DEPT OF PHARMACOLOGY
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Researcher
: Chan KYC |
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List of Research Outputs |
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Chan K.Y.C., Mak J.C.W., Man R.Y.K. and Vanhoutte P.M.G.R., RHO kinase and endothelum-dependent contractions in the SHR and WKY aorta, Basic & Clinical Pharmacology & Toxicology, 5th International EDHF Symposium, Tampere, Finaland, June 24-27, 2008. 102 (suppl.1): 55. |
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Researcher
: Chan LY |
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List of Research Outputs |
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Chan L.Y., Leung S.W.S. and Man R.Y.K., Acute actions of osthole in the modulation of the vascular system, 12th Research Postgraduate Symposium, Hong Kong, December 12 & 14, 2007. 144 (1.14). |
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Researcher
: Che CM |
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Project Title: |
Blue light photoluminescent materials |
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Investigator(s): |
Che CM |
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Department: |
Chemistry |
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Source(s) of Funding: |
Hung Hing Ying Physical Sciences Research Fund |
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Start Date: |
02/1999 |
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Abstract: |
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To design and prepare highly robust and luminous materials for fabrication of bright blue-light emitting diode (LED) devices. |
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Project Title: |
Institute of molecular technology for drug discovery and synthesis |
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Investigator(s): |
Che CM |
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Department: |
Chemistry |
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Source(s) of Funding: |
Areas of Excellence Scheme |
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Start Date: |
11/2001 |
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Abstract: |
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To pursue world-class fundamental research in Chemical Biology; to develop novel compounds for new medicine and to engender the development of local and regional pharmaceutical industries through high quality research. |
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Project Title: |
High-valent metal complexes and their photochemical studies |
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Investigator(s): |
Che CM |
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Department: |
Chemistry |
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Source(s) of Funding: |
Matching Fund for NSFC Young Researcher Award |
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Start Date: |
01/2002 |
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Abstract: |
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To study high-valent metal complexes and their photochemical studies. |
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Project Title: |
Shanghai-Hong Kong Joint Laboratory on chemical synthesis |
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Investigator(s): |
Che CM |
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Department: |
Chemistry |
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Source(s) of Funding: |
University Research Committee / Committee on Research and Conference Grants - General Award |
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Start Date: |
05/2002 |
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Abstract: |
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To conduct research activties at Shanghai-Hong Kong Joint Laboratory on chemical synthesis |
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Project Title: |
Research and development of luminescent biosensors for drug screening and environmental monitoring |
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Investigator(s): |
Che CM |
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Department: |
Chemistry |
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Source(s) of Funding: |
Seed Funding Programme for Applied Research |
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Start Date: |
11/2002 |
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Abstract: |
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To optimize the luminescent materials developed by Che and co-workers for optical pH, oxygen and chlorinated hydrocarbons sensing technology; to fabricate optical biosensors using the newly developed luminescent materials; to apply the newly developed fluorescent pH/oxygen biosensors for cell viability assay, drug screening and monitoring of environmental pollutants. |
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Project Title: |
Novel photoluminescent, sensory and photocatalytic materials derived from closed-shell metal ions and pi-conjugated organics: impact of weak intermolecular interactions and metal-functionalization upon photophysical and photochemical properties |
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Investigator(s): |
Che CM, Lai SW |
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Department: |
Chemistry |
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Source(s) of Funding: |
Competitive Earmarked Research Grants (CERG) |
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Start Date: |
09/2003 |
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Abstract: |
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The objective is to identify new 1-, 2- and 3- dimensional nanostructures of metal-capped oligomeric carbon materials with tunable spectroscopic properties and to develop novel applicantions in organic optoelectronics and sensory devices. |
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Project Title: |
Functional nanomaterials research |
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Investigator(s): |
Che CM, Chan MCW |
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Department: |
Chemistry |
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Source(s) of Funding: |
Small Project Funding |
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Start Date: |
11/2003 |
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Abstract: |
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To develop new nanostructured and
nanocomposite materials, based on the existing research expertise in
synthetic chemistry, semiconductors, and ongoing collaborations with |
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Project Title: |
Metal-nitrogen multiple bonded complexes. Synthesis and applications in carbon-nitrogen bond formation reactions |
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Investigator(s): |
Che CM, Tong SM, Chan PWH |
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Department: |
Chemistry |
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Source(s) of Funding: |
Competitive Earmarked Research Grants (CERG) |
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Start Date: |
09/2004 |
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Abstract: |
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To probe the mechanism of H atom abstraction and subsequent C-N bond formation by highly reactive metal-imido complexes; to develop non-porphyrin ruthenium catalysts including metal-metal bonded diruthenium systems for amidation of C-H bonds by the "PhI(OA)2 + RNH2 protocol; to prepare new classes of ruthenium and osmium-imido complexes other than those bearing tosylimido ligands; to explore and develop Fe catalysts containing strongly chelating polypyridine ligand systems for amidation of organic compounds; to study systematically the ruthenium-catalyzed amidation of C(sp2)-H bonds of aromatic hydrocarbons and develop its application in organic synthesis; to investigate systematically the proton-coupled electron transfer reactions of Ru-NH2R complexes by electrochemical means. |
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Project Title: |
Functionalized phosphorescent metal-organic materials for biomedical, photocatalytic and organic optoelectronic applications |
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Investigator(s): |
Che CM, Lai SW |
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Department: |
Chemistry |
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Source(s) of Funding: |
NSFC/RGC Joint Research Scheme |
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Start Date: |
01/2005 |
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Abstract: |
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To develop new classes of water-soluble phosphorescent metal-organic compounds and polymer derivatives, including those appended with polysaccharide groups, for practical applications in luminescent signaling and biomedical sciences; to develop robust polymer/matrix-supported copper(I) and platinum(II) photocatalysts for light-induced C-H bond activation and atom transfer radical addition polymerization reactions; to study the effect of π-conjugation between transition metal ions and carbon-rich organic materials upon their spectroscopic and excited-states characteristics; to develop new families of phosphorescent platinum(II) dendritic materials exhibiting tunable emission energies for organic optoelectronic applications; to prepare multinuclear Pt(II)-Ru(II) complexes which exhibit low-energy Ru(II)-to-Pt(II) and ligand-to-Pt(II) charge-transfer excited states and to study the electro-optical properties of these heterometallic compounds. |
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Project Title: |
Photoluminescent properties and applications of luminescent d8 and d10 metal complexes with metal-metal interactions |
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Investigator(s): |
Che CM |
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Department: |
Chemistry |
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Source(s) of Funding: |
Germany/Hong Kong Joint Research Scheme |
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Start Date: |
01/2005 |
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Abstract: |
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To exploit the photoluminescence, determined by weak meatllophilic interactions between metal ions with d8 or d10 electronic configuration, weak ligand-ligand interactions in phosphorescent organoplatinum(II) and organogold(I) complexes and intermolecular metal-ligand interactions of d8 and d10 metal species; to elucidate the electronic origin of the emission by spectroscopic methods; to apply the effects of weak interactions upon the emissive characteristics of phosphorescent metal-organic materials to the development of new operating principles for luminescent molecular sensors and nanodevices; to synthesize phosphorescent materials with potential applications in optoelectronics of OLEDs. |
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Project Title: |
Strategic Theme on Drug Discovery and Synthesis |
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Investigator(s): |
Che CM, Man RYK, Lau ASY, Li Y, Chen G |
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Department: |
Chemistry |
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Source(s) of Funding: |
Seed Funding for Strategic Research Theme |
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Start Date: |
05/2005 |
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Abstract: |
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To enhance collaborative interdisciplinary research between Science and Medicines with objectives to develop new drug leads and/or innovative research in biomedical sciences. To establish HKU as a leading centre in synergistic, interdisciplinary research on drug discovery and synthesis. |
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Project Title: |
Metal-Carbon Multiple Bonded Complexes in Catalysis and Supramolecular Chemistry |
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Investigator(s): |
Che CM, Wong MK |
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Department: |
Chemistry |
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Source(s) of Funding: |
Competitive Earmarked Research Grants (CERG) |
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Start Date: |
11/2005 |
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Abstract: |
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Due to the shortfall of budget, spectroscopic, electronic and energy transfer studies of metal-carbon multiple bonded compounds could not be covered. The revised components of study include the followings: [1] reactive metal-carbene/alkylidyene complexes particularly the bis(carbene/alkylidene)osmium and high-valent ruthenium alkylidene complexes, [2] carbenoid transfer reactions in aqueous medium, and [3] design and synthesis of new classes of polymeric metal-containing carbon-rich materials. |
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Project Title: |
Development of Ruthenium and Iron Catalysts for Green and Biological Oxidations |
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Investigator(s): |
Che CM, Wong MK |
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Department: |
Chemistry |
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Source(s) of Funding: |
Seed Funding Programme for Basic Research |
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Start Date: |
02/2006 |
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Abstract: |
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Oxidation Chemistry plays a pivotal role in biological processes and fine chemical industries, and the development of efficient, selective and environmentally friendly oxidation technologies remains a significant challenge in Chemical Sciences in the forthcoming decades. Metal-catalyzed oxidation reactions that utilizes air or hydrogen peroxide as a terminal oxidant is an area of great interest. In this context, there is a continued and growing interest in the design of oxidatively robust catalysts of ruthenium and iron. High-valent ruthenium- and iron-oxo complexes are widely known to have rich oxidation chemistry but applications of their oxidation chemistry in practical organic synthesis have yet to be achieved. Over the years, we have extensively developed metalloporphyrins as efficient catalysts in oxidation reactions. By virtue of the structural diversity of the macrocyclic ligand, steric and electronic properties of metalloporphyrin catalysts can be fine-tuned for stereo- and enantioselective oxidation reactions. We envisage that metalloporphyrins would have tremendous potential to be the future catalysts of choice for selective oxidation reactions in Chemical Industries. Recently, we have developed a practical and mild method for highly selective conversion of terminal alkenes to aldehydes catalyzed by ruthenium porphyrins. More interestingly, we have discovered that this Wacker type oxidation of alkenes can be conducted using air as oxidant. Apart from metalloporphyrin-based catalysts, we have recently prepared a series of iron(II) oligopyridyl complexes, which have been characterized by X-ray crystallography. We are delighted to find that these iron complexes are highly efficient catalysts for alkene epoxidation using Oxone as a terminal oxidant. The main objective of this project is to develop new classes of ruthenium- and iron-oxo complexes for catalytic organic oxidations using air, hydrogen peroxide or Oxone as a terminal oxidant with special emphasis to address several important problems in organic oxidations. The deliverables of this project include a collection of new oxidatively robust catalysts, application studies of ruthenium-catalyzed aerobic Wacker type oxidation of alkenes to aldehydes and iron-catalyzed selective alkene epoxidation and biological oxidation. The ultimate goal is to develop efficient and green oxidation reactions that have useful applications in practical organic synthesis and fine chemical industries. |
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Project Title: |
Reactive metal-oxo complexes of group VIII metals for organic oxidations |
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Investigator(s): |
Che CM, Wong MK, Tong SM |
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Department: |
Chemistry |
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Source(s) of Funding: |
Competitive Earmarked Research Grants (CERG) |
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Start Date: |
01/2007 |
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Abstract: |
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This project aims to establish an interdisciplinary research program to expand the scope of research in metal-catalyzed organic oxidations previously developed in the laboratories [The University of Hong Kong and Shanghai-Hong Kong Joint Laboratory on Chemical Synthesis] of the HKU team. Synergetic efforts would be made to employ metalloporphyrins as key catalysts in organic synthesis, develop practical iron catalysts for organic oxidations, the latter is an area receiving a rapidly growing attention after the recent works of Que and co-workers (Science, 2003, 299, 1037), development of alternative and inexpensive catalysts for cis-dihydroxylation of alkenes and green oxidation catalysis. In essence, the objectives include. (1) To develop metalloporphyrin-catalyzed alkyne oxidations for biomolecule modification and practical protocols for construction of synthetically useful epoxides using environmentally friendly oxidants. (2) To develop ruthenium-catalyzed organic oxidations using air or hydrogen peroxide as a terminal oxidant. Of particular interest is to develop the chemistry of ruthenium-catalyzed Wacker oxidation of alkenes to aldehydes recently discovered at Shanghai-Hong Kong Joint Laboratory on Chemical Synthesis. (3) To develop practical iron catalysts using oligopyridine ligand systems for organic oxidations. (4) To design new classes of ruthenium-oxo complexes including those containing chiral auxiliary ligands for cis-dihydroxylation of alkenes. This work also aims to inquire as to whether a cis-dioxometal unit is a necessary requisite to accomplish cis-dihydroxylation of alkenes. (5) To examine the chemistry and reactivities of hitherto unknown reactive oxo complexes of ruthenium and iron using density functional theory calculations, and to systematically compare the ligand[pp(O2-)]-to-metal charge-transfer excited states of iron, ruthenium and osmium possessing the same dn electronic configuration. (6) To develop supported metal catalysts including those containing ruthenium nanoparticles for organic oxidations. This project is a concerted effort to tackle some difficult problems in the field of organic oxidations. Completion of this project could lead to important findings in ruthenium-catalyzed organic oxidations using air or hydrogen peroxide as a terminal oxidant. The outcomes would be rewarding as inexpensive and green oxidation technologies for fine chemical industry and organic synthesis could be developed. The development of practical and robust iron-based catalysts for organic oxidations with high selectivity and product turnovers is likely to have a long lasting impact in the forthcoming decade. |
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Project Title: |
Atom and Group Transfer Reactions for Carbon-Nitrogen Bond Formation |
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Investigator(s): |
Che CM, Ho CM |
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Department: |
Chemistry |
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Source(s) of Funding: |
Seed Funding Programme for Basic Research |
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Start Date: |
03/2007 |
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Abstract: |
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Nitrogen atom insertion to saturated C-H bonds catalyzed by transition metal complexes provides a convenient synthetic route to amine and amine derivatives, which are important intermediates generally used for the synthesis of pharmaceuticals and bioactive natural products. Metal complexes of Rh(II) and Ru(II) are effective catalysts for inter- and intramolecular amidation of saturated C-H bonds and aziridination of alkenes with PhI=NTs as a nitrogen source. However, these processes involve the usage of the highly toxic and expensive late transition metal catalysts and halogenated organic solvents. In this connection, it continues to be a challenge for chemists to develop new green catalysts (such as Fe) that can reduce the use of highly toxic metal catalyst, and achieve high product turnovers amidation reactions. Over the years, we have extensively investigated high-valent ruthenium- and osmium-ligand multiple bonded complexes in catalytic atom/group transfer reactions (over 250 papers and reviews published in international chemistry journals). By virtue of the structural diversity of the auxiliary ligands, the steric and electronic properties of transition metal catalysts can be tuned for stereo- and enantioselective reactions. For example, we showed that formation of sulfamte esters and carbamates can be achieved in high yields and e.e. values using chiral Ru(II) porphyrin catalysts [Che et al, Angew. Chem. Int. Ed. 2002, 41, 3465]. On the other hand, little is known about the high-valent iron-nitrogen multiple bonded complexes. High-valent iron-imido complexes are usually proposed to be the reactive intermediates in Fe-porphyrin catalyzed amidation of hydrocarbons. Very recently, Berry et al reported the isolation and characterization of the first octahedral Fe(VI)-nitrido complexes [Science 2006, 312, 1937]. Our recent studies showed that reaction of [Fe(py5)(CH3CN)]2+ with PhI=NTs in MeCN produced a rapid color change and a yellow solid was obtained after evaporation to dryness. ESI mass spectral analysis revealed a molecular ion peak at m/z = 612, tentatively assigned to [TsN=Fe(py5)]+. Recently, we have determined the X-ray crystal structures of two bis(tosylimido)ruthenium(VI) porphyrin complexes and revealed that the Ru-N(imido) distances depended on the para-substituent on the phenyl ring of the tosylimido ligand. We envisage that iron catalyst would have tremedous potential to be the future catalysts of choice for selective amidation of hydrocarbons. We have found that [Fe(Cl3terpy)2]2+ is an active catalyst for aziridination of alkenes and amidation of activated C-H bond with moderate to good product yields. We propose to extensively develop such chemistry, including isolation of the Fe=NTs species for X-ray and spectroscopic characterization and reactivity studies. With our existing research capability and promising findings, we aim (1) to explore and develop new class of Fe catalysts containing chelating polypyridine ligand systems for selective amidation of organic compounds, (2) to synthesize and characterize the high-valent iron-imido compounds, (3) to probe the mechanism of C-H insertion and subsequent C-N bond formation by highly reactive metal-imido complexes, and (4) to prepare and/or generate cis-oxo-imido metal complexes for aminohydroxylation of C=C bonds and to develop robust metal catalysts for this transformation. |
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Researcher
: Cho CH |
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Project Title: |
Adrenaline and its receptor activation on colon cancer growth |
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Investigator(s): |
Cho CH |
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Department: |
Pharmacology |
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Source(s) of Funding: |
Seed Funding Programme for Basic Research |
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Start Date: |
02/2006 |
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Abstract: |
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B-Adrenoceptor, a G-protein coupled
receoptr, has recently been implicated in the carcinogenesis of different
kinds of cancers. It has been reported that actiavtion of B-adrenoceptors
could stimulate pulmonary, pancreatic and colon carcinoma cell growth (
Carcinogenesis 1898, 10:1753; Carcinogenesis 2001, 22: 473; Cancer Res. 2005,
65: 5272). Polymorphisms in B-adrenoceptor genes are also associated with
increased risk of breast, colon and endometrial cancers (Cancer Res. 2001,
3:264; Int. J. Clin. Oncol 2001, 6:117; Obstet. Gynecol 2003, 102: 506;
J.Exp. Clin. Cacner Res. 2004, 23: 669). In addition, B-blockers could
inhibit the migration of colon cancer cells induced by noradrenaline (Cancer
Res. 2001, 61: 2866). Recent clincial studies also reveal that using
B-blockers is negatively associated cancer risk (Rev. Epidemiol. Sante
Publiqu 2004, 52: 53; Lancet 1997, 349: 525; Am. J. Hypertens. 1996, 9: 695).
All thes findings converge to suggest that adrenoceptors especially
B-adrenoceptors indeed play a crucial role in the development of cancer. On
the other hand, biobehavioral stresses may influence growth and progression
of cancer (Clin. |
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List of Research Outputs |
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Liu E.S.L., Ye Y., Shin V.Y., Wu W.K., Wong B.C.Y. and Cho C.H., Interaction of cigarette smoking with cyclooxygenase-2 on ulcerative colitis-associated neoplasia in mice., Cancer Invest.. 2007, 25(8): 750-7. |
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Wu W.K., Li G.R., Wong T.M., Wang J.Y., Yu L. and Cho C.H., Involvement of voltage-gated K(+) and Na (+) channels in gastric epithelial cell migration. , Mol Cell Biochem. 2008, 308(1-2): 219-26. |
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Researcher
: Ho YW |
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List of Research Outputs |
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Ho
Y.W., Leung
G.P.H., Man R.Y.K., Vanhoutte P.M.G.R. and Ng J.K.F., Distributions of alpha 2
adrenoceptor subtypes in porcine coronary vasculature, Experimental
Biology 2008, |
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Researcher
: Keung WWY |
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List of Research Outputs |
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Ng W.W.H., Keung W.W.Y., Xu Y., Ng J.K.F., Leung G.P.H., Vanhoutte P.M.G.R., Choy P.C. and Man R.Y.K., Genistein potentiates protein kinase A activity in porcine coronary artery, Molecular and Cellular Biochemistry. 2008, 311: 37-44. |
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Researcher
: Kong WCB |
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List of Research Outputs |
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Kong W.C.B., Leung S.W.S. and Man R.Y.K., Endothelium-derived hyperpolarizing factor (EDHF)-mediated responses in aging , 5th International EDHF Symposium. 2008. |
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Researcher
: Koo MWL |
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Project Title: |
Effects of antioxidants and the roles of heat shock protein 32 on cognitive functions in aging |
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Investigator(s): |
Koo MWL |
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Department: |
Pharmacology |
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Source(s) of Funding: |
Small Project Funding |
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Start Date: |
11/2002 |
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Abstract: |
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To carify the roles of HOs in aging and its involvement in cognitive functions; to elucidate the usefulness of antioxidants in delaying cognitive function loss during aging. |
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Project Title: |
Alleviating effect of Bu-zhong-yi-qi-tang on chemotherapy-induced bone marrow suppression in mice |
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Investigator(s): |
Koo MWL |
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Department: |
Pharmacology |
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Source(s) of Funding: |
Small Project Funding |
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Start Date: |
11/2003 |
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Abstract: |
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To investigate the mechanisms of action from herbs particularly on bone marrow recovery and CSFs production. |
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Project Title: |
Effect of tea on lipoprotein lipase and lipid metabolism |
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Investigator(s): |
Koo MWL |
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Department: |
Pharmacology |
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Source(s) of Funding: |
Small Project Funding |
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Start Date: |
03/2006 |
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Abstract: |
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Key issues and problems More and more
people in developed countries are becoming obese. In the |
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List of Research Outputs |
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Chan K.H., Ho S.P., Yeung S.C., Cho C.H., Koo M.W.L., Lam W.K., Man R.Y.K. and Mak J.C.W., Effects of Lung Chen tea on antioxidant enzyme activity in rat lungs after exposure to cigarette smoke, Pro Am Thorac Soc. 2008, 3: A241. |
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Cheung
K.W., Sze D.M.Y., Koo M.W.L.
and Chan G.C.F., The Immunomodulatory
Effects of Propolis from Different Origins on Human Immune Cells, 12th Research
Postgraduate Symposium, |
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Song L., Koo M.W.L., Cheung B.M.Y. and Lau C.P., Effects of green tea on hypercholesterolemia induced hypertension in rats, Southeast Asian Western Pacific Regional Federation of Pharmacologists and the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists Meeting. 2007. |
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Researcher
: Lee MYK |
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List of Research Outputs |
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Lee M.Y.K., Tse H.F., Zhu S., Man R.Y.K. and Vanhoutte P.M.G.R., Genomic changes in regenerated porcine coronary arterial endothelial cells , Arterioscler Thromb Vasc Biol. 2007, 27: 2443-2449. |
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Researcher
: Lee YKM |
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List of Research Outputs |
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Lee Y.K.M. and Vanhoutte P.M.G.R., Surfactant protein D and activation of porcine cultured endothelial cells by TNF-a, Third International Symposium on Healthy Aging, Research Centre of Heart, Brain, Hormone and Healthy Aging, Hong Kong, March 1-2, 2008. 54 (P21). |
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Researcher
: Leung CYI |
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List of Research Outputs |
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Leung C.Y.I., Vanhoutte P.M.G.R., Man R.Y.K. and Leung G.P.H., Tissue-type plasminogen
activator: a possible candidate of endothelium-derived hyperpolarization
factor?, Basic & clinical Pharmacology & Toxicology, 5th
International EDHF Symposium, |
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Researcher
: Leung GPH |
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Project Title: |
Cloning and characterization of novel equilibrative nucleoside transporter type 4 (ENT4) |
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Investigator(s): |
Leung GPH |
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Department: |
Pharmacology |
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Source(s) of Funding: |
Seed Funding Programme for Basic Research |
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Start Date: |
03/2005 |
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Abstract: |
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Background: The physiological important nucleoside, adenosine, acts through adenosine receptors to exert diverse effects on cellular functions such as inhibition of platelet aggregation, slowing of heart rate and vasodilation. Nucleoside transporters are important in adenosine functions by fine-tuning its concentration in the vicinity of adenosine receptors. There are two classes of nucleoside transporters: Na+-dependent concentrative nucleoside transporters (CNTs) and Na+-independent equilibrative nucleoside transporters (ENTs). So far three equilibrative nucleoside transporters (ENTs) have been cloned and characterized. Both ENT1 and ENT2 are broadly selective, transporting purine and pyrimidine nucleosides. Nevertheless, ENT1 is nitrobenzylmercaptopurine ribonucleoside (NBMPR)-sensitive and has an IC50 of 1nM while ENT2 is relatively NBMPR-insensitive and has an IC50 > 1µM. Unlike ENT1 and ENT2, which are plasma membrane proteins, ENT3 is an intracellular protein. It may be responsible for salvaging nucleosides between the cytoplasm and the lumen of Golgi apparatus. Adenosine transport in endothelial cells is Na+-independent. Interestingly, we found that in physiological levels of adenosine (0.1 to 1µM), high concentrations of NBMPR (> 200µM, a concentration that can completely inhibit both ENT1 and ENT2) only reduce 20% of the adenosine transport. It indicates that another nucleoside transporter, which is characteristically distinct from the ENT1 and ENT2, is present in the endothelial cells. Recently, we have cloned a protein from endothelial cells which has 18% amino acid identity with ENT1. We term it ENT4 and hypothesize that it may be a novel isoform of nucleoside transporter. Objectives: In this grant application, we propose to characterize ENT4. In aim I, we will stably transfect ENT4 into nucleoside transporter-deficient cells. In aim II, we will functionally characterize ENT4. We will determine its affinities to different nucleosides and its sensitivities to different inhibitors such as NBMPR. In aim III, we will study the tissue distribution of ENT4. |
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Project Title: |
Physiological and pharmacological studies of equilibrative nucleoside transporter-2 |
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Investigator(s): |
Leung GPH, Man RYK |
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Department: |
Pharmacology |
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Source(s) of Funding: |
Seed Funding Programme for Basic Research |
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Start Date: |
03/2006 |
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Abstract: |
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Adenosine is an endogenous purine nucleoside and modulates a variety of physiological functions by interacting with the adenosine receptors on cell surface. Under adverse conditions such as ischemia, hypoxia, stress and inflammation, extracellular levels of adenosine are increased. The increased extracellular adenosine protects tissues from excessive damage. It has been demonstrated that adenosine attentuates the ischemic heart injury, reduces inflammation and is vasodilatory. However, the therapeutic application of adenosine is limited because extracellular adenosine usually disappears quickly due to its rapid uptake into adjacent cells and subsequent metabolism. Adenosine is taken up from the extracellular space into adjacent cells through the nucleoside transporters on plasma membrane. Equilibrative nucleoside transporter (ENT)-1 and ENT2 are the major nucleoside transporters found in heart, endothelial cells and vascular smooth muscle cells. Physiologically, ENT1 is regulated by protein kinase A, protein kinase C, tyrosine kinase, nitrogen-activating protein kinase and casein kinase II. Pharmacologically, ENT1 is potently inhibited by nitrobenzylmercaptopurine riboside (NBMPR), dipyridamole and dilazep. In contrast, little is known about the physiological regulation of ENT2. Specific inhibitor for ENT2 is also not available. Therefore, in this grant application, we propose to 1) study the regulation of ENT2 2) screen for the potential lead compounds for the development of specific ENT2 inhibitor. |
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Project Title: |
Development of a high-thoughput screening system for prediction of drug interactions |
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Investigator(s): |
Leung GPH, Man RYK, Vanhoutte PMGR |
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Department: |
Pharmacology |
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Source(s) of Funding: |
Seed Funding Programme for Applied Research |
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Start Date: |
01/2007 |
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Abstract: |
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Cytochrome P450 (CYP) comprises a superfamily of enzymes, which can metabolise both endogenous compounds and drugs. Induction and inhibition of CYP are undesirable characteristics for therapeutic agents. For instance, induction of CYP may increase the metabolism of co-administrated drugs, causing drug-drug interactions. Induction of drug metabolism enzymes may also predispose the individual to chemical carcinogenesis because many known procarcinogens are activated by CYP. We can examine the effects of liver enzymes on drugs easily by studying the drug metabolites after enzymatic digestion. However, it is more difficult to study the inducing and inhibitory effects of drugs on liver enzymes. Many models have been used but all of them have limitations. The liver enzyme preparations (i.e. liver S9 fraction, microsomes and supersomes) show a low sensitivity of the endpoints. More importantly, the use of such pure enzyme systems is unable to measure the impact of pre-translational modifications on reaction. The use of primary human hepatocytes, is often said to represent the closest possible model to the in vivo situation. Unfortunately, it is apparent that CYP expression diminishes during cell culture so the drug metabolizing enzyme profile cannot accurately represent that observed in vivo. Batch-to-batch variation is also seen in the primary cultured hepatocytes. Besides, even all the CYP isoforms are stably expressed in the primary cultured hepatocytes, the specificity of probe substrates used in the assays is always questioned. The data is only indicative of the role of an enzyme family but not of which isoform. In addition, the expensive cost and the need of fresh human livers do not lend them well to high-throughput system. Taken together, therefore, the development of another system is necessary. The aim of our project is to develop a stable, reliable, cost effecive and high-throughput system which can evaluate the effects of drugs on specific drug metabolizing enzymes and predict the possibility of drug interactions. |
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List of Research Outputs |
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Ho
Y.W., Leung G.P.H., Man R.Y.K., Vanhoutte P.M.G.R. and Ng J.K.F., Distributions of alpha 2
adrenoceptor subtypes in porcine coronary vasculature, Experimental
Biology 2008, |
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Hoque K.M., Chen L., Leung G.P.H. and Tse C.M., A purine-selective nucleobase/nucleoside transporter in PK15NTD cells, American Journal of Physiology Regulation and Integrative and Comparative Physiology. 2008, 294: R1988-1995. |
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Leung
C.Y.I., Vanhoutte P.M.G.R., Man R.Y.K. and Leung G.P.H., Tissue-type
plasminogen activator: a possible candidate of endothelium-derived
hyperpolarization factor?, Basic & clinical Pharmacology &
Toxicology, 5th International EDHF Symposium, |
|
Leung
G.P.H., Man
R.Y.K., Vanhoutte P.M.G.R. and Li R.W.S., Stimulation of endothelial
ecto |
|
Leung G.P.H. and Tse C.M., The role of mitochondrial and plasma membrane nucleoside transporters in drug toxicity, Expert Opinion on Drug Metabolism and Toxicology. 2007, 3: 705-718. |
|
Li
R.W.S., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Regulation of
extracellular adenosine level by equilibrative nucleoside transporters and
ecto |
|
Li W.S.R., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Control of extracellular adenosine levels in inflammation, Third International Symposium on Healthy Aging, Research Centre of Heart, Brain, Hormone and Healthy Aging, Hong Kong, March 1-2, 2008. 54 (P22). |
|
Lin A.H.Y., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Receptor and signaling pathways underlying the vascular actions of genistein, 10th Scientific Meeting of Hong Kong Pharmacology Society, Hong Kong, 15 December 2007. 15 (O8). |
|
Lin H.Y.A., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Characterization and Identification of a putative phytoestrogen receptor that mediates rapid non-genomic vascular actions, 12th Research Postgraduate Symposium, Hong Kong, 12 & 14 December 2007. 54 (1.18). |
|
Lin H.Y.A., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Rapid, nongenomic vascular actions of genistein suggests a phytoestrogen receptor, Experimental Biology 2008, San Diego, USA, April 5-9, 2008. B173 (912.14). |
|
Man R.Y.K., Leung S.W.S. and Leung G.P.H., Effects of flavonoids on cell proliferation: comparison with estrogen , Experimental Biology 2008. |
|
Ng W.W.H., Keung W.W.Y., Xu Y., Ng J.K.F., Leung G.P.H., Vanhoutte P.M.G.R., Choy P.C. and Man R.Y.K., Genistein potentiates protein kinase A activity in porcine coronary artery, Molecular and Cellular Biochemistry. 2008, 311: 37-44. |
|
Seto S.W., Lam T.Y., Leung G.P.H., Au A.L.S., Ngai S.M., Chan S.W. and Kwan Y.W., Comparison of vascular relaxation, lipolysis and glucose uptake by peroxisome proliferator-activated receptor- activation in +db/+m and +db/+db mice, European Journal of Pharmacology. 2007, 572: 40-48. |
|
Tang
H.C., Jensen B.L., Skott O., Leung
G.P.H., Feletou M., Man R.Y.K.
and Vanhoutte P.M.G.R., The role of
prostaglandin E and thromboxane-prostanoid receptors in the response to
prostaglandin E |
|
Xu Y.C., Leung G.P.H., Wong P.Y.D., Vanhoutte P.M.G.R. and Man R.Y.K., Kaempferol stimulates large conductance 2+-activated K+ (BKCa) channels in human umbilical vein endothelial cells via a cAMP/PKA-dependent pathway, British Journal of Pharmacology. 2008, 154: 1247-1253. |
|
Yang
C., Vanhoutte P.M.G.R., Man R.Y.K. and Leung G.P.H., Effects of
epoxyeicosatrienoic acids on volume-activated chloride channels via cyclic
GMP pathway in rat mesenteric artery, Experimental Biology 2008, |
|
Yang C., Vanhoutte P.M.G.R., Man R.Y.K. and Leung G.P.H., Involvement of volume-activated chloride channels in EDHF-induced vasodiation in rats, 12th Research Postgraduate Symposium, Hong Kong, December 12 & 14, 2007. 62 (1.35). |
|
Researcher
: Leung SWS |
|
Project Title: |
The role of calcium calmodulin dependent protein kinase II in the regulation of endothelial-derived hyperpolarizing factor-mediated responses |
|
Investigator(s): |
Leung SWS, Man RYK |
|
Department: |
Pharmacology |
|
Source(s) of Funding: |
Seed Funding Programme for Basic Research |
|
Start Date: |
02/2005 |
|
Abstract: |
|
Introduction: The endothelium plays an
important role in the regulation of the vascular tone, through the release of
many vasoactive substances such as nitric oxide, endothelial-derived
hyperpolarizing factor (EDHF), prostaglandins and endothelin-1. Of the
endothelial-derived relaxing factors, EDHF is the least characterized.
Several putative EDHF candidates are the metabolites of arachidonic acid,
including anandamide [1], epoxyeicosatrienoic acids (EET) [2] and hydrogen
peroxide (H2O2) [3]. Anandamide is the metabolic product of the action of
amidohydrolase on arachidonic acid, whereas both EET and H2O2 are generated
by cytochrome P450 epoxygenase. It appears that the release of EDHF, like
other vasoactive agents, can be activated by an increase of intracellular
concentration of free calcium, which then associates with calmodulin in the
endothelial cells [4]. While most research effort has been devoted to
identify the chemical entity and the mechanisms of action of EDHF, little is
known regarding the regulation of the production of EDHF. Objectives: In view
of the involvement of the calcium/calmodulin complex in the stimulation of
the production of EDHF, it is hypothesized that calcium/calmodulin dependent
protein kinase II (CaMK II) plays a role in regulating the release of EDHF.
Therefore, the aim of the present study is to investigate the contributions
of CaMK II to the regulation of EDHF-mediated relaxation. References: 1.
Randall MD, Alexander SP, Bennett T et al., Biochem Biophys Res Commun 1996;
229: 114-120. 2. |
|
Project Title: |
The role of extracellular signal-regulated kinases in the pathophysiology of hypertension |
|
Investigator(s): |
Leung SWS, Man RYK |
|
Department: |
Pharmacology |
|
Source(s) of Funding: |
Seed Funding Programme for Basic Research |
|
Start Date: |
02/2006 |
|
Abstract: |
|
Introduction: Hypertension is a disease
characterized by spontaneous arterial tone, enhanced contraction, reduced
relaxation and vascular smooth muscle hypertrophy. If not managed properly,
hypertension is associated with vascular complications such as
arteriosclerotic lesions and further increase in arterial pressure. Elevation
of blood pressure is associated with increased sheer stress [1], which is
generated by the streaming blood on the endothelial layer. Acute increases in
sheer stress in rat arteries in vitro and in vivo lead to activation of
extracellular signal-regulated kinase-1/2 (ERK 1/2) [2-4], and this, in turn,
results in vascular smooth muscle cell growth [5]. In addition to the
involvement of vascular remodeling, recent studies suggest that ERK 1/2
modulate vascular contraction and relaxation. These latter actions of ERK 1/2
may also play an important role in the progress of vascular disease in
hypertension [6-10]. Hypothesis: We hypothesize that the activity of ERK 1/ |
|
Project Title: |
Investigation on the role of phosphatidylinositol 3-kinase in endothelial dysfunction induced by atherogenic lipids |
|
Investigator(s): |
Leung SWS, Man RYK |
|
Department: |
Pharmacology |
|
Source(s) of Funding: |
Seed Funding Programme for Basic Research |
|
Start Date: |
04/2007 |
|
Abstract: |
|
Background Oxidation of low-density lipoprotein is a key event in the pathogenesis of atherosclerosis, and this process is associated with a dramatic increase in lysophosphatidylcholine (LPC). Both oxidized low-density lipoprotein and LPC have been known to disturb the regulation of vascular tone, resulting in increased constriction and reduced dilation [1-3]. Current consensus recognizes nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) as two major relaxing factors responsible for mediating endothelium-dependent relaxation [4, 5]. The mechanisms of actions through which LPC interferes with NO and EDHF pathways have not been identified [6-12]. Recent evidence suggests that LPC can activate phosphatidylinositol-3-kinase (PI3K) in monocytes, and this action is related to the initiation of chemotaxis, leading to the formation of foam cells hence atherosclerotic plague [13]. The enzyme, PI3K, has also been implicated in modulation of vasomotor tone [14-17]. Hypothesis We hypothesize that activation of PI3K by atherogenic phospholipids is responsible for endothelial dysfunction that is associated with hypercholesterolemia. Purpose of the proposed investigation: The mechanism(s) through which atherogenic lipids in impairing endothelium-dependent relaxation remains unclear. The present proposed study aims at investigating the regulation of endothelium-dependent relaxation by PI3K, an enzyme shown to be activated by atherogenic lipids. The influence of atherogenic lipids on the activity and expression of PI3K, as well as its downstream enzymes, will also be examined. Key issues and problem addressed: i. The importance of the signaling mechanisms of PI3K and its downstream targets, namely protein kinase B (PKB, also known as Akt) and extracellular signal-regulated kinase-1/2 (ERK 1/2), in the regulation of the vascular tone will be examined under physiological conditions, as well as under the influence of the atherogenic phospholipid, LPC. ii. Alteration of the expression, phosphorylation and activity of these enzymes due to acute and chronic exposure to atherogenic phospholipids will be studied in isolated porcine coronary artery, and the results will be correlated to the degree of endothelial dysfunction as indicated by the decrease in endothelium-dependent relaxation. iii. The potential of interfering PI3K signaling pathway using pharmacological approaches to reverse the influence of atherogenic phospholipid on endothelium-dependent relaxation will be examined. Reference: [1] Kugiyama K, Kerns SA, Morrisett JD, et al. Nature 1990; 344: 160-162. [2] Tanner FC, Noll G, Boulanger CM, et al. Circulation 1991; 83: 2012-2020 [3] Yokoyama M, Hirata K-I, Miyake R, et al. Biochem Biophys Res Comm 1990; 168: 301–308. [4] Palmer RMJ, Ferrige AG, Moncada S. Nature 1987; 327: 524-526. [5] Chen G, Suzuki H, Weston AH. Br J Pharmacol 1988; 95: 1165-1174. [6] Cox DA, Cohen ML. Am J Physiol 1996; 271: H1706–H1710. [7] Freeman JE, Kuo WY, Drenger B, et al. J Cardiovasc Pharmacol 1996; 28: 345–352. [8] Miwa Y, Hirata K-i, Kawashima S, et al. Arterioscler Thromb Vasc Biol 1997; 17: 1561–1567. [9] Kikuta K-i, Sawamura T, Miwa S, et al. Circ Res 1998; 83: 1088–1096. [10] Fukao M, Hattori Y, Kanno M, et al. Br J Pharmacol 1995; 116: 1541-1543. [11] Cowan CL, Steffen RP. Arterioscler Thromb Vasc Biol 1995; 15: 2290–2297. [12] Eizawa H, Yui Y, Inoue R, Kosuga K, et al. Circulation 1995; 92: 3520–3526. [13] Jing Q, Xin SM, Zhang WB, et al. Cir Res 2000; 87: 52-59. [14] Macrez N, Mironneau C, Carricaburu V, et al. Circ Res 2001; 89: 692-699. [15] Viard P, Exner T, Maier U, et al. FASEB J 1999; 13: 685-694. [16] Cantrell DA. J Cell Sci 2002; 114: 1439-1445. [17] Cantley LC. Science 2002; 296: 1655-1657. |
|
List of Research Outputs |
|
Chan L.Y., Leung S.W.S. and Man R.Y.K., Acute actions of osthole in the modulation of the vascular system, 12th Research Postgraduate Symposium, Hong Kong, December 12 & 14, 2007. 144 (1.14). |
|
Kong W.C.B., Leung S.W.S. and Man R.Y.K., Endothelium-derived hyperpolarizing factor (EDHF)-mediated responses in aging , 5th International EDHF Symposium. 2008. |
|
Leung S.W.S. and Man R.Y.K., Effects of hawthorn, a herbal medicine, on arterial blood pressure in anaesthetized rats, Experimental Biology 2008. |
|
Leung S.W.S., In vivo models to study vascular complications Advanced Study Institute on Recent Advances in Diabetes and its Complications 2007, Hong Kong (3-7 September 2007), 2007. |
|
Lin A.H.Y., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Receptor and signaling pathways underlying the vascular actions of genistein, 10th Scientific Meeting of Hong Kong Pharmacology Society, Hong Kong, 15 December 2007. 15 (O8). |
|
Lin H.Y.A., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Characterization and Identification of a putative phytoestrogen receptor that mediates rapid non-genomic vascular actions, 12th Research Postgraduate Symposium, Hong Kong, 12 & 14 December 2007. 54 (1.18). |
|
Lin H.Y.A., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Rapid, nongenomic vascular actions of genistein suggests a phytoestrogen receptor, Experimental Biology 2008, San Diego, USA, April 5-9, 2008. B173 (912.14). |
|
Man R.Y.K., Leung S.W.S. and Leung G.P.H., Effects of flavonoids on cell proliferation: comparison with estrogen , Experimental Biology 2008. |
|
Ng J.K.F., Leung S.W.S., Man R.Y.K. and Vanhoutte P.M.G.R., C-Type natriuretic peptide (CNP) release does not contribute to endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in porcine coronary artery, Experimental Biology 2008 . 2008. |
|
Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Effect of chronic inhibition of nitric oxide synthase on the production of endothelium dependent contractions in the rat aorta, Basic & clinical Pharmacology & Toxicology, 5th International EDHF Symposium, tampere, Finalnd, June 24-27, 2008. 102 (Suppl.1): 32. |
|
Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Modulation of endothelium-dependent contractions by chronic inhibition of nitric oxide synthase in the rat aorta, Experimental Biology 2008. |
|
Researcher
: Li RWS |
|
List of Research Outputs |
|
Leung
G.P.H., Man R.Y.K., Vanhoutte P.M.G.R. and Li R.W.S., Stimulation of
endothelial ecto |
|
Li
R.W.S., Man
R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Regulation of
extracellular adenosine level by equilibrative nucleoside transporters and
ecto |
|
Researcher
: Li WSR |
|
List of Research Outputs |
|
Li W.S.R., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Control of extracellular adenosine levels in inflammation, Third International Symposium on Healthy Aging, Research Centre of Heart, Brain, Hormone and Healthy Aging, Hong Kong, March 1-2, 2008. 54 (P22). |
|
Researcher
: Lin AHY |
|
List of Research Outputs |
|
Lin A.H.Y., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Receptor and signaling pathways underlying the vascular actions of genistein, 10th Scientific Meeting of Hong Kong Pharmacology Society, Hong Kong, 15 December 2007. 15 (O8). |
|
Researcher
: Lin HYA |
|
List of Research Outputs |
|
Lin H.Y.A., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Characterization and Identification of a putative phytoestrogen receptor that mediates rapid non-genomic vascular actions, 12th Research Postgraduate Symposium, Hong Kong, 12 & 14 December 2007. 54 (1.18). |
|
Lin H.Y.A., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Rapid, nongenomic vascular actions of genistein suggests a phytoestrogen receptor, Experimental Biology 2008, San Diego, USA, April 5-9, 2008. B173 (912.14). |
|
Researcher
: Liu ESL |
|
List of Research Outputs |
|
Liu E.S.L., Ye Y., Shin V.Y., Wu W.K., Wong B.C.Y. and Cho C.H., Interaction of cigarette smoking with cyclooxygenase-2 on ulcerative colitis-associated neoplasia in mice., Cancer Invest.. 2007, 25(8): 750-7. |
|
Researcher
: Mak JCW |
|
Project Title: |
Effects of pseudomonas aeruginosa pyocyanin and 1-hydroxyphenazine on the regulation of glucocorticoid receptor activation and function in airway epithelial cells in vitro |
|
Investigator(s): |
Mak JCW, Tsang KWT |
|
Department: |
Medicine |
|
Source(s) of Funding: |
Competitive Earmarked Research Grants (CERG) |
|
Start Date: |
11/2003 |
|
Abstract: |
|
To evaluate the effects of Pseudomonas aeruginosa (PA) exotoxins, pyocyanin (PYO) and 1-hydroxyphenazine (1-HP), on the functional and immunological aspects of human airway epithelial cells in vitro, and examine the signaling pathways involved in PYO- or 1-HP-induced responses; to assess the efficacy of various potential novel therapeutic and chemical agents on the effects of these toxins. |
|
Project Title: |
Role of
transforming growth factor-beta1 variants in susceptibility to tuberculosis
in |
|
Investigator(s): |
Mak JCW, Chan MMW |
|
Department: |
Medicine |
|
Source(s) of Funding: |
Seed Funding Programme for Basic Research |
|
Start Date: |
02/2005 |
|
Abstract: |
|
i) To study the role of two common single
nucleotide polymorphisms (SNPs) at the promoter (C-509T) and coding regions
(T |
|
Project Title: |
Role of
senescence marker protein |
|
Investigator(s): |
Mak JCW, Chan MMW |
|
Department: |
Medicine |
|
Source(s) of Funding: |
Seed Funding Programme for Basic Research |
|
Start Date: |
04/2007 |
|
Abstract: |
|
Chronic obstructive pulmonary disease
(COPD) is a major public health concern worldwide, and is projected to be the
third leading cause of mortality worldwide within 10 years [1]. COPD is a
disease characterized by slowly progressive development of airflow limitation
that is not fully reversible. The airflow limitation is associated with an
abnormal inflammatory response of the lungs to noxious particles or gases,
mainly from cigarette smoke [2]. Smoking accounts for 90% of cases of COPD,
but only 15% of smokers develop clinically symptomatic COPD [3]. There are no
therapies that can reduce the inevitable progression of this disease at
present. COPD is an age-related lung disease that occurs after a prolonged
period of cigarette smoking. Oxidative stress is an important feature of
COPD. Cigarette smoke is a rich source of oxidants containing over 1015 free
radicals/puff in both the gaseous and tar phase [4]. In patients with COPD,
biomarkers of oxidative stress, such as protein carbonyls and lipid
peroxidation products, are reported to be elevated in the lungs and
respiratory muscles [5,6]. Senescence marker protein-30 (SMP30) Senescence
marker protein-30 (SMP30), a 34-kD protein that decreases with age, is a
multifunctional protein providing protection to cellular functions from
age-associated deterioration [7]. It has been proposed as an important aging
marker and is functionally identified as a Ca2+ binding protein. In mice,
SMP30 transcripts are detected in various organs including lung [8]. In
humans, the SMP30 gene is located in the p11.3-q11.2 segment of the X
chromosome [9]. The SMP30 knockout (SMP30Y/-) mouse has been developed with
gene targeting from C57BL6 mice [10]. Recent findings showed that SMP30
protects mice lungs from oxidative stress, aging and smoking [11]. However,
the precise function of SMP |
|
List of Research Outputs |
|
Chan K.Y.C., Mak J.C.W., Man R.Y.K. and Vanhoutte P.M.G.R., RHO kinase and endothelum-dependent contractions in the SHR and WKY aorta, Basic & Clinical Pharmacology & Toxicology, 5th International EDHF Symposium, Tampere, Finaland, June 24-27, 2008. 102 (suppl.1): 55. |
|
Researcher
: Man RYK |
|
Project Title: |
Cloning and characterization of phytoestrogen receptors in vascular cells |
|
Investigator(s): |
Man RYK, Leung GPH, Leung SWS |
|
Department: |
Pharmacology |
|
Source(s) of Funding: |
Small Project Funding |
|
Start Date: |
12/2005 |
|
Abstract: |
|
Epidemiological studies have demonstrated that women are less vulnerable to cardiovascular diseases during their pre-menopausal years. However, the incidence of cardiovascular diseases increases after menopause, stating the importance of female hormone in cardiovascular protective effects. Estrogen replacement therapy has been demonstrated to be beneficial to the cardiovascular system. For instance, it can decrease low-density lipoprotein and increase high density lipoprotein. Besides, estrogen shows antioxidant and vasodilatory effects. Unfortunately, the actual benefit of estrogen therapy is questionable because it increases the risk of endometrial and breast cancer. The hormonal effects also make estrogen not useful in male. Phytoestrogens are an alternative. Soybean is rich in phytoestrogens. A number of studies have suggested the beneficial effects of soy-rich diet in lowering the mobility and mortality of cardiovascular diseases. Same as estrogen, soybean products reduce the blood levels of low density lipoprotein and triglyceride. Our laboratory has also proved that genistein, a phytoestrogen, enhances the endothelium-independent relaxation in coronary artery. These effects may contribute to the prevention of cardiovascular disorders. Most importantly, although genistein is structurally similar to estrogen, its affinity to the genomic estrogen receptors is 100-1000 times less than the estrogen. Therefore, it is assumed that phytoestrogens, while producing beneficial cardiovascular effects, should show negligible hormonal effects. Our tissue bath studies have demonstrated the vasodilatory effects of several other phytoestrogens. Interestingly, the actions of all those phytoestrogens occur within 30 minutes. It is too rapid to have been attributed to the genomic action. This notion is supported by the lack of effect of actinomycin D, a DNA transcription inhibitor, or cycloheximide, a mRNA translation inhibitor, to block the vascular effects of phytoestrogens. Moreover, the inability of the classic estrogen receptor antagonist, ICI 182,780, to block the effects of phytoestrogens further indicates that phytoestrogen may act on receptors which are distinct from the classic genomic estrogen receptors. In this grant application, we propose to clone and characterize phytoestrogen receptors in vascular cells. In aim I, we will clone phytoestrogen receptors. In aim II, we will express the cloned phytoestrogen receptors in COS-7 cells. We will study their molecular sizes, cellular localization and affinities to phytoestrogens and estrogen. If they show high affinities to phytoestrogen, we will study if they are linked to cAMP or cGMP production in vascular smooth muscle. In aim III, we will determine the tissue distribution of phytoestrogen receptors. |
|
Project Title: |
Gender differences in the regulation of endothelium-dependent contracting factor |
|
Investigator(s): |
Man RYK, Vanhoutte PMGR, Leung SWS |
|
Department: |
Pharmacology |
|
Source(s) of Funding: |
Competitive Earmarked Research Grants (CERG) |
|
Start Date: |
09/2006 |
|
Abstract: |
|
(1) Gender differences exist in the production and/or actions of EDCF, in particular in hypertensive and aging rats. This different between male and female are caused by the non-genomic action of the major female hormone, estrogen. (2) Estrogen modulates the changes in the key proteins that are involved in the production and the action of EDCF in arteries from hypertensive and aging rats. Examples of these proteins are muscarinic receptor(s) in endothelial cells, prostanoid receptors in vascular smooth muscle cells and prostanoid synthase(s) in both cell types. (2) The activation of soluble guanylyl cyclase in endothelial cells has an autocrine effect to diminish the activity and/or expression of prostanoid synthase(s) resulting in inhibition of the production of EDCF. The extent of activation of this enzyme is influenced by the hormonal status of rats. |
|
Project Title: |
Hormonal effects of flavonoids with selective vascular actions: comparison with estrogen |
|
Investigator(s): |
Man RYK, Leung SWS, Leung GPH |
|
Department: |
Pharmacology |
|
Source(s) of Funding: |
Small Project Funding |
|
Start Date: |
12/2006 |
|
Abstract: |
|
Prior to menopause, women have a lower incidence of coronary heart disease (CHD) compared to age-matched men [1-3]. Estrogen replacement therapy reduces CHD mortality in post-menopausal women [4,5]. The protective effects of estrogen are partially attributable to its favorable vascular effects. Unfortunately, the therapeutic potential of estrogen for cardiovascular protection is complicated by its hormonal actions, which make it an inappropriate agent for male. Moreover, the hormonal actions of estrogen results in an increased risk of endometrial and breast cancer. Being structurally similar to estrogen, some flavonoids have been considered as phytoestrogens and are likely to provide similar cardiovascular benefit to estrogen. Indeed, a number of studies have suggested that flavonoid-rich diet reduced the mobility and mortality of cardiovascular diseases. Our previous studies have demonstrated that several flavonoids, such as genistein, puerarin and kaempferol, favourably modulated vascular responses in a similar manner to 17beta-estradiol [6-9]. These effects were rapid in onset (occuring within 30 minutes) and were not affected by the classical estrogen receptor antagonist, ICI 182,780. Therefore, the modulatory actions of flavonoids, like 17beta-estradiol, on vascular reactivity were likely to be non-genomic in nature. Moreover, these vascular effects of flavonoids appeared to be mediated through a cyclic AMP-dependent signaling cascade similar to that involved in the vascular actions of 17beta-estradiol [7,10]. Hence, some flavonoids may act at the same cellular targets, possibly membrane-bounded receptors, as 17beta-estradiol in vascular tissues. While the above suggested a non-genomic actions of estrogen, estrogen has well known genomic actions via intracellular estrogen receptors. These include stimulation of breast and uterine tissues, lowering of LDL and raising HDL cholesterol levels, and maintanence of bone density. If flavonoids possess significant genomic effects of estrpgen, they may increase the risk of breast and uterine cancers, and increase the risk of thrombosis. While our findings on the non-genomic vascular actions of flavonoids suggested a likely therapeutic potential of flavonoids against the development of vascular diseases, the potential of these compounds to exert genomic hormonal effects that are similar to those of 17beta-estradiol needed to be taken into account. It is desirable to have flavonoids that possess the vascular action but have little or no hormonal action. Some of the flavonoids, such as genistein and daidzein, have been shown to compete with 17beta-estradiol for the classical genomic estrogen receptors that are responsible for the hormonal effects [11]. However, in those studies, the binding affinity of flavonoids to the genomic estrogen receptors was at least 100-fold less than estrogen. Therefore, it is hypothesized that flavonoids have selectivity in eliciting vascular actions compared to hormonal actions, and that different flavonoids have different vascular-hormonal profiles, which may be determined by their chemical structures. The purpose of the present proposal is to determine the vascular-hormonal profiles of different flavonids, and compared to that of 17beta-estradiol. Specificially, the potency of different flavonoids to elicit hormonal actions, in terms of their ability to stimulate the proliferation of human MCF-7 breast cancer cell line and/or human HEC-1-A endometrial cancer cell line, will be examinied. The order of potency of hormonal actions will be compared with that of vascular actions. The relative potency of the hormonal effects of flavonoids will also be studied in relation to their chemical structures. References: 1. Barrett-Connor E. Circulation 1997; 95: 252-264. 2. Phillips GB, Pinkernell BH, Jing, T-Y. Arterioscler Thromb Vasc Biol 1997; 17: 695-701 3. Van der Schouw YT, Van der Graaf Y, Steyerberg EW, et al. Lancet 1996; 347: 714-718. 4. Ettinger N, Friedman GD, Bush T, et al. Obstet Gynecol 1996; 87: 6-12. 5. Stampfer JM, Colditz FA, Willett WC, et al. N Engl J Med 1991; 325: 756-762. 6. Teoh H, Leung SWS, Man RYK. Cardiovasc Res 1999; 42: 224-231. 7. Teoh H, Man RYK. Br J Pharmacol 2000; 1739-1747. 8. Lee MYK, Man RYK. Eur J Pharmacol 2003; 481: 227-232. 9. Xu YC, Yeung DKY, Man RYK ,et al. Mol Cell Biochem 2006; 287: 61-67. 10. Lee MYK, Leung SWS, Vanhoutte, et al. Eur J Pharmacol 2004; 503: 165-172. 11. Kuiper GGJM, Lemmen JG, Carlsson B, et al. Endocrinology 1998; 139: 4252-4263. |
|
List of Research Outputs |
|
Chan K.H., Ho S.P., Yeung S.C., Cho C.H., Koo M.W.L., Lam W.K., Man R.Y.K. and Mak J.C.W., Effects of Lung Chen tea on antioxidant enzyme activity in rat lungs after exposure to cigarette smoke, Pro Am Thorac Soc. 2008, 3: A241. |
|
Chan K.Y.C., Mak J.C.W., Man R.Y.K. and Vanhoutte P.M.G.R., RHO kinase and endothelum-dependent contractions in the SHR and WKY aorta, Basic & Clinical Pharmacology & Toxicology, 5th International EDHF Symposium, Tampere, Finaland, June 24-27, 2008. 102 (suppl.1): 55. |
|
Chan L.Y., Leung S.W.S. and Man R.Y.K., Acute actions of osthole in the modulation of the vascular system, 12th Research Postgraduate Symposium, Hong Kong, December 12 & 14, 2007. 144 (1.14). |
|
Ho
Y.W., Leung G.P.H., Man R.Y.K., Vanhoutte P.M.G.R. and Ng J.K.F., Distributions of alpha 2
adrenoceptor subtypes in porcine coronary vasculature, Experimental
Biology 2008, |
|
Kong W.C.B., Leung S.W.S. and Man R.Y.K., Endothelium-derived hyperpolarizing factor (EDHF)-mediated responses in aging , 5th International EDHF Symposium. 2008. |
|
Lee M.Y.K., Tse H.F., Zhu S., Man R.Y.K. and Vanhoutte P.M.G.R., Genomic changes in regenerated porcine coronary arterial endothelial cells , Arterioscler Thromb Vasc Biol. 2007, 27: 2443-2449. |
|
Leung
C.Y.I., Vanhoutte P.M.G.R., Man R.Y.K. and Leung G.P.H., Tissue-type plasminogen
activator: a possible candidate of endothelium-derived hyperpolarization
factor?, Basic & clinical Pharmacology & Toxicology, 5th
International EDHF Symposium, |
|
Leung
G.P.H., Man R.Y.K., Vanhoutte P.M.G.R. and Li R.W.S., Stimulation of endothelial
ecto |
|
Leung S.W.S. and Man R.Y.K., Effects of hawthorn, a herbal medicine, on arterial blood pressure in anaesthetized rats, Experimental Biology 2008. |
|
Li
R.W.S., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Regulation of extracellular
adenosine level by equilibrative nucleoside transporters and ecto |
|
Li W.S.R., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Control of extracellular adenosine levels in inflammation, Third International Symposium on Healthy Aging, Research Centre of Heart, Brain, Hormone and Healthy Aging, Hong Kong, March 1-2, 2008. 54 (P22). |
|
Lin A.H.Y., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Receptor and signaling pathways underlying the vascular actions of genistein, 10th Scientific Meeting of Hong Kong Pharmacology Society, Hong Kong, 15 December 2007. 15 (O8). |
|
Lin H.Y.A., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Characterization and Identification of a putative phytoestrogen receptor that mediates rapid non-genomic vascular actions, 12th Research Postgraduate Symposium, Hong Kong, 12 & 14 December 2007. 54 (1.18). |
|
Lin H.Y.A., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Rapid, nongenomic vascular actions of genistein suggests a phytoestrogen receptor, Experimental Biology 2008, San Diego, USA, April 5-9, 2008. B173 (912.14). |
|
Man R.Y.K., Leung S.W.S. and Leung G.P.H., Effects of flavonoids on cell proliferation: comparison with estrogen , Experimental Biology 2008. |
|
Ng J.K.F., Leung S.W.S., Man R.Y.K. and Vanhoutte P.M.G.R., C-Type natriuretic peptide (CNP) release does not contribute to endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in porcine coronary artery, Experimental Biology 2008 . 2008. |
|
Ng W.W.H., Keung W.W.Y., Xu Y., Ng J.K.F., Leung G.P.H., Vanhoutte P.M.G.R., Choy P.C. and Man R.Y.K., Genistein potentiates protein kinase A activity in porcine coronary artery, Molecular and Cellular Biochemistry. 2008, 311: 37-44. |
|
Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Effect of chronic inhibition of nitric oxide synthase on the production of endothelium dependent contractions in the rat aorta, Basic & clinical Pharmacology & Toxicology, 5th International EDHF Symposium, tampere, Finalnd, June 24-27, 2008. 102 (Suppl.1): 32. |
|
Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Modulation of endothelium-dependent contractions by chronic inhibition of nitric oxide synthase in the rat aorta, Experimental Biology 2008. |
|
Shi Y., So K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Oxygen-derived free radicals mediate endothelium-dependent contractions in femoral arteries of rats with streptozotocin-induced diabetes, British Journal of Pharmacology. 2007, 152: 1033-1041. |
|
Shi Y., Man R.Y.K. and Vanhoutte P.M.G.R., Two isoforms of cyclooxygenase contribute to augmented endothelium-dependent contractions in femoral arteries of 1-year-old rats, Acta Pharmaceutica Sinica. 2008, 29(2): 185-192. |
|
Tang
H.C., Jensen B.L., Skott O., Leung
G.P.H., Feletou M., Man R.Y.K.
and Vanhoutte P.M.G.R., The role of
prostaglandin E and thromboxane-prostanoid receptors in the response to
prostaglandin E |
|
Tang
J., Feng Y., Tong Y., Jia R., Sy L.K. and Man R.Y.K., The Mucilage Cavity is a
Distinct Microscopic Characteristic Showing in the Phloem but not Pith of
Rhizomes for the Identification of Radix et Rhizoma Rhei., In: Editoral
Department of Wuhan University Journal of Natural Sciences, Wuhan
University Journal of Natural Sciences. |
|
Wong
S.K., Man R.Y.K. and Vanhoutte P.M.G.R., Active metabolite of
vitamin D acutely reduces endothelium-dependent contractions in the isolated
SHR aorta, Experimental Biology 2008, |
|
Wong
S.K., Man R.Y.K. and Vanhoutte P.M.G.R., Metabolite of
vitamin D reduces endothelium-dependent contractions in isolated SHR aorta, 10th
Scientific Meeting of Hong Kong Pharmacology Society, |
|
Wong S.K., Delansorne R., Man R.Y.K. and Vanhoutte P.M.G.R., Vitamin D derivatives acutely reduce endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat, Am J Physiol Heart Circ Physiol. 2008, 295: H289-H296. |
|
Wong S.W.E., Ng J.K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Effects of dexmedetomidine in isolated arteries of pig and rat, EDHF 2008, 5th International EDHF Symposium. 2008. |
|
Xu Y.C., Leung G.P.H., Wong P.Y.D., Vanhoutte P.M.G.R. and Man R.Y.K., Kaempferol stimulates large conductance 2+-activated K+ (BKCa) channels in human umbilical vein endothelial cells via a cAMP/PKA-dependent pathway, British Journal of Pharmacology. 2008, 154: 1247-1253. |
|
Yang
C., Vanhoutte P.M.G.R., Man R.Y.K. and Leung G.P.H., Effects of
epoxyeicosatrienoic acids on volume-activated chloride channels via cyclic
GMP pathway in rat mesenteric artery, Experimental Biology 2008, |
|
Yang C., Vanhoutte P.M.G.R., Man R.Y.K. and Leung G.P.H., Involvement of volume-activated chloride channels in EDHF-induced vasodiation in rats, 12th Research Postgraduate Symposium, Hong Kong, December 12 & 14, 2007. 62 (1.35). |
|
Researcher
: Michel FSJ |
|
Project Title: |
Prejunctional and endothelial effects of acetylcholine in rat arteries constricted by activation of the sympathetic nerves |
|
Investigator(s): |
Michel FSJ |
|
Department: |
Pharmacology |
|
Source(s) of Funding: |
Small Project Funding |
|
Start Date: |
12/2006 |
|
Abstract: |
|
The autonomic nervous system consists of
two usually antagonistic subsystems: the sympathetic and the parasympathetic
nervous system. The sympathetic nervous system controls the diameter of the
blood vessels, heart rate and the strength of the myocardial contractions.
Norepinephrine is the primary neurotransmitter of the peripheral sympathetic
nervous system. The physiological role of the release of norepinephrine from
nerve endings on blood vessels is to adjust continuously the performance of
the cardiovascular system. Norepinephrine acts on adrenoceptors, divided into
three main groups: α1-, α2- and β-adrenoceptor. Norepinephrine is the most
potent ligand of the vascular smooth muscle α1-adrenoceptors, which play an
important role in the regulation of peripheral resistance and systemic
arterial blood pressure [1]. Electrical stimulation of the sympathetic nerve
endings induces the release of endogenous norepinephrine into the
extracellular space in concentrations sufficient to cause contraction of the
innervated vascular smooth muscle cells [2]. Thus, electrical stimulation
increases the muscle tension and tritiated-norepinephrine efflux in the rat
tail artery [3], human and canine veins [4,5] and other vascular beds [6,7].
The peripheral vasoconstrictor response to sympathetic nerve activity is
regulated by pre and postjunctional control mechanisms. In canine veins,
exogenous acetylcholine evokes relaxation during electrical stimulation and
decreases the release of norepinephrine [8]. This is because the activation
of muscarinic receptors, located on the postganglionic sympathetic nerve
terminals, acetylcholine inhibits the release of the adrenergic neurotransmitter
[9] Furchgott and Zawadzki (1980) reported the obligatory role of the
endothelium in the relaxation of isolated arteries to acetylcholine [10].
Nitric oxide is the primary endothelium-derived relaxing factor [11] and is
formed in endothelial cells in response to vasodilator agents such as
acetylcholine, bradykinin or substance P. These agonists activate the
endothelial isoform of nitric oxide synthase to synthesize nitric oxide
[12,13]. Nitric oxide diffuses out of the endothelium toward the smooth muscle
cells to cause their relaxation [14]. The lack of nitric oxide-dependent
tonic vasodilatation leaves unopposed the actions of endogenous
vasoconstrictors. The constriction evoked by stimulation of sympathetic
terminals is enhanced by a nitric oxide synthase inhibitor (L-NAME) or
without the endothelium, whereas the release of tritiated-norepinephrine is
not modified [15]. After long-term NOS inhibition a persistent activation of
the sympathetic nervous system is responsible for the hypertension [16,17].
However, a specific postjunctional interaction between nitric and
norepinephrine may exist. The inhibition by the endothelium of the
constrictor response to sympathetic nerve stimulation can result from the
disposition of norepinephrine by the endothelial cells [18]. L-NAME enhances
vasoconstrictor responses to norepinephrine to a greater extent than that to
angiotensin II [19]. Atomoxetine is a selective norepinephrine reuptake
inhibitor that possesses no antimuscarinic properties. The neuronal reuptake
is the reabsorption of the neurotransmitter by presynaptic neurons after they
have transmitted the neural impulse. The clearance of the released
norepinephrine occurs by such neuronal uptake [20] and the inhibition of
norepinephrine reuptake augments sympathetic neuronal responses [21,22].
Atomoxetine increases by a factor of ten the potassium-evoked release of
norepinephrine in the lower urinary tract tissues, as compared to non
selective reuptake inhibitors [23]. It is approved for the treatment of attention-deficit
hyperactivity disorder, but has cardiovascular side effects. In human, acute
administrations increase heart rate and arterial blood pressure [24]. A
chronic treatment with atomoxetine can induce hypertension in 3 young
patients out of 9 [25]. Since the endothelium can attenuate vasoconstrictor
responses to norepinephrine, the purpose of the present study will be to
determine whether or not nitric oxide released by the endothelium in response
to exogenous acetylcholine administration can induce a relaxation of the rat
tail artery contracted by electrical stimulation of the adrenergic nerve
ending. The contribution of presynaptic inhibition of norepinephrinerelease
and the endothelium-dependent formation of nitric oxide, respectively, in the
acetylcholine-induced relaxation will be also defined. Preparations will be
examined taken from animals with a potentiated response to sympathetic
activation, as obtained with a chronic treatment with atomoxetine. The
acetylcholine-mediated relaxation during electrical stimulation of the tail
artery from rats made hypertensive with atomoxetine will be analyzed. The
reactivity will be correlated with the arterial blood pressure to answer
whether or not the prejunctional or the endothelial effects of acetylcholine
on the response to sympathetic nerve stimulation is modified in the context
of an elevation of blood pressure due to a norepinephrine reuptake
inhibition. 1. Tanoue A, Koshimizu TA, Shibata K, Nasa Y, Takeo S, Tsujimoto
G. Trends Endocrinol Metab. 2003;14(3):107-13. 2. Smith AD. Biochem Soc Symp.
1972;(36):103-31. 3. Hicks PE, Najar M, Vidal M, Langer SZ. Naunyn
Schmiedebergs Arch Pharmacol. 1986;333(4):354-61. 4. Rorie DK, |
|
Researcher
: Ng JKF |
|
Project Title: |
Thrombelastographic profile in elderlies |
|
Investigator(s): |
|
|
Department: |
Anaesthesiology |
|
Source(s) of Funding: |
Other Funding Scheme |
|
Start Date: |
06/1999 |
|
Abstract: |
|
To compare thrombelastrographic profile of healthy elderlies to healthy young adults. |
|
Project Title: |
Effect of non-steroidal anti-inflammatory agents on platelet function and blood loss in patients undergoing knee replacement surgery |
|
Investigator(s): |
Ng JKF, Lam CCK, Tang WM |
|
Department: |
Anaesthesiology |
|
Source(s) of Funding: |
Low Budget High Impact Programme |
|
Start Date: |
11/2001 |
|
Abstract: |
|
To evaluate a new platelet function analyser (PFA)-100TM) as a preoperative platelet function monitor. |
|
Project Title: |
In vitro effect of desmopressin on hypothermia induced platelet dysfunction |
|
Investigator(s): |
Ng JKF |
|
Department: |
Anaesthesiology |
|
Source(s) of Funding: |
Small Project Funding |
|
Start Date: |
08/2006 |
|
Abstract: |
|
Mild hypothermia (32 to 35 degC) during
surgery is common [1] and is associated with more bleeding, increased
transfusion requirement and poorer outcome [2-4]. While inhibition of the
coagulation cascade is known to occur with hypothermia [5] and may contribute
to these changes, hypothermia also induces platelet dysfunction which can
accentuate this problem. The underlying mechanism of hypothermia-induced
platelet dysfunction remains poorly understood. In vitro studies showed
impaired platelet aggregation and adhesion under mild hypothermia [6].
Moreover, shed blood thromboxane A2 from bleeding time wound is diminished
and the rise in p-selectin expression on platelet surface is obtunded [7,8].
Nevertheless, there are also some conflicting results showing that
hypothermia may lead to enhanced platelet activation [9,10]. Such platelet
dysfunction is reversible when normal body temperature is restored [11,12],
but this is not always achievable or desirable. Hypothermia occurs in 5 to
10% of multiple trauma patients at admission [13,14]. It may not be rapidly
reversible, particularly in those who require massive infusion of fluids and
blood products. The incidence of hypothermia actually increases to over 70%
when the trauma patients receive emergency surgery [15]. Restoration of
normothermia may not be desirable in some patients as induced hypothermia has
been shown to improve patient outcome after successful cardiopulmonary
resuscitation [16] and has become the recommended treatment in selected
patients [17]. Induced hypothermia is also useful in the intensive care unit
[18] and in neurosurgery [19]. Desmopressin (1-deamino-8-D-arginine
vasopressin, DDAVP), the synthetic analogue of vasopressin, was first used to
treat cranial diabetes insipidus. Later, it was found that desmopressin
elevates circulating coagulation factor (F)VIII, von Willebrand factor (vWF)
and tissue plasminogen activator (tPA) in patients who suffer from hemophilia
A and von Willebrand disease [20]. Since then, it remains the treatment of
choice for these congenital bleeding disorders [21]. Desmopressin can also
correct certain acquired bleeding disorders, such as patients with uremia and
liver cirrhosis [22,23]. However, the effect of desmopressin on platelet
dysfunction due to hypothermia is still unknown. We have therefore designed
this study to investigate the effects of different doses of desmopressin on
hypothermia-induced platelet dysfunction. Platelet function will be measured
by the PFA-100® system, which is a relatively new technique that simulates
primary hemostasis using whole blood [24,25]. 1 Sessler DI. Mild
perioperative hypothermia. N Engl J Med 1997; 336: 1730-7. 2 Hofer CK, Worn
M, Tavakoli R, Sander L, Maloigne M, Klaghofer R, Zollinger A. Influence of
body core temperature on blood loss and transfusion requirements during
off-pump coronary artery bypass grafting: a comparison of 3 warming systems.
J Thorac Cardiovasc Surg 2005; 129: 838-43. 3 Kurz A, Sessler DI, Lenhardt R.
Perioperative normothermia to reduce the incidence of surgical-wound
infection and shorten hospitalization. Study of Wound Infection and
Temperature Group. N Engl J Med 1996; 334: 1209-15. 4 Schmied H, Kurz A,
Sessler DI, Kozek S, Reiter A. Mild hypothermia increases blood loss and
transfusion requirements during total hip arthroplasty. Lancet 1996; 347:
289-92. 5 Boldt J, Knothe C, Welters I, |
|
List of Research Outputs |
|
Ng J.K.F., Leung S.W.S., Man R.Y.K. and Vanhoutte P.M.G.R., C-Type natriuretic peptide (CNP) release does not contribute to endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in porcine coronary artery, Experimental Biology 2008 . 2008. |
|
Wong S.W.E., Ng J.K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Effects of dexmedetomidine in isolated arteries of pig and rat, EDHF 2008, 5th International EDHF Symposium. 2008. |
|
Researcher
: Ng WWH |
|
List of Research Outputs |
|
Ng W.W.H., Keung W.W.Y., Xu Y., Ng J.K.F., Leung G.P.H., Vanhoutte P.M.G.R., Choy P.C. and Man R.Y.K., Genistein potentiates protein kinase A activity in porcine coronary artery, Molecular and Cellular Biochemistry. 2008, 311: 37-44. |
|
Researcher
: Qu C |
|
List of Research Outputs |
|
Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Effect of chronic inhibition of nitric oxide synthase on the production of endothelium dependent contractions in the rat aorta, Basic & clinical Pharmacology & Toxicology, 5th International EDHF Symposium, tampere, Finalnd, June 24-27, 2008. 102 (Suppl.1): 32. |
|
Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Modulation of endothelium-dependent contractions by chronic inhibition of nitric oxide synthase in the rat aorta, Experimental Biology 2008. |
|
Researcher
: Shi Y |
|
List of Research Outputs |
|
Shi Y. and Vanhoutte P.M.G.R., Oxidative stress and COX cause hyper-responsiveness in vascular smooth muscle of the femoral artery from diabetic rats, British Journal of Pharmacology. 2008, 154: 639-651. |
|
Shi Y., So K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Oxygen-derived free radicals mediate endothelium-dependent contractions in femoral arteries of rats with streptozotocin-induced diabetes, British Journal of Pharmacology. 2007, 152: 1033-1041. |
|
Shi Y., Man R.Y.K. and Vanhoutte P.M.G.R., Two isoforms of cyclooxygenase contribute to augmented endothelium-dependent contractions in femoral arteries of 1-year-old rats, Acta Pharmaceutica Sinica. 2008, 29(2): 185-192. |
|
Researcher
: Shin VY |
|
List of Research Outputs |
|
Liu E.S.L., Ye Y., Shin V.Y., Wu W.K., Wong B.C.Y. and Cho C.H., Interaction of cigarette smoking with cyclooxygenase-2 on ulcerative colitis-associated neoplasia in mice., Cancer Invest.. 2007, 25(8): 750-7. |
|
Researcher
: Tang HC |
|
List of Research Outputs |
|
Feletou M., Tang H.C. and Vanhoutte P.M.G.R., Nitric oxide the gatekeeper of endothelial vasomotor control, Frontiers in Bioscience . 2008, 13: 4198-4217. |
|
Tang H.C. and Vanhoutte P.M.G.R., Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension, Physiol Genomics. 2008, 32: 409-418. |
|
Tang
H.C., Jensen B.L., Skott O., Leung G.P.H., Feletou M., Man R.Y.K. and Vanhoutte P.M.G.R., The role of
prostaglandin E and thromboxane-prostanoid receptors in the response to
prostaglandin E |
|
Tang H.C. and Vanhoutte P.M.G.R.,
Upregulation of the non-neurogenic cholinergic system in the aorta of
apontaneously hypertensive rats, Experimental Biology 2008, |
|
Researcher
: Tang HC |
|
List of Research Outputs |
|
Feletou M., Tang H.C. and Vanhoutte P.M.G.R., Nitric oxide the gatekeeper of endothelial vasomotor control, Frontiers in Bioscience . 2008, 13: 4198-4217. |
|
Tang H.C. and Vanhoutte P.M.G.R., Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension, Physiol Genomics. 2008, 32: 409-418. |
|
Tang
H.C., Jensen B.L., Skott O., Leung G.P.H., Feletou M., Man R.Y.K. and Vanhoutte P.M.G.R., The role of
prostaglandin E and thromboxane-prostanoid receptors in the response to
prostaglandin E |
|
Tang H.C. and Vanhoutte P.M.G.R.,
Upregulation of the non-neurogenic cholinergic system in the aorta of
apontaneously hypertensive rats, Experimental Biology 2008, |
|
Researcher
: Vanhoutte PMGR |
|
Project Title: |
Genomic and proteomic basis of endothelial dysfunction in regenerated endothelium |
|
Investigator(s): |
Vanhoutte PMGR, Tse HF, Man RYK |
|
Department: |
Pharmacology |
|
Source(s) of Funding: |
Competitive Earmarked Research Grants (CERG) |
|
Start Date: |
09/2006 |
|
Abstract: |
|
Unravel the molecular basis of endothelial dysfunction after regeneration, and thus identify potential new targets for further research permitting the design of therapeutic agents aimed at the prevention and the early treatment of vascular disease. |
|
Project Title: |
Calcium and the balance between nitric oxide (NO) and endothelium-derived contracting factor (EDCF) |
|
Investigator(s): |
Vanhoutte PMGR |
|
Department: |
Pharmacology |
|
Source(s) of Funding: |
Small Project Funding |
|
Start Date: |
09/2006 |
|
Abstract: |
|
The endothelial cells control the tone
and the growth of the underlying vascular smooth muscle by secreting opposing
mediators, nitric oxide [NO; produced by endothelial NO synthase (eNOS)] and
vasoconstrictor prostanoids [endothelium-derived contracting factors (EDCF);
produced by endothelial cyclooxygenase-1 (COX1)]. The production of EDCF is
exacerbated in blood vessels of spontaneously hypertensive rats (SHR)
compared to those of the normotensive control rat (Wistar-Kyoto rats, WKY)
(Vanhoutte et al , 2005). It is unclear how the endothelial cell balances the
production of EDRF from eNOS and that of EDCF from COX1. Calcium may activate
both enzymes simultaneously producing endothelium-derived relaxing factor
(EDRF) and EDCF, which then act as opposing functional antagonists, whereby
the dominant one determines the occurrence of either relaxation or
contraction. Earlier work of the Principal Investigator (PI) and his
collaborators demonstrates that the endothelium-dependent vasodilator
acetylcholine causes a modest calcium increase in endothelial cells of the
WKY but evokes a full relaxation (Yang et al., 2004; Tang et al., |
|
List of Research Outputs |
|
Chan K.Y.C., Mak J.C.W., Man R.Y.K. and Vanhoutte P.M.G.R., RHO kinase and endothelum-dependent contractions in the SHR and WKY aorta, Basic & Clinical Pharmacology & Toxicology, 5th International EDHF Symposium, Tampere, Finaland, June 24-27, 2008. 102 (suppl.1): 55. |
|
Feletou M. and Vanhoutte P.M.G.R., Endothelium-dependent hyperpolarizations: Past beliefs and present facts, Annals of Medicine. 2007, 39: 495-519. |
|
Feletou M. and Vanhoutte P.M.G.R., In: Pivotal contribution of potassium channels in endothelium-dependent responses 1) Endothelium-dependent contractions, New Frontiers in Smooth Muscle Biology and Physiology. 2007, 195-222. |
|
Feletou M. and Vanhoutte P.M.G.R., In: Pivotal contribution of potassium channels in endothelium-dependent responses 2) endothelium-dependent relaxations, New Frontiers in smooth Muscle biology and Physiology. 2007, 223-249. |
|
Feletou M., Tang H.C. and Vanhoutte P.M.G.R., Nitric oxide the gatekeeper of endothelial vasomotor control, Frontiers in Bioscience . 2008, 13: 4198-4217. |
|
Ho
Y.W., Leung G.P.H., Man R.Y.K., Vanhoutte P.M.G.R. and Ng J.K.F., Distributions of alpha 2
adrenoceptor subtypes in porcine coronary vasculature, Experimental
Biology 2008, |
|
Hristovska A.M., Rasmussen L.E., Hansen P.B.L., Nielsen S.S., Nüsing R.M., Narumiya S., Vanhoutte P.M.G.R., Skott O. and Jensen B.L., Prostaglandin E2 induces vascular relaxation by E-prostanoid 4 receptor-mediated activation of endothelial nitric oxide synthase, Hypertension. 2007, 50: 525-530. |
|
Lee M.Y.K., Tse H.F., Zhu S., Man R.Y.K. and Vanhoutte P.M.G.R., Genomic changes in regenerated porcine coronary arterial endothelial cells , Arterioscler Thromb Vasc Biol. 2007, 27: 2443-2449. |
|
Lee Y.K.M. and Vanhoutte P.M.G.R., Surfactant protein D and activation of porcine cultured endothelial cells by TNF-a, Third International Symposium on Healthy Aging, Research Centre of Heart, Brain, Hormone and Healthy Aging, Hong Kong, March 1-2, 2008. 54 (P21). |
|
Leung
C.Y.I., Vanhoutte P.M.G.R.,
Man R.Y.K. and Leung G.P.H., Tissue-type plasminogen
activator: a possible candidate of endothelium-derived hyperpolarization
factor?, Basic & clinical Pharmacology & Toxicology, 5th
International EDHF Symposium, |
|
Leung
G.P.H., Man R.Y.K., Vanhoutte P.M.G.R. and Li R.W.S., Stimulation of endothelial
ecto |
|
Leuranguer V., Vanhoutte P.M.G.R., Verbeuren T. and Feletou M., C-type natriuretic peptide and endothelium-dependent hyperpolarization in the guinea-pig carotid artery, British Journal of Pharmacology. 2008, 153: 57-65. |
|
Leuranguer V., Gluais P., Vanhoutte P.M.G.R., Verbeuren T.J. and Feletou M., Openers of calcium-activated potassium channels and endothelium-dependent hyperpolarizations in the guinea pig carotid artery, Naunyn-Schmiedeberg's Arch Pharmacol . 2008, 377: 101-109. |
|
Li G.R., Wang H.B., Qin G.W., Jin M.W., Tang Q., Sun H., Du X.L., Deng X., Zhang X.H., Chen J., Chen L., Xu X.H., Cheng L.C., Chiu S.W., Tse H.F., Vanhoutte P.M.G.R. and Lau C.P., Acacetin, a natural flavone, selectively inhibits human atrial repolarization potassium currents and prevents atrial fibrillation in dogs., Circulation. 2008, 117(19): 2449-57. |
|
Li
R.W.S., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Regulation of
extracellular adenosine level by equilibrative nucleoside transporters and
ecto |
|
Li W.S.R., Man R.Y.K., Vanhoutte P.M.G.R. and Leung G.P.H., Control of extracellular adenosine levels in inflammation, Third International Symposium on Healthy Aging, Research Centre of Heart, Brain, Hormone and Healthy Aging, Hong Kong, March 1-2, 2008. 54 (P22). |
|
Ng J.K.F., Leung S.W.S., Man R.Y.K. and Vanhoutte P.M.G.R., C-Type natriuretic peptide (CNP) release does not contribute to endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in porcine coronary artery, Experimental Biology 2008 . 2008. |
|
Ng W.W.H., Keung W.W.Y., Xu Y., Ng J.K.F., Leung G.P.H., Vanhoutte P.M.G.R., Choy P.C. and Man R.Y.K., Genistein potentiates protein kinase A activity in porcine coronary artery, Molecular and Cellular Biochemistry. 2008, 311: 37-44. |
|
Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Effect of chronic inhibition of nitric oxide synthase on the production of endothelium dependent contractions in the rat aorta, Basic & clinical Pharmacology & Toxicology, 5th International EDHF Symposium, tampere, Finalnd, June 24-27, 2008. 102 (Suppl.1): 32. |
|
Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Modulation of endothelium-dependent contractions by chronic inhibition of nitric oxide synthase in the rat aorta, Experimental Biology 2008. |
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Shi Y. and Vanhoutte P.M.G.R., Oxidative stress and COX cause hyper-responsiveness in vascular smooth muscle of the femoral artery from diabetic rats, British Journal of Pharmacology. 2008, 154: 639-651. |
|
Shi Y., So K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Oxygen-derived free radicals mediate endothelium-dependent contractions in femoral arteries of rats with streptozotocin-induced diabetes, British Journal of Pharmacology. 2007, 152: 1033-1041. |
|
Shi Y., Man R.Y.K. and Vanhoutte P.M.G.R., Two isoforms of cyclooxygenase contribute to augmented endothelium-dependent contractions in femoral arteries of 1-year-old rats, Acta Pharmaceutica Sinica. 2008, 29(2): 185-192. |
|
Tang H.C. and Vanhoutte P.M.G.R., Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension, Physiol Genomics. 2008, 32: 409-418. |
|
Tang
H.C., Jensen B.L., Skott O., Leung
G.P.H., Feletou M., Man R.Y.K.
and Vanhoutte P.M.G.R., The
role of prostaglandin E and thromboxane-prostanoid receptors in the response
to prostaglandin E |
|
Tang
H.C. and Vanhoutte P.M.G.R.,
Upregulation of the non-neurogenic cholinergic system in the aorta of
apontaneously hypertensive rats, Experimental Biology 2008, |
|
Vanhoutte P.M.G.R., Arginine and Arginase: Endothelial NO Synthase Double Crossed?, Circulation Research. 2008, 102: 866-868. |
|
Vanhoutte P.M.G.R., Endothelial Dysfunction in Hypertension, Journal of Hong Kong College of Cardiology, eleventh Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, Hong Kong, December 8, 2007. 15:2: IL1. |
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Vanhoutte P.M.G.R., The endothelium: Thirty years of surprises , In: , Annales de Cardiologie et d'Angéiologie . 2008, 57: 133-135. |
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Wong S.L., Leung F.P., Lau C.W., Yung L.M., Qao X.Q., Vanhoutte P.M.G.R. and Huang Y., Prostaglandin F2Aacts as the major endothelium-derived contracting factor in the hamster aorta, Journal of the Hong Kong College of Cardiology, Eleventh Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 8, 2007. 15:2: 87. |
|
Wong
S.K., Man R.Y.K. and Vanhoutte P.M.G.R., Active
metabolite of vitamin D acutely reduces endothelium-dependent contractions in
the isolated SHR aorta, Experimental Biology 2008, |
|
Wong S.K. and Vanhoutte P.M.G.R., Acute and chronic effects of vitamin D on endothelium-dependent contractions of the isolated SHR aorta, 12th Research Postgraduate Symposium, Hong Kong, December 12 & 14, 2007. 61 (1.31). |
|
Wong
S.K., Man R.Y.K. and Vanhoutte P.M.G.R., Metabolite of
vitamin D reduces endothelium-dependent contractions in isolated SHR aorta, 10th
Scientific Meeting of Hong Kong Pharmacology Society, |
|
Wong S.K., Delansorne R., Man R.Y.K. and Vanhoutte P.M.G.R., Vitamin D derivatives acutely reduce endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat, Am J Physiol Heart Circ Physiol. 2008, 295: H289-H296. |
|
Wong S.W.E., Ng J.K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Effects of dexmedetomidine in isolated arteries of pig and rat, EDHF 2008, 5th International EDHF Symposium. 2008. |
|
Wong W.T., Tain X.Y., Yung L.M., Leung F.P., Xu A.M., Yao X.Q., Vanhoutte P.M.G.R. and Huang Y., Up-regulated angiotensin II type 1 receptors mediate endothelial dysfunction in DB/DB diabetic mice, Journal of the Hong Kong College of Cardiology, Eleventh Annual Scientific Meeting, Institute of Cardiovascular Science and Medicine, December 8, 2007 . 2007, 15:2: 87. |
|
Xu Y.C., Leung G.P.H., Wong P.Y.D., Vanhoutte P.M.G.R. and Man R.Y.K., Kaempferol stimulates large conductance 2+-activated K+ (BKCa) channels in human umbilical vein endothelial cells via a cAMP/PKA-dependent pathway, British Journal of Pharmacology. 2008, 154: 1247-1253. |
|
Yang
C., Vanhoutte P.M.G.R., Man R.Y.K. and Leung G.P.H., Effects of
epoxyeicosatrienoic acids on volume-activated chloride channels via cyclic
GMP pathway in rat mesenteric artery, Experimental Biology 2008, |
|
Yang C., Vanhoutte P.M.G.R., Man R.Y.K. and Leung G.P.H., Involvement of volume-activated chloride channels in EDHF-induced vasodiation in rats, 12th Research Postgraduate Symposium, Hong Kong, December 12 & 14, 2007. 62 (1.35). |
|
Yung L.M., Wong W.T., Tian X.Y., Leung F.P.,
Lau C.W., Yao X.Q., Chen Y., Vanhoutte P.M.G.R. and Huang Y.,
Crauberry juice consumption ameliorates endothelial dysfunction during
estrogen deficiency, Journal of the |
|
Yung L.M., Wong W.T., Leung F.P., Tian X.Y., Lau C.W., Yao X.Q., Chen Z.Y., Vanhoutte P.M.G.R. and Huang Y., Endothelial dysfunction in estrogen deficiency: the key role of AT1R, 10th Scientific Meeting of Hong Kong Pharmacology Society, Hong Kong, 15 December 2007. 9 (O2). |
|
Zhu W., Cheng K.Y., Vanhoutte P.M.G.R., Lam K.S.L. and Xu A., Vascular effects of adiponectin: molecular mechanisms and potential therapeutic intervention, Clin Sci (London). 2008, 114: 361-74 (Invited Review). |
|
Researcher
: Wang Y |
|
Project Title: |
The Fat-Derived Hormone Adiponectin as a Potential Factor Linking Obesity and Breast Cancer |
|
Investigator(s): |
Wang Y, Xu A |
|
Department: |
Genome Research Centre |
|
Source(s) of Funding: |
Seed Funding Programme for Basic Research |
|
Start Date: |
06/2006 |
|
Abstract: |
|
1. Background and Research hypothesis: Obesity and its related diseases are now reaching an epidemic level and form one of the major burdens for our current healthcare system worldwide [1]. Recent epidemiological studies suggested that an increase in the risk of cancer is one of the consequences of obesity. The predominant cancers associated with obesity are lifestyle-related and have a hormonal base including breast, prostate, endometrium, colon and gallbladder cancers etc. [2]. Although the exact mechanism of this relationship remains to be determined, many evidence indicated that excess formation of adipose tissue surrounding the malignant cells might play important roles in tumor-microenvironment interaction and in controlling local cancer growth, invasion and distant metastasis [3]. Adipose tissue was traditionally considered to be an inert energy storage organ. However, recent evidences suggested that adipocytes (fat cells) can also produce a variety of biologically active polypeptides, hormones, growth factors and cytokines, collectively called adipokines [4]. Adipokines elicit their diversified actions on angiogenesis, inflammation, lipid/glucose metabolism, haemostasis, immunity and stress-response etc in an endocrine, paracrine and autocrine manner [5]. It is now generally accepted that endocrine dysfunction of adipose tissue may represent one of the causal links between obesity and systemic insulin resistance/diabetes. Interestingly, diabetes and hyperglycemia are also associated with an elevated risk of developing pancreatic, liver, colon, breast, and endometrial cancer [6], suggesting that the dysregulated secretion of adipokines might represent a general mechanism linking obesity and cancer formation. Indeed, many adipokines, such as leptin, tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6), not only causatively link to metabolic diseases but also play important roles in carcinogenesis. In addition, various growth factors/hormones produced from adipocytes in the local tumor environment might act directly on carcinoma cells to stimulate tumor growth and angiogenesis [7,8]. Breast cancer is the most frequent cancer in women and represents the second leading cause of cancer death among women [9]. Obesity is an independent risk factor for the development of breast cancer and is associated with late-stage disease and poor prognosis [10]. Post-menopausal women with upper body fat predominance have a higher risk of breast cancer [11]. The past several years have provided substantial evidence for the vital roles of stromal cells on the tumorigenesis of the mammary ductal epithelial cells [3]. Stromal cells can influence the level of invasiveness and malignancy of the tumor by producing various matrix metalloproteases (MMPs) and growth/angiogenesis stimulators including IGF, VEGF, HGF, FGF and TGF etc. Notably, adipocyte (fat cell) is one of the predominant stromal cell types in the microenvironment of mammary tissue and the proximity suggests that adipocytes could be a key player in the stromal-ductal epithelium interactions. Indeed, the close relationship between adipocytes and mammary tumor growth has been demonstrated by many in vitro and in vivo pharmacological studies [3]. Aromatase in adipose tissue stroma provides an important source of estrogen for the postmenopausal woman. Mature adipocytes can promote the growth of breast carcinoma cells in a collagen gel matrix culture through cancer-stromal cell interactions [12]. Co-transplantation of tumor cells with adipocytes into mice results in increased tumor growth and metastasis [13]. Leptin, a hormone mainly produced in adipose tissue, could act as a paracrine/endocrine growth factor towards mammary epithelial cells and contribute to the development of breast cancer [14,15]. A recent report by Iyengar P. et al suggested that collagen VI secreted from adipocytes could affect early mammary tumor progression and might represent one of the adipokines that have pro-tumorigenic functions [16]. In summary, these evidences suggest that adipose tissue-derived factors might significantly influence the growth and proliferation of tumorous stroma and malignant cells in the local environment of mammary tissue.Adiponectin is a circulating hormone exclusively secreted from adipocytes. Unlike many other adipokines, such as TNFα, IL-6, leptin, heparin-binding epidermal growth factor-like growth factor, hepatocyte growth factor and resistin etc that are increased in obesity, the circulating levels of adiponectin are inversely correlated with obesity and insulin resistance, two risk factors of breast cancer [10]. Adiponectin has been demonstrated to have insulin-sensitizing, anti-inflammatory, anti-diabetic and anti-atherogenic activities whereas most other adipokines are causatively linked to obesity-related diseases [17]. Replenishment of adiponectin in animal models can reduce the body weight, improve glucose/lipid homeostasis, increase insulin sensitivity, prevent atherosclerosis and ameliorate fatty liver diseases. In addition, adiponectin possesses anti-angiogenic and anti-tumor activities as demonstrated by its ability to inhibit cell growth and migration of vascular endothelial cells, prevent new blood vessel formation, and attenuate the growth of transplanted fibrosarcoma cell tumors in mice [18]. Although the detailed relationship between adiponectin expression in local mammary tissue and the development of breast cancer have not been fully established, recent clinical studies have shown that obese women have reduced serum adiponectin levels and low serum adiponectin levels are significantly associated with an increased risk for breast cancer [10,19-22]. Moreover, tumours in women with the low serum adiponectin levels are more likely to show a biologically aggressive phenotype [22]. Notably, we and others have shown that adiponectin has inhibitory activities on the proliferation of a variety of different types of cells, including aortic smooth muscle cells, myelomonocytic cells, endothelial cells and hepatic stellate cells etc [23-27]. It can selectively bind to various carcinogenic growth factor and prevent the interactions of these growth factors to their respective receptors [24]. In line with these clinical findings, our preliminary studies revealed that recombinant adiponectin could significantly attenuate the cell growth of an estrogen receptor (ER)-negative breast cancer cell line, MDA-MB-231, in a time-dependent manner. It could also inhibit the proliferation stimulated by insulin and several other growth factors in an ER-positive breast cancer cell line, T47D. Moreover, our results from DNA fragmentation assay suggest that apoptosis was significantly induced in MDA-MB-231 cells after 48 hours treatment with adiponectin. Based on aforementioned clinical and experimental evidences, we hypothesize that adiponectin might be a negative regulator in breast cancer development, and that replenishment of this protein might represent a novel therapeutic strategy for the treatment of obesity-related breast cancer. 2. Specific objectives:(1). To test whether adiponectin has inhibitory roles on the migration/invasion of breast carcinoma cells and the angiogenesis stimulated by these cells. (2). To investigate the potential mechanism that underlies the growth-inhibitory effects of adiponectin in breast cancer cells. (3). To evaluate the effects of adiponectin on tumor growth/metastasis in athymic nude mice inoculated with breast cancer cells using adenovirus-mediated overexpression system. |
|
Project Title: |
Role of Mitochondria in Adiponectin-mediated Protective Effects Against Obesity-related Hepatic Steatosis and Steatohepatitis |
|
Investigator(s): |
Wang Y, Xu A |
|
Department: |
Genome Research Centre |
|
Source(s) of Funding: |
Seed Funding Programme for Basic Research |
|
Start Date: |
07/2007 |
|
Abstract: |
|
Non-alcoholic fatty liver disease (NAFLD) is one of the major health concerns closely associated with obesity, which is now reaching an epidemic level worldwide [1]. Recent studies suggest that NAFLD is also the component of the metabolic syndrome, a constellation of several inter-related risk factors for Type 2 Diabetes and cardiovascular diseases [2]. NAFLD is the most frequent hepatic lesion in developed countries, with an estimated prevalence of 10-25% [3]. The presence of steatosis in liver is an important risk factor for the development of additional liver injuries, such as non-alcoholic steatohepatitis (NASH), viral hepatitis, drug-induced hepatotoxicity and alcoholic steatohepatitis (ASH) etc [4]. About 5 % of hepatic steatosis will progress to significant fibrosis and cirrhosis and over 80 % of these cases will further develop liver cancer [1]. Adiponectin is an important adipokine abundantly produced from adipose tissues [5]. This adipokine has recently attracted great attention due to its anti-diabetic and anti-atherogenic activitities [6]. Circulating concentrations of adiponectin are decreased in obesity and its related pathologies, including insulin resisatnce, type 2 diabetes and cardiovascular diseases [6]. Supplementation with recombinant adiponectin could improve insulin sensitivity, decrease blood glucose levels, reverse atherogenic dyslipidemia and alleviate atherosclerosis in various animal models [5]. A previous study from our group provided the first evidence demonstrating that adiponectin possesses potent protective effects against both alcoholic and nonalcoholic fatty liver disease and steatohepatitis [7]. In both ethanol-fed mice and ob/ob obese mice, chronic treatment with recombinant adiponectin markedly attenuated hepatomegaly and steatosis, and also significantly decreased the hepatic inflammation loci and serum alanine aminotransferase (ALT), an established marker of liver injury [7]. More recently, we demonstrated that adiponectin treatment could also attenaute liver injury and fibrosis induced by pharmacological compounds and bile duct ligations [8]. Consistent with our data, several other group has recently confirmed the hepato-protective effects in different animal models with liver injury, such as carbon tetrachloride-treated mice with fibrosis and lipopolysaccharide (LPS)/D-galactosamine-treated mice with steatosis and inflammation [9-11]. These animal data were also supported by our clinical observations showing an inverse association between serum levels of adiponectin and ALT in Chinese obese subjects [7]. Moreover, plasma adiponectin levels are significantly lower in patients with NAFLD compared to the sex and age matched healthy controls [12, 13]. NASH patients with lower levels of adiponectin show higher grades of inflammation [14]. In addition, decreased plasma adiponectin concentrations are closely related to steatosis in hepatitis C virus-infected patients [15]. Taken together, these clinical and animal data suggest that low plasma levels of adiponectin might be an important risk factor for the development of fatty liver, steatohepatatis and other forms of liver injury. Adiponectin and its agonists might represent an effective strategy for treatment and prevention of these diseases. Nevertheless, the molecular and cellular mechanisms underlying the hepato-protective effects of adiponectin remain largely elusive so far. It is now known that mitochondrial dysfunction plays a central role in various forms of hepatic steatosis and liver injury [16-18]. Mitochondria are involved in fatty acid β-oxidation, tricarboxylic acid cycle (TCA) and oxidative phosphorylation. In patients with NASH, the hepatic mitochondria exhibit ultrastructural lesions and decreased activity of respiratory chain complexes [19, 20]. In this condition, the decreased activity of the respiratory chain results in accumulation of reactive oxygen species (ROS), and oxidization of fat deposits to form lipid peroxidation products, which in turn , may cause the diverse lesions of steatohepatitis, necrosis, inflammation, and fibrosis [21, 22]. The increased mitochondrial ROS formation in steatohepatitis could directly damage mitochondria DNA (mtDNA) and respiratory chain polypeptides, which further block the flow of electrons within the respiratory chain [20, 23]. Moreover, ROS cause NF-κB activation and induce the hepatic synthesis of tumor necrosis factor-α (TNF α), which triggers mitochondria membrane permeability and apoptosis [24]. Impaired mitochondrial integrity and transcriptional capacity have also been observed in LPS- and retrovirus-mediated hepatic injury [25, 26]. Taken together, these evidences suggest that mitochondria dysfunction might play a key role in the pathogenesis of NAFLD, NASH and other forms of liver injuries. In this study, we will test our hypothesis that adiponectin exerts its hepato-protective effects partly through promoting mitochondrial biogenesis and allevaiting mitochondria dysfunctions. The specific objectives are: 1. To investigate whether the accelerated liver injury is associated with impaired mitochondria dysfunction in adiponectin knockout mice; 2. To test whether adenovirus-mediated overexpression of adiponectin stimulates mitochondria biogenesis and reverses mitochondria dysfunction associated with obese mice. 3. To elucidate the potential signalling pathways involved in adiponectin-mediated modulation of mitochondria functions in liver. |
|
List of Research Outputs |
|
Poppitt S.D., Keogh G.F., Lithander F.E., Wang Y. and Cooper G.J., Postprandial response of adiponectin, interleukin-6, tumor necrosis factor-alpha, and C-reactive protein to a high-fat dietary load., Nutrition. 2008, 24: 322-9. |
|
Wang Y., Lam K.S.L. and Xu A., Adipokines at the crossroad of obesity, inflammation and type 2 diabetes, Annual Meeting of Korean Endocrine Society. 2008. |
|
Wang Y., Lam K.S.L. and Xu A., Post-translational modifications of adiponectin: mechanisms and functional implications. , Biochemical Journal. 2008, 409: 623-33. |
|
Yang Y.H., Wang Y., Lam K.S.L., Yao M.H., Cheng K.Y., Zhang J., Zhu W., Wu D. and Xu A., Suppression of the Raf/MEK/ERK signaling cascade and inhibition of angiogenesis by the carboxyl terminus of angiopoietin-like protein 4., Arterioscler Thromb Vasc Biol. . 2008, 28: 835-40. |
|
List of Research Outputs |
|
Wong S.K., Man R.Y.K. and Vanhoutte P.M.G.R., Active metabolite of
vitamin D acutely reduces endothelium-dependent contractions in the isolated
SHR aorta, Experimental Biology 2008, |
|
Wong S.K. and Vanhoutte P.M.G.R., Acute and chronic effects of vitamin D on endothelium-dependent contractions of the isolated SHR aorta, 12th Research Postgraduate Symposium, Hong Kong, December 12 & 14, 2007. 61 (1.31). |
|
Wong S.K., Man R.Y.K. and Vanhoutte P.M.G.R., Metabolite of
vitamin D reduces endothelium-dependent contractions in isolated SHR aorta, 10th
Scientific Meeting of Hong Kong Pharmacology Society, |
|
Wong S.K., Delansorne R., Man R.Y.K. and Vanhoutte P.M.G.R., Vitamin D derivatives acutely reduce endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat, Am J Physiol Heart Circ Physiol. 2008, 295: H289-H296. |
|
Researcher
: Wong SWE |
|
List of Research Outputs |
|
Wong S.W.E., Ng J.K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Effects of dexmedetomidine in isolated arteries of pig and rat, EDHF 2008, 5th International EDHF Symposium. 2008. |
|
Researcher
: Xu A |
|
Project Title: |
Characterization of the receptor and postreceptor events that underlie the anti-atherogenic and anti-diabetic actions of adiponectin |
|
Investigator(s): |
Xu A, Lam KSL |
|
Department: |
Medicine |
|
Source(s) of Funding: |
Competitive Earmarked Research Grants (CERG) |
|
Start Date: |
01/2005 |
|
Abstract: |
|
The proposal seeks to address the following three questions: (1) how does adiponectin activate its receptors? (2) what are the membrane proximal down-stream signaling events of adiponectin receptors? how does adiponectin exert its anti-atherogenic actions via macrophage cells? |
|
Project Title: |
Angiopoitein-like protein 4 (ANGPTL4) as a novel therapeutic target for the treatment of insulin resistance and hyperglycemia |
|
Investigator(s): |
Xu A, Lam KSL |
|
Department: |
Medicine |
|
Source(s) of Funding: |
Competitive Earmarked Research Grants (CERG) |
|
Start Date: |
12/2005 |
|
Abstract: |
|
To investigate the direct metabolic effects of angiopoietin-like protein 4 on liver and muscle, the two major organs involved in the regulation of systemic energy metabolism and insulin sensitivity; to elucidate the detailed metabolic pathways and signal transduction events that mediate the hypoglycemia and insulin-sensitizing effects of angiopoietin-like protein 4..; to study whether oligomerization and/or proteolysis plays a role in modulating the biological activities of angiopoietin-like protein 4. |
|
Project Title: |
The use of adiponectin as a biomarker to identify novel anti-diabetic and anti-atherogenic agents from Chinese herbs |
|
Investigator(s): |
Xu A, Qin GW, Lam KSL |
|
Department: |
Medicine |
|
Source(s) of Funding: |
NSFC/RGC Joint Research Scheme |
|
Start Date: |
01/2006 |
|
Abstract: |
|
To determine and optimize the chemical structures for the three bioactive compounds isolated from Rhizoma Dioscoreae and Radix Astragali; to study the molecular mechanisms by which the three bioactive compounds induce adiponectin production from fat cells; to explore the therapeutic potentials of the three bioactive compounds in the treatment of T2DM, endothelial dysfunction, atherosclerosis and other obesity-related metabolic disorders in several well-established animal models. |
|
Project Title: |
Inflammation in adipose tissue as a novel mechanism that link obesity with insulin reistance and type 2 diabetes |
|
Investigator(s): |
Xu A, Lam KSL, Chung SK |
|
Department: |
Medicine |
|
Source(s) of Funding: |
Seed Funding Programme for Basic Research |
|
Start Date: |
03/2006 |
|
Abstract: |
|
Obesity and its associated pathologies, including Type 2 Diabetes Mellitus (T2DM) and atherosclerosis, are chronic inflammatory diseases, characterized by elevated plasma concentrations of pro-inflammatory biomarkers, such as C-reactive proteins, TNF alpha and interleulin (IL) 6 (Bouloumie, Curat et al. 2005). Recent studies have found that adipose tissue (fat) is the predominant site that contributes to obesity-associated systemic inflammation and metabolic disorders (Wellen and Hotamisligil 2005). Macrophage infiltration and up-regulation of the inflammation-related genes in obese adipose tissue occur at the early phase of obesity and precede the development of insulin resistance (Xu, Barnes et al. 2003). It is suggested that activated macrophages in obese adipose tissue, in concert with the enlarged adipocytes, secrete a variety of pro-inflammatory adipokines/cytokines, which either act locally to perpetuate adipose tissue inflammation, or are released into the blood stream to induce systemic inflammation, insulin resistance and metabolic disorders in the periphery organs. Nevertheless, the mechanism responsible for triggering and perpetuating macrophage infiltration into obese adipose tissue remains poorly understood. It is also unclear whether inhibition of local inflammation in adipose tissue is sufficient to alleviate obesity-induced systemic inflammation and insulin resistance. Hypoxia inducible factor (HIF) 1alpha, a major transcription factor involved in the cellular response to hypoxia, has recently neen shown to be an important player in the inflammatory process (Paul, Simons et al. 2004). Studies in both human subjects and rodents have found that the expressions of HIF 1alpha in obese adipose tissue are substantially elevated (Trayhurn and Wood 2004; Cancello, Henegar et al. 2005). Weight loss, on the other hand, results in decreased expression of this transcription factor as well as reduced adipose tissue inflammation. Our in vitro studies showed that hypoxia, via induction of HIF 1alpha, could inhibit the production of the anti-inflammatory hormone adiponectin, but increase the expression of a cluster of pro-angiogenic and pro-inflammatory mediators from adipocytes, including leptin, VEGF, PAI-1 and IL6 (Chen, Wang et al.). In addition, we also demonstrated that HIF 1alpha activation could significantly enhance adipocyte-mediated adhesion and transmigration of human blood monocytes to/through the endothelial cells, the key step involved in macrophage tissue infiltration. Based on these evidences, we propose that HIF 1alpha plays a key role in initiating and/or maintaining chronic inflammation of adipose tissue and in triggering aberrant production of adipokines in obesity. As obesity develops, enlarged fat mass causes local micro-hypoxia and oxidative stress, both of which can induce HIF 1alpha accumulation and activation. Activated HIF 1alpha can decrease production of adiponectin and increase expression of macrophage attractants (such as leptin, VEGF, PAI-1, IL6, proteases and other chemokines). These changes can stimulate transport of monocytes to adipose tissue and promote adhesion and transmigration of monocytes to/through endothelial cells. Infiltrated monocytes in adipose tissue can be differentiated into macrophages by other locally produced inflammatory mediators. Activated macrophages in turn secrete a cluster of pro-inflammatory cytokines (such as IL1, TNFalpha and MCP1), which can act in a paracrine manner to induce further accumulation of HIF 1alpha in adipocytes, macrophage infiltration and aberrant production of adipokines. The macrophage-adipocyte interaction will perpetuate a viscous cycle that aggravates inflammatory responses in adipose tissue, and eventually induces systemic inflammation and insulin resistance. To test this hypothesis, the major objectives of this study are:1. To generate the transgenic mice with adipose tissue specific over-expression of dominant negative or constitutively active forms of HIF 1alpha; 2. To investigate the role of HIF 1alpha in obesity-induced macrophage infiltration and aberrant production of adipokines in adipose tissue, systemic inflammation and insulin resistance in the transgenic mouse models;3. To elucidate the molecular mechanisms by which HIF 1alpha induces endothelial cell activation and monocyte recruitment in adipose tissue; 4. To evaluate whether berberine, a compound with potent HIF 1alpha inhibitor activity, has therapeutic effects on obesity-associated chronic inflammation, insulin resistance and other metabolic abnormalities in mice. |
|
Project Title: |
Hypoxia inducible factor 1α as a mediator of obesity-induced chronic inflammation, aberrant production of adipokines, and insulin resistance |
|
Investigator(s): |
Xu A, Lam KSL, Chung SK |
|
Department: |
Medicine |
|
Source(s) of Funding: |
Competitive Earmarked Research Grants (CERG) |
|
Start Date: |
01/2007 |
|
Abstract: |
|
To generate the transgenic mice with adipose tissue specific over-expression of the dominant negative form of HIF 1α to investigate the role of HIF 1α in obesity-induced macrophage infiltration and aberrant production of adipokines in adipose tissue, systemic inflammation and insulin resistance in the transgenic mouse models; to evaluate whether berberine, a compound with potent HIF 1α inhibitor activity, has therapeutic effects on obesity-associated chronic inflammation, insulin resistance and other metabolic abnormalities in mice. |
|
Project Title: |
Endoplasmic reticulum (ER) stress alleviators as the novel therapeutic agents for treatment of obesity-related metabolic diseases |
|
Investigator(s): |
Xu A, Lam KSL, Hoo RLC, Wang Y |
|
Department: |
Medicine |
|
Source(s) of Funding: |
Seed Funding Programme for Basic Research |
|
Start Date: |
05/2007 |
|
Abstract: |
|
The dramatic increase in the incidence of obesity becomes a major public health concern worldwide. Obesity is the main risk factor for a cluster of inter-related metabolic and cardiovascular diseases, including insulin resistance, dyslipidemia, type 2 diabetes, non-alcoholic steatohepatitis (NASH), hypertension and coronary heart diseases, which are the major contributors to the mortality and morbidity in our aging population. Although the detailed mechanisms that link obesity with its associated pathologies is not fully understood, growing evidence suggest that chronic inflammation within adipose tissue is a key culprit (1,2). Both clinical and experimental studies have demonstrated that obese adipose tissue is characterized by increased macrophage infiltration and activation of the inflammatory pathways, such c-Jun NH2-terminal kinase (JNK) and NF-kB (3-5). The number of macrophages present in adipose tissue is closely correlated with adiposity and adipocyte size in both humans and animal models (4). Notably, inflammation in adipose tissue preceded the development of hyperinsulinemia in high fat diet-induced obese mice, suggesting that adipose inflammation is causally linked with systemic insulin resistance (3). The causal link between inflammation of adipose tissue and insulin resistance is also supported by the findings that weight reduction and anti-inflammatory drugs can reduce adipose macrophage infiltration and currently improve systemic insulin sensitivity (3,6). Adipose tissue is a major endocrine organ that secretes a wide spectrum of bioactive molecules (such as adipokines, cytokines and acute phase proteins) into the blood stream (7). Some of the “good” adipokines, such as adiponectin, visfatin and recently characterized vaspin, can increase insulin sensitivity, improve glucose tolerance and vascular reactivity. We and others have demonstrated that adiponectin possesses potent anti-diabetic, anti-atherogenic and anti-inflammatory activities, and also protects against obesity-associated nonalcoholic fatty liver diseases (8-10). On the other hand, “noxious” adipokines and cytokines, such as TNFa, PAI-1, resistin, adipocyte-fatty acid binding protein (A-FABP) and lipocalin-2, possesses adverse effects. As obesity develops, macrophage infiltration and interactions between macrophages and adipocytes cause abnormal production of these secretory proteins from adipose tissue, such as decreased adiponectin and increased TNFa, lipocalin-2, A-FABP, IL6 and PAI-1 (1,2). Discordant production of adipokines/cytokines from inflamed adipose tissue is a central mediator in the pathogenesis of obesity-related insulin resistance and metabolic abnormalities. Endoplasmic reticulum (ER) stress has recently been shown to play a central role in triggering inflammation in obese adipose tissue (11,12). The ER is a critical organelle where all secreted and transmembrane proteins are synthesized, folded into their correct three-dimensional structures, posttranslationally modified, and transported to their final cellular destinations. Pathological conditions, such as nutrient overloads, viral infections, hypoxia and metabolic stress, cause the accumulation of misfolded or unfolded proteins in the ER lumen which known as ER stress. The unfolded protein response (UPR) is the mechanism to alleviate ER stress by activating the synthesis of proteins that can facilitate folding of protein in ER lumen. On the other hand, ER stress can induce activation of several major inflammatory pathways, including JNK and NF-kB (11). In both dietary and genetic animal models of obesity, the biochemical parameters of ER stress were detected in both adipose tissue and liver (12). Transgenic studies have demonstrated that the ER stress responses might be responsible for activation of the JNK inflammatory pathway in obese adipose tissue and causation of obesity-linked insulin resistance (12), suggesting that alleviation of ER stress may offer novel therapeutic or preventive strategies for obesity-related metabolic diseases, especially type 2 diabetes. Indeed, a latest study published in Science has identified two small chemical compounds (4-phenyl butyric acid (PBA) and taurine-conjugated ursodeoxycholic acid (TUDCA)) that can alleviate the ER stress in cells and whole animals(13). Remarkably, oral administration of PBA or TUDCA into obese and diabetic mice leads to the normalization of hyperglycemia, restoration of the systemic insulin sensitivity and resolution of fatty liver disease within 4 days after treatment (13). This exciting finding suggests that ER chemical chaperones, such as PBA and TUDCA, represent a novel class of drugs for the treatment of obesity-related disorders. In this study, we will further explore the therapeutic potentials of these two ER chemical chaperones (PBA and TUDCA), and investigate the detailed cellular mechanisms underlying the therapeutic actions of PBA and TUDCA. Our specific objectives are: 1. To evaluate the therapeutic effects of PBA and TUDCA in both dietary and genetic obese mouse models, with particular focus on their roles in alleviation of adipose tissue inflammation; 2. To comprehensively analyze the effects of PBA and TUDCA on circulating levels of adipokines, cytokines and metabolic hormones using antibody suspension array-based multiplex immunoassays. 3. To elucidate the cellular pathways by which the two ER chemical chaperones (PBA and TUDCA) increase insulin sensitivity in liver and muscle tissues. PLEASE REFER TO SECTION VII for the references cited. |
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List of Research Outputs |
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Wang Y., Lam K.S.L. and Xu A., Adipokines at the crossroad of obesity, inflammation and type 2 diabetes, Annual Meeting of Korean Endocrine Society. 2008. |
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Researcher
: Xu Y |
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List of Research Outputs |
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Ng W.W.H., Keung W.W.Y., Xu Y., Ng J.K.F., Leung G.P.H., Vanhoutte P.M.G.R., Choy P.C. and Man R.Y.K., Genistein potentiates protein kinase A activity in porcine coronary artery, Molecular and Cellular Biochemistry. 2008, 311: 37-44. |
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Researcher
: Xu YC |
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List of Research Outputs |
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Xu Y.C., Leung G.P.H., Wong P.Y.D., Vanhoutte P.M.G.R. and Man R.Y.K., Kaempferol stimulates large conductance 2+-activated K+ (BKCa) channels in human umbilical vein endothelial cells via a cAMP/PKA-dependent pathway, British Journal of Pharmacology. 2008, 154: 1247-1253. |
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List of Research Outputs |
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Vellaisamy A.L.R., Wong E.L.M., Ko B.C.B., Chao C.T., Yan S.C., Yan B., Wu J.C. and Che C.M., Ambipolar Charge Transport in DNA Molecules, Advanced Materials. Wiley InterScience, 2008, 20: 1258-1262. |
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Researcher
: Yang C |
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List of Research Outputs |
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Yang
C., Vanhoutte
P.M.G.R., Man R.Y.K. and Leung G.P.H., Effects of
epoxyeicosatrienoic acids on volume-activated chloride channels via cyclic
GMP pathway in rat mesenteric artery, Experimental Biology 2008, |
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Yang C.,
Vanhoutte P.M.G.R., Man R.Y.K. and Leung G.P.H., Involvement of
volume-activated chloride channels in EDHF-induced vasodiation in rats, 12th
Research Postgraduate Symposium, |
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Researcher
: Yang C |
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List of Research Outputs |
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Yang
C., Vanhoutte
P.M.G.R., Man R.Y.K. and Leung G.P.H., Effects of
epoxyeicosatrienoic acids on volume-activated chloride channels via cyclic
GMP pathway in rat mesenteric artery, Experimental Biology 2008, |
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Yang C.,
Vanhoutte P.M.G.R., Man R.Y.K. and Leung G.P.H., Involvement of
volume-activated chloride channels in EDHF-induced vasodiation in rats, 12th
Research Postgraduate Symposium, |
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Researcher
: Ye Y |
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List of Research Outputs |
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Liu E.S.L., Ye Y., Shin V.Y., Wu W.K., Wong B.C.Y. and Cho C.H., Interaction of cigarette smoking with cyclooxygenase-2 on ulcerative colitis-associated neoplasia in mice., Cancer Invest.. 2007, 25(8): 750-7. |
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Researcher
: Yu L |
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List of Research Outputs |
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Wu W.K., Li G.R., Wong T.M., Wang J.Y., Yu L. and Cho C.H., Involvement of voltage-gated K(+) and Na (+) channels in gastric epithelial cell migration. , Mol Cell Biochem. 2008, 308(1-2): 219-26. |
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