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Toyohashi, Japan

Zhong C.,CAS Institute of Biophysics | Li C.,CAS Institute of Biophysics | Wang X.,CAS Institute of Biophysics | Toyoda T.,Choju Medical Institute | And 2 more authors.
Cell Death and Differentiation

The influenza A virus is a causative agent of influenza, which infects human cells and uses host factors to accomplish viral genome replication as part of its life cycle. The nucleoprotein (NP) and PB2 of the influenza virus associate with importin α1 to gain access to the host nucleus through a ternary import complex. Killer cell-mediated cytotoxicity is the primary mechanism of eliminating the influenza virus. Here, we showed that lymphokine-activated killer cells participated in the elimination of the influenza virus. Granzyme (Gzm) K inhibition elevated viral replication in vitro and aggravated viral infection in vivo. We identified that importin α1 and its transport partner protein importin β are physiological substrates of GzmK. Proteolysis of these two substrates wrecked their association to generate the importin α1/β dimer and disrupted transportation of viral NP to the nucleus, leading to inhibition of influenza virus replication. © 2012 Macmillan Publishers Limited. All rights reserved. Source

Mishra M.,Nanyang Technological University | Akatsu H.,Choju Medical Institute | Heese K.,Nanyang Technological University
Journal of Cellular and Molecular Medicine

Neuronal regeneration and axonal re-growth in the injured mammalian central nervous system remains an unsolved field. To date, three myelin-associated proteins [Nogo or reticulon 4 (RTN4), myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG)] are known to inhibit axonal regenerationviaactivation of the neuronal glycosylphosphatidylinositol-anchored Nogo receptor [NgR, together with p75 neurotrophin receptor (p75NTR) and Lingo-1]. In the present study we describe the novel protein MANI (myelin-associated neurite-outgrowth inhibitor) that localizes to neural membranes. Functional characterization of MANI overexpressing neural stem cells (NSCs) revealed that the protein promotes differentiation into catecholaminergic neurons. Yeast two-hybrid screening and co-immunoprecipitation experiments confirmed the cell division cycle protein 27 (Cdc27) as an interacting partner of Mani. The analyses of Mani-overexpressing PC12 cells demonstrated that Mani retards neuronal axonal growth as a positive effector of Cdc27 expression and activity. We show that knockdown of Cdc27, a component of the anaphase-promoting complex (APC), leads to enhanced neurite outgrowth. Our finding describes the novel MANI-Cdc27-APC pathway as an important cascade that prevents neurons from extending axons, thus providing implications for the potential treatment of neurodegenerative diseases. © 2011 The Authors Journal compilation © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. Source

Datta A.,Nanyang Technological University | Akatsu H.,Choju Medical Institute | Heese K.,Hanyang University | Sze S.K.,Nanyang Technological University
Journal of Proteomics

Ischemic stroke, still lacking an effective neuroprotective therapy is the third leading cause of global mortality and morbidity. Here, we have applied an 8-plex iTRAQ-based 2D-LC-MS/MS strategy to study the commonly regulated infarct proteome from three different brain regions (putamen, thalamus and the parietal lobe) of female Japanese patients. Infarcts were compared with age-, post-mortem interval- and location-matched control specimens.The iTRAQ experiment confidently identified 1520 proteins with 0.1% false discovery rate. Bioinformatics data mining and immunochemical validation of pivotal perturbed proteins revealed a global failure of the cellular energy metabolism in the infarcted tissues as seen by the parallel down-regulation of proteins related to glycolysis, pyruvate dehydrogenase complex, TCA cycle and oxidative phosphorylation. The concomitant down-regulation of all participating proteins (SLC25A11, SLC25A12, GOT2 and MDH2) of malate-aspartate shuttle might be responsible for the metabolic in-coordination between the cytosol and mitochondria resulting in the failure of energy metabolism. The levels of proteins related to reactive gliosis (VIM, GFAP) and anti-inflammatory response (ANXA1, ANXA2) showed an increasing trend. The elevation of ferritin (FTL, FTH1) may indicate an iron-mediated oxidative imbalance aggravating the mitochondrial failure and neurotoxicity. The deregulated proteins could be useful as potential therapeutic targets or biomarkers for ischemic stroke. Biological significance: Clinical proteomics of stroke has been lagging behind other areas of clinical proteomics like Alzheimer's disease or schizophrenia. Our study is the first quantitative clinical proteomics study where iTRAQ-2D-LC-MS/MS has been utilized in the area of ischemic stroke to obtain a comparative profile of human ischemic infarcts and age-, sex-, location- and post-mortem interval-matched control brain specimens. Different pathological attributes of ischemic stroke well-known through basic and pre-clinical research such as failure of cellular energy metabolism, reactive gliosis, activation of anti-inflammatory response and aberrant iron metabolism have been observed at the bedside. Our dataset could act as a reference for similar studies done in the future using ischemic brain samples from various brain banks across the world. A meta-analysis of these studies could help to map the pathological proteome specific to ischemic stroke that will guide the scientific community to better evaluate the pros and cons of the pre-clinical models for efficacy and mechanistic studies.Infarct being the core of injury should have the most intense regulation for several key proteins involved in the pathophysiology of ischemic stroke. Hence, a part of the up-regulated proteome could leak into the general circulation that may offer candidates of interest as potential biomarkers. In support of our proposed hypothesis, we report ferritin in the current study as one of the most elevated proteins in the infarct, which has been documented as a biomarker in the context of ischemic stroke by an independent study. Overall, our approach has the potential to identify probable therapeutic targets and biomarkers in the area of ischemic stroke. © 2013 Elsevier B.V. Source

Fukushimura Brain Bank (FBB) was established in 1994, and to date, has accumulated 477 fresh frozen brain tissue samples. Our brain bank is based in Choju Medical Institute, Fukushimura Hospital, Toyohashi in Japan. At the time of its foundation, the institute could not establish working relationships with clinicopathological investigators and others engaged in basic neuroscience research. At this stage, we received the assistance of Yokohama City University in setting up standards for neuropathological diagnosis as well as the aid of Chiba University in establishing a method for Vancouver style snap-frozen sampling of brain tissue. However, both systems require considerable manpower and time. We now plan to introduce several improvements in these systems. At its inception, the Brain Bank operated without financial support from grants or foundation funding and was managed only as a hospital expense. However, since 1998, we have collaborated with researchers from several institutes, and the results of our labors have been presented at congresses, in journal publications and in foundation reports. In 2004, we obtained the status required to apply for a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Fukushimura Hospital is a geriatric institution that specializes in dementia. There are no other hospitals or nursing homes in the Toyohashi area that specialize in this field. Half of our patients have Alzheimer's disease,and a number of them have enormous plaques and huge neurofibrillary tangles patient for over 10 years. In general,private geriatric hospitals that care for such patients with severe AD lack the systems required for performing autopsies. Research carried out with animal models are not comparable with neuropathological and biochemical investigations using human tissues,and in terms of the quality,the range and size of our collection at FBB is unique. In the future,we intend to expand our network in order to share samples of interest,and to optimize the network by establishing similar sampling protocols and diagnostic standards. It is with great pleasure that we at the FBB look forward to our collaboration with the Comprehensive Brain Science. Source

Manavalan A.,Nanyang Technological University | Mishra M.,Nanyang Technological University | Feng L.,University of California at Irvine | Sze S.K.,Nanyang Technological University | And 2 more authors.
Experimental and Molecular Medicine

This study is aimed at gaining insights into the brain site-specific proteomic senescence signature while comparing physiologically aged brains with aging-related dementia brains (for example, Alzheimer's disease (AD)). Our study of proteomic differences within the hippocampus (Hp), parietal cortex (pCx) and cerebellum (Cb) could provide conceptual insights into the molecular mechanisms involved in aging-related neurodegeneration. Using an isobaric tag for relative and absolute quantitation (iTRAQ)-based two-dimensional liquid chromatography coupled with tandem mass spectrometry (2D-LC-MS/MS) brain sitespecific proteomic strategy, we identified 950 proteins in the Hp, pCx and Cb of AD brains. Of these proteins, 31 were significantly altered. Most of the differentially regulated proteins are involved in molecular transport, nervous system development, synaptic plasticity and apoptosis. Particularly, proteins such as Gelsolin (GSN), Tenascin-R (TNR) and AHNAK could potentially act as novel biomarkers of aging-related neurodegeneration. Importantly, our Ingenuity Pathway Analysis (IPA)- based network analysis further revealed ubiquitin C (UBC) as a pivotal protein to interact with diverse AD-associated pathophysiological molecular factors and suggests the reduced ubiquitin proteasome degradation system (UPS) as one of the causative factors of AD. © 2013 KSBMB. All rights reserved. Source

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