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Research Interest

Research Interest of the Fan Lab

Angiogenesis is the development of new blood vessels from an existing vascular bed. Normal vascular proliferation only occurs during embryonic development, the female reproductive cycle and wound healing. However, over 80 pathological conditions are characterised by persistent, unregulated angiogenesis [1]. Excessive angiogenesis leads to cancer, diabetic retinopathy, endometriosis and atherosclerosis, while inadequate angiogenesis is responsible for chronic wounds, duodenal ulcers, myocardial infarct and possibly stroke.

In the early phase of our investigations, we focused on the mechanisms of action of three angiogenic factors: thymidine phosphorylase (TP), hepatocyte growth factor/scatter factor (HGF/SF) and vascular endothelial growth factor (VEGF) [2-5]. In 2003, we initiated studies on the pharmacology of traditional medicine, aiming to optimize active compounds derived from clinically effective natural products for the prevention and treatment of angiogenic diseases [6].

Since antiquity, plants have been used to treat many ailments. However, it was not until the 1800s that pure compounds were isolated from plants, paving the way for modern pharmaceuticals. The following examples illustrate the rich history of plant-based medicines.

  • morphine was isolated from the opium poppy (Papaver somniferum),
  • salicylic acid from the bark of the willow tree (Salix alba) was used to synthesize aspirin
  • the anti-asthma drug sodium cromoglyate is a khellin derivative from Egyptian khella seeds (Ammi visnaga)
  • the anti-malarial drug artemisinin was developed from the Chinese herb qinghao (sweet wormwood, Artemisia annua L.)

Newman and Cragg [7] strongly advocate expanding, not decreasing, the exploration of Nature as a source of novel active agents that may serve as the leads and scaffolds for elaboration into desperately needed efficacious drugs for a multitude of disease indications.

We have considerably strengthened our resources to build a platform to investigate the angiogenesis-modulating effects of pure compounds from traditional Chinese medicine (TCM) and natural products from other traditional medicine. In particular we aim to identify the actives from plant extracts, test their activities and elucidate their mechanisms of action at the cellular and molecular levels.

In collaboration with Hong Kong Baptist University, MIT and TNO (the Netherlands), we carried out a mass spectrometric compositional analysis of American, Chinese and Korean, and Sanqi ginseng and reported distinct “sterol ginsenoside” fingerprints, especially in the ratio between a triol, Rg1, and a diol, Rb1, the 2 most prevalent constituents [8]. We were the first to show modulation of angiogenesis by distinct ratios of Rg1 and Rb1.  While Rg1 promotes angiogenesis via the expression of nitric oxide synthase [8] and induces VEGF expression through the glucocorticoid receptor-related phosphatidylinositol 3-kinase/Akt and beta-catenin/T-cell factor-dependent pathway in human endothelial cells [9], Rb1 inhibits angiogenesis via the expression of anti-angiogenic peptide pigment epithelium derived factor [10]. Similarly, Angelica sinensis contains both pro- and anti-angiogenic compounds [11].

In collaboration Northwest University in Xi’an, we are investigating the cardio-protective and anti-atherosclerotic effects of novel chimeric compounds derived from Salvia miltiorrhiza, as well as their mechanisms of action.  With Second Military Medical University and Shanghai Hutchison Pharmaceuticals Ltd., we have discovered angiogenesis modulators from a proprietary formulation (Shexiang Baoxin Pills, 麝香保心丸) for the treatment of angina pectoris. Using our in-house 96-well co-culture system of “vascular tube formation”, we have shown the protective effects of some compounds against homocysteine-induced damage to endothelial cells. 

Recent research indicates Alzheimer’s disease is accompanied by neuroinflammation and angiogenesis.  In collaboration with Chinese Academy of Medical Sciences Institute of Medicinal Plant Development, we have studied the protective effects of Polygala tenuifolia extracts against Ab25-35-induced amnesia [12] and memory-enhancing effect in aged mice [13].  To unravel the molecular mechanisms of action of these compounds, we have established collaboration with colleagues in Cambridge University, and three WHO Collaborating Centres for Traditional Medicine in China and Korea. Combining cell biology, genetics and transcriptomics to investigate the novel mechanisms of Alzheimer’s disease as well as pharmacology, phytochemistry and chemogenomics of natural products [14], we aim to discover new pathways and optimize natural molecules as potential prophylactic and therapeutic agents.

 

Current collaborators (in alphabetical order):

 

  • Dr Andreas Bender (Unilever Centre for Molecular Science Informatics, Cambridge).
  • Professor Stephen Charnock-Jones (Department of Obstetrics & Gynaecology, Cambridge)
  • Dr Damian Crowther (Department of Genetics, Cambridge)
  • Professor Junguo Duan (Chengdu University of TCM, Chengdu, China)
  • Professor Jingyan Han (Peking University, Beijing, China)
  • Professor Yeong Shik Kim (Seoul National University, Seoul, Korea)
  • Professor Chenghai Liu (Shanghai University of TCM, Shanghai, China)
  • Professor Xinmin Liu (Chinese Academy of Medical Sciences Institute of Medicinal Plant Development, Beijing, China)
  • Professor Peter St George-Hyslop, FRS (Cambridge Institute for Medical Research)
  • Dr Giles Yeo (Metabolic Research Laboratories, Cambridge)
  • Professor Weidong Zhang (Second Military Medical University, Shanghai, China)
  • Professor Xiaohui Zheng (Northwest University, Xi’an, China)


References

 

  1. The Angiogenesis Foundation.  http://www.angio.org
  2. Moghaddam A, Zhang HT, Fan TP, Hu DE, Lees VC, Turley H, Fox SB, Gatter KC, Harris AL, Bicknell R. (1995) Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc Natl Acad Sci U S A. 92(4):998-1002.
  3. Boyle JJ, Wilson B, Bicknell R, Harrower S, Weissberg PL, Fan TP. (2000) Expression of angiogenic factor thymidine phosphorylase and angiogenesis in human atherosclerosis. J Pathol. 192(2):234-42.
  4. Sengupta S, Sellers LA, Li RC, Gherardi E, Zhao G, Watson N, Sasisekharan R, Fan TP. (2003) Targeting of mitogen-activated protein kinases and phosphatidylinositol 3 kinase inhibits hepatocyte growth factor/scatter factor-induced angiogenesis. Circulation. 107(23):2955-61.
  5. Hull ML, Charnock-Jones DS, Chan CL, Bruner-Tran KL, Osteen KG, Tom BD, Fan TP, Smith SK. (2003) Antiangiogenic agents are effective inhibitors of endometriosis. J Clin Endocrinol Metab. 88(6):2889-99.
  6. Fan TP, Yeh JC, Leung KW, Yue PY, Wong RN. (2006) Angiogenesis: from plants to blood vessels. Trends Pharmacol Sci. 27(6):297-309
  7. Newman DJ and Cragg GM. (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod. 75:311-335
  8. Sengupta S, Toh SA, Sellers LA, Skepper JN, Koolwijk P, Leung HW, Yeung HW, Wong RN, Sasisekharan R, Fan TP. (2004) Modulating angiogenesis: the yin and the yang in ginseng. Circulation, 110(10):1219-25.
  9. Leung KW, Pon YL, Wong RN, Wong AS. (2006). Ginsenoside-Rg1 induces vascular endothelial growth factor expression through the glucocorticoid receptor-related phosphatidylinositol 3-kinase/Akt and beta-catenin/T-cell factor-dependent pathway in human endothelial cells. J Biol Chem. 281(47):36280-8.
  10. Leung KW, Cheung LWT, Pon YL, Wong RNS, Mak NK, Fan TP, Au CL, Tombran-Tink J, Wong AST. (2007) Ginsenoside-Rb1 inhibits tube-like structure formation of endothelial cells by regulating pigment epithelium-derived factor through estrogen receptor beta. Br J Pharmacol. 152(2):207-15.
  11. Yeh JC, Cindrova-Davies T, Belleri M, Morbidelli L, Miller N, Cho CW, Chan K, Wang YT, Luo GA, Ziche M, Presta M, Charnock-Jones DS, Fan TP. (2011) The natural compound n-butylidenephthalide derived from the volatile oil of Radix Angelica sinensis inhibits angiogenesis in vitro and in vivo. Angiogenesis 14(2):187-97.
  12. Xu SP, Yang YY, Dan Xue, Liu JX, Liu XM, Fan TP, Li PT. (2011) Cognitive enhancing effects of polygalasaponins hydrolysate in A25-35-induced amnesic mice. Evid Based Complement Alternat Med. 2011:839720. Epub 2011 Mar 6. [Epub ahead of print]
  13. Li ZY, Liu YM, Wang LW, Liu XM, Chang Q, Guo Z, Liao YH,1 Pan RL, Fan TP. (2014) Memory-enhancing effects of the crude extract of Polygala tenuifolia on aged mice. Evid Based Complement Alternat Med. 2014 (in press).
  14. Mohd Fauzi F, Koutsoukas A, Lowe R, Joshi K, Fan TP, Glen RC, Bender A. (2013) Chemogenomics approaches to rationalizing the mode-of-action of traditional Chinese and Ayurvedic medicines. J Chem Inf Model. 53(3):661-73