Genistein acutely potentiates acetylcholine-induced relaxation through a G-protein coupled pathway in spontaneously hypertensive rats

Abstracts for Oral Communications: OC5OBJECTIVES: Genistein, a phytoestrogen rich in soy beans and soy products, was reported to be a vasorelaxant. This study examined the receptor and related signaling pathways in the ...published_or_final_versionThe 12th Annual Scientific Meeting of Institute of the Cardiovascular Science and Medince (ICSM), Hong Kong, 13-14 December 2008. In Journal of the Hong Kong College of Cardiology, 2008, v. 16 n. 2, p. 59, abstract no. OC

Lipid levels and major adverse cardiovascular events in patients initiated on statins for primary prevention: an international population-based cohort study protocol

Background : Clinical guidelines recommend specific targets for low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) for primary prevention of cardiovascular disease (CVD). Furthermore, individual variability in lipid response to statin therapy requires assessment of the association in diverse populations. Aim: To assess whether lower concentrations of LDL-C and non-HDL-C are associated with a reduced risk of major adverse cardiovascular events (MACE) in primary prevention of CVD. Design & setting: An international, new-user, cohort study will be undertaken. It will use data from three electronic health record databases from three global regions: Clinical Practice Research Datalink, UK; PREDICT-CVD, New Zealand (NZ); and the Clinical Data and Analysis Reporting System, Hong Kong (HK). Method: New statin users without a history of atherosclerotic CVD, heart failure, or chronic kidney disease, with baseline and follow-up lipid levels will be eligible for inclusion. Patients will be classified according to LDL-C (<1.4, 1.4–1.7, 1.8–2.5, and ≥2.6 mmol/l) and non-HDL-C (<2.2, 2.2–2.5, 2.6–3.3, and ≥3.4 mmol/l) concentrations 24 months after initiating statin therapy. The primary outcome of interest is MACE, defined as the first occurrence of coronary heart disease, stroke, or cardiovascular death. Secondary outcomes include all-cause mortality and the individual components of MACE. Sensitivity analyses will be conducted using lipid levels at 3 and 12 months after starting statin therapy. Conclusion: Results will inform clinicians about the benefits of achieving guideline recommended concentrations of LDL-C for primary prevention of CVD

Global epidemiology of hip fractures: a study protocol using a common analytical platform among multiple countries

INTRODUCTION: Hip fractures are associated with a high burden of morbidity and mortality. Globally, there is wide variation in the incidence of hip fracture in people aged 50 years and older. Longitudinal and cross-geographical comparisons of health data can provide insights on aetiology, risk factors, and healthcare practices. However, systematic reviews of studies that use different methods and study periods do not permit direct comparison across geographical regions. Thus, the objective of this study is to investigate global secular trends in hip fracture incidence, mortality and use of postfracture pharmacological treatment across Asia, Oceania, North and South America, and Western and Northern Europe using a unified methodology applied to health records. METHODS AND ANALYSIS: This retrospective cohort study will use a common protocol and an analytical common data model approach to examine incidence of hip fracture across population-based databases in different geographical regions and healthcare settings. The study period will be from 2005 to 2018 subject to data availability in study sites. Patients aged 50 years and older and hospitalised due to hip fracture during the study period will be included. The primary outcome will be expressed as the annual incidence of hip fracture. Secondary outcomes will be the pharmacological treatment rate and mortality within 12 months following initial hip fracture by year. For the primary outcome, crude and standardised incidence of hip fracture will be reported. Linear regression will be used to test for time trends in the annual incidence. For secondary outcomes, the crude mortality and standardised mortality incidence will be reported. ETHICS AND DISSEMINATION: Each participating site will follow the relevant local ethics and regulatory frameworks for study approval. The results of the study will be submitted for peer-reviewed scientific publications and presented at scientific conferences

The ligand binding properties of human membrane estrogen receptors

Paper no. 1205 - Focused Conference Group: P11 - G Protein-coupled 7tm Receptors: from Molecular to Physiological FunctionEstrogen (17b-estradiol) exerts rapid non-genomic effects in various cell types. Surface binding sites for estrogen has been demonstrated using confocal microscopy. However, the identity of the putative membrane estrogen receptor (mER) and how well they bind with estrogen remained elusive. The present study aims to determine the binding affinities of estrogen to the mER candidates recently identified and to investigate the importance for mERs to be transported to the membrane for estrogen binding. Moreover, the relative binding affinities of the mERs with various estrogenic chemicals and phytoestrogens were evaluated. Human estrogen receptor-a66 (ER66), estrogen receptor-a46 (ER46), estrogen receptor-a36 (ER36) and G protein-coupled receptor 30 (GPR30) were cloned and expressed using cell-free expression systems in the presence of nanolipoprotein molecules as the membrane substitute. Expressed receptor proteins were used in radioactive binding assay. ER66 and ER46 have similar binding affinities towards estrogen (KdG79 pM), whereas ER36 and GPR30 displayed no specific binding. ER66 and ER46 expressed in prokaryotic system have lower binding affinities than the receptors expressed in eukaryotic system. Removal of nanolipoprotein molecules also reduced the binding affinities of ER66 and ER46. Our results suggested that post-translational modification and membrane trafficking of mERs are important for proper conformation for binding. Moreover, relative binding affinities to ER66 and ER46 are similar for the compounds tested, except for the estrogen antagonist, ICI 182 780

Binding of genistein with membrane estrogen receptor and the potentiating effect of genistein in rapid, non-genomic vascular action

Abstracts for Oral Communications: no. OC7Open Access JournalBACKGROUND: Genistein is a phytoestrogen which enhances endothelial functions in a receptor-mediated manner. The present study was designed to characterize the mechanism involved in the rapid vascular actions of genistein and to determine whether genistein share the same receptor with estrogen in its non-genomic action. METHODS: Using tissue bath studies, isometric tension was measured in aortic rings isolated from 32-week-old male spontaneously hypertensive rats. The nuclear and membranous isoforms of estrogen receptor (ER)-α, ER-α66 and ER-α46, were cloned and expressed using a cell-free expression system. Binding study was performed subsequently. RESULTS: Genistein acutely potentiated acetylcholine-induced relaxation. This effect was insensitive to the transcription and translation inhibitors, actinomycin D and cycloheximide, respectively. The potentiation of acetylcholine and A23187-induced relaxation by genistein was inhibited by NF023 and GP antagonist-2A, the selective Gi and Gq α-subunit antagonists, respectively, but not by NF449, a selective Gs α-subunit antagonist. ER-α66 and ER-α46 were successfully cloned and expressed in vitro, with molecular sizes confirmed by Western blotting. 17β-estradiol bound to the ER-α66 and ER-α46 with similar affinity and genistein competed with 17β-estradiol for binding to both receptors. CONCLUSION: The tissue bath studies demonstrate that rapid potentiating effect of genistein in acetylcholine-induced relaxation is non-genomic and G protein-coupled. In addition, our data also suggests that genistein may bind to nuclear and membranous estrogen receptors. Further studies are required to reveal whether the non-genomic vascular effect of genistein is mediated through the membranous estrogen receptors.link_to_OA_fulltex

Rapid, non-genomic vascular actions of genistein involves a G-protein coupled receptor

Oral presentations: Session 1 - Healthy Aging: no. 1.0

Genistein enhances relaxation of the spontaneously hypertensive rat aorta by transactivation of epidermal growth factor receptor following binding to membrane estrogen receptors-α and activation of a G protein-coupled, endothelial nitric oxide synthase-dependent pathway

Genistein, a phytoestrogen present in soybeans, has well established vasodilator properties. The present study examined the mechanisms involved in the rapid vascular effects of genistein. Endothelium-dependent relaxations and contractions, induced by acetylcholine and the calcium ionophore A23187, were obtained in isolated aortic rings from male spontaneously hypertensive rats (SHR). Acute exposure to genistein potentiated relaxations and reduced contractions induced by the two agonists. Both effects of genistein were not affected by transcription- and translation-inhibitors or by tyrosine kinase inhibition. The potentiation of acetylcholine and A23187-induced relaxation by genistein was inhibited by NF023 and GP antagonist-2A, selective G i and G q α-subunit antagonists, respectively, but not by NF449, a selective G s α-subunit antagonist. These G protein antagonists did not alter the inhibitory effect of genistein on acetylcholine and A23187-induced contractions. The potentiation of A23187-induced relaxations by genistein was not inhibited by the conventional estrogen receptor (ER) antagonist, ICI 182,780, but inhibited by the specific ER-α antagonist, MPP, and by the epidermal growth factor receptor (EGFR) inhibitor, AG1478. It was mimicked by heparin-binding epidermal growth factor (HB-EGF). Activation of EGFR and endothelial nitric oxide synthase (eNOS) was detected in genistein-treated rings using Western blotting. These data suggest that the rapid vascular actions of genistein are mediated by non-genomic pathways and are unrelated to its tyrosine kinase inhibitory properties. Furthermore, genistein transactivates EGFR through membrane ERα via G protein-coupled pathways. This in turn enhances eNOS phosphorylation and hence endothelial function in the aorta of the SHR. © 2010 Elsevier Ltd.link_to_subscribed_fulltex

Attitudes, knowledge, and actions with regard to organ donation among Hong Kong medical students

Objective: To study attitudes, knowledge, and actions of local medical students with regard to organ donation and self-perceived confidence and competence in approaching potential organ donors. Design: Cross-sectional questionnaire survey. Setting: Faculty of Medicine, The University of Hong Kong, Hong Kong. Participants: Medical students, years 1-5. Main outcome measures: Knowledge on various aspects of organ donation was assessed, and students' self-evaluated competence and confidence about counselling for organ donation was evaluated. Factors influencing attitudes and actions were determined. Results: The response rate was 94% (655/694). A majority (85%) had a 'positive' attitude, but only a small proportion (23%) had signed the organ donation card. Inconvenience and lack of knowledge about organ donor registration, and concerns about premature termination of medical treatment accounted for such discrepancies. Socio-cultural factors such as the traditional Chinese belief in preservation of an intact body after death, unease discussing death-related issues, and family objections to organ donation were significantly associated with a 'negative' attitude. Knowledge and action increased with medical education yet only a small proportion of medical students felt competent and confident in counselling patients on organ donation. Conclusions: The medical curriculum should increase medical students' awareness of the organ shortage problem. The donor registration system should be made more convenient and public education is recommended to correct misconceptions.published_or_final_versio