Activation of Insulin-Like Growth Factor II Receptor Induces Mitochondrial-Dependent Apoptosis through G alpha q and Downstream Calcineurin Signaling in Myocardial Cells

[[abstract]]In previous studies, we have found that IGF-II and IGF-II receptor (IGF-IIR) dose dependently correlated with the progression of pathological hypertrophy after complete abdominal aorta ligation, which may play a critical role in angiotensin II-induced cardiomyocyte apoptosis. However, the detail mechanisms of IGF-IIR in the regulation of cell apoptosis in response to IGF-II remain unclear. By using IGF-IR short hairpin RNA to inhibit IGF-IR expression and using Leu27 IGF-II analog to activate specifically the IGF-IIR, we investigated the role of IGF-II/IGF-IIR activation and its downstream signaling. Our results revealed that IGF-II synergistically increased the cell apoptosis induced by suppressing of IGF-IR in neonatal rat ventricular myocytes. After binding of Leu27IGF-II, IGF-IIR became associated with alpha-q polypeptide, acted like a protein-coupled receptor to activate calcineurin, led to the translocation of Bad into mitochondria and release of cytochrome c into cytoplasm, and contributed to mitochondrial-dependent apoptosis in neonatal rat ventricular myocytes. Furthermore, inhibition of IGF-IIR, alpha-q polypeptide, or calcineurin by RNA interference could block the Leu27IGF-II-induced cell apoptosis. Together, this study provides a new insight into the effects of the IGF-IIR and its downstream signaling in myocardial apoptosis. Suppression of IGF-IIR signaling pathways may be a good strategy for both the protection against myocardial cell apoptosis and the prevention of heart failure progression. (Endocrinology 150: 2723-2731, 2009

IGF-II/mannose-6-phosphate receptor signaling induced cell hypertrophy and atrial natriuretic peptide/BNP expression via G alpha q interaction and protein kinase C-alpha/CaMKII activation in H9c2 cardiomyoblast cells

[[abstract]]The role played by IGF-II in signal transduction through the IGF-II/mannose-6-phosphate receptor (IGF2R) in heart tissue has been poorly understood. In our previous studies, we detected an increased expression of IGF-II and IGF2K in cardiomyocytes that had undergone pathological hypertrophy. We hypothesized that after binding with IGF-II, IGF2K may trigger intracellular signaling cascades involved in the progression of pathologically cardiac hypertrophy. In this study, we used immunohistochemical analysis of the human cardiovascular tissue array to detect expression of IGF2K. In Our study of H9c2 cardiomyoblast cell cultures, we used the rhodamine phalloidin staining, to measure the cell hypertrophy and western blot to measure the expression of cardiac hypertrophy markets atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in cells treated with IGF-II. We found that a significant association between IMP, overexpression and myocardial infarction. The treatment of H9c2 cardiomyoblast cells with IGF-II not only induced cell hypertrophy but also increased the protein level of ANP and BNP. Using Leu27IGF-II, an analog of IGF-II which interacts selectively with the IGF2R to specifically activate IGF2R signaling cascades, we found that binding of Leu271GF-II to IGF2R), led to all increase in the phosphorylation of protein Kinase C (PKC)-alpha and calcium/calmodulin-dependent protein kinase II (CaMKII) in a G alpha q-dependent manner. By the inhibition of PKC-alpha/CaMKII activity, we found that IGF-II and Leu271GF-II-induced cell hypertrophy and upregulation of ANP and BNP were significantly suppressed. Taken together, this study provides a new insight into the effects of the IGF2R and its downstream signaling in cardiac hypertrophy. The suppression of IGF2R signaling pathways may be a good strategy to prevent the progression of pathological hypertrophy

Strategies for Preventing Drug Recidivism Cycle in Taiwan

Drug abuse is currently a worldwide problem and Taiwan is no exception. Drug abuse is a disease that must be treated on the basis of evidence (United Nations Office on Drugs and Crime 2007; World Health Organisation 2004). In order to reduce the damage caused by drug abuse to the nation, society and people, the government not only developed two anti-drug strategies - that of supply eradication and demand reduction - but since May 1994, has mobilised relevant government departments to take assertive action. Some of the actions include law enforcement enhancement, anti-drug enforcement and drug rehabilitation utilisation. In 2005, new anti-drug programs, such as the sterile needle exchange program and substitution therapy program, were also introduced. The cities implementing the Harm Reduction Program (HR Program) showed lower HIV infection rates in comparison to others without the HR Program. The income and employment conditions of drug addicted patients receiving Methadone Maintenance Treatment have been improved. The future drug policies in Taiwan will focus on drug rehabilitation (treatment), anti-drug actions (prevention) and law enforcement (punishment). The educational system, community recovery and aftercare for drug addicts will also be indispensable (WHO/UNODC/UNAIDS 2004)

α-Synuclein, a chemoattractant, directs microglial migration via H 2 O 2 -dependent Lyn phosphorylation

α-Synuclein (α-syn) aggregates released from neurons activate microglia, leading to chronic neuroinflammation that causes damage to neurons in brains with synucleinopathies, such as Parkinson’s disease (PD). However, little is known about the mechanism by which α-syn affects microglial activity, especially motility, and why microglia migrate toward the injured neurons and preferentially accumulate along with α-syn aggregates in the affected areas, e.g., in the substantia nigra of PD brains. Here we show that neuron-derived α-syn aggregates are chemoattractants that direct microglial migration by acting on NADPH oxidase and several specific downstream proteins. Blocking the targets involved in α-syn–mediated microglial directional migration may represent a therapeutic strategy to protect against progressive neuronal loss in PD and related synucleinopathies

Evaluating and Mapping of Spatial Air Ion Quality Patterns in a Residential Garden Using a Geostatistic Method

Negative air ions (NAI) produce biochemical reactions that increase the levels of the mood chemical serotonin in the environment. Moreover, they benefit both the psychological well being and the human body’s physiological condition. The aim of this research was to estimate and measure the spatial distributions of negative and positive air ions in a residential garden in central Taiwan. Negative and positive air ions were measured at thirty monitoring locations in the study garden from July 2009 to June 2010. Moreover, Kriging was applied to estimate the spatial distribution of negative and positive air ions, as well as the air ion index in the study area. The measurement results showed that the numbers of NAI and PAI differed greatly during the four seasons, the highest and the lowest negative and positive air ion concentrations were found in the summer and winter, respectively. Moreover, temperature was positively affected negative air ions concentration. No matter what temperature is, the ranges of variogram in NAI/PAI were similar during four seasons. It indicated that spatial patterns of NAI/PAI were independent of the seasons and depended on garden elements and configuration, thus the NAP/PAI was a good estimate of the air quality regarding air ions. Kriging maps depicted that the highest negative and positive air ion concentration was next to the waterfall, whereas the lowest air ions areas were next to the exits of the garden. The results reveal that waterscapes are a source of negative and positive air ions, and that plants and green space are a minor source of negative air ions in the study garden. Moreover, temperature and humidity are positively and negatively affected negative air ions concentration, respectively. The proposed monitoring and mapping approach provides a way to effectively assess the patterns of negative and positive air ions in future landscape design projects

Fibrate and the risk of cardiovascular disease among moderate chronic kidney disease patients with primary hypertriglyceridemia

IntroductionHypertriglyceridemia is the most prevalent dyslipidemia in patients with chronic kidney disease (CKD). However, research about fibrate treatment in CKD patients is limited, and assessing its benefits becomes challenging due to the frequent concurrent use of statins. Thus, this study is aimed to investigate the role of fibrate in CKD stage 3 patients with hypertriglyceridemia who did not receive other lipid-lowering agents.MethodsThis study enrolled patients newly diagnosed CKD3 with LDL-C<100mg/dL and had never received statin or other lipid-lowering agents from Chang Gung Research Database. The participants were categorized into 2 groups based on the use of fibrate: fibrate group and non-fibrate group (triglyceride >200mg/dL but not receiving fibrate treatment). The inverse probability of treatment weighting was performed to balance baseline characteristics.ResultsCompared with the non-fibrate group (n=2020), the fibrate group (n=705) exhibited significantly lower risks of major adverse cardiac and cerebrovascular events (MACCEs) (10.4% vs. 12.8%, hazard ratios [HRs]: 0.69, 95% confidence interval [CI]: 0.50 to 0.95), AMI (2.3% vs. 3.9%, HR: 0.52, 95% CI: 0.37 to 0.73), and ischemic stroke (6.3% vs. 8.0%, HR: 0.67, 95% CI: 0.52 to 0.85). The risk of all-cause mortality (5.1% vs. 4.5%, HR: 1.09, 95% CI: 0.67 to 1.79) and death from CV (2.8% vs. 2.3%, HR: 1.07, 95% CI: 0.29 to 2.33) did not significantly differ between the 2 groups.ConclusionThis study suggests that, in moderate CKD patients with hypertriglyceridemia but LDL-C < 100mg/dL who did not take other lipid-lowering agents, fibrates may be beneficial in reducing cardiovascular events

miRTarBase update 2014: an information resource for experimentally validated miRNA-target interactions

MicroRNAs (miRNAs) are small non-coding RNA molecules capable of negatively regulating gene expression to control many cellular mechanisms. The miRTarBase database (http://mirtarbase.mbc.nctu.edu.tw/) provides the most current and comprehensive information of experimentally validated miRNA-target interactions. The database was launched in 2010 with data sources for >100 published studies in the identification of miRNA targets, molecular networks of miRNA targets and systems biology, and the current release (2013, version 4) includes significant expansions and enhancements over the initial release (2010, version 1). This article reports the current status of and recent improvements to the database, including (i) a 14-fold increase to miRNA-target interaction entries, (ii) a miRNA-target network, (iii) expression profile of miRNA and its target gene, (iv) miRNA target-associated diseases and (v) additional utilities including an upgrade reminder and an error reporting/user feedback system

The Yuan-Tseh Lee Array for Microwave Background Anisotropy

The Yuan-Tseh Lee Array for Microwave Background Anisotropy (AMiBA) is the first interferometer dedicated to studying the cosmic microwave background (CMB) radiation at 3mm wavelength. The choice of 3mm was made to minimize the contributions from foreground synchrotron radiation and Galactic dust emission. The initial configuration of seven 0.6m telescopes mounted on a 6-m hexapod platform was dedicated in October 2006 on Mauna Loa, Hawaii. Scientific operations began with the detection of a number of clusters of galaxies via the thermal Sunyaev-Zel'dovich effect. We compare our data with Subaru weak lensing data in order to study the structure of dark matter. We also compare our data with X-ray data in order to derive the Hubble constant.Comment: accepted for publication in ApJ (13 pages, 7 figures); a version with high resolution figures available at http://www.asiaa.sinica.edu.tw/~keiichi/upfiles/AMiBA7/pho_highreso.pd

Detection of SARS-associated Coronavirus in Throat Wash and Saliva in Early Diagnosis

Early detection of SARS-CoV in throat wash and saliva suggests that these specimens are ideal for SARS diagnosis

Dual Targeted Extracellular Vesicles Regulate Oncogenic Genes in Advanced Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) tumours carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation release abundant targeted EVs with high RNA loading. Together with a low dose chemotherapy drug, Gemcitabine, dtEVs suppress large orthotopic PANC-1 and patient derived xenograft tumours and metastasis in mice and extended animal survival. Our work presents a clinically accessible and scalable way to produce abundant EVs for delivering multiple gene cargoes to large solid tumours