Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Enhanced antidiabetic efficacy and safety of compound K/β-cyclodextrin inclusion complex in zebrafish

  • Nam, Youn Hee (Graduate School of Biotechnology, Kyung Hee University, Global Campus) ;
  • Le, Hoa Thi (Graduate School of East-West Medical Science, Kyung Hee University) ;
  • Rodriguez, Isabel (Graduate School of Biotechnology, Kyung Hee University, Global Campus) ;
  • Kim, Eun Young (Graduate School of Biotechnology, Kyung Hee University, Global Campus) ;
  • Kim, Keonwoo (Graduate School of Biotechnology, Kyung Hee University, Global Campus) ;
  • Jeong, Seo Yule (Graduate School of Biotechnology, Kyung Hee University, Global Campus) ;
  • Woo, Sang Ho (Graduate School of Biotechnology, Kyung Hee University, Global Campus) ;
  • Lee, Yeong Ro (Graduate School of Biotechnology, Kyung Hee University, Global Campus) ;
  • Castaneda, Rodrigo (Graduate School of Biotechnology, Kyung Hee University, Global Campus) ;
  • Hong, Jineui (Graduate School of Biotechnology, Kyung Hee University, Global Campus) ;
  • Ji, Min Gun (Department of Oriental Medicine Biotechnology, College of Life Sciences, Kyung Hee University, Global Campus) ;
  • Kim, Ung-Jin (Graduate School of Biotechnology, Kyung Hee University, Global Campus) ;
  • Hong, Bin Na (Department of Oriental Medicine Biotechnology, College of Life Sciences, Kyung Hee University, Global Campus) ;
  • Kim, Tae Woo (Graduate School of East-West Medical Science, Kyung Hee University) ;
  • Kang, Tong Ho (Graduate School of Biotechnology, Kyung Hee University, Global Campus)
  • Received : 2016.06.29
  • Accepted : 2016.08.17
  • Published : 2017.01.15
Download PDF
⟨ Previous Next ⟩

Abstract

Background: 20(S)-Protopanaxadiol 20-O-D-glucopyranoside, also called compound K (CK), exerts antidiabetic effects that are mediated by insulin secretion through adenosine triphosphate (ATP)-sensitive potassium ($K_{ATP}$) channels in pancreatic ${\beta}$-cells. However, the antidiabetic effects of CK may be limited because of its low bioavailability. Methods: In this study, we aimed to enhance the antidiabetic activity and lower the toxicity of CK by including it with ${\beta}$-cyclodextrin (CD) (CD-CK), and to determine whether the CD-CK compound enhanced pancreatic islet recovery, compared to CK alone, in an alloxan-induced diabetic zebrafish model. Furthermore, we confirmed the toxicity of CD-CK relative to CK alone by morphological changes, mitochondrial damage, and TdT-UTP nick end labeling (TUNEL) assays, and determined the ratio between the toxic and therapeutic dose for both compounds to verify the relative safety of CK and CD-CK. Results: The CD-CK conjugate ($EC_{50}=2.158{\mu}M$) enhanced the recovery of pancreatic islets, compared to CK alone ($EC_{50}=7.221{\mu}M$), as assessed in alloxan-induced diabetic zebrafish larvae. In addition, CD-CK ($LC_{50} =20.68{\mu}M$) was less toxic than CK alone ($LC_{50}=14.24{\mu}M$). The therapeutic index of CK and CD-CK was 1.98 and 9.58, respectively. Conclusion: The CD-CK inclusion complex enhanced the recovery of damaged pancreatic islets in diabetic zebrafish. The CD-CK inclusion complex has potential as an effective antidiabetic efficacy with lower toxicity.

Keywords

References

  1. Liu CY, Zhou RX, Sun CK, Jin YH, Yu HS, Zhang TY, Xu LQ, Jin FX. Preparation of minor ginsenosides C-Mc, CY, F2, and CK from American ginseng PPDginsenoside using the special ginsenosidase type-I from Aspergillus Niger g.848. J Ginseng Res 2015;39:221-9. https://doi.org/10.1016/j.jgr.2014.12.003
  2. Bae EA, Choo MK, Park EK, Park SY, Shin HY, Kim DH. Metabolism of ginsenoside R (c) by human intestinal bacteria and its related antiallergic activity. Biol Pharm Bull 2002;25:743-7. https://doi.org/10.1248/bpb.25.743
  3. Yan X, Fan Y, Wei W, Wang P, Liu Q, Wei Y, Zhang L, Zhou G, Yue J, Zhou Z. Production of bioactive ginsenoside compound K in metabolically engineered yeast. Cell Res 2014;24:770-3. https://doi.org/10.1038/cr.2014.28
  4. Wu L, Jin Y, Yin C, Bai L. Co-transformation of Panax major ginsenosides Rb1 and Rg1 to minor ginsenosides CeK and F1 by Cladosporium cladosporioides. J Ind Microbiol Biotechnol 2012;39:521-7. https://doi.org/10.1007/s10295-011-1058-9
  5. Zhou W, Yan Q, Li JY, Zhang XC, Zhou P. Biotransformation of Panax notoginseng saponins into ginsenoside compound K production by Paecilomyces bainier sp 229. J Appl Microbiol 2008;104:699-706. https://doi.org/10.1111/j.1365-2672.2007.03586.x
  6. Kim DY, Park MW, Yuan HD, Lee HJ, Kim SH, Chung SH. Compound K induces apoptosis via CAMK-IV/AMPK pathways in HT-29 colon cancer cells. J Agric Food Chem 2009;57:10573-8. https://doi.org/10.1021/jf902700h
  7. Lee IK, Kang KA, Lim CM, Kim KC, Kim HS, Kim DH, Kim BJ, Chang WY, Choi JH, Hyun JW. Compound K, a metabolite of ginseng saponin, induces mitochondria-dependent and caspase-dependent apoptosis via the generation of reactive oxygen species in human colon cancer cells. Int J Mol Sci 2010;11(12):4916-31. https://doi.org/10.3390/ijms11124916
  8. Kim AD, Kang KA, Kim HS, Kim DH, Choi YH, Lee SJ, Hyun JW. A ginseng metabolite, compound K, induces autophagy and apoptosis via generation of reactive oxygen species and activation of JNK in human colon cancer cells. Cell Death Dis 2013;4:e750. https://doi.org/10.1038/cddis.2013.273
  9. Joh EH, Lee IA, Jung IH, Kim DH. Ginsenoside Rb1 and its metabolite compound K inhibit IRAK-1 activationdthe key step of inflammation. Biochem Pharmacol 2011;82:278-86. https://doi.org/10.1016/j.bcp.2011.05.003
  10. Chen W, Wang J, Luo Y, Wang T, Li X, Li A, Li J, Liu B. Ginsenoside Rb1 and compound K improve insulin signaling and inhibit ER stress-associated NLRP3 inflammasome activation in adipose tissue. J Ginseng Res 2015;40:351-8.
  11. Hossen MJ, Hong YD, Baek KS, Yoo S, Hong YH, Kim JH, Lee JO, Kim D, Park J, Cho JY. In vitro antioxidative and anti-inflammatory effects of the compound K-rich fraction BIOGF1K, prepared from Panax ginseng. J Ginseng Res 2017;41:43-51. https://doi.org/10.1016/j.jgr.2015.12.009
  12. Kim DY, Ro JY, Lee CH. 20 (S)-Protopanaxatriol inhibits release of inflammatory mediators in immunoglobulin E-mediated mast cell activation. J Ginseng Res 2015;39:189-98. https://doi.org/10.1016/j.jgr.2014.11.001
  13. Han GC, Ko SK, Sung JH, Chung SH. Compound K enhances insulin secretion with beneficial metabolic effects in db/db mice. J Agric Food Chem 2007;55:10641-8. https://doi.org/10.1021/jf0722598
  14. Mathiyalagan R, Subramaniyam S, Kim YJ, Kim YC, Yang DC. Ginsenoside compound K-bearing glycol chitosan conjugates: synthesis, physicochemical characterization, and in vitro biological studies. Carbohydr Polym 2014;112:359-66. https://doi.org/10.1016/j.carbpol.2014.05.098
  15. Lee PS, Han JY, Song TW, Sung JH, Kwon OS, Song S, Chung YB. Physicochemical characteristics and bioavailability of a novel intestinal metabolite of ginseng saponin (IH901) complexed with ${\beta}$-cyclodextrin. Int J Pharm 2006;316:29-36. https://doi.org/10.1016/j.ijpharm.2006.02.035
  16. Wang X, Brusseau ML. Solubilization of some low-polarity organic compounds by hydroxypropyl-.beta.-cyclodextrin. Environ Sci Technol 1993;27:2821-5. https://doi.org/10.1021/es00049a023
  17. Pitha J, Pitha J. Amorphous water-soluble derivatives of cyclodextrins: nontoxic dissolution enhancing excipients. J Pharm Sci 1985;74:987-90. https://doi.org/10.1002/jps.2600740916
  18. Samperio C, Boyer R, Eigel III WN, Holland KW, McKinney JS, O'Keefe SF, Smith R, Marcy JE. Enhancement of plant essential oils' aqueous solubility and stability using alpha and beta cyclodextrin. J Agric Food Chem 2010;58:12950-6. https://doi.org/10.1021/jf103275a
  19. Szejtli J. Introduction and general overview of cyclodextrin chemistry. Chem Rev 1998;98:1743-54. https://doi.org/10.1021/cr970022c
  20. Irie T, Uekama K. Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation. J Pharm Sci 1997;86:147-62. https://doi.org/10.1021/js960213f
  21. Loftsson T, Jarho P, Masson M, Jarvinen T. Cyclodextrins in drug delivery. Expert Opin Drug Deliv 2005;2:335-51. https://doi.org/10.1517/17425247.2.1.335
  22. Gao YL, Liu ZF, Li CM, Shen JY, Yin HX, Li GS. Subchronic toxicity studies with ginsenoside compound K delivered to dogs via intravenous administration. Food Chem Toxicol 2011;49:1857-62. https://doi.org/10.1016/j.fct.2011.05.003
  23. Shin JE, Park EK, Kim EJ, Hong YH, Lee KT, Kim DH. Cytotoxicity of compound K (IH-901) and ginsenoside Rh2, main biotransformants of ginseng saponins by bifidobacteria, against some tumor cells. J Ginseng Res 2003;27:129-34. https://doi.org/10.5142/JGR.2003.27.3.129
  24. Klepzig H, Kober G, Matter C, Luus H, Schneider H, Boedeker KH, Kiowski W, Amann KW, Gruber D, Harris S, et al. Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled evaluation of glimepiride and glibenclamide. Eur Heart J 1999;20:439-46. https://doi.org/10.1053/euhj.1998.1242
  25. Huang Q, Bu S, Yu Y, Guo Z, Ghatnekar G, Bu M, Yang L, Lu B, Feng Z, Lin S, et al. Diazoxide prevents diabetes through inhibiting pancreatic ${\beta}$-cells from apoptosis via Bcl-2/Bax rate and p38-b mitogen-activated protein kinase. J Endocrinol 2007;148:81-91. https://doi.org/10.1210/en.2006-0738
  26. Desgraz R, Bonal C, Herrera PL. ${\beta}$-cell regeneration: the pancreatic intrinsic faculty. Trends Endocrinol Metab 2011;22:34-43. https://doi.org/10.1016/j.tem.2010.09.004
  27. Dunn JS, McLetchie NGB. Experimental alloxan diabetes in the rat. Lancet 1943;242:384-7. https://doi.org/10.1016/S0140-6736(00)87397-3
  28. Soto C, Del Razo LM, Neri L. Alloxan decreases intracellular potassium content of the isolated frog skin epithelium. Comp Biochem Physiol C Toxicol Pharmacol 2001;130:19-27. https://doi.org/10.1016/S1532-0456(01)00213-7
  29. Nam YH, Hong BN, Rodriguez I, Ji MG, Kim K, Kim UJ, Kang TH. Synergistic potentials of coffee on injured pancreatic islets and insulin action via KATP channel-blocking in zebrafish. J Agric Food Chem 2015;63:5612-21. https://doi.org/10.1021/acs.jafc.5b00027
  30. Sane RT, Menon SN, Inamdar S, Mote M, Gundi G. Simultaneous determination of pioglitazone and glimepiride by high-performance liquid chromatography. Chromatographia 2004;59(7-8):451-3. https://doi.org/10.1365/s10337-004-0209-9
  31. Guan FY, Gu J, Li W, Zhang M, Ji Y, Li J, Chen L, Hatch GM. Compound K protects pancreatic islet cells against apoptosis through inhibition of the AMPK/JNK pathway in type 2 diabetic mice and in MIN6 ${\beta}$-cells. Life Sci 2014;107:42-9. https://doi.org/10.1016/j.lfs.2014.04.034
  32. Ashcroft FM. ATP-sensitive K+ channels and disease: from molecule to malady. Am J Physiol Endocrinol Metab 2007;293:E880-9. https://doi.org/10.1152/ajpendo.00348.2007
  33. Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 2000;49:1751-60. https://doi.org/10.2337/diabetes.49.11.1751
  34. Tabachnick IIA, Gulbenkian A, Seidman F. The effect of a benzothiadiazine, diazoxide, on carbohydrate metabolism. Diabetes 1964;13:408-18. https://doi.org/10.2337/diab.13.4.408
  35. Muller PY, Milton MN. The determination and interpretation of the therapeutic index in drug development. Nat Rev Drug Discov 2012;11:751-61. https://doi.org/10.1038/nrd3801
  36. Gorrindo P, Williams KC, Lee EB, Walker LS, McGrew SG, Levitt P. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res 2012;5:101-8. https://doi.org/10.1002/aur.237

Cited by

  1. Flavonoid 8- O -Glucuronides from the Aerial Parts of Malva verticillata and Their Recovery Effects on Alloxan-Induced Pancreatic Islets in Zebrafish vol.23, pp.4, 2017, https://doi.org/10.3390/molecules23040833
  2. Preparation, Characterization, and Bioavailability of Host-Guest Inclusion Complex of Ginsenoside Re with Gamma-Cyclodextrin vol.26, pp.23, 2017, https://doi.org/10.3390/molecules26237227