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http://dx.doi.org/10.1016/j.jgr.2017.03.004

New metabolites from the biotransformation of ginsenoside Rb1 by Paecilomyces bainier sp.229 and activities in inducing osteogenic differentiation by Wnt/β-catenin signaling activation  

Zhou, Wei (Department of Chemistry, Fudan University)
Huang, Hai (School of Pharmacy, Fudan University)
Zhu, Haiyan (School of Pharmacy, Fudan University)
Zhou, Pei (School of Pharmacy, Fudan University)
Shi, Xunlong (School of Pharmacy, Fudan University)
Publication Information
Journal of Ginseng Research / v.42, no.2, 2018 , pp. 199-207 More about this Journal
Abstract
Background: Ginseng is a well-known traditional Chinese medicine that has been widely used in a range of therapeutic and healthcare applications in East Asian countries. Microbial transformation is regarded as an effective and useful technology in modification of nature products for finding new chemical derivatives with potent bioactivities. In this study, three minor derivatives of ginsenoside compound K were isolated and the inducing effects in the Wingless-type MMTV integration site (Wnt) signaling pathway were also investigated. Methods: New compounds were purified from scale-up fermentation of ginsenoside Rb1 by Paecilomyces bainier sp. 229 through repeated silica gel column chromatography and high pressure liquid chromatography. Their structures were determined based on spectral data and X-ray diffraction. The inductive activities of these compounds on the Wnt signaling pathway were conducted on MC3T3-E1 cells by quantitative real-time polymerase chain reaction analysis. Results: The structures of a known 3-keto derivative and two new dehydrogenated metabolites were elucidated. The crystal structure of the 3-keto derivative was reported for the first time and its conformation was compared with that of ginsenoside compound K. The inductive effects of these compounds on osteogenic differentiation by activating the Wnt/b-catenin signaling pathway were explained for the first time. Conclusion: This study may provide a new insight into the metabolic pathway of ginsenoside by microbial transformation. In addition, the results might provide a reasonable explanation for the activity of ginseng in treating osteoporosis and supply good monomer ginsenoside resources for nutraceutical or pharmaceutical development.
Keywords
biotransformation; ginsenoside; osteogenic differentiation; $Wnt/{\beta}-catenin$ signal;
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1 Glass DA, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, Taketo MM, Long F, McMahon AP, Lang RA, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 2005;8:751-64.   DOI
2 Lim SI, Cho CW, Choi UK, Kim YC. Antioxidant activity and ginsenoside pattern of fermented white ginseng. J Gin Res 2010;34:168-74.   DOI
3 He BC, Gao JL, Luo X, Luo J, Shen J, Wang L, Zhou Q, Wang YT, Luu HH, Haydon RC, et al. Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/${\beta}$-catenin signaling. Int J Oncol 2011;38:437-45.
4 Shin HS, Park SY, Hwang ES, Lee DG, Song HG, Mavlonov GT, Yi TH. The inductive effect of ginsenoside F2 on hair growth by altering the WNT signal pathway in telogen mouse skin. Eur J Pharmacol 2014;740:82-9.
5 Bi XL, Xia XC, Mou T, Jiang BW, Fan DD, Wang P, Liu YF, Hou Y, Zhao YQ. Antitumor activity of three ginsenoside derivatives in lung cancer is associated with Wnt/${\beta}$-catenin signaling inhibition. Eur J Pharmacol 2014;742:145-52.   DOI
6 Cui L, Wu T, Li QN, Lin LS, Liang NC. Preventive effects of ginsenosides on osteopenia of rats induced by ovariectomy. Acta Pharmacol Sin 2001;22:428-34.
7 Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 2013;19:179-92.   DOI
8 Park JD, Rhee DK, Lee YH. Biological activities and chemistry of saponins from Panax ginseng C.A. Meyer. Phytochem Rev 2005;4:159-75.   DOI
9 Jia L, Zhao YQ, Liang XJ. Current evaluation of the millennium phytomedicineginseng (ii): Collected chemical entities, modern pharmacology, and clinical applications emanated from traditional Chinese medicine. Cur Med Chem 2009;16:2924-42.
10 Shin BK, Kwon SW, Park JH. Chemical diversity of ginseng saponins from Panax ginseng. J Gin Res 2015;39:287-98.   DOI
11 Karikura M, Miyase T, Tanizawa H, Taniyama T, Takino Y. Studies on absorption, distribution, excretion and metabolism of ginseng saponins. VII. Comparison of the decomposition modes of ginsenoside-Rb1 and -Rb2 in the digestive tract of rats. Chem Pharm Bull 1991;39:2357-61.   DOI
12 Takino T. Studies on the pharmacodynamics of ginsenoside Rg1, Rb1, and Rb2 in rats. Yakugaku Zasshi 1994;114:550-64.   DOI
13 Bae EA, Choo MK, Park EK, Park SY, Shin HY, Kim DH. Metabolism of ginsenoside Rc by intestinal bacteria and its related antiallergic activity. Chem Pharm Bull 2002;25:743-7.   DOI
14 Hasegawa H. Proof of the mysterious efficacy of ginseng. Basic and clinical trials: Metabolic activation of ginsenoside: Deglycosylation by intestinal bacteria and esterification with fatty acid. J Pharmacol Sci 2004;95:153-7.
15 Park CS, Yoo MH, Noh KH, Oh DK. Biotransformation of ginsenosides by hydrolyzing the sugar moieties of ginsenosides using microbial glycosidases. Appl Microbiol Biotechnol 2010;87:9-19.
16 Cui L, Wu SQ, Zhao CA, Yin CR. Microbial conversion of major ginsenosides in ginseng total saponins by Platycodon grandiflorum endophytes. J Gin Res 2016;40:366-74.   DOI
17 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.   DOI
18 Zhou W, Li JY, Li XW, Yan Q, Zhou P. Development and validation of a reversed-phase HPLC method for quantitative determination of ginsenosides Rb1, Rd, F2, and compound K during the process of biotransformation of ginsenoside Rb1. J Sep Sci 2008;31:921-5.   DOI
19 Liu QH, Zhou P, Bai H, Zhou W, Li JJ, Feng MQ, Hua ML, Xu JY. New use of ginsenoside compound-K for the prevention of rheumatoid arthritis. PCT/CN2007/002354.
20 Kuban M, Ogen G, Kha IA, Bedi E. Microbial transformation of cycloastragenol. Phytochemistry 2013;88:99-104.   DOI
21 Bhattia HN, Khan SS, Khan A, Rani M, Ahmad VU, Choudhary MI. Biotransformation of monoterpenoids and their antimicrobial activities. Phytomedicine 2014;21:1597-626.   DOI
22 Zhou W, Feng MQ, Li XW, Yan Q, Zhou CQ, Li JY, Zhou P. X-ray structure investigation of 20(S)-O-b-D-glucopyranosyl-protopanaxadiol and antitumor effect on Lewis lung carcinoma in vivo. Chem Biodivers 2009;6:380-8.   DOI
23 Sheldrick GM. SHELXS-97, Program for the solution of crystal structure. Gotingen, Germany: University of Gotingen; 1997.
24 Sheldrick GM. SHELXL-97, Program for the refinement of crystal structure. Gotingen, Germany: University of Gotingen; 1997.
25 Chen GT, Yang M, Song Y, Lu ZQ, Zhang JQ, Huang HL, Wu LJ, Guo DA. Microbial transformation of ginsenoside Rb1 by Acremonium strictum. Appl Microbiol Biotechnol 2008;77:1345-50.   DOI
26 Serigano K, Sakai D, Hiyama A, Tamura F, Tanaka M, Mochida J. Effect of cell number on mesenchymal stem cell transplantation in a canine disc degeneration model. J Orthop Res 2010;28:1267-75.   DOI
27 Lee HS, Jung EY, Bae SH, Kwon KH, Kim JM, Suh HJ. Stimulation of osteoblastic differentiation and mineralization in MC3T3-E1 cells by yeast hydrolysate. Phytother Res 2011;25:716-23.   DOI
28 Thomas GP, Baker SU, Eisman JA, Gardiner EM. Changing RANKL/OPG mRNA expression in differentiating murine primary osteoblasts. J Endocrinol 2001;170:451-60.   DOI
29 Tanaka H, Mine T, OgasaH, Taguchi T, Liang CT. Expression of RANKL/OPG during bone remodeling in vivo. Biochem Biophys Res Commun 2011;411:690-4.   DOI
30 Bennett CN, Ouyang H, Ma YL, Zeng Q, Gerin I, Sousa KM, Lane TF, Krishnan V, Hankenson KD, MacDougald OA. Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. J Bone Miner Res 2007;22:1924-32.   DOI
31 Chen GT, Yang X, Li JL, Ge HJ, Songa Y, Ren J. Biotransformation of 20(S)-protopanaxadiol by Aspergillus niger AS 3.1858. Fitoterapia 2013;91:256-60.
32 Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem 2006;281:22429-33.   DOI
33 Krishnan V, Bryant HU, Macdougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest 2006;116:1202-9.   DOI
34 Li HF, Ye M, Guo HZ, Tian Y, Zhang J, Zhou JP, Hu YC, Guo D. Biotransformation of 20(S)-protopanaxadiol by Mucor spinosus. Phytochemistry 2009;70:1416-20.   DOI
35 Wang JR, Yau LF, Zhang R, Xia Y, Ma J, Ho HM, Hu P, Hu M, Liu L, Jiang ZH. Transformation of ginsenosides from notoginseng by artificial gastric juice can increase cytotoxicity toward cancer cells. J Agric Food Chem 2014;62:2558-73.   DOI
36 Li XW, Zhou W, Yan Q, Zhou P. 20-O-D-xylopyranosyl(1,6)-${\beta}$-D-glucopyranosyl-20(S)-protopanaxdiol methanol solvate. Acta Crystalgr Sect E. Struct Rep Online 2008;E64:o165. http://dx.doi.org/10.1107/S1600536807063118.   DOI
37 Moon RT, Kohn AD, De Ferrari GV, Kaykas A. WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 2004;5:691-701.
38 Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165-76.   DOI
39 Almeida M, Han L, Bellido T, Manolagas SC, Kousteni S. Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by beta-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT. J Biol Chem 2005;280:41342-51.   DOI