School of Chemistry - Research Publications

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    The lipid network.
    Sani, M-A ; Separovic, F ; Gehman, JD (Springer Science and Business Media LLC, 2012-12)
    Natural cell membranes are composed of a remarkable variety of lipids, which provide specific biophysical properties to support membrane protein function. An improved understanding of this complexity of membrane composition may also allow the design of membrane active drugs. Crafting a relevant model of a cell membrane with controlled composition is becoming an art, with the ability to reveal the molecular mechanisms of biological processes and lead to better treatment of pathologies. By matching physiological observations from in vivo experiments to high-resolution information, more easily obtained from in vitro studies, complex interactions at the lipid interface are determined. The role of the lipid network in biological membranes is, therefore, the subject of increasing attention.
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    ExoCarta 2012: database of exosomal proteins, RNA and lipids
    Mathivanan, S ; Fahner, CJ ; Reid, GE ; Simpson, RJ (OXFORD UNIV PRESS, 2012-01-01)
    Exosomes are membraneous nanovesicles of endocytic origin released by most cell types from diverse organisms; they play a critical role in cell-cell communication. ExoCarta (http://www.exocarta.org) is a manually curated database of exosomal proteins, RNA and lipids. The database catalogs information from both published and unpublished exosomal studies. The mode of exosomal purification and characterization, the biophysical and molecular properties are listed in the database aiding biomedical scientists in assessing the quality of the exosomal preparation and the corresponding data obtained. Currently, ExoCarta (Version 3.1) contains information on 11,261 protein entries, 2375 mRNA entries and 764 miRNA entries that were obtained from 134 exosomal studies. In addition to the data update, as a new feature, lipids identified in exosomes are added to ExoCarta. We believe that this free web-based community resource will aid researchers in identifying molecular signatures (proteins/RNA/lipids) that are specific to certain tissue/cell type derived exosomes and trigger new exosomal studies.
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    Vesiclepedia: A Compendium for Extracellular Vesicles with Continuous Community Annotation
    Kalra, H ; Simpson, RJ ; Ji, H ; Aikawa, E ; Altevogt, P ; Askenase, P ; Bond, VC ; Borras, FE ; Breakefield, X ; Budnik, V ; Buzas, E ; Camussi, G ; Clayton, A ; Cocucci, E ; Falcon-Perez, JM ; Gabrielsson, S ; Gho, YS ; Gupta, D ; Harsha, HC ; Hendrix, A ; Hill, AF ; Inal, JM ; Jenster, G ; Kraemer-Albers, E-M ; Lim, SK ; Llorente, A ; Lotvall, J ; Marcilla, A ; Mincheva-Nilsson, L ; Nazarenko, I ; Nieuwland, R ; Nolte-'t Hoen, ENM ; Pandey, A ; Patel, T ; Piper, MG ; Pluchino, S ; Prasad, TSK ; Rajendran, L ; Raposo, G ; Record, M ; Reid, GE ; Sanchez-Madrid, F ; Schiffelers, RM ; Siljander, P ; Stensballe, A ; Stoorvogel, W ; Taylor, D ; Thery, C ; Valadi, H ; van Balkom, BWM ; Vazquez, J ; Vidal, M ; Wauben, MHM ; Yanez-Mo, M ; Zoeller, M ; Mathivanan, S (PUBLIC LIBRARY SCIENCE, 2012-12-01)
    Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field.
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    A Purpose-Synthesised Anti-Fibrotic Agent Attenuates Experimental Kidney Diseases in the Rat
    Gilbert, RE ; Zhang, Y ; Williams, SJ ; Zammit, SC ; Stapleton, DI ; Cox, AJ ; Krum, H ; Langham, R ; Kelly, DJ ; Dussaule, J-C (PUBLIC LIBRARY SCIENCE, 2012-10-10)
    BACKGROUND AND PURPOSE: Locally-active growth factors have been implicated in the pathogenesis of many diseases in which organ fibrosis is a characteristic feature. In the setting of chronic kidney disease (CKD), two such pro-fibrotic factors, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) have emerged as lead potential targets for intervention. Given the incomplete organ protection afforded by blocking the actions of TGF-β or PDGF individually, we sought to determine whether an agent that inhibited the actions of both may have broader effects in ameliorating the key structural and functional abnormalities of CKD. EXPERIMENTAL APPROACH: Accordingly, we studied the effects of a recently described, small molecule anti-fibrotic drug, 3-methoxy-4-propargyloxycinnamoyl anthranilate (FT011, Fibrotech Therapeutics, Australia), which should have these effects. KEY RESULTS: In the in vitro setting, FT011 inhibited both TGF-β1 and PDGF-BB induced collagen production as well as PDGF-BB-mediated mesangial proliferation. Consistent with these in vitro actions, when studied in a robust model of non-diabetic kidney disease, the 5/6 nephrectomised rat, FT011 attenuated the decline in GFR, proteinuria and glomerulosclerosis (p<0.05 for all). Similarly, in the streptozotocin-diabetic Ren-2 rat, a model of advanced diabetic nephropathy, FT011 reduced albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. CONCLUSIONS AND IMPLICATIONS: Together these studies suggest that broadly antagonising growth factor actions, including those of TGF-β1 and PDGF-BB, has the potential to protect the kidney from progressive injury in both the diabetic and non-diabetic settings.
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    Localization of Oleuropeyl Glucose Esters and a Flavanone to Secretory Cavities of Myrtaceae
    Heskes, AM ; Goodger, JQD ; Tsegay, S ; Quach, T ; Williams, SJ ; Woodrow, IE ; Blazquez, MA (PUBLIC LIBRARY SCIENCE, 2012-07-20)
    We report the widespread occurrence of structurally diverse oleuropeyl glucose esters, including the new diester eucaglobulin B, localized specifically to the essential oil secretory cavities of myrtaceous species. Clear taxonomic patterns in the composition of cavity extracts within the genus Eucalyptus are shown with species from subgenus Symphyomyrtus dominated by oleuropeyl glucose esters and species from subgenus Eucalyptus dominated instead by the flavanone, pinocembrin. We also examined the intra-species occurrence of oleuropeyl glucose esters by quantifying the abundant constituents cuniloside B and froggattiside A in trees from two populations of Eucalyptus polybractea R.T. Baker. All trees contained both compounds, which were positively correlated with total essential oil concentration. This apparent ubiquity of oleuropeyl glucose esters at both intra- and inter-specific levels in Eucalyptus is indicative of important physiological or ecological functions. The significance of their prevalence and the sequestration of these esters and also pinocembrin to the extracellular domain of secretory cavities is discussed in light of their potential biological activities and our findings that they are spatially segregated to the exterior of cavity lumina. The localization of oleuropeyl glucose esters to a specific and isolatable tissue type has the potential to aid in future elucidation of function and biosynthesis.
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    Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor
    Lindqvist, LM ; Vikstroem, I ; Chambers, JM ; McArthur, K ; Anderson, MA ; Henley, KJ ; Happo, L ; Cluse, L ; Johnstone, RW ; Roberts, AW ; Kile, BT ; Croker, BA ; Burns, CJ ; Rizzacasa, MA ; Strasser, A ; Huang, DCS (NATURE PUBLISHING GROUP, 2012-10-01)
    There is significant interest in treating cancers by blocking protein synthesis, to which hematological malignancies seem particularly sensitive. The translation elongation inhibitor homoharringtonine (Omacetaxine mepesuccinate) is undergoing clinical trials for chronic myeloid leukemia, whereas the translation initiation inhibitor silvestrol has shown promise in mouse models of cancer. Precisely how these compounds induce cell death is unclear, but reduction in Mcl-1, a labile pro-survival Bcl-2 family member, has been proposed to constitute the critical event. Moreover, the contribution of translation inhibitors to neutropenia and lymphopenia has not been precisely defined. Herein, we demonstrate that primary B cells and neutrophils are highly sensitive to translation inhibitors, which trigger the Bax/Bak-mediated apoptotic pathway. However, contrary to expectations, reduction of Mcl-1 did not significantly enhance cytotoxicity of these compounds, suggesting that it does not have a principal role and cautions that strong correlations do not always signify causality. On the other hand, the killing of T lymphocytes was less dependent on Bax and Bak, indicating that translation inhibitors can also induce cell death via alternative mechanisms. Indeed, loss of clonogenic survival proved to be independent of the Bax/Bak-mediated apoptosis altogether. Our findings warn of potential toxicity as these translation inhibitors are cytotoxic to many differentiated non-cycling cells.
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    Discovery of Inhibitors of Leishmania beta-1,2-Mannosyltransferases Using a Click-Chemistry-Derived Guanosine Monophosphate Library
    van der Peet, P ; Ralton, JE ; McConville, MJ ; Williams, SJ ; Croft, AK (PUBLIC LIBRARY SCIENCE, 2012-02-29)
    Leishmania spp. are a medically important group of protozoan parasites that synthesize a novel intracellular carbohydrate reserve polymer termed mannogen. Mannogen is a soluble homopolymer of β-1,2-linked mannose residues that accumulates in the major pathogenic stages in the sandfly vector and mammalian host. While several steps in mannogen biosynthesis have been defined, none of the enzymes have been isolated or characterized. We report the development of a simple assay for the GDP-mannose-dependent β-1,2-mannosyltransferases involved in mannogen synthesis. This assay utilizes octyl α-D-mannopyranoside to prime the formation of short mannogen oligomers up to 5 mannose residues. This assay was used to screen a focussed library of 44 GMP-triazole adducts for inhibitors. Several compounds provided effective inhibition of mannogen β-1,2-mannosyltransferases in a cell-free membrane preparation. This assay and inhibitor compounds will be useful for dissecting the role of different mannosyltransferases in regulating de novo biosynthesis and elongation reactions in mannogen metabolism.
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    The hypoxia imaging agent Cu-II(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson's disease
    Hung, LW ; Villemagne, VL ; Cheng, L ; Sherratt, NA ; Ayton, S ; White, AR ; Crouch, PJ ; Lim, S ; Leong, SL ; Wilkins, S ; George, J ; Roberts, BR ; Pham, CLL ; Liu, X ; Chiu, FCK ; Shackleford, DM ; Powell, AK ; Masters, CL ; Bush, AI ; O'Keefe, G ; Culvenor, JG ; Cappai, R ; Cherny, RA ; Donnelly, PS ; Hill, AF ; Finkelstein, DI ; Barnham, KJ (ROCKEFELLER UNIV PRESS, 2012-04-09)
    Parkinson's disease (PD) is a progressive, chronic disease characterized by dyskinesia, rigidity, instability, and tremors. The disease is defined by the presence of Lewy bodies, which primarily consist of aggregated α-synuclein protein, and is accompanied by the loss of monoaminergic neurons. Current therapeutic strategies only give symptomatic relief of motor impairment and do not address the underlying neurodegeneration. Hence, we have identified Cu(II)(atsm) as a potential therapeutic for PD. Drug administration to four different animal models of PD resulted in improved motor and cognition function, rescued nigral cell loss, and improved dopamine metabolism. In vitro, this compound is able to inhibit the effects of peroxynitrite-driven toxicity, including the formation of nitrated α-synuclein oligomers. Our results show that Cu(II)(atsm) is effective in reversing parkinsonian defects in animal models and has the potential to be a successful treatment of PD.
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    Microwave Synthesis of Prion Protein Fragments up to 111 Amino Acids in Length Generates Biologically Active Peptides
    Karas, JA ; Boland, M ; Haigh, C ; Johanssen, V ; Hill, A ; Barnham, K ; Collins, S ; Scanlon, D (Springer Verlag, 2012)
    Misfolded conformers of the prion protein are aetiologically implicated in neurodegenerative conditions termed prion diseases (also known as transmissible spongiform encephalopathies). Two constitutively expressed N-terminal peptides corresponding to human residues 23–90 and 23–111 are thought to serve normal physiological roles related to neuronal protection with membrane binding possibly playing a part in their mechanism of action. These peptides, along with several derivatives up to 111 residues in length, have been produced by microwave assisted peptide synthesis. HPLC and MS characterisation showed that the peptides were manufactured in good yields at high purity. Peptides were assayed by fluorescence spectroscopy for synthetic lipid-membrane binding activity and by dichlorodihydrofluorescein diacetate assay for the amelioration of reactive oxygen species production. Results of these assays were similar to those reported for the wild type recombinant PrP, demonstrating that these synthetic peptides are useful for biological and chemical assays of PrP activity. Further, the longest peptide 1–111 was dimerised via a single internal cystine residue with good yield. The high yields and low purification burden of the microwave assisted synthesis method lends itself to the production of difficult to produce peptides for such studies.
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    Molecular properties of lysozyme-microbubbles: towards the protein and nucleic acid delivery
    Melino, S ; Zhou, M ; Tortora, M ; Paci, M ; Cavalieri, F ; Ashokkumar, M (SPRINGER WIEN, 2012-08-01)
    Microbubbles (MBs) have specific acoustic properties that make them useful as contrast agents in ultrasound imaging. The use of the MBs in clinical practice led to the development of more sensitive imaging techniques both in cardiology and radiology. Protein-MBs are typically obtained by dispersing a gas phase in the protein solution and the protein deposited/cross-linked on the gas-liquid interface stabilizes the gas core. Innovative applications of protein-MBs prompt the investigation on the properties of MBs obtained using different proteins that are able to confer them specific properties and functionality. Recently, we have synthesized stable air-filled lysozyme-MBs (LysMBs) using high-intensity ultrasound-induced emulsification of a partly reduced lysozyme in aqueous solutions. The stability of LysMBs suspension allows for post-synthetic modification of MBs surface. In the present work, the protein folded state and the biodegradability property of LysMBs were investigated by limited proteolysis. Moreover, LysMBs were coated and functionalized with a number of biomacromolecules (proteins, polysaccharides, nucleic acids). Remarkably, LysMBs show a high DNA-binding ability and protective effects of the nucleic acids from nucleases and, further, the ability to transform the bacteria cells. These results highlight on the possibility of using LysMBs for delivery of proteins and nucleic acids in prophylactic and therapeutic applications.