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Planta Med 2014; 80(04): 283-289
DOI: 10.1055/s-0033-1360391
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Biomarker-Guided Screening of Juzen-taiho-to, an Oriental Herbal Formulation for Immunostimulation

Anna Takaoka
1   Department of Chemistry, Hunter College of CUNY, New York, NY, USA
,
Maria Iacovidou
1   Department of Chemistry, Hunter College of CUNY, New York, NY, USA
,
Tal H. Hasson
1   Department of Chemistry, Hunter College of CUNY, New York, NY, USA
,
Diego Montenegro
1   Department of Chemistry, Hunter College of CUNY, New York, NY, USA
,
Xiangming Li
2   HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA
,
Moriya Tsuji
2   HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA
,
Akira Kawamura
1   Department of Chemistry, Hunter College of CUNY, New York, NY, USA
› Author Affiliations
Further Information

Publication History

received 12 June 2013
revised 13 November 2013

accepted 20 January 2014

Publication Date:
18 February 2014 (online)

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Abstract

Juzen-taiho-to is an immunostimulatory herbal formulation that is clinically used in East Asia for cancer patients undergoing chemotherapy and radiation. The formulation stimulates various leukocytes, including T, B, and NK cells and macrophages. Although Juzen-taiho-to is known to contain numerous compounds with various pharmacological activities, it is not clear which compounds are responsible for the stimulation of individual cell types. Here, we conducted what we call “biomarker-guided screening” to purify compounds responsible for the macrophages stimulatory activity. To this end, gene expression was analyzed by a DNA array for macrophages treated with Juzen-taiho-to and DMSO (vehicle control), which identified intercellular adhesion molecule 1 as a biomarker of macrophage stimulation by Juzen-taiho-to. A quantitative reverse transcription polymerase chain reaction assay of intercellular adhesion molecule 1 was then used to guide the purification of active compounds. The screening resulted in the purification of a glycolipid mixture, containing β-glucosylceramides. The glycolipid mixture potently stimulated intercellular adhesion molecule 1 expression in primary dendritic cells as well as in primary CD14+ (macrophages) cells. The identification of this glycolipid mixture opens up an opportunity for further studies to understand how plant-derived glycolipids stimulate macrophages and dendritic cells in a safe and effective manner as demonstrated by Juzen-taiho-to.

Key words

biomarker-guided screening - glycolipid - immunostimulation - β-glucosylceramides

Supporting Information

 

  • References

  • 1 Yamada H, Saiki I. Juzen-taiho-to (shi-quan-da-bu-tang): scientific evaluation and clinical applications. Boca Raton, Fla.; London: Taylor & Francis; 2005
    CrossrefGoogle Scholar
  • 2 Zee-Cheng RK. Shi-quan-da-bu-tang (ten significant tonic decoction), SQT. A potent Chinese biological response modifier in cancer immunotherapy, potentiation and detoxification of anticancer drugs. Methods Find Exp Clin Pharmacol 1992; 14: 725-736
    PubMedGoogle Scholar
  • 3 Huang SM, Chien LY, Tai CJ, Chiou JF, Chen CS. Effectiveness of 3-week intervention of Shi Quan Da Bu Tang for alleviating hematotoxicity among patients with breast carcinoma receiving chemotherapy. Integr Cancer Ther 2013; 12: 136-144
    CrossrefPubMedGoogle Scholar
  • 4 Ogawa K, Omatsu T, Matsumoto C, Tsuchiya N, Yamamoto M, Naito Y, Yoshikawa T. Protective effect of the Japanese traditional medicine juzentaihoto on myelosuppression induced by the anticancer drug TS-1 and identification of a potential biomarker of this effect. BMC Complement Altern Med 2012; 12: 118
    CrossrefPubMedGoogle Scholar
  • 5 Ohnishi Y, Fujii H, Hayakawa Y, Sakukawa R, Yamaura T, Sakamoto T, Tsukada K, Fujimaki M, Nunome S, Komatsu Y, Saiki I. Oral administration of a Kampo (Japanese herbal) medicine Juzen-taiho-to inhibits liver metastasis of colon 26-L5 carcinoma cells. Jpn J Cancer Res 1998; 89: 206-213
    CrossrefPubMedGoogle Scholar
  • 6 Hisha H, Yamada H, Sakurai MH, Kiyohara H, Li Y, Yu C, Takemoto N, Kawamura H, Yamaura K, Shinohara S, Komatsu Y, Aburada M, Ikehara S. Isolation and identification of hematopoietic stem cell-stimulating substances from Kampo (Japanese herbal) medicine, Juzen-taiho-to. Blood 1997; 90: 1022-1030
    PubMedGoogle Scholar
  • 7 Hisha H, Kohdera U, Hirayama M, Yamada H, Iguchi-Uehira T, Fan TX, Cui YZ, Yang GX, Li Y, Sugiura K, Inaba M, Kobayashi Y, Ikehara S. Treatment of Shwachman syndrome by Japanese herbal medicine (Juzen-taiho-to): stimulatory effects of its fatty acids on hemopoiesis in patients. Stem Cells 2002; 20: 311-319
    CrossrefPubMedGoogle Scholar
  • 8 Dai Y, Kato M, Takeda K, Kawamoto Y, Akhand AA, Hossain K, Suzuki H, Nakashima I. T-cell-immunity-based inhibitory effects of orally administered herbal medicine juzen-taiho-to on the growth of primarily developed melanocytic tumors in RET-transgenic mice. J Invest Dermatol 2001; 117: 694-701
    CrossrefPubMedGoogle Scholar
  • 9 Inagaki M, Harada Y, Yamada K, Isobe R, Higuchi R, Matsuura H, Itakura Y. Isolation and structure determination of cerebrosides from garlic, the bulbs of Allium sativum L. Chem Pharm Bull 1998; 46: 1153-1156
    CrossrefPubMedGoogle Scholar
  • 10 Kawamura A. Uncovering the therapeutic potential of natural products with biomarker-guided screening. IDrugs 2010; 13: 321-324
    PubMedGoogle Scholar
  • 11 Auwerx J. The human leukemia cell line, THP-1: a multifacetted model for the study of monocyte-macrophage differentiation. Experientia 1991; 47: 22-31
    CrossrefPubMedGoogle Scholar
  • 12 Qin Z. The use of THP-1 cells as a model for mimicking the function and regulation of monocytes and macrophages in the vasculature. Atherosclerosis 2012; 221: 2-11
    CrossrefPubMedGoogle Scholar
  • 13 Tsuchiya S, Yamabe M, Yamaguchi Y, Kobayashi Y, Konno T, Tada K. Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer 1980; 26: 171-176
    CrossrefPubMedGoogle Scholar
  • 14 Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S. Macrophage receptors and immune recognition. Annu Rev Immunol 2005; 23: 901-944
    CrossrefPubMedGoogle Scholar
  • 15 Michielsen AJ, Hogan AE, Marry J, Tosetto M, Cox F, Hyland JM, Sheahan KD, OʼDonoghue DP, Mulcahy HE, Ryan EJ, OʼSullivan JN. Tumour tissue microenvironment can inhibit dendritic cell maturation in colorectal cancer. PLoS One 2011; 6: e27944
    CrossrefPubMedGoogle Scholar
  • 16 Wright J, McInnes A, Shimizu S, Smith D, Walter J, Idler D, Khalil W. Identification of C-24 alkyl epimers of marine sterols by C-13 nuclear magnetic resonance spectroscopy. Can J Chem 1978; 56: 1898-1903
    CrossrefPubMedGoogle Scholar
  • 17 Kojima H, Sato N, Hatano A, Ogura H. Sterol glucosides from Prunella vulgaris . Phytochemistry 1990; 29: 2351-2355
    CrossrefPubMedGoogle Scholar
  • 18 Shibuya H, Kawashima K, Sakagami M, Kawanishi H, Shimomura M, Ohashi K, Kitagawa I. Sphingolipids and glycerolipids. I. Chemical structures and ionophoretic activities of soya-cerebrosides I and II from soybean. Chem Pharm Bull (Tokyo) 1990; 38: 2933-2938
    CrossrefPubMedGoogle Scholar
  • 19 Brix S, Bovetto L, Fritsché R, Barkholt V, Frøkiaer H. Immunostimulatory potential of beta-lactoglobulin preparations: effects caused by endotoxin contamination. J Allergy Clin Immunol 2003; 112: 1216-1222
    CrossrefPubMedGoogle Scholar
  • 20 Marincek BC, Kühnle MC, Srokowski C, Schild H, Hämmerling G, Momburg F. Heat shock protein-antigen fusions lose their enhanced immunostimulatory capacity after endotoxin depletion. Mol Immunol 2008; 46: 181-191
    CrossrefPubMedGoogle Scholar
  • 21 Wiesner P, Choi SH, Almazan F, Benner C, Huang W, Diehl CJ, Gonen A, Butler S, Witztum JL, Glass CK, Miller YI. Low doses of lipopolysaccharide and minimally oxidized low-density lipoprotein cooperatively activate macrophages via nuclear factor kappa B and activator protein-1: possible mechanism for acceleration of atherosclerosis by subclinical endotoxemia. Circ Res 2010; 107: 56-65
    CrossrefPubMedGoogle Scholar
  • 22 Bouic PJ, Lamprecht JH. Plant sterols and sterolins: a review of their immune-modulating properties. Altern Med Rev 1999; 4: 170-177
    PubMedGoogle Scholar
  • 23 Bouic PJ. The role of phytosterols and phytosterolins in immune modulation: a review of the past 10 years. Curr Opin Clin Nutr Metab Care 2001; 4: 471-475
    CrossrefPubMedGoogle Scholar
  • 24 Bouic PJ. Sterols and sterolins: new drugs for the immune system?. Drug Discov Today 2002; 7: 775-778
    CrossrefPubMedGoogle Scholar
  • 25 Breytenbach U, Clark A, Lamprecht J, Bouic P. Flow cytometric analysis of the Th1-Th2 balance in healthy individuals and patients infected with the human immunodeficiency virus (HIV) receiving a plant sterol/sterolin mixture. Cell Biol Int 2001; 25: 43-49
    CrossrefPubMedGoogle Scholar
  • 26 Bouic PJ, Etsebeth S, Liebenberg RW, Albrecht CF, Pegel K, Van Jaarsveld PP. beta-Sitosterol and beta-sitosterol glucoside stimulate human peripheral blood lymphocyte proliferation: implications for their use as an immunomodulatory vitamin combination. Int J Immunopharmacol 1996; 18: 693-700
    CrossrefPubMedGoogle Scholar
  • 27 Long J, Zhou B, Li H, Dai Q, Zhang B, Xing S, Zeng Z, Chen W, Yang J. Improvement of HBsAg gene-modified dendritic cell-based vaccine efficacy by optimizing immunization method or the application of β-glucosylceramide. Immunol Invest 2013; 42: 137-155
    CrossrefPubMedGoogle Scholar
  • 28 Mizrahi M, Lalazar G, Ben Yaʼacov A, Livovsky DM, Horowitz Y, Zolotarov L, Adler R, Shouval D, Ilan Y. Beta-glycoglycosphingolipid-induced augmentation of the anti-HBV immune response is associated with altered CD8 and NKT lymphocyte distribution: a novel adjuvant for HBV vaccination. Vaccine 2008; 26: 2589-2595
    CrossrefPubMedGoogle Scholar
  • 29 Lee IA, Popov AM, Sanina NM, Kostetsky EY, Novikova OD, Reunov AV, Nagorskayaand VP, Shnyrov VL. Morphological and immunological characterization of immunostimulatory complexes based on glycoglycerolipids from Laminaria japonica . Acta Biochim Pol 2004; 51: 263-272
    PubMedGoogle Scholar
  • 30 Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine 2009; 16: 97-110
    CrossrefPubMedGoogle Scholar
  • 31 Clements CJ, Griffiths E. The global impact of vaccines containing aluminium adjuvants. Vaccine 2002; 20 (Suppl. 03) S24-S33
    CrossrefPubMedGoogle Scholar
  • 32 Kawamura A, Iacovidou M, Takaoka A, Soll CE, Blumenstein M. A polyacetylene compound from herbal medicine regulates genes associated with thrombosis in endothelial cells. Bioorg Med Chem Lett 2007; 17: 6879-6882
    CrossrefPubMedGoogle Scholar