Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Restoration of Declined Immune Responses and Hyperlipidemia by Rubus occidenalis in Diet-Induced Obese Mice

  • Received : 2016.03.01
  • Accepted : 2016.06.14
  • Published : 2017.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

Hyperlipidemia, which is closely associated with a fatty diet and aging, is commonly observed in the western and aged society. Therefore, a novel therapeutic approach for this disease is critical, and an immunological view has been suggested as a novel strategy, because hyperlipidemia is closely associated with inflammation and immune dysfunction. In this study, the effects of an aqueous extract of Rubus occidentalis (RO) in obese mice were investigated using immunological indexes. The mice were fed a high-fat diet (HFD) to induce hyperlipidemia, which was confirmed by biochemical analysis and examination of the mouse physiology. Two different doses of RO and rosuvastatin, a cholesterol synthesis inhibitor used as a control, were orally administered. Disturbances in immune cellularity as well as lymphocyte proliferation and cytokine production were significantly normalized by oral administration of RO, which also decreased the elevated serum tumor necrosis factor $(TNF)-{\alpha}$ level and total cholesterol. The specific immune-related actions of RO comprised considerable improvement in cytotoxic T cell killing functions and regulation of antibody production to within the normal range. The immunological evidence confirms the significant cholesterol-lowering effect of RO, suggesting its potential as a novel therapeutic agent for hyperlipidemia and associated immune decline.

Keywords

References

  1. Bhandary, B., Lee, G. H., Marahatta, A., Lee, H. Y., Kim, S. Y., So, B. O., Kwon, J. W., Song, J. Y., Lee, H. K., Kim, H. R., Chae, S. W. and Chae H. J. (2012) Water extracts of immature Rubus coreanus regulate lipid metabolism in liver cells. Biol. Pharm. Bull. 35, 1907-1913. https://doi.org/10.1248/bpb.b12-00022
  2. Bradley, J. R. (2008) TNF-mediated inflammatory disease. J. Pathol. 214, 149-160. https://doi.org/10.1002/path.2287
  3. Cha, H. S., Park, M. S. and Park, K. M. (2001) Physiological activities of Rubus coreanus Miquel. Korean J. Food Sci. Technol. 33, 409-415.
  4. Choi, H. R., Lee, S. J., Lee, J. H., Kwon, J. W., Lee, H. K., Jeong, J. T. and Lee, T. B. (2013) Cholesterol-lowering effects of unripe black raspberry water extract. J. Korean Soc. Food Sci. Nutr. 42, 1899-1907. https://doi.org/10.3746/jkfn.2013.42.12.1899
  5. Emanuela, F., Grazia, M., Marco de, R., Maria Paola, L., Giorgio, F. and Marco, B. (2012) Inflammation as a Link between Obesity and Metabolic Syndrome. J. Nutr. Metab. 2012, 476380.
  6. Feingold, K. R. and Grunfeld, C. (1992) Role of cytokines in inducing hyperlipidemia. Diabetes 41 Suppl 2, 97-101. https://doi.org/10.2337/diab.41.2.S97
  7. Geerlings, S. E. and Hoepelman, A. I. (1999) Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunol. Med. Microbiol. 26, 259-265. https://doi.org/10.1111/j.1574-695X.1999.tb01397.x
  8. Gottschlich, M. M., Mayes, T., Khoury, J. C. and Warden, G. D. (1993) Significance of obesity on nutritional, immunologic, hormonal, and clinical outcome parameters in burns. J. Am. Diet. Assoc. 93, 1261-1268. https://doi.org/10.1016/0002-8223(93)91952-M
  9. Im, S. A., Lee, Y. R., Lee, Y. H., Lee, M. K., Park, Y. I., Lee, S., Kim, K. and Lee, C. K. (2010) In vivo evidence of the immunomodulatory activity of orally administered Aloe vera gel. Arch. Pharm. Res. 33, 451-456. https://doi.org/10.1007/s12272-010-0315-1
  10. Jeong, M. Y., Kim, H. L., Park, J., Jung, Y., Youn, D. H., Lee, J. H., Jin, J. S., So, H. S., Park, R., Kim, S. H., Kim, S. J., Hong, S. H. and Um, J. Y. (2015) Rubi Fructus (Rubus coreanus) activates the expression of thermogenic genes in vivo and in vitro. Int. J. Obes. (Lond). 39, 456-464. https://doi.org/10.1038/ijo.2014.155
  11. Kim, Y. J., Han, S. H., Jeon, J. Y., Hwang, M. H., Im, Y. J., Chae, S. W. and Kim, M. G. (2012) Method development of ellagic acid as marker compound for standardization of gochangbokbunja (Rubus coreanus Miquel) as functional ingredient. J. Korean Soc. Food Sci. Nutr. 41, 1554-1558. https://doi.org/10.3746/jkfn.2012.41.11.1554
  12. Lee, J. E., Cho, S. M., Park, E., Lee, S. M., Kim, Y., Auh, J. H., Choi, H. K., Lim, S., Lee, S. C. and Kim, J. H. (2014a) Anti-inflammatory effects of Rubus coreanus Miquel through inhibition of NF-${\kappa}B$ and MAP Kinase. Nutr. Res. Pract. 8, 501-508. https://doi.org/10.4162/nrp.2014.8.5.501
  13. Lee, J. E., Park, E., Lee, J. E., Auh, J. H., Choi, H. K., Lee, J., Cho, S. and Kim, J. H. (2011) Effects of a Rubus coreanus Miquel supplement on plasma antioxidant capacity in healthy Korean men. Nutr. Res. Pract. 5, 429-434. https://doi.org/10.4162/nrp.2011.5.5.429
  14. Lee, M. J., Lee, S. J., Choi, H. R., Lee, J. H., Kwon, J. W., Chae, K. S., Jeong, J. T. and Lee, T. B. (2014b) Improvement of cholesterol and blood pressure in fruit, leaf and stem extracts from black raspberry in vitro. Korean J. Med. Crop. Sci. 22, 177-187. https://doi.org/10.7783/KJMCS.2014.22.3.177
  15. Lei, L., Li, H., Yan, F. and Xiao, Y. (2013) Hyperlipidemia impaired innate immune response to periodontal pathogen porphyromonas gingivalis in apolipoprotein E knockout mice. PLoS One. 8, e71849. https://doi.org/10.1371/journal.pone.0071849
  16. Ludewig, B., Jaggi, M., Dumrese, T., Brduscha-Riem, K., Odermatt, B., Hengartner, H. and Zinkernagel, R. M. (2001) Hypercholesterolemia exacerbates virus-induced immunopathologic liver disease via suppression of antiviral cytotoxic T cell responses. J. Immunol. 166, 3369-3376. https://doi.org/10.4049/jimmunol.166.5.3369
  17. Lumeng, C. N. and Saltiel, A. R. (2011) Inflammatory links between obesity and metabolic disease. J. Clin. Invest. 121, 2111-2117. https://doi.org/10.1172/JCI57132
  18. Nam, M. K., Choi, H. R., Cho, J. S., Cho, S. M., Ha, K. C., Kim, T. H., Ryu, H. Y. and Lee, Y. I. (2014) Inhibitory effects of Rubi Fructus extracts on hepatic steatosis development in high-fat diet-induced obese mice. Mol. Med. Rep. 10, 1821-1827. https://doi.org/10.3892/mmr.2014.2398
  19. Okla, M., Kang, I., Kim da, M., Gourineni, V., Shay, N., Gu, L. and Chung, S. (2015) Ellagic acid modulates lipid accumulation in primary human adipocytes and human hepatoma Huh7 cells via discrete mechanisms. J. Nutr. Biochem. 26, 82-90. https://doi.org/10.1016/j.jnutbio.2014.09.010
  20. Popa, C., Netea, M. G., van Riel, P. L., van der Meer, J. W. and Stalenhoef, A. F. (2007) The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism and cardiovascular risk. J. Lipid Res. 48, 751-762. https://doi.org/10.1194/jlr.R600021-JLR200
  21. Pope, C. R. (1991) Pathology of lymphoid organs with emphasis on immunosuppression. Vet. Immunol. Immunopathol. 30, 31-44. https://doi.org/10.1016/0165-2427(91)90006-X
  22. Saleem, A., Husheem, M., Härkönen, P. and Pihlaja, K. (2002) Inhibition of cancer cell growth by crude extract and the phenolics of Terminalia chebutaretz. fruit. J. Ethnopharmacol. 81, 327-336. https://doi.org/10.1016/S0378-8741(02)00099-5
  23. Sato Mito, N., Suzui, M., Yoshino, H., Kaburagi, T. and Sato, K. (2009) Long term effects of high fat and sucrose diets on obesity and lymphocyte proliferation in mice. J. Nutr. Health Aging 13, 602-606. https://doi.org/10.1007/s12603-009-0170-2
  24. Seeram, N. P., Adams, L. S., Henning, S. M., Niu, Y., Zhang, Y., Nair, M. G. and Heber, D. (2005) In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegrante juice. J. Nutr. Biochem. 16, 360-367. https://doi.org/10.1016/j.jnutbio.2005.01.006
  25. van Diepen, J. A., Berbée, J. F., Havekes, L. M. and Rensen, P. C. (2013) Interactions between inflammation and lipid metabolism: Relevance for efficacy of anti-inflammatory drugs in the treatment of atherosclerosis. Atherosclerosis 228, 306-315. https://doi.org/10.1016/j.atherosclerosis.2013.02.028
  26. Winer, D. A., Winer, S., Shen, L., Wadia, P. P., Yantha, J., Paltser, G., Tsui, H., Wu, P., Davidson, M. G., Alonso, M. N., Leong, H. X., Glassford, A., Caimol, M., Kenkel, J. A., Tedder, T. F., McLaughlin, T., Miklos, D. B., Dosch, H. M. and Engleman, E. G. (2011) B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 17, 610-617. https://doi.org/10.1038/nm.2353
  27. Wisse, B. E. (2004) The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J. Am. Soc. Nephrol. 15, 2792-2800. https://doi.org/10.1097/01.ASN.0000141966.69934.21
  28. Yang, H., Youm, Y. H., Vandanmagsar, B., Rood, J., Kumar, K. G., Butler, A. A. and Dixit, V. D. (2009) Obesity accelerates thymic aging. Blood 114, 3803-3812. https://doi.org/10.1182/blood-2009-03-213595
  29. Yoon, I., Wee, J. H., Moon, J. H., Ahn, T. H. and Park, K. H. (2003) Isolation and identification of quercetin with antioxidative activity from the fruits of Rubus coreanum Miquel. Korean J. Food Sci. Technol. 35, 499-502.
  30. Yoshimura, Y., Nishii, S., Zaima, N., Moriyama, T. and Kawamura, Y. (2013) Ellagic acid improves hepatic steatosis and serum lipid composition through reduction of serum resistin levels and transcriptional activation of hepatic ppara in obese, diabetic KK-A(y) mice. Biochem. Biophys. Res. Commun. 434, 486-491. https://doi.org/10.1016/j.bbrc.2013.03.100

Cited by

  1. Metabolic Regulation of Glycolysis and AMP Activated Protein Kinase Pathways during Black Raspberry-Mediated Oral Cancer Chemoprevention vol.9, pp.7, 2017, https://doi.org/10.3390/metabo9070140