Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

[6]-Gingerol Attenuates Autophagy and Increases Activities of Antioxidative Defense Enzymes in Mice with Cerulein-induced Acute Pancreatitis

Cerulein 유도 급성췌장염 마우스모델에서 자가분해 조절과 항산화 활성에 미치는 [6]-gingerol의 영향

  • Kim, Sung Ok (Team for Scientification of Korean Medical Intervention (BK21 Plus) & Department of Herbal Pharmacology, College of Oriental Medicine, Daegu Haany University) ;
  • Choi, Yung Hyun (Department of Biochemistry, Dongeui University College of Oriental Medicine, Anti-Aging Research Center & Blue-Bio Industry RIC, Dongeui University)
  • 김성옥 (BK21 Plus Team & 대구한의대학교 한의과대학 본초약리학교실) ;
  • 최영현 (동의대학교 한의과대학 생화학교실, 항노 화연구소 및 블루바이오소재개발센터)
  • Received : 2013.09.24
  • Accepted : 2013.10.24
  • Published : 2013.10.30
Download PDF
⟨ Previous Next ⟩

Abstract

The current study investigated the effects of [6]-gingerol, a ginger phytochemical, on the expression of autophagy-related genes and the activation of antioxidative enzymes in the pancreas of mice with cerulein-induced acute pancreatitis. The following were studied: pancreatic edema, ${\alpha}$-amylase activity in serum, expression of autophagy genes, activities of antioxidative defense enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the production of lipid peroxidation (LPO). The results revealed that cerulein-induced edema in the pancreas and ${\alpha}$-amylase activity in the cerulein group significantly increased compared with that of the control. However, that of the [6]-gingerol pretreated group was significantly decreased compared with that of the cerulein-alone injected group (positive control). There was no significant difference compared with that of control. The expression of autophagy-related proteins, including Beclin-1 and cleaved microtubule-associated protein 1 light chain 3, were significantly increased in the positive control but significantly decreased in the [6]-gingerol-pretreated group. Furthermore, the activities of SOD and GSH-Px in the positive control were decreased compared with those of the control. However, those of the [6]-gingerol pretreated group were significantly increased compared with those of the cerulein-alone group. The mRNA levels and antioxidant enzyme activities were similar. The production of LPO in the cerulein with and without [6]-gingerol groups was increased by 133.1% and 26.3%, respectively, compared with that of the control, whereas that of the [6]-gingerol-pretreated group was significantly decreased by 48.5% compared with that of the positive control. Therefore, [6]-gingerol may be a strong candidate in reducing autophagy and LPO production and in enhancing antioxidative enzyme activities to help prevent acute and chronic pancreatitis.

열대아시아 원산의 다년생 초본 생강의 주성분인 [6]-gingerol은 항산화 및 항염증 등의 특성이 잘 알려져 있지만 cerulein 유도 급성췌장염에서의 자가분해 관련 유전자 발현 조절과 항산화 효소 활성에 대한 연구는 거의 없다. 본 연구에서는 cerulein 유도 급성췌장염 동물모델에서 [6]-gingerold의 자가분해 조절과 항산화 작용을 조사하였다. 급성췌장염 유발 전 4일 동안 [6]-gingerol (0.1 mg/20 g mouse/day)을 경구투여 한 후 $50{\mu}g/kg$ cerulein을 복강주사로 급성 췌장염을 유도하였다. 그 결과 혈중 ${\alpha}$-amyase 활성, 자가분해 표적 유전자(Beclin-1 및 cleaved LC3-II)의 발현, 지질과산화는 [6]-gingerol 투여군에서 유의적으로 감소하였으며, 항산화지표 효소인 SOD와 GSH-Px 활성은 [6]-gingerol 투여군에서 유의적으로 증가하였다. 이상의 결과들은 천연식물소재 생강의 유효성분 중 하나인 [6]-gingerol이 cerulein 유도 급성 췌장염에서 자가분해 조절과 감소된 항산화효소 활성을 강화하는 효과를 나타내므로 생강이 급성췌장염의 예방과 치료에 대한 기능성 식품소재로 그 활용이 매우 높을 것으로 사료된다.

Keywords

References

  1. Chance, B., Sies, H. and Boveris, A. 1979. Hydroperoxide metabolism in mammalian organs. Physiol Rev 59, 527-605. https://doi.org/10.1152/physrev.1979.59.3.527
  2. Dabrowski, A., Gabryelewicz, A., Wereszczynska-Siemiatkowska, U. and Chyczewski, L. 1998. Oxygen-derived free radicals in cerulein-induced acute pancreatitis. Scand J Gastroenterol 23, 1245-1249.
  3. Devy, C. and Gautier, R. 1990. New perspectives on the biochemistry of superoxide anion and the efficiency of superoxide dismutase. Biochem Pharmacol 39, 399-405. https://doi.org/10.1016/0006-2952(90)90043-K
  4. Dugasani, S., Pichika, M. R., Nadarajah, V. D., Balijepalli, M. K., Tandra, S. and Korlakunta, J. N. 2010. Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. J Ethnopharmacol 127, 515-520. https://doi.org/10.1016/j.jep.2009.10.004
  5. Duthie, G. G., Duthie, S. J. and Kyle, J. A. 2000. Plant polyphenols in cancer and heart disease: implications as nutritional antioxidants. Nutr Res Rev 13, 79-106. https://doi.org/10.1079/095442200108729016
  6. Esrefoglu, M. 2012. Oxidative stress and benefits of antioxidant agents in acute and chronic hepatitis. Hepat Mon 12, 160-167. https://doi.org/10.5812/hepatmon.5090
  7. Fortunato, F., Burgers, H., Bergmann, F., Rieger, P., Buchler, M. W., Kroemer, G. and Werner, J. 2009. Impaired autolysosome formation correlates with Lamp-2 depletion: role of apoptosis, autophagy and necrosis in pancreatitis. Gastroenterology 137, 350-360. https://doi.org/10.1053/j.gastro.2009.04.003
  8. Hashimoto, D., Ohmuraya, M., Hirota, M., Yamamoto, A., Suyama, K., Ida, S., Okumura, Y., Takahashi, E., Kido, H., Araki, K., Baba, H., Mizushima, N. and Yamamura, K. 2008. Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells. J Cell Biol 181, 1065-1072. https://doi.org/10.1083/jcb.200712156
  9. Horton, A. A. and Fairhurst, S. 1987. Lipid peroxidation and mechanisms of toxicity. Crit Rev Toxicol 18, 27-79. https://doi.org/10.3109/10408448709089856
  10. Jung, K. W., Won, Y. J., Kong, H. J., Oh, C. M., Seo, H. G. and Lee, J. S. 2013. Cancer statistics in Korea: incidence, mortality, survival and prevalence in 2010. Cancer Res Treat 45, 1-14. https://doi.org/10.4143/crt.2013.45.1.1
  11. Katiyar, S. K, Agarwal, R. and Mukhtar, H. 1996. Inhibition of tumor promotion in SENCAR mouse skin by ethanol extract of Zingiber officinale rhizome. Cancer Res 56, 1023-1030.
  12. Kiuchi, F., Shibuya, M. and Sankawa, U. 1982. Inhibitors of prostaglandin biosynthesis from ginger. Chem Pharm Bull (Tokyo) 30, 754-757. https://doi.org/10.1248/cpb.30.754
  13. Kim, E. H., Sohn, S., Kwon, H. J., Kim, S. U., Kim, M. J., Lee, S. J. and Choi, K. S. 2007. Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant 21 glioma cells. Cancer Res 67, 6314-6324. https://doi.org/10.1158/0008-5472.CAN-06-4217
  14. Kim, S. O. and Choe, W. K. 2011. Effect of EGCG on expression of neurogenin 3 via the MAP kinase signaling pathway in AR42J cells, a rat pancreatic tumor cell line. Korean J Nutr 44, 196-202. https://doi.org/10.4163/kjn.2011.44.3.196
  15. Kim, S. O., Kim, M. R. and Choe, W. K. 2012. Green tea polyphenol (-)-epigallocatechin-3-gallate regulated autophagy in cerulein-induced acute pancreastitis via inhibition of MAP kinase pathway. Cancer Prev Res 17, 232-238.
  16. Kondo, Y., Kanzawa, T., Sawaya, R. and Kondo, S. 2005. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5, 726-734. https://doi.org/10.1038/nrc1692
  17. Lee, B. S., Ko, M. S., Kim, H. J., Kwak, I. S., Kim, D. H. and Chung, B. W. 2006. Separation of 6-gingerol from ginger (Zingiber officinale Roscoe) and antioxidative activity. Korean J Biotechnol Bioeng 21, 484-488.
  18. Liu, Y., Borchert, G. L., Donald, S. P., Surazynski, A., Hu, C. A., Weydert, C. J., Oberley, L. W. and Phang, J. M. 2005. MnSOD inhibits proline oxidase-induced apoptosis in colorectal cancer cells. Carcinogenesis 26, 1335-1342. https://doi.org/10.1093/carcin/bgi083
  19. Levine, B. and Kroemer, G. 2008. Autophagy in the pathogenesis of disease. Cell 132, 27-42. https://doi.org/10.1016/j.cell.2007.12.018
  20. Melov, S. 2009. Mitochondrial oxidative stress. Physiologic consequences and potential for a role in aging. Ann N Y Acad Sci 908, 219-225.
  21. Mizushima, N., Yoshimori, T. and Levine, B. 2010. Methods in mammalian autophagy research. Cell 140, 313-326. https://doi.org/10.1016/j.cell.2010.01.028
  22. Morimitsu, Y., Nakagawa, Y., Hayashi, K., Fujii, H., Kumagai, T., Nakamura, Y., Osawa, T., Horio, F., Itoh, K., Iida. K., Yamamoto, M. and Uchida, K. A. 2002. Sulforaphane analogue that potently activates the Nrf2- dependent detoxification pathway. J Biol Chem 277, 3456-3463. https://doi.org/10.1074/jbc.M110244200
  23. Paterniti, I., Mazzon, E., Riccardi, L., Galuppo, M., Impellizzeri, D., Esposito, E., Bramanti, P., Cappellani, A. and Cuzzocrea, S. 2012. Peroxisome proliferator-activated receptor ${\beta}/{\delta}$ agonist GW0742 ameliorates cerulein- and taurocholate-induced acute pancreatitis in mice. Surgery 152, 90-106. https://doi.org/10.1016/j.surg.2012.02.004
  24. Patlolla, A. K., Barnes, C., Hackett, D. and Tchounwou, P. B. 2009. Potassium dichromate induced cytotoxicity, genotoxicity and oxidative stress in human liver carcinoma (HepG2) cells. Int J Environ Res Public Health 6, 643-653. https://doi.org/10.3390/ijerph6020643
  25. Pharmacology of Oriental Medicine Textbook Editing Committee. 2010. Pharmacology of Oriental medicine, pp. 594, 3rd ed., Shinilbooks,Yungdongfor-gu, Seoul, Repbulic of Korea.
  26. Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., Rosen, J., Eskelinen, E. L., Mizushima, N., Ohsumi, Y., Cattoretti, G. and Levine, B. 2003. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112, 1809-1920. https://doi.org/10.1172/JCI20039
  27. Rosenfeldt, M. T. and Ryan, K. M. 2009. The role of autophagy in tumour development and cancer therapy. Expert Rev Mol Med 11, 1-20. https://doi.org/10.1017/S1462399409000921
  28. Shanmugam, M. K. and Bhatia, M. 2010. The role of pro-inflammatory molecules and pharmacological agents in acute pancreatitis and sepsis. Inflamm Allergy Drug Targets 9, 20-31. https://doi.org/10.2174/187152810791292881
  29. Spencer, S. R., Xue, L. A., Klenz, E. M. and Talalay, P. 1991. The potency of inducers of NAD(P)H: (quinone-acceptor) oxidoreductase parallels their efficiency as substrates for glutathione transferases. Structural and electronic correlations. Biochem J 273, 711- 717. https://doi.org/10.1042/bj2730711
  30. Steinberg, W. and Tenner, S. 1994. Acute pancreatitis. N Engl J Med 330, 1198-1210. https://doi.org/10.1056/NEJM199404283301706
  31. Takabayashi, F. and Harada, N. 1997. Effects of green tea catechins (polyphenon 100) on cerulein-induced acute pancreatitis in rats. Pancreas 14, 276-279. https://doi.org/10.1097/00006676-199704000-00009
  32. Takahashi, M., Shibata, M. and Niki, E. 2001. Estimation of lipid peroxidation of live cells using fluorescent probe. Free Radic Biol Med 31, 164-174. https://doi.org/10.1016/S0891-5849(01)00575-5
  33. Thomson, M., Al-Qattan, K. K., Al-Sawan, S. M., Alnaqeeb, M. A., Khan, I. and Ali, M. 2002. The use of ginger (Zingiber officinale Roscoe) as a potential anti-inflammatory and antithrombotic agent. Prostaglandins Leukot Essent Fatty Acids 67, 475-478. https://doi.org/10.1054/plef.2002.0441
  34. Zaninovic, V., Gukovskaya, A. S., Gukovsky, I., Mouria, M. and Pandol, S. J. 2000. Cerulein upregulates ICAM-1 in pancreatic acinar cells, which mediates neutrophil adhesion to these cells. Am J Physiol Gastrointest Liver Physiol 279, G666-G676.