investigated the antiglycation effect of isoferulic acid against compositional modifications of HDL and loss of biological activity of HDL-paraoxonase induced on incubation with different aldehydes. Protective effect of isoferulic acid was assessed by subjecting purified HDL from human plasma to glycation with methylglyoxal, glyoxal, or glycolaldehyde and varying concentrations of isoferulic acid. The effect of isoferulic acid was analyzed by determining amino group number, tryptophan and advanced glycation end-product fluorescence, thermal denaturation studies, carboxymethyl lysine content, and activity of HDL-paraoxonase. Concentration-dependent inhibitory action of isoferulic acid was observed against extensive structural perturbations, decrease in amino group number, increase in carboxymethyl lysine content, and decrease in the activity of HDL-paraoxonase caused by aldehyde-associated glycation in the HDL molecule. Isoferulic acid, when taken in concentration equal to that of aldehydes, was most protective, as 82-88% of paraoxonase activity was retained for all studied aldehydes. Isoferulic acid shows antiglycation action against aldehyde-associated glycation in HDL, which indicates its therapeutic potential for diabetic patients, especially those with micro-/macrovascular complications.

Key words

aldehydes glycation high-density lipoprotein-AGEs isoferulic acid paraoxonase 



advanced glycation end products


carboxymethyl lysine


enzyme linked immunosorbent assay


high-density lipoprotein


isoferulic acid


low-density lipoprotein


diethyl p-nitrophenylphosphate


phosphate-buffered saline


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Rashid, I., Van Reyk, D. M., and Davies, M. J. (2007) Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro, FEBS Lett., 581, 1067–1070.CrossRefPubMedGoogle Scholar
  2. 2.
    Younis, N. N., Soran, H., Charlton-Menys, V., Sharma, R., Hama, S., Pemberton, P., Elseweidy, M. M., and Durrington, P. N. (2013) High-density lipoprotein impedes glycation of low-density lipoprotein, Diab. Vasc. Dis. Res., 10, 152–160.CrossRefPubMedGoogle Scholar
  3. 3.
    Matafome, P., Sena, C., and Seica, R. (2013) Methylglyoxal, obesity and diabetes, Endocrine, 43, 472–484.CrossRefPubMedGoogle Scholar
  4. 4.
    Karathanasis, S. K. (1992) Lipoprotein metabolism: high-density lipoprotein, in Molecular Genetics of Coronary Artery Disease (Lusis, A. J., Rotter, J. I., and Sparkes, R. S., eds.) Karger, Basel, pp. 140–171.Google Scholar
  5. 5.
    Ferretti, G., Bacchetti, T., Busni, D., Rabini, R. A., and Curatola, G. (2004) Protective effect of paraoxonase activity in high-density lipoproteins against erythrocyte membranes peroxidation: a comparison between healthy subjects and type 1 diabetic patients, J. Clin. Endocrinol. Metab., 89, 2957–2962.CrossRefPubMedGoogle Scholar
  6. 6.
    Bachetti, T., Masciangelo, S., Armeni, T., Bicchiega, V., and Ferretti, G. (2014) Glycation of high-density lipoprotein by methylglyoxal: effect on HDL-paraoxonase activity, Metabolism, 63, 307–311.CrossRefGoogle Scholar
  7. 7.
    Verges, B. (2009) Lipid modification in type 2 diabetes: the role of LDL and HDL, Fundam. Clin. Pharmacol., 23, 681–685.CrossRefPubMedGoogle Scholar
  8. 8.
    Sadowska-Bartosz, I., Galiniak, S., and Bartosz, G. (2014) Kinetics of glycoxidation of bovine serum albumin by methylglyoxal and glyoxal and its prevention by various compounds, Molecules, 19, 4880–4896.CrossRefPubMedGoogle Scholar
  9. 9.
    Tajes, M., Guivernau, B., Ramos-Fernandez, E., Bosch-Morato, M., Palomer, E., Guix, F. X., and Munoz, F. J. (2013) The pathophysiology of triose phosphate isomerase dysfunction in Alzheimer’s disease, Histol. Histopathol., 28, 43–51.PubMedGoogle Scholar
  10. 10.
    Perla-Kajan, J., and Jakubowski, H. (2012) Paraoxonase 1 and homocysteine metabolism, Amino Acids, 43, 1405–1417.CrossRefPubMedGoogle Scholar
  11. 11.
    Odani, H., Shinzato, T., Matsumoto, Y., Usami, J., and Maeda, K. (1999) Increase in three α,β-dicarbonyl compound levels in human uremic plasma: specific in vivo determination of intermediates in advanced Maillard reaction, Biochem. Biophys. Res. Commun., 256, 89–93.CrossRefPubMedGoogle Scholar
  12. 12.
    Brown, B. E., Mahroof, F. M., Cook, N. L., Van Reyk, D. M., and Davies, M. J. (2006) Hydrazine compounds inhibit glycation of low-density lipoproteins and prevent the in vitro formation of model foam cells from glycolaldehyde-modified low-density lipoproteins, Diabetologia, 49, 775–783.CrossRefPubMedGoogle Scholar
  13. 13.
    Kurosaki, Y., Tsukushi, T., Munekata, S., Akahoshi, T., Moriya, T., and Ogawa, Z. (2013) Semiquantitative analysis of apolipoprotein A-I modified by advanced glycation end products in diabetes mellitus, J. Clin. Lab. Anal., 27, 231–236.CrossRefPubMedGoogle Scholar
  14. 14.
    Soule, B. P., Hyodo, F., Matsumoto, K., Simone, N. L., Cook, J. A., Krishna, M. C., and Mitchell, J. B. (2007) The chemistry and biology of nitroxide compounds, Free Radic. Biol. Med., 42, 1632–1650.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bournival, J., Francoeur, M. A., Renaud, J., and Msrtinoli, M. G. (2012) Quercetin and sesamin protect neuronal PC12 cells from high-glucose-induced oxidation, nitrosative stress and apoptosis, Rejuv. Res., 15, 322–333.CrossRefGoogle Scholar
  16. 16.
    Bolton, W. K., Cattran, D. C., Williams, M. E., Adler, S. G., Appel, G. B., Cartwright, K., Foiles, P. G., Freedom, B. I., Raskin, P., Ratner, R. E., Spinowitz, B. S., Whittier, F. C., and Wuerth, J. P. (2004) Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy, Am. J. Nephrol., 24, 32–40.CrossRefPubMedGoogle Scholar
  17. 17.
    Kousar, S., Sheikh, M. A., and Habibi-Rezaei, M. (2010) Nicotine reduces the cytotoxic effect of glycated proteins on microglial cells, Neurochem. Res., 35, 548–558.CrossRefGoogle Scholar
  18. 18.
    Ishibashi, Y., Matsui, T., Takeuchi, M., and Yamagishi, S. (2012) Metformin inhibits advanced glycation end products (AGEs)-induced renal tubular cell injury by suppressing reactive oxygen species generation via reducing receptor for AGEs (RAGE) expression, Horm. Metab. Res., 44, 891–895.CrossRefPubMedGoogle Scholar
  19. 19.
    Ardestani, A., and Yazdanparast, R. (2007) Cyperus rotundus suppresses age formation and protein oxidation in a model of fructose-mediated protein glycoxidation, Int. J. Biol. Macromol., 41, 572–578.CrossRefPubMedGoogle Scholar
  20. 20.
    Iwanaga, A., Kusano, G., Warashina, T., and Miyase, T. (2010) Hyaluronidase inhibitors from “Cimicifugae rhizome” (a mixture of the rhizomes of Cimicifuga dahurica and C. heracleifolia), J. Nat. Prod., 73, 573–578.CrossRefPubMedGoogle Scholar
  21. 21.
    Schmid, D., Woehs, F., Svoboda, M., Thalhammer, T., Chiba, P., and Moeslinger, T. (2009) Aqueous extracts of Cimicifuga racemosa and phenolcarboxylic constituents inhibit production of proinflammatory cytokines in LPS-stimulated human whole blood, Can. J. Physiol. Pharmacol., 87, 963–972.CrossRefPubMedGoogle Scholar
  22. 22.
    Sakai, S., Ochiai, H., Mantani, N., Kogure, T., Shibahara, N., and Terasawa, K. (2001) Administration of isoferulic acid improved the survival rate of lethal influenza virus pneumonia in mice, Med. Inflamm., 10, 93–96.CrossRefGoogle Scholar
  23. 23.
    Wang, X., Li, X., and Chen, D. (2011) Evaluation of antioxidant activity of isoferulic acid in vitro, Nat. Prod. Commun., 6, 1285–1288.PubMedGoogle Scholar
  24. 24.
    Liu, I. M., Hsu, F. L., Chen, C. F., and Cheng, J. T. (2000) Antihyperglycemic action of isoferulic acid in streptozotocin-induced diabetic rats, Br. J. Pharmacol., 129, 631–636.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Meeprom, A., Sompong, W., Chan, C. B., and Adisakwattana, S. (2013) Isoferulic acid, a new anti-glycation agent, inhibits fructose-and glucose-mediated protein glycation in vitro, Molecules, 18, 6439–6454.CrossRefPubMedGoogle Scholar
  26. 26.
    Hedrick, C. C., Thorpe, S. R., Fu, M. X., Harper, C. M., Yoo, J., Kim, S. M., Wong, H., and Peters, A. L. (2000) Glycation impairs high-density lipoprotein function, Diabetologia, 43, 312–320.CrossRefPubMedGoogle Scholar
  27. 27.
    Bradford, M. A. (1976) Rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding, Anal. Biochem., 72, 248–254.CrossRefPubMedGoogle Scholar
  28. 28.
    Habeeb, A. F. S. A., and Hiramoto, R. (1968) Reaction of proteins with glutaraldehyde, Arch. Biochem. Biophys., 126, 16–26.CrossRefPubMedGoogle Scholar
  29. 29.
    Ahmad, S., Akhter, F., Moinuddin, Shahab, U., and Khan, M. S. (2013) Studies on glycation of human low-density lipoprotein: a functional insight into physicochemical analysis, Int. J. Biol. Macromol., 62, 167–171.CrossRefPubMedGoogle Scholar
  30. 30.
    Brown, B. E., Nobecourt, E., Zeng, J., Jenkins, A. J., Rye, K. A., and Davies, M. J. (2013) Apolipoprotein A-I glycation by glucose and reactive aldehydes alters phospholipid affinity but not cholesterol export from lipid-laden macrophages, PLoS One, 8, 65430–65436.CrossRefGoogle Scholar
  31. 31.
    Akhter, F., Khan, M. S., Shahab, U., and Ahmad, S. (2013) Biophysical characterization of ribose induced glycation: a mechanistic study on DNA perturbations, Int. J. Biol. Macromol., 58, 206–210.CrossRefPubMedGoogle Scholar
  32. 32.
    Adisakwattana, S., Sompong, W., Meeprom, A., Ngamukote, S., and Yibchok-anun, S. (2012) Cinnamic acid and its derivatives inhibit fructose-mediated protein glycation, Int. J. Mol. Sci., 13, 1778–1789.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Cai, Y. Z., Sun, M., Xing, J., Luo, Q., and Corke, H. (2006) Structural-radical scavenging activity relationships of phenolic compounds from traditional Chinese medicinal plants, Life Sci., 78, 2872–2888.CrossRefPubMedGoogle Scholar
  34. 34.
    Price, D. L., Rhett, P. M., Thorpe, S. R., and Baynes, J. W. (2001) Chelating activity of advanced glycation end-products inhibitors, J. Biol. Chem., 276, 48967–48972.CrossRefPubMedGoogle Scholar
  35. 35.
    Singh, R., Barden, A., Mori, T., and Beilin, L. (2001) Advanced glycation end-products: a review, Diabetologia, 44, 129–146.CrossRefPubMedGoogle Scholar
  36. 36.
    Fu, M., Requena, J. R., Jenkins, A. J., Lyons, T. J., Baynes, J. W., and Thorpe, S. R. (1996) The advanced end product, N-(carboxymethyl) lysine, is a product of both lipid peroxidation and glyoxidation reactions, J. Biol. Chem., 271, 9982–9986.CrossRefPubMedGoogle Scholar
  37. 37.
    Acimovic, J. M., Stanimirovic, B. D., and Mandic, L. M. (2009) The role of the thiol group in protein modification with methylglyoxal, J. Serb. Chem. Soc., 74, 867–883.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2016

Authors and Affiliations

  1. 1.College of Medicine and Medical Sciences, Department of Medical BiochemistryArabian Gulf UniversityManamaKingdom of Bahrain
  2. 2.Hamdard Institute of Medical Sciences and Research, Department of PathologyHamdard UniversityNew DelhiIndia

Personalised recommendations