Download PDF
Planta Med 2012; 78(2): 122-127
DOI: 10.1055/s-0031-1280356
Biological and Pharmacological Activity
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Fo Shou San, an Ancient Herbal Decoction Prepared from Angelicae Sinensis Radix and Chuanxiong Rhizoma, Induces Erythropoietin Expression: A Signaling Mediated by the Reduced Degradation of Hypoxia-Inducible Factor in Cultured Liver Cells

Cathy W. C. Bi1 , Li Xu1 , Wendy L. Zhang1 , Janis Y. X. Zhan1 , Qiang Fu1 , Ken Y. Z. Zheng1 , Vicky P. Chen1 , David T. W. Lau1 , Roy C. Y. Choi1 , Tie J. Wang1 , 2 , Tina T. X. Dong1 , Karl W. K. Tsim1
  • 1Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong, P. R. China
  • 2Shenzhen Municipal Institute for Drug Control, Shenzhen, P. R. China
Further Information

Publication History

received January 17, 2011 revised August 24, 2011

accepted October 18, 2011

Publication Date:
17 November 2011 (online)

    Permissions and Reprints

Abstract

Fo Shou San (FSS) is an ancient herbal decoction composed of Angelicae Sinensis Radix (ASR; Danggui) and Chuanxiong Rhizoma (CR; Chuanxiong) in a ratio of 3 : 2. FSS is mainly prescribed for patients having a deficiency of blood supply, and it indeed has been shown to stimulate the production of erythropoietin (EPO) in cultured cells. In order to reveal the mechanism of this FSS-induced EPO gene expression, the upstream regulatory cascade, via hypoxia-induced signaling, was revealed here in cultured hepatocellular carcinoma cell line Hep3B. The induction of EPO gene expression, triggered by FSS, was revealed in cultured hepatocytes by: (i) the increase of EPO mRNA; and (ii) the activation of the hypoxia response element (HRE), an upstream regulator of the EPO gene. The FSS-induced EPO gene expression was triggered by an increased expression of hypoxia-inducible factor-1α (HIF-1α) protein; however, the mRNA expression of HIF-1α was not altered by the treatment of FSS. The increased HIF-1α was a result of reduced protein degradation after the FSS treatment. The current results therefore provide one of the molecular mechanisms of this ancient herbal decoction for its hematopoietic function.

Key words

Angelica sinensis - Ligusticum chuanxiong - Umbelliferae

Supporting Information

References

  • 1 Bi C W C, Xie H Q H, Xu L, Li J, Cheung A W H, Zhu J T T, Zheng Y Z, Chen V P, Law D T W, Choi R C Y, Wang T J, Dong T T X, Tsim K W K. Fo Shou San, an ancient herbal decoction prepared from Rhizoma Chuanxiong and Radix Angelicae Sinensis, stimulates the production of hemoglobin and erythropoietin in cultured cells.  Planta Med. 2010;  76 1525-1529
    Google Scholar
  • 2 Gregory C J, Eaves A C. Human marrow cells capable of erythropoietic differentiation in vitro: definition of three erythroid colony responses.  Blood. 1977;  49 855-864
    Google Scholar
  • 3 Gregory C J, Eaves A C. Three stages of erythropoietic progenitor cell differentiation distinguished by a number of physical and biologic properties.  Blood. 1978;  51 527-537
    Google Scholar
  • 4 Wu H, Lin X, Jaenisch R, Lodish H F. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor.  Cell. 1995;  83 59-67
    Google Scholar
  • 5 Lin C S, Lim S K, D'Agati V, Costantini F. Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis.  Genes Dev. 1995;  10 154-164
    Google Scholar
  • 6 Lin F K, Suggs S, Lin C H, Browne J K, Smalling R, Egrie J C, Chen K K, Fox G M, Martin F, Stabinsky Z, Badrawi S M, Lai P H, Goldwasser E. Cloning and expression of the human erythropoietin gene.  Proc Natl Acad Sci USA. 1985;  82 7580-7584
    Google Scholar
  • 7 Lai P H, Everett R, Wang F F, Arakawa T, Goldwasser E. Structural characterization of human erythropoietin.  J Biol Chem. 1986;  261 3116-3121
    Google Scholar
  • 8 Fukuda M N, Sasaki H, Lopez L, Fukuda M. Survival of recombinant erythropoietin in the circulation: the role of carbohydrates.  Blood. 1989;  73 84-89
    Google Scholar
  • 9 Sasaki R, Masuda S, Nagao M. Erythropoietin: multiple physiological functions and regulation of biosynthesis.  Biosci Biotechnol Biochem. 2000;  64 1775-1793
    Google Scholar
  • 10 Fandrey J. Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression.  Am J Physiol Regul Integr Comp Physiol. 2004;  286 R977-R988
    Google Scholar
  • 11 Eckardt K U, Kurtz A. Regulation of erythropoietin production.  Eur J Clin Invest. 2005;  35 13-19
    Google Scholar
  • 12 Warnecke C, Zaborowska Z, Kurreck J, Erdmann V A, Frei U, Wiesener M, Eckardt K U. Differentiating the functional role of hypoxia-inducible factor (HIF)-1α and HIF-2α (EPAS-1) by the use of RNA interference.  FASEB J. 2004;  18 1462-1487
    Google Scholar
  • 13 Goldberg M A, Glass G A, Cunningham J M, Bunn H F. The regulated expression of erythropoietin by two human hepatoma cell lines.  Proc Natl Acad Sci USA. 1987;  84 7972-7976
    Google Scholar
  • 14 Haase V H. Hypoxic regulation of erythropoiesis and iron metabolism.  Am J Physiol Renal Physiol. 2010;  299 F1-F13
    Google Scholar
  • 15 Ebert B L, Bunn H F. Regulation of the erythropoietin gene.  Blood. 1999;  94 1864-1877
    Google Scholar
  • 16 Smith T G, Robbins P A, Ratcliffe P J. The human side of hypoxia-inducible factor.  Br J Haematol. 2008;  141 325-334
    Google Scholar
  • 17 Wang G L, Jiang B H, Rue E A, Semenza G L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.  Proc Natl Sci USA. 1995;  92 5510-5514
    Google Scholar
  • 18 Jaakkola P, Mole D R, Tian Y M, Wilson M I, Gielbert J, Gaskell S J, Kriegsheim A V, Hebestreit H F, Mukherji M, Schofield C J, Maxwell P H, Pugh C W, Ratcliffe P J. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.  Science. 2001;  292 468-472
    Google Scholar
  • 19 Ke Q D, Costa M. Hypoxia-inducible factor-1 (HIF-1).  Mol Pharmacol. 2006;  70 1469-1480
    Google Scholar
  • 20 Gao Q T, Cheung J K H, Choi R C Y, Cheung A W H, Li J, Jiang Z Y, Chu G K Y, Duan R, Zhao K J, Dong T T X, Tsim K W K. A Chinese herbal decoction prepared from Radix Astragali and Radix Angelicae Sinensis induces the expression of erythropoietin in cultured Hep3B cells.  Planta Med. 2008;  74 392-395
    Google Scholar
  • 21 Uchimura E, Yamada S, Uebersax L, Fujita S, Miyake M, Miyake J. Method for reverse transfection using gold colloid as a nano-scaffold.  J Biosci Bioeng. 2007;  103 101-103
    Google Scholar
  • 22 Metzen E, Ratcliffe P J. HIF hydroxylation and cellular oxygen sensing.  Biol Chem. 2004;  385 223-230
    Google Scholar
  • 23 Su Y, Loos M, Giese N, Hines O J, Diebold I, Gorlach A, Metzen E, Pastorekova S, Friess H, Buchler P. PHD3 regulates differentiation, tumour growth and angiogenesis in pancreatic cancer.  Br J Cancer. 2010;  103 1571-1579
    Google Scholar
  • 24 Shao M L. Pharmacopoeia of the People's Republic of China. (Part I). Beijing: Chemical Industry Press; 2010: 144
    Google Scholar
  • 25 Liang Q D, Gao Y, Tan H L, Guo P, Li Y F, Zhou Z, Tan W, Ma Z C, Ma B P, Wang S Q. Effects of four Si-Wu-Tang's constituents and their combination on irradiated mice.  Biol Pharm Bull. 2006;  29 1378-1382
    Google Scholar
  • 26 Lin C M, Chiu J H, Wu I H, Wang B W, Pan C M, Chen Y H. Ferulic acid augments angiogenesis via VEGF, PDGF and HIF-1α.  J Nutr Biochem. 2010;  21 627-633
    Google Scholar
  • 27 Ma Z C, Hong Q, Wang Y G, Tan H L, Xiao C R, Liang Q D, Cai S H, Gao Y. Ferulic acid attenuates adhesion molecule expression in gamma-radiated human umbilical vascular endothelial cells.  Biol Pharm Bull. 2010;  33 752-758
    Google Scholar
  • 28 Chan S S K, Cheng T Y, Lin G. Relaxation effects of ligustilide and senkyunolide A, two main constituents of Ligusticum chuanxiong, in rat isolated aorta.  J Ethnopharmacol. 2007;  111 677-680
    Google Scholar
  • 29 Park S S, Bae I, Lee Y J. Flavonoids-induced accumulation of hypoxia-inducible factor (HIF)-1α/2α is mediated through chelation of iron.  J Cell Biochem. 2008;  103 1989-1998
    Google Scholar
  • 30 Zheng K Y Z, Guo A J Y, Bi C W C, Zhu K Y, Chan G K L, Fu Q, Xu S L, Zhan J Y Z, Lau D T W, Dong T T X, Choi R C Y, Tsim K W K. The extract of Rhodiolae Crenulatae Radix et Rhizoma induces the accumulation of HIF-1α via blocking the degradation pathway in cultured kidney fibroblasts.  Planta Med. 2011;  77 894-899
    Google Scholar
  • 31 Zheng K Y Z, Choi R C Y, Xie H Q H, Cheung A W H, Guo A J Y, Leung K W, Chen V P, Bi C W C, Zhu K Y, Chan G K L, Fu Q, Lau D T W, Dong T T X, Zhao K J, Tsim K W K. The expression of erythropoietin triggered by Danggui Buxue Tang, a Chinese herbal decoction prepared from Radix Astragali and Radix Angelicae Sinensis, is mediated by the hypoxia-inducible factor in cultured HEK293T cells.  J Ethnopharmacol. 2010;  132 259-267
    Google Scholar

Prof. Karl W. K. Tsim

Division of Life Science and Center for Chinese Medicine
The Hong Kong University of Science and Technology

Clear Water Bay Road

Hong Kong

PR China

Phone: +85 2 23 58 73 32

Fax: +85 2 23 58 15 59

Email: botsim@ust.hk

>