Investigating the protective role of the natural hormone Melatonin, in reducing drug-induced cardiotoxicity in the therapy of chronic diseases

Heart failure (HF) is a highly complex disorder and a major end-point of cardiovascular diseases (CVD). The pathogenesis of HF is mostly unresolved but involves interplay between cardiac structural and electrical remodelling, metabolic alterations, cell death and altered gene expression. Mitochondrial dysfunction and HF are common complications of chronic treatment from diverse groups of drugs, in particular anticancer drugs such as doxorubicin (DOX). Treatment of animals and cardiomyocytes with cardiotoxic chemicals such as β-adrenergic receptor agonists (such as isoproterenol) induces cardiac dysfunction and HF. Previous work done by the group have identified the pineal hormone melatonin was protective against stress-induced cardiac arrhythmias and simulated heart failure in cardiomyocytes in vitro. Melatonin synthesis is also dramatically decreased with age and in patients with CVD. The aim of the present project was to better understand the pathogenesis of druginduced cardiac dysfunction and delineate the role of melatonin in cardioprotection in H9c2, a model rat cell line in vitro. Using the Seahorse XF analyser method, it was demonstrated that commonly used medication for chronic diseases such as amiodarone, amitriptyline, and statins all caused altered mitochondrial dysfunction. In addition, cardiotoxic chemicals (isoproterenol, hydrogen peroxide, DOX) altered oxidative phosphorylation and glycolysis in living cardiomyocyte-derived H9c2 cells; these deleterious metabolic changes were ameliorated by melatonin. Flowcytometry and Alamar Blue staining methods demonstrated that DOX robustly induced apoptosis in H9c2 cells (~30%) which was reversed by melatonin. Doxorubicin-induced stress in H9c2 cells dramatically altered gene expression in several key signalling pathways integral in cardiac function and disease. These included mitochondrial metabolism (UCP2, PPARɣ, Drp1, Mfn1, Parp 1, Parp2, Sirt3 and Cav3), apoptosis (Bcl2 and Bcl-xL), cardiac electrophysiology and arrhythmia (Scn5a, SERCA2a), calcium handling (SERCA2a) and cardiac remodelling (Myh7, ms1). Melatonin pre-treatment attenuated or completely blocked this DOX-induced alteration in gene expression in cardiomyocytes. In conclusion, the present result demonstrated for the first time that melatonin is cardioprotective against drug-induced cardiotoxicity and apoptosis via modifying diverse heart failure-related signalling pathways. This provides novel insight on the possible use of melatonin as an adjunct intervention in several therapies including anti-cancer

FDI and Innovation as Drivers of Export Behaviour: Firm-level Evidence from East Asia

This paper examines the links between ownership, innovation and exporting in electronics firms in three late industrializing East Asian countries (China, Thailand and the Philippines) drawing on recent developments in applied international trade and innovation and learning. Technology-based approaches to trade offer a plausible explanation for firm-level exporting behavior. The econometric results (using probit) confirm the importance of foreign ownership and innovation in increasing the probability of exporting in electronics. Higher levels of skills, managers' education and capital also matter in China as well as accumulated experience in Thailand. Furthermore, a technology index composed of technical functions performed by firms emerges as a more robust indicator of innovation than the R&D to sales ratio. Accordingly, technological effort in electronics in these countries mostly focuses on assimilating and using imported technologies rather than formal R&D by specialized engineers.foreign direct investment, innovation, technological capabilities, R&D, firm-level exports, electronics, East Asia, China, Thailand and the Philippines

Regionalism as an Engine of Multilateralism: A Case for a Single East Asian FTA

As East Asia becomes increasingly integrated through market-driven trade and FDI activities, free trade agreements (FTAs) are proliferating. Consolidation of multiple and overlapping FTAs into a single East Asian FTA can help mitigate the harmful noodle bowl effects of different or competing tariffs, standards, and rules. A region-wide FTA will also encourage participation of low-income countries and reduce trade-related business costs, particularly for small and medium enterprises. A computable general equilibrium (CGE) model examines the economic impact of various types of FTAs in East Asia (among ASEAN+1's, ASEAN+3, and ASEAN+6) finding that consolidation at the ASEAN+6 level would yield the largest gains to East Asia among plausible regional trade arrangements.Free Trade Agreement; ASEAN; multilateralism

Central Asia : Mapping Future Prospects

Central Asia has emerged as one of the worlds fastest growing regions since the late 1990s and has shown notable development potential. This is significant for a region comprising largely of small landlocked economies with no access to the sea for trade. Among the advantages, of the region are its high- priced commodities (oil, gas, cotton and gold), reasonable infrastructure and human capital as legacies of Soviet rule; and a strategic location between Asia and Europe. Furthermore, many Central Asian Republics (CARs) have embarked on market-oriented economic reforms to boost economic performance and private sector competitiveness. Central Asia : Mapping Future Prospects considers the regions economic prospects to 2015. It charts recent economic performance, highlighting the economic revival. It also synthesizes recent forecasts and constructs scenarios for future economic variables against a constant global background. Projections include, among others, gross domestic product (GDP), manufactured exports per head, GDP per capita and poverty. A special theme chapter develops a manufacturing competitiveness index to compare the CARs with other transition economies and explores the impact of economic reform and supply-side factors (e.g. foreign investment and human capital) on industrial performancecentral Asia, future economic variables, gross domestic product, manufactured exports per head, GDP per capita, poverty, manufacturing competitiveness index