2024-03-29T15:56:25Z
http://ro.uow.edu.au/do/oai/
oai:ro.uow.edu.au:scipapers-1209
2014-05-21T04:37:03Z
publication:data
publication:smh
publication:scipapers
publication:ihmri
publication:cmmb
publication:data_collections
publication:document_types
Preclinical Evaluation of Novel All-in-one Formulations of 5-Fluorouracil and Folinic Acid with Reduced Toxicity Profiles - Supplementary Data
Stutchbury, Tamantha K.
Vine, Kara L
Locke, Julie M.
Chrisp, Jeremy S.
Bremner, J. B.
Clingan, P
Ranson, Marie
Data
10.1097/CAD.0b013e32833f6d22
2010-01-01T08:00:00Z
CMMB
<p>This supplementary data is related to the following article: Stutchbury, T.K. et al., Preclinical Evaluation of Novel All-in-one Formulations of 5-Fluorouracil and Folinic Acid with Reduced Toxicity Profiles, Anti-Cancer Drugs, 2010 (in press).</p>
<p><strong>Objectives</strong>: 5-Fluorouracil (5-FU) in combination with its synergistic biomodulator folinic acid maintains a pivotal position in cancer chemotherapy. However, clinical limitations persist with the administration of these drugs in combination including phlebitis and catheter blockages, which are associated with reduced efficacy and/or quality of life for patients. We have previously reported novel all-in-one, pH neutral, parenteral 5-FU and folinic acid formulations (termed Fluorodex) incorporating beta-cyclodextrins. Fluorodex maintains potency while overcoming the accepted incompatibility of 5-FU and folinic acid.<br /><strong>Methods</strong>: We performed toxicological, pharmacokinetic and biodistribution, and efficacy evaluations of Fluorodex compared to 5-FU:folinic acid using several administration routes and schedules in two rodent models. These were compared to dose-matched sequential administration of 5-FU:folinic acid.<br /><strong>Results</strong>: Fluorodex showed bioequivalence to 5-FU:folinic acid as assessed by tissue distribution and pharmacokinetics of 5-FU, but was generally better tolerated as determined by weight loss, hematological and other clinical parameters. Compared to 5-FU:folinic acid, Fluorodex was also associated with reduced phlebitis using a rabbit ear vein model. Furthermore, equivalent to enhanced efficacy of Fluorodex compared to 5-FU:folinic acid against human carcinoma tumour models in mice was observed.<br /><strong>Conclusions</strong>: These novel all-in-one formulations represent a superior injectable form of 5- FU that allows co-delivery of folinic acid. This should translate to improved patient tolerability with potential for enhanced efficacy.</p>
Life Sciences
Physical Sciences and Mathematics
Social and Behavioral Sciences
https://ro.uow.edu.au/scipapers/177
oai:ro.uow.edu.au:ihmri-1016
2011-05-09T00:54:22Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
The possible role of IL-17 in obesity-associated cancer
Gislette, Tiphaine
Chen, Jiezhong
Journal Article
2010-01-01T08:00:00Z
Gislette, T. & Chen, J. (2010). The possible role of IL-17 in obesity-associated cancer. The Scientific World Journal, 10 (November), 2265-2271.
10.1100/tsw.2010.212
Obesity and overweight have become major medical and social problems. Both are increasing worldwide; two-thirds of the population in developed countries is obese or overweight. Obesity has been associated with many comorbidities, including diabetes and heart disease. Studies have also found that obesity is one of the risk factors involved in increased cancer incidence. Many obesity-related factors are responsible, including increased blood levels of insulin/IGF, IL-6, TNF-alpha, and leptin, and decreased blood levels of adiponectin. Recently, it has been shown that IL-17 levels increase in obese patients. IL-17 is well known to increase carcinogenesis; thus, increased IL-17 levels in obesity may contribute to increased cancer incidence in obesity. IL-17 could activate Src/PI3K, MAPK, Stat3, and PKC, resulting in carcinogenesis. It may also change the microenvironment of tumors. Thus, inhibition of IL-17 may have preventive and therapeutic implications in obese patients.
associated
obesity
il
role
cancer
possible
17
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/5
oai:ro.uow.edu.au:ihmri-1013
2011-05-09T01:06:38Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
The heart and soul of change: delivering what works in therapy, second edition (Book Review)
Grenyer, B. F. S.
Journal Article
2010-01-01T08:00:00Z
<p>Grenyer, B. F. S. . (2010). The heart and soul of change: delivering what works in therapy, second edition (Book Review). Psychotherapy in Australia, 16 (4), 81-81.</p>
<p>In 1936 Saul Rosenzweig (19072004) published a scientific paper concluding that psychotherapies of different theoretical and practical orientations all produce equivalent effectiveness-a conclusion that remains unchanged today despite 75 years of empirical research seeking to find differential effectiveness for different forms of psychotherapy treatment. What is less well know, however, is that despite equivalent effectiveness of therapy brand names, there is considerable variation in effectiveness between individual therapists. It is therefore fitting that this book begins with a message from Rosenzweig, which sets the scene for a very different volume from the first edition. The first edition (1999), edited by Hubble, Duncan and Miller, quickly became a classic text in the field because it took Rosenzweig's conclusion, and then turned it into a set of principles to help therapists become more effective. The idea at the time was that therapists should capitalise on four common factors: (1) mobilise the client's life circumstances and environment; (2) enhance the therapy relationship; (3) create an atmosphere of hope and expectation of change; and (4) use therapy techniques in the service of helping the client to make their own changes. These principles were patched together based on past research to create an argument for change.</p>
book
soul
heart
review
change
delivering
second
works
edition
therapy
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/2
oai:ro.uow.edu.au:ihmri-1018
2011-07-12T04:10:16Z
publication:smh
publication:ihmri
publication:books
publication:document_types
Guide d'aide a l'arret du cannabis (Guide to quitting cannabis)
Grenyer, B. F. S.
Solowij, Nadia
Peters, R
Book
2009-01-01T08:00:00Z
<p>Grenyer, B. F. S. ., Solowij, N. & Peters, R. (2009). Guide d'aide a l'arret du cannabis (Guide to quitting cannabis). (1 ed.). Paris: INPES Institut National de Prevention et d'Education pour la Sante.</p>
<p>Ce guide a pour objectif d’aider les personnes qui envisagent d’arrêter de consommer du cannabis. Il peut aussi apporter des informations utiles à des personnes qui n’éprouvent pas actuellement le besoin d’arrêter. Il vous accompagnera de manière pratique, au long des différentes étapes du processus d’arrêt. Il vous aidera à identifi er les motivations qui vous poussent à consommer, les circonstances dans lesquelles vous fumez, mais également les raisons qui vous incitent à arrêter.</p>
du
arret
cannabis
l
aide
quitting
guide
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/6
oai:ro.uow.edu.au:ihmri-1021
2014-04-09T08:42:58Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Study of the effects of dietary polyunsaturated fatty acids: Molecular mechanisms involved in intestinal inflammation
Knoch, Bianca
Barnett, Matthew
Roy, Nicole
McNabb, Warren
Journal Article
2009-01-01T08:00:00Z
<p>Knoch, B., Barnett, M., Roy, N. & McNabb, W. (2009). Study of the effects of dietary polyunsaturated fatty acids: Molecular mechanisms involved in intestinal inflammation. Grasas y Aceites, 60 (1), 8-21.</p>
10.3989/gya.086508
<p>The use of “omics” techniques in combination with model systems and molecular tools allows to understand how foods and food components act on metabolic pathways to regulate transcriptional processes. Polyunsaturated fatty acids have distinctive nutritional and metabolic effects because they give rise to lipid mediated products and affect the expression of various genes involved in intestinal inflammation. The present review focuses on the molecular effects of dietary polyunsaturated fatty acids on intestinal inflammation</p>
molecular
mechanisms
involved
intestinal
study
inflammation
effects
dietary
polyunsaturated
fatty
acids
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/7
oai:ro.uow.edu.au:ihmri-1026
2011-10-18T00:12:08Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Peroxisome proliferator-activated receptor alpha target genes
Rakhshandehroo, Maryam
Knoch, Bianca
Muller, Michael
Kersten, Sander
Journal Article
2010-01-01T08:00:00Z
Rakhshandehroo, M., Knoch, B., Muller, M. & Kersten, S. (2010). Peroxisome proliferator-activated receptor alpha target genes. PPAR Research, 2010 (Article ID 612089), 1-20.
10.1155/2010/612089
The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor involved in the regulation
of a variety of processes, ranging from inflammation and immunity to nutrientmetabolism and energy homeostasis. PPARα serves
as amolecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is
activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression
of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target
genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed
analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although
many of the results likely apply to other organs and tissues as well.
alpha
activated
peroxisome
receptor
genes
target
proliferator
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/12
oai:ro.uow.edu.au:ihmri-1025
2014-04-09T08:41:37Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Molecular characterization of the onset and progression of colitis in inoculated interleukin-10 gene-deficient mice: a role for PPARcx
Knoch, Bianca
Barnett, Matthew
Cooney, Janine
McNabb, Warren
Barraclough, Diane
Laing, William
Zhu, Shuotun
Park, Zaneta A
MacLean, Paul
Knowles, Scott O
Roy, Nicole
Journal Article
2010-01-01T08:00:00Z
<p>Knoch, B., Barnett, M., Cooney, J., McNabb, W., Barraclough, D., Laing, W., Zhu, S., Park, Z. A., MacLean, P., Knowles, S. O. & Roy, N. (2010). Molecular characterization of the onset and progression of colitis in inoculated interleukin-10 gene-deficient mice: a role for PPARcx. PPAR Research, 2010 (Article ID 621069), 1-18.</p>
10.1155/2010/621069
<p>The interleukin-10 gene-deficient (Il10−/−) mouse is a model of human inflammatory bowel disease and Ppara has been identified as one of the key genes involved in regulation of colitis in the bacterially inoculated Il10−/− model. The aims were to (1) characterize colitis onset and progression using a histopathological, transcriptomic, and proteomic approach and (2) investigate links between PPARα and IL10 using gene network analysis. Bacterial inoculation resulted in severe colitis in Il10−/− mice from 10 to 12 weeks of age. Innate and adaptive immune responses showed differences in gene expression relating to colitis severity. Actin cytoskeleton dynamics, innate immunity, and apoptosis-linked gene and protein expression data suggested a delayed remodeling process in 12-week-old Il10−/− mice. Gene expression changes in 12-week-old Il10−/− mice were related to PPARα signaling likely to control colitis, but how PPARα activation might regulate intestinal IL10 production remains to be determined.</p>
interleukin
inoculated
colitis
progression
onset
deficient
characterization
role
molecular
mice
gene
10
pparcx
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/11
oai:ro.uow.edu.au:ihmri-1024
2014-12-02T05:15:28Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Changes in colon gene expression associated with increased colon inflammation in interleukin-10 gene-deficient mice inoculated with Enterococcus species
Barnett, Matthew PG
McNabb, Warren C
Cookson, Adrian L
Zhu, Shuotun
Davy, Marcus
Knoch, Bianca
Nones, Katie
Hodgkinson, Alison J
Roy, Nicole
Journal Article
2010-01-01T08:00:00Z
<p>Barnett, M. PG., McNabb, W. C., Cookson, A. L., Zhu, S., Davy, M., Knock, B., Nones, K., Hodgkinson, A. J. & Roy, N. C. (2010). Changes in colon gene expression associated with increased colon inflammation in interleukin-10 gene-deficient mice inoculated with Enterococcus species. BMC Immunology, 11 (July), 39-1-39-21.</p>
10.1186/1471-2172-11-39
<p>Background: Inappropriate responses to normal intestinal bacteria may be involved in the development of Inflammatory Bowel Diseases (IBD, e.g. Crohn's Disease (CD), Ulcerative Colitis (UC)) and variations in the host genome may mediate this process. IL-10 gene-deficient (Il10-/-) mice develop CD-like colitis mainly in the colon, in part due to inappropriate responses to normal intestinal bacteria including Enterococcus strains, and have therefore been used as an animal model of CD. Comprehensive characterization of changes in cecum gene expression levels associated with inflammation in the Il10-/- mouse model has recently been reported. Our aim was to characterize changes in colonic gene expression levels in Il10-/- and C57BL/6J (C57; control) mice resulting from oral bacterial inoculation with 12 Enterococcus faecalis and faecium (EF) strains isolated from calves or poultry, complex intestinal flora (CIF) collected from healthy control mice, or a mixture of the two (EF·CIF). We investigated two hypotheses: (1) that oral inoculation of Il10-/- mice would result in greater and more consistent intestinal inflammation than that observed in Il10-/- mice not receiving this inoculation, and (2) that this inflammation would be associated with changes in colon gene expression levels similar to those previously observed in human studies, and these mice would therefore be an appropriate model for human CD. Results: At 12 weeks of age, total RNA extracted from intact colon was hybridized to Agilent 44 k mouse arrays. Differentially expressed genes were identified using linear models for microarray analysis (Bioconductor), and these genes were clustered using GeneSpring GX and Ingenuity Pathways Analysis software. Intestinal inflammation was increased in Il10-/- mice as a result of inoculation, with the strongest effect being in the EF and EF·CIF groups. Genes differentially expressed in Il10-/- mice as a result of EF or EF·CIF inoculation were associated with the following pathways: inflammatory disease (111 genes differentially expressed), immune response (209 genes), antigen presentation (11 genes, particularly major histocompatability complex Class II), fatty acid metabolism (30 genes) and detoxification (31 genes). Conclusions: Our results suggest that colonic inflammation in Il10-/- mice inoculated with solutions containing Enterococcus strains is associated with gene expression changes similar to those of human IBD, specifically CD, and that with the EF·CIF inoculum in particular this is an appropriate model to investigate food-gene interactions relevant to human CD.</p>
increased
expression
gene
inflammation
colon
species
changes
deficient
associated
10
interleukin
mice
inoculated
enterococcus
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/10
oai:ro.uow.edu.au:ihmri-1038
2014-04-09T08:42:18Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Regulation of alpha-synuclein expression by liver X receptor ligands in vitro
Cheng, Danni
Kim, Woojin Scott
Garner, Brett
Journal Article
2008-01-01T08:00:00Z
<p>Cheng, D., Kim, W. & Garner, B. (2008). Regulation of alpha-synuclein expression by liver X receptor ligands in vitro. NeuroReport, 19 (17), 1685-1689.</p>
10.1097/WNR.0b013e32831578b2
<p>Alpha-synuclein is a lipid-binding protein expressed in neurons and oligodendrocytes which is increased in Parkinson's disease. We identified two putative liver X receptor (LXR) response elements in the human oc-synuclein gene and used synthetic (TO901317, GW3695) and physiological (27-hydroxycholesterol) LXR activators to assess regulation of α-synuclein. LXR ligands upregulated α-synuclein m RNA by two-five-fold in human SK-N-SH neurons and three-six-fold in human MO3.13 oligodendrocytes. Significant 50% to four-fold induction of α-synuclein protein was also detected. Under these conditions, m RNA for LXR-responsive gene ABCAI was significantly upregulated 15-40-fold and 5-25-fold in neurons and oligodendrocytes, respectively. LXR may, therefore, contribute to the regulation of α-synuclein expression in neurons and oligodendrocytes. © 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.</p>
x
liver
expression
synuclein
ligands
vitro
receptor
regulation
alpha
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/23
oai:ro.uow.edu.au:ihmri-1035
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
HPLC analysis of discrete haptoglobin isoform N-linked oligosaccharides following 2D-PAGE isolation
He, Zhija
Aristoteli, L P
Kritharides, L
Garner, Brett
Journal Article
2006-01-01T08:00:00Z
He, Z., Aristoteli, L. P., Kritharides, L. & Garner, B. (2006). HPLC analysis of discrete haptoglobin isoform N-linked oligosaccharides following 2D-PAGE isolation. Biochemical and Biophysical Research Communications, 343 (2), 496-503.
10.1016/j.bbrc.2006.03.007
Glycosylation is a common but variable modification that regulates glycoprotein structure and function. We combined small format 2D-PAGE with HPLC to analyse discrete human haptoglobin isoform N-glycans. Seven major and several minor haptoglobin isoforms were detected by 2D-PAGE. N-Glycans released from Coomassie-stained gel spots using PNGase were labeled at their reducing termini with 2-aminobenzamide. HPLC analysis of selected major isoform N-glycans indicated that sialic acid composition determined their Separation by isoelectric focussing. N-Glycans from two doublets of quantitatively minor isoforms were also analysed. Although separation of each pair of doublets was influenced by sialylation, individual spots within each doublet contained identical N-glycans. Thus, heterogeneity in minor haptoglobin isoforms was due to modifications distinct from N-glycan structure. These studies describe a simple method for analysing low abundance protein N-glycans and provide details of discrete haptoglobin isoform N-glycan structures which will be useful in proteomic analysis of human plasma samples. (c) 2006 Elsevier Inc. All rights reserved.
linked
n
isolation
isoform
page
haptoglobin
discrete
analysis
hplc
2d
following
oligosaccharides
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/20
oai:ro.uow.edu.au:ihmri-1031
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Modulation of brain metabolism by very low concentrations of the commonly used drug delivery vehicle dimethyl sulfoxide (DMSO)
Nasrallah, F A
Garner, Brett
Ball, Graham E
Rae, C
Journal Article
2008-01-01T08:00:00Z
Nasrallah, F., Garner, B., Ball, G. & Rae, C. (2008). Modulation of brain metabolism by very low concentrations of the commonly used drug delivery vehicle dimethyl sulfoxide (DMSO). Journal of Neuroscience Research, 86 (1), 208-214.
10.1002/jnr.21477
Dimethyl sulfoxide (DMSO) has long been used in studies as a vehicle to enhance the solubility and transport of ligands in biological systems. The effects of this drug on the outcomes of such studies are still unclear, with concentrations of DMSO reported as "safe" varying considerably. In the present work, we investigated the effects of very low concentrations of DMSO on the brain metabolism of [3-13C]pyruvate and D-[1- 13C]glucose using 1H/13C NMR spectroscopy and a guinea pig cortical brain slice model. Our results show that DMSO is accumulated by brain slices. DMSO at all concentrations [0.000025%-0.25% (v/v)] increased the metabolic rate when [3-13C]pyruvate was used as a substrate and also in the presence of D-[1-13C]glucose (0.00025%-0.1% DMSO). These results are consistent with DMSO stimulating respiration, which it may do through altering the kinetics of ATP-requiring reactions. Our results also emphasize that there is no practical concentration of DMSO that can be used in metabolic experiments without effect. Therefore, care should be taken when evaluating the actions of drugs administered in combination with DMSO. © 2007 Wiley-Liss, Inc.
very
metabolism
brain
modulation
dimethyl
vehicle
delivery
drug
dmso
used
sulfoxide
commonly
concentrations
low
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/16
oai:ro.uow.edu.au:ihmri-1028
2014-04-09T08:41:45Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein E discs and suppression of amyloid-β peptide generation
Kim, Woojin
Rahmanto, Aldwin
Kamili, Alvin
Rye, Kerry-Anne
Guillemin, Gilles J
Gelissen, Ingrid C
Jessup, Wendy
Hill, Andrew F
Garner, Brett
Journal Article
2007-01-01T08:00:00Z
<p>Kim, W., Rahmanto, A., Kamili, A., Rye, K., Guillemin, G. J., Gelissen, I. C., Jessup, W., Hill, A. F. & Garner, B. (2007). Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein E discs and suppression of amyloid-β peptide generation. Journal of Biological Chemistry, 282 (5), 2851-2861.</p>
10.1074/jbc.M607831200
<p>Maintenance of an adequate supply of cholesterol is important for neuronal function, whereas excess cholesterol promotes amyloid precursor protein (APP) cleavage generating toxic amyloid-β (Aβ) peptides. To gain insights into the pathways that regulate neuronal cholesterol level, we investigated the potential for reconstituted apolipoprotein E (apoE) discs, resembling nascent lipoprotein complexes in the central nervous system, to stimulate neuronal [3H]cholesterol efflux. ApoE discs potently accelerated cholesterol efflux from primary human neurons and cell lines. The process was saturable (17.5 μg of apoE/ml) and was not influenced by APOE genotype. High performance liquid chromatography analysis of cholesterol and cholesterol metabolites effluxed from neurons indicated that <25% of the released cholesterol was modified to polar products (e.g. 24-hydroxycholesterol) that diffuse from neuronal membranes. Thus, most cholesterol (∼75%) appeared to be effluxed from neurons in a native state via a transporter pathway. ATP-binding cassette transporters ABCA1, ABCA2, and ABCG1 were detected in neurons and neuroblastoma cell lines and expression of these cDNAs revealed that ABCA1 and ABCG1 stimulated cholesterol efflux to apoE discs. In addition, ABCA1 and ABCG1 expression in Chinese hamster ovary cells that stably express human APP significantly reduced Aβ generation, whereas ABCA2 did not modulate either cholesterol efflux or Aβ generation. These data indicate that ABCA1 and ABCG1 play a significant role in the regulation of neuronal cholesterol efflux to apoE discs and in suppression of APP processing to generate Aβ peptides. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.</p>
role
abcg1
abca1
regulation
neuronal
cholesterol
efflux
apolipoprotein
peptide
amyloid
discs
e
suppression
generation
β
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/13
oai:ro.uow.edu.au:ihmri-1029
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Apoptosis induces neuronal apolipoprotein-E synthesis and localization in apoptotic bodies
Elliott, David A
Kim, Woojin S
Jans, David A
Garner, Brett
Journal Article
2007-01-01T08:00:00Z
Elliott, D. A., Kim, W. S., Jans, D. A. & Garner, B. (2007). Apoptosis induces neuronal apolipoprotein-E synthesis and localization in apoptotic bodies. Neuroscience Letters, 416 (2), 206-210.
10.1016/j.neulet.2007.02.014
Neuronal apoptosis is crucial for central nervous system development and also contributes to neurodegenerative disease. Apolipoprotein-E (apoE) regulates brain lipid transport and specific neuronal functions and previous research, investigating non-neuronal cell types, identified an association between apoptosis and increased apoE expression. In the present study we used the human SK-N-SH neuronal cell line to investigate potential changes in apoE expression during apoptosis which occurs as a consequence of extended culture (up to 5 days) without replenishing trophic factors. Standard and real-time PCR analysis indicated a significant 6-fold increase in apoE mRNA after 3 days which was correlated with caspase-3 activation, TUNEL positivity and the formation of apoptotic bodies. ApoE protein levels were low in the absence of apoptosis but increased by 8-fold when apoptosis was induced. Analysis of cellular debris that accumulated in the culture supernatants indicated that apoE levels became progressively concentrated in apoptotic bodies. These data indicate that apoE is up-regulated during neuronal apoptosis and raise the possibility that apoE may play a role in the clearance of apoptotic bodies through apoE-receptor interactions. © 2007 Elsevier Ireland Ltd. All rights reserved.
localization
synthesis
e
apolipoprotein
neuronal
apoptotic
induces
bodies
apoptosis
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/14
oai:ro.uow.edu.au:ihmri-1030
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Inhibition of atherosclerosis by the serine palmitoyl transferase inhibitor myriocin is associated with reduced plasma glycosphingolipid concentration
Glaros, Elias N
Kim, Woojin S
Wu, Benjamin J
Suarna, Cacang
Quinn, Carmel M
Rye, Kerry-Anne
Stocker, Roland
Jessup, Wendy
Garner, Brett
Journal Article
2007-01-01T08:00:00Z
Glaros, E. N., Kim, W. S., Wu, B. J., Suarna, C., Quinn, C. M., Rye, K., Stocker, R., Jessup, W. & Garner, B. (2007). Inhibition of atherosclerosis by the serine palmitoyl transferase inhibitor myriocin is associated with reduced plasma glycosphingolipid concentration. Biochemical Pharmacology, 73 (9), 1340-1346.
10.1016/j.bcp.2006.12.023
Glycosphingolipids (GSL) have been implicated as potential atherogenic lipids. Inhibition of hepatic serine palmitoyl transferase (SPT) reduces plasma sphingomyelin (SM) levels in the absence of changes in cholesterol or triglyceride (TG) concentration and this leads to a reduction of atherosclerosis in apolipoprotein-E gene knockout (apoE-/-) mice. The possibility that the reduced atherosclerosis resulting from SPT inhibition is associated with decreases in plasma GSL concentration has not been examined and was the primary aim of this investigation. We show that intraperitoneal delivery of the SPT inhibitor myriocin for 9 weeks inhibits atherosclerosis in apoE-/- mice fed a high fat diet. Lesion inhibition was most pronounced at the aortic arch and distal sites of the thoracic and abdominal aorta. There was also a trend towards a reduction in lesion area at the aortic root. Myriocin treatment resulted in significant reductions in both plasma SM and GSL concentration of 42% and 25%, as assessed by enzymatic and HPLC methods, respectively. Moreover, SM and GSL concentrations were significantly correlated, indicating that SPT inhibition suppresses the synthesis of both these sphingolipids concomitantly. The inhibition of atherosclerosis induced by myriocin was not associated with changes in plasma cholesterol or TG concentrations or lipoprotein profiles as determined by FPLC. These data indicate that therapeutic reduction of plasma SM and/or GSL concentrations may offer a novel treatment for atherosclerosis. © 2006 Elsevier Inc. All rights reserved.
plasma
glycosphingolipid
atherosclerosis
serine
palmitoyl
transferase
inhibitor
concentration
myriocin
inhibition
associated
reduced
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/15
oai:ro.uow.edu.au:ihmri-1032
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Analysis of apolipoprotein E nuclear localization using green fluorescent protein and biotinylation approaches
Kim, Woojin Scott
Elliott, D A
Kockx, M
Kritharides, L
Rye, Kerry-Anne
Jans, D A
Garner, Brett
Journal Article
2008-01-01T08:00:00Z
Kim, W., Elliott, D., Kockx, M., Kritharides, L., Rye, K., Jans, D. & Garner, B. (2008). Analysis of apolipoprotein E nuclear localization using green fluorescent protein and biotinylation approaches. Biochemical Journal, 409 (3), 701-709.
10.1042/BJ20071261
Previous results indicate that apoE (apolipoprotein E) may be associated with the nucleus in specific cell types, particularly under stress conditions such as serum starvation. In addition, nuclear apoE localization in ovarian cancer was recently shown to be correlated with patient survival. In order to better understand the factors associated with apoE nuclear localization, we examined intracellular apoE trafficking using live-cell imaging of CHO (Chinese-hamster ovary) cells that constitutively expressed apoE-GFP (green fluorescent protein). In addition, we used biotinylated apoE (in a lipid-free state and as a lipidated discoidal complex) to track the uptake and potential nuclear targeting of exogenous apoE. Our results indicate that a small proportion of apoE-GFP is detected in the nucleus of living apoE-GFP-expressing CHO cells and that the level of apoE-GFP in the nucleus is increased with serum starvation. Exposure of control CHO cells to exogenous apoE-GFP did not result in nuclear apoE-GFP localization in the recipient cells. Similarly, biotinylated apoE did not reach the nucleus of control CHO cells or SK-N-SH neurons. In contrast, when biotinylated apoE was delivered to recipient cells as a lipidated apoE disc, apoE was detected in the nucleus, suggesting that the lipoprotein complex alters the intracellular degradation or trafficking of apoE. Biotinylated apoE discs containing each of the three common human apoE isoforms (E2, E3 and E4) were also tested for nuclear trafficking. All three apoE isoforms were equally detected in the nucleus. These studies provide new evidence that apoE may be targeted to the nucleus and shed light on factors that regulate this process. © The Authors Journal compilation.
apolipoprotein
e
nuclear
localization
green
analysis
fluorescent
approaches
protein
biotinylation
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/17
oai:ro.uow.edu.au:ihmri-1033
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Myriocin slows the progression of established atherosclerotic lesions in apolipoprotein E gene knockout mice
Glaros, Elias N
Kim, Woojin Scott
Quinn, C M
Jessup, W
Rye, Kerry-Anne
Garner, Brett
Journal Article
2008-01-01T08:00:00Z
Glaros, E. N., Kim, W., Quinn, C., Jessup, W., Rye, K. & Garner, B. (2008). Myriocin slows the progression of established atherosclerotic lesions in apolipoprotein E gene knockout mice. Journal of Lipid Research, 49 (2), 324-331.
10.1194/jlr.M700261-JLR200
The serine palmitoyl transferase inhibitor myriocin potently suppresses the development of atherosclerosis in apolipoprotein E (apoE) gene knockout (apoE-/-) mice fed a high-fat diet. This is associated with reduced plasma sphingomyelin (SM) and glycosphingolipid levels. Furthermore, oral administration of myriocin decreases plasma cholesterol and triglyceride (TG) levels. Here, we aimed to determine whether myriocin could inhibit the progression (or stimulate the regression) of established atherosclerotic lesions and to examine potential changes in hepatic and plasma lipid concentrations. Adult apoE-/- mice were fed a high-fat diet for 30 days, and lesion formation was histologically confirmed. Replicate groups of mice were then transferred to either regular chow or chow containing myriocin (0.3 mg/kg/day) and maintained for a further 60 days. Myriocin significantly inhibited the progression of established atherosclerosis when combined lesion areas (aortic sinus, arch, and celiac branch point) were measured. Although the inhibition of lesion progression was observed mainly in the distal regions of the aorta, regression of lesion size was not detected. The inhibition of lesion progression was associated with reductions in hepatic and plasma SM, cholesterol, and TG levels and increased hepatic and plasma apoA-I levels, indicating that the modulation of pathways associated with several classes of atherogenic lipids may be involved. Copyright ©2008 by the American Society for Biochemistry and Molecular Biology, Inc.
lesions
atherosclerotic
gene
e
progression
apolipoprotein
slows
knockout
myriocin
established
mice
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/18
oai:ro.uow.edu.au:ihmri-1036
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Quantitation of ATP-binding cassette subfamily-A transporter gene expression in primary human brain cells
Kim, Woojin Scott
Guillemin, Gilles
Glaros, Elias N
Lim, C K
Garner, Brett
Journal Article
2006-01-01T08:00:00Z
Kim, W., Guillemin, G., Glaros, E. N., Lim, C. K. & Garner, B. (2006). Quantitation of ATP-binding cassette subfamily-A transporter gene expression in primary human brain cells. NeuroReport, 17 (9), 891-896.
10.1097/01.wnr.0000221833.41340.cd
Five ATP-binding cassette (ABC) subfamily-A transporters (ABCA1, ABCA2, ABCA3, ABCA7 and ABCA8) are expressed in the brain. These transporters may regulate brain lipid transport; however, their relative expression level in isolated human brain cells is unknown. We developed real-time polymerase chain reaction assays to quantify the expression of these genes in human neurons, astrocytes, oligodendrocytes, microglia and cell lines. Neurons expressed predominantly ABCA1 and ABCA3; astrocytes ABCA1, ABCA2 and ABCA3; microglia ABCA1 and oligodendrocytes ABCA2 and ABCA3. Although ABCA7 and ABCA8 expression was relatively low in all cells, the highest expression occurred in microglia and neurons, respectively. ABCA gene expression in the NTERA-2 and MO3.13 cell lines closely resembled the ABCA expression pattern of primary neurons and oligodendrocytes, respectively. © 2006 Lippincott Williams & Wilkins.
cassette
quantitation
subfamily
transporter
gene
expression
primary
human
brain
cells
binding
atp
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/21
oai:ro.uow.edu.au:ihmri-1037
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Investigation of the lipid component of neuromelanin
Fedorow, H
Pickford, R
Kettle, E
Cartwright, M
Halliday, G
Gerlach, M
Riederer, P
Garner, Brett
Journal Article
2006-01-01T08:00:00Z
Fedorow, H., Pickford, R., Kettle, E., Cartwright, M., Halliday, G., Gerlach, M., Riederer, P. & Garner, B. (2006). Investigation of the lipid component of neuromelanin. Journal of Neural Transmission, 113 (6), 735-739.
10.1007/s00702-006-0451-4
Objective: Neuromelanin (NM) is different to other melanins in that its ultrastructure includes a lipid component. The objectives of this study were to identify and quantify lipids associated with NM. Results: Quantification of the lipid component associated with the pigment on electron micrographs demonstrated that this component comprises 35% of the NM granule volume in the normal brain. The irregular ultrastructural appearance of the NM granules was quite different to the round regular boundary of melanin granules. Using reversed phase high performance liquid chromatography (HPLC) coupled with atmospheric pressure chemical ionization (APCI) mass spectrometry we demonstrated that the isoprenoid dolichol accounted for approximately 12% of total NM pigment mass. Low levels of other lipids were detectable (cholesterol, ubiquinone-10 and α-tocopherol) and account for <0.05% of NM lipid, in contrast to cholesterol accounting for 35% of total brain lipids. Conclusion: Unlike other melanins, a substantial proportion of NM volume is comprised of lipid and the major type of lipid associated with NM granules is the isoprenoid dolichol. © Springer-Verlag 2006.
lipid
component
investigation
neuromelanin
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/22
oai:ro.uow.edu.au:ihmri-1039
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Reduction of plasma glycosphingolipid levels has no impact on atherosclerosis in apolipoprotein E-null mice
Glaros, Elias N
Kim, Woojin Scott
Rye, Kerry-Anne
Shayman, J A
Garner, Brett
Journal Article
2008-01-01T08:00:00Z
Glaros, E. N., Kim, W., Rye, K., Shayman, J. & Garner, B. (2008). Reduction of plasma glycosphingolipid levels has no impact on atherosclerosis in apolipoprotein E-null mice. Journal of Lipid Research, 49 (8), 1677-1681.
10.1194/jlr.E800005-JLR200
Glycosphingolipids (GSLs) have been implicated as potential atherogenic lipids. Studies in apolipoprotein E-null (apoE-/-) mice indicate that exacerbated tissue GSL accumulation resulting from a-galactosidase deficiency promotes atherosclerosis, whereas the serine palmitoyl transferase inhibitor myriocin (which reduces plasma and tissue levels of several sphingolipids, including sphingomyelin, ceramide, sphingosine-1-phosphate, and GSLs) inhibits atherosclerosis. It is not clear whether GSL synthesis inhibition per se has an impact on atherosclerosis. To address this issue, apoE-/- mice maintained on a high-fat diet were treated with a potent glucosylceramide synthesis inhibitor, D-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol (EtDO-P4), 10 mg/kg/day for 94 days, and lesion development was compared in mice that were treated with vehicle only. EtDO-P4 reduced plasma GSL concentration by approximately 50% but did not affect cholesterol or triglyceride levels. Assessment of atherosclerotic lesions at four different sites indicated that EtDO-P4 had no significant impact on lesion area. Thus, despite the previously observed positive correlations between plasma and aortic GSL concentrations and the development of atherosclerosis, and the in vitro evidence implying that GSLs may be pro-atherogenic, our current data indicate that inhibition of GSL synthesis does not inhibit atherosclerosis in vivo. Copyright © 2008 by the American Society for Biochemistry and Molecular Biology, Inc.
plasma
glycosphingolipid
levels
has
no
reduction
impact
mice
atherosclerosis
apolipoprotein
e
null
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/24
oai:ro.uow.edu.au:ihmri-1040
2013-08-09T00:03:59Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro
Chan, Sharon L.
Kim, Woojin Scott
Kwok, John B.
Hill, Andrew F.
Cappai, Roberto
Rye, Kerry-Anne
Garner, Brett
Journal Article
2008-01-01T08:00:00Z
<p>Chan, S., Kim, W., Kwok, J., Hill, A., Cappai, R., Rye, K. & Garner, B. (2008). ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro. Journal of Neurochemistry, 106 (2), 793-804.</p>
10.1111/j.1471-4159.2008.05433.x
<p>ATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and, like its closest homolog ABCA1, belongs to the ABCA subfamily of full-length ABC transporters. ABCA1 promotes cellular cholesterol efflux to lipid-free apolipoprotein acceptors and also inhibits the production of neurotoxic p-amyloid (Ap) peptides in vitro. The potential functions of ABCA7 in the brain are unknown. This study investigated the ability of ABCA7 to regulate cholesterol efflux to extracellular apolipoprotein acceptors and to modulate Aβ production. The transient expression of ABCA7 in human embryonic kidney cells significantly stimulated cholesterol efflux (fourfold) to apolipoprotein E (apoE) discoidal lipid complexes but not to lipid-free apoE orapoA-I. ABCA7 also significantly inhibited Aβ secretion from Chinese hamster ovary cells stably expressing human amyloid precursor protein (APP) or APP containing the Swedish K670M671 → N670L671 mutations when compared with mock-transfected cells. Studies with fluorogenic substrates indicated that ABCA7 had no impact on α-, β-, or γ- secretase activities. Live cell imaging of Chinese hamster ovary cells expressing APP-GFP indicated an apparent retention of APP in a perinuclear location in ABCA7 co-transfected cells. These studies indicate that ABCA7 has the capacity to stimulate cellular cholesterol efflux to apoE discs and regulate APP processing resulting in an inhibition of Ap production. © 2008 International Society for Neurochemistry.</p>
binding
vitro
atp
protein
precursor
amyloid
processing
regulates
a7
transporter
cassette
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/25
oai:ro.uow.edu.au:ihmri-1041
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
The comparative biology of neuromelanin and lipofuscin in the human brain
Double, K L
Dedov, V N
Fedorow, H
Kettle, E
Halliday, G
Garner, Brett
Brunk, U T
Journal Article
2008-01-01T08:00:00Z
Double, K., Dedov, V., Fedorow, H., Kettle, E., Halliday, G., Garner, B. & Brunk, U. (2008). The comparative biology of neuromelanin and lipofuscin in the human brain. Cellular and Molecular Life Sciences, 65 (11), 1669-1682.
10.1007/s00018-008-7581-9
Neuromelanin and lipofuscin are two pigments produced within the human brain that, until recently, were considered inert cellular waste products of little interest to neuroscience. Recent research has increased our understanding of the nature and interactions of these pigments with their cellular environment and suggests that these pigments may, indeed, influence cellular function. The physical appearance and distribution of the pigments within the human brain differ, but both accumulate in the aging brain and the pigments share some structural features. Lipofuscin accumulation has been implicated in postmitotic cell aging, while neuromelanin is suggested to function as an iron-regulatory molecule with possible protective functions within the cells which produce this pigment. This review presents comparative aspects of the biology of neuromelanin and lipofuscin, as well as a discussion of their hypothesized functions in brain and their possible roles in aging and neurodegenerative disease. © 2008 Birkhaueser.
brain
comparative
biology
neuromelanin
lipofuscin
human
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/26
oai:ro.uow.edu.au:ihmri-1044
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Macrophage apolipoprotein-E knockdown modulates caspase-3 activation without altering sensitivity to apoptosis
Elliott, D A
Kim, Woojin Scott
Jans, D A
Garner, Brett
Journal Article
2008-01-01T08:00:00Z
Elliott, D., Kim, W., Jans, D. & Garner, B. (2008). Macrophage apolipoprotein-E knockdown modulates caspase-3 activation without altering sensitivity to apoptosis. Biochimica et Biophysica Acta - General Subjects, 1780 (2), 145-153.
10.1016/j.bbagen.2007.10.021
Apolipoprotein-E (apoE) expression may be associated with apoptosis resistance. Since macrophages constitutively synthesize apoE we speculated that this may contribute to apoptosis resistance. Using siRNA, human monocyte derived macrophage (hMDM) apoE mRNA and protein was reduced by 97% and 61%, respectively. ApoE knockdown increased staurosporine-induced caspase-3 activation by 78% without altering cell survival or apoptosis as assessed by TUNEL analysis and morphological changes. This result was confirmed using murine bone marrow derived macrophages (mBMDM) from apoE null and wild type mice. In these experiments, staurosporine-induced caspase-3 activation was increased by 49% in apoE null compared to wild type mBMDM and this was not associated with differences in TUNEL signal, annexin-V binding or DNA fragmentation. ApoE is also important for cholesterol transport and macrophage cholesterol can regulate apoptosis. Knockdown of hMDM apoE inhibited basal cholesterol efflux by 20% without altering apolipoprotein-AI mediated cholesterol efflux over 24 h. Similarly, in apoE null mBMDM a non significant trend for a 16% reduction in basal cholesterol efflux was observed as compared to wild type mBMDM. In conclusion, apoE expression modulates capase-3 activity, but this has no significant impact on sensitivity to apoptosis and only a moderate impact on basal cholesterol efflux. © 2007 Elsevier B.V. All rights reserved.
sensitivity
altering
without
activation
3
caspase
modulates
apoptosis
knockdown
macrophage
e
apolipoprotein
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/29
oai:ro.uow.edu.au:ihmri-1046
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Human fecal water inhibits COX-2 in colonic HT-29 cells: Role of phenolic compounds
Karlsson, P C
Huss, U
Jenner, Andrew M
Halliwell, Barry
Bohlin, L
Rafter, J J
Journal Article
2005-01-01T08:00:00Z
Karlsson, P., Huss, U., Jenner, A. M., Halliwell, B., Bohlin, L. & Rafter, J. (2005). Human fecal water inhibits COX-2 in colonic HT-29 cells: Role of phenolic compounds. Journal of Nutrition, 135 (10), 2343-2349.
The inducible enzyme cyclooxygenase-2 (COX-2) plays a major role in the regulation of inflammation and possibly in the development of colon cancer. The aim of the present study was to screen for COX-2 inhibitors in samples of fecal water (the aqueous phase of feces) and investigate whether phenolic compounds are responsible for any observed effects on COX-2. Volunteers (n = 20) were recruited and asked to supply a 24-h stool sample. Fecal water samples were prepared and analyzed by GC-MS for their content of phenolic compounds. These samples were also evaluated for their effects on COX-2 protein levels (Western blot) and prostaglandin (PG)E2 production in tumor necrosis-α-stimulated HT-29 cells and pure enzymatic activity in a COX-2-catalyzed prostaglandin biosynthesis in vitro assay. The major phenolic compounds identified were phenylpropionic acid, phenylacetic acid, cinnamic acid, and benzoic acid derivatives. Of 13 fecal water samples analyzed, 12 significantly decreased PGE2 production (range 5.4-39.7% inhibition, P-value < 0.05) compared with control cells and 13 of 14 samples analyzed decreased COX-2 protein levels in HT-29 cells (19-63% inhibition). Of the 20 fecal water samples, 2 also weakly inhibited enzymatic activity of purified COX-2 (22-24% inhibition). Three compounds identified in fecal water, 3-phenylpropionic acid, 3-hydroxyphenylacetic acid, and 3-(4-hydroxyphenyl)- propionic acid, decreased the protein level at 250 μmol/L (15-62% inhibition). This study shows for the first time that human fecal water contains components that can affect both the COX-2 protein level and enzymatic activity. © 2005 American Society for Nutrition.
fecal
water
inhibits
cox
2
colonic
ht
phenolic
human
29
compounds
cells
role
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/31
oai:ro.uow.edu.au:ihmri-1059
2012-09-06T23:46:28Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Roles of glial p75NTR in axonal regeneration
Zhou, Xin-Fu
Li, Hong-Yun
Journal Article
2007-01-01T08:00:00Z
<p>Zhou, X. & Li, H. (2007). Roles of glial p75NTR in axonal regeneration. Journal of Neuroscience Research, 85 (8), 1601-1605.</p>
10.1002/jnr.21220
<p>The neurotrophin receptor p75 (p75NTR) is expressed by both neurons and glia. Nerve injury triggers up-regulation of p75NTR in Schwann cells (SC) but not in central glia. In contrast to neuronal p75NTR, which mediates negative signals from myelin-associated proteins resulting in neurite collapse, glial p75NTR may play a positive role in nerve regeneration by forming neurotrophin chemoattractant gradients or by competitively antagonizing the NOGO/NgR/LINGO-1 signal through cell-cell contact or regulated intramembranous proteolysis (RIP) of p75NTR. This piece presents some recent evidence supporting this hypothesis. © 2007 Wiley-Liss, Inc.</p>
regeneration
glial
roles
p75ntr
axonal
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/44
oai:ro.uow.edu.au:ihmri-1042
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Myriocin as an atherosclerosis inhibitor
Garner, Brett
Journal Article
2008-01-01T08:00:00Z
Garner, B. (2008). Myriocin as an atherosclerosis inhibitor. Future Lipidology, 3 (3), 221-224.
10.2217/17460875.3.3.221
atherosclerosis
myriocin
inhibitor
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/27
oai:ro.uow.edu.au:ihmri-1045
2012-09-06T23:57:07Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Human fecal water content of phenolics: The extent of colonic exposure to aromatic compounds
Jenner, Andrew M
Rafter, J J
Halliwell, Barry
Journal Article
2005-01-01T08:00:00Z
<p>Jenner, A. M., Rafter, J. & Halliwell, B. (2005). Human fecal water content of phenolics: The extent of colonic exposure to aromatic compounds. Free Radical Biology and Medicine, 38 (6), 763-772.</p>
10.1016/j.freeradbiomed.2004.11.020
<p>Phenolic compounds are not completely absorbed in the small intestine and so enter the colon, where they might exert physiological effects. To identify phenolics that are present in normal human colon, fecal water was prepared from 5 free-living volunteers with no dietary restrictions and analyzed by gas chromatography-mass spectrometry. Daily measurements were also performed on a single individual to examine the variation more closely. Levels of polyphenols were variable between individuals. Naringenin and quercetin had mean concentrations of 1.20 and 0.63 μM. All other flavonoids examined were present ≤0.17 μM. Simple phenolic and other aromatic acids were present at much higher concentrations. The major components were phenylacetic acid, 479 μM; 3-phenylpropionic acid, 166 μM; 3-(4-hydroxy)-phenylpropionic acid, 68 μM; 3,4-dihydroxycinnamic acid, 52 μM; benzoic acid, 51 μM; 3-hydroxyphenylacetic acid, 46 μM; and 4-hydroxyphenylacetic acid, 19 μM. Other phenolic acids ranged from 0.04 to 7 μM. Decreased dietary phenolic intake caused a decrease in polyphenol and monophenolic acid concentration in fecal water 24 h later. This study is the first to measure the range of aromatic compounds in human fecal water and demonstrates that phenolic acid concentrations are high. The biological effects of phenolics may play an important role in colon function. © 2004 Elsevier Inc. All rights reserved.</p>
fecal
water
content
aromatic
human
phenolics
compounds
extent
colonic
exposure
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/30
oai:ro.uow.edu.au:ihmri-1060
2013-08-09T01:12:58Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Differential effects of pro-BDNF on sensory neurons after sciatic nerve transection in neonatal rats
Fan, Yong-jun
Wu, Linda Lin-yan
Li, Hongyun
Wang, Yan-Jiang
Zhou, Xin-Fu
Journal Article
2008-01-01T08:00:00Z
<p>Fan, Y., Wu, L., Li, H., Wang, Y. & Zhou, X. (2008). Differential effects of pro-BDNF on sensory neurons after sciatic nerve transection in neonatal rats. European Journal of Neuroscience, 27 (9), 2380-2390.</p>
10.1111/j.1460-9568.2008.06215.x
<p>Brain-derived neurotrophic factor (BDNF) plays a critical role in the development of the central and peripheral nervous systems, and also in neuronal survival after injury. The actions of BDNF are mediated by its high-affinity receptors TrkB and p75NTR. Recent studies have shown that proneurotrophins bind p75NTR and sortilin with high affinity, and trigger apoptosis of neurons in vitro. As proneurotrophins are a dominant form of gene products in developing and adult animals, it is imperative to understand their physiological functions in animals. Here, we showed differential roles of proBDNF in injured and uninjured sensory neurons. proBDNF, p75NTR and sortilin are highly expressed in dorsal root ganglia (DRG) neurons. Recombinant proBDNF induced a dose-dependent death of PC12 cells and the death activity was completely abolished in the presence of antibodies against the prodomain of BDNF. The exogenous proBDNF enhanced the death of axotomized sensory neurons and the neutralizing antibodies to the prodomain or exogenous sortilin-extracellular domain-Fc fusion molecule reduced the death of axotomized sensory neurons. Interestingly, the treatment of neutralizing antibody in vivo increased the number of sensory neurons in the contralateral DRG. We conclude that proBDNF may induce the death of axotomized sensory neurons and suppress neuronal addition in the intact DRG in neonatal rats, and the suppression of endogenous proBDNF may protect neurons after neurotrauma. © The Authors (2008).</p>
sciatic
after
neurons
sensory
transection
neonatal
rats
pro
nerve
bdnf
differential
effects
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/45
oai:ro.uow.edu.au:ihmri-1052
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Changes in cytochrome P450 side chain cleavage expression in the rat hippocampus after kainate injury
Chia, W-J
Jenner, Andrew M
Farooqui, A A
Ong, W-Y
Journal Article
2008-01-01T08:00:00Z
Chia, W., Jenner, A. M., Farooqui, A. & Ong, W. (2008). Changes in cytochrome P450 side chain cleavage expression in the rat hippocampus after kainate injury. Experimental Brain Research, 186 (1), 143-149.
10.1007/s00221-007-1209-4
Our previous study showed an increase in total cholesterol level of the hippocampus after kainate-induced injury, but whether this is further metabolized to neurosteroids is not known. The first step in neurosteroid biosynthesis is the conversion of cholesterol to pregnenolone by the enzyme cytochrome P450 side chain cleavage (P450scc). This study was carried out to elucidate the expression of this enzyme in the kainate-lesioned rat hippocampus. A net decrease in P450scc protein was detected in hippocampal homogenates by Western blots at 2 weeks post-kainate injection (time of peak cholesterol concentration after kainate injury). Immunohistochemistry showed decreased labeling of the enzyme in neurons, but increased expression in a small number of astrocytes. The level of pregnenolone was also analyzed using a newly developed gas chromatography-mass spectrometry (GC-MS) method, optimized for the rat hippocampus. A non-significant tendency to a decrease in pregnenolone level was detected 2 weeks post-lesion. This is in contrast to a large increase in oxysterols in the lesioned hippocampus at this time (He et al. 2006). Together, they indicate that increased cholesterol in the kainate lesioned hippocampus is mostly metabolized to oxysterols, and not neurosteroids. © 2007 Springer-Verlag.
kainate
cytochrome
changes
after
hippocampus
rat
expression
cleavage
chain
side
injury
p450
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/37
oai:ro.uow.edu.au:ihmri-1058
2012-09-06T23:41:03Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Primary sensory neuron addition in the adult rat trigeminal ganglion: evidence for neural crest glio-neuronal precursor maturation
Lagares, Alfonso
Li, Hong-Yun
Zhou, Xin-Fu
Avendano, Carlos
Journal Article
2007-01-01T08:00:00Z
<p>Lagares, A., Li, H., Zhou, X. & Avendano, C. (2007). Primary sensory neuron addition in the adult rat trigeminal ganglion: evidence for neural crest glio-neuronal precursor maturation. Journal of Neuroscience, 27 (30), 7939-7953.</p>
10.1523/JNEUROSCI.1203-07.2007
<p>It is debated whether primary sensory neurons of the dorsal root ganglia increase the number in adult animals and, if so, whether the increase is attributable to postnatal neurogenesis or maturation of dormant, postmitotic precursors. Similar studies are lacking in the trigeminal ganglion (TG). Here we demonstrate by stereological methods that the number of neurons in the TG of adult male rats nearly doubles between the third and eighth months of age. The increase is mainly attributable to the addition of small, B-type neurons, with a smaller contribution of large, A-neurons. We looked for possible proliferative or maturation mechanisms that could explain this dramatic postnatal expansion in neuron number, using bromodeoxyuridine (BrdU) labeling, immunocytochemistry for neural precursor cell antigens, retrograde tracing identification of peripherally projecting neurons, and in vitro isolation of precursor cells from adult TG explant cultures. Cell proliferation identified months after an extended BrdU administration was sparse and essentially corresponded to glial cells. No BrdU-labeled cell took up the peripherally injected tracer, and only a negligible number coexpressed BrdU and the pan-neuronal tracer neuron-specific enolase. In contrast, a population of cells not recognizable as mature neurons in the TG and neighboring nerve expressed neuronal precursor antigens, and neural crest glioneuronal precursor cells were successfully isolated from adult TG explants. Our data suggest that a protracted maturation process persists in the TG that can be responsible for the neuronal addition found in the adult rat. Copyright © 2007 Society for Neuroscience.</p>
neural
crest
glio
addition
neuronal
precursor
neuron
sensory
rat
primary
trigeminal
maturation
ganglion
evidence
adult
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/43
oai:ro.uow.edu.au:ihmri-1049
2012-09-06T23:07:47Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Apolipoprotein D modulates F2-isoprostane and 7-ketocholesterol formation and has a neuroprotective effect on organotypic hippocampal cultures after kainate-induced excitotoxic injury
He, Xin
Jittiwat, Jinatta
Kim, Ji-Hyun
Jenner, Andrew M
Farooqui, Akhlaq A
Patel, Shutish C
Ong, Wei-Yi
Journal Article
2009-01-01T08:00:00Z
<p>He, X., Jittiwat, J., Kim, J., Jenner, A. M., Farooqui, A. A., Patel, S. C. & Ong, W. (2009). Apolipoprotein D modulates F2-isoprostane and 7-ketocholesterol formation and has a neuroprotective effect on organotypic hippocampal cultures after kainate-induced excitotoxic injury. Neuroscience Letters, 455 (3), 183-186.</p>
10.1016/j.neulet.2009.03.038
<p>Apolipoprotein D (apoD), a member of the lipocalin family of transporter proteins binds a number of small lipophilic molecules including arachidonic acid and cholesterol. Recent studies showed a protective function of mammalian apoD as well as its insect and plant homologs against oxidative stress. In this study we investigated the effect of direct addition of exogenous human apoD protein purified from breast cystic fluid to rat hippocampal slice cultures after excitotoxic injury induced by the glutamate analog kainate. ApoD at a concentration of 10 μg/ml partially prevented loss of MAP2 immunostaining and LDH release from injured hippocampal neurons after kainate injury. ApoD also attenuated the increase in oxidative products of arachidonic acid and cholesterol, F2-isoprostanes and 7-ketocholesterol, respectively, after kainate treatment. In view of the molecular structure of apoD which consists of an eight stranded β barrel that forms a binding pocket for a number of small hydrophobic molecules, we propose that apoD promotes its neuroprotective effects by binding to arachidonic acid and cholesterol thus preventing their oxidation to neurotoxic products such as 4-hydroxynonenal (4-HNE) and 7-ketocholesterol. © 2009 Elsevier Ireland Ltd. All rights reserved</p>
excitotoxic
neuroprotective
has
formation
ketocholesterol
7
isoprostane
f2
modulates
apolipoprotein
induced
kainate
after
cultures
hippocampal
organotypic
injury
effect
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/34
oai:ro.uow.edu.au:ihmri-1048
2014-04-09T08:42:27Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
A metabolite profiling approach to identify biomarkers of flavonoid intake in humans
Loke, Wai Mun
Jenner, Andrew M
Proudfoot, Julie M
McKinley, Allen J
Hodgson, Jonathan M
Halliwell, Barry
Croft, Kevin D
Journal Article
2009-01-01T08:00:00Z
<p>Loke, W. Mun., Jenner, A. M., Proudfoot, J. M., McKinley, A. J., Hodgson, J. M., Halliwell, B. & Croft, K. D. (2009). A metabolite profiling approach to identify biomarkers of flavonoid intake in humans. The Journal of Nutrition, 139 (12), 2309-2314.</p>
10.3945/jn.109.113613
<p>Flavonoids are phytochemicals that are widespread in the human diet. Despite limitations in their bioavailability, experimental and epidemiological data suggest health benefits of flavonoid consumption. Valid biomarkers of flavonoid intake may be useful for estimating exposure in a range of settings. However, to date, few useful flavonoid biomarkers have been identified. In this study, we used a metabolite profiling approach to examine the aromatic and phenolic profile of plasma and urine of healthy men after oral consumption of 200 mg of the pure flavonoids, quercetin, (-)-epicatechin, and epigallocatechin gallate, which represent major flavonoid constituents in the diet. Following enzymatic hydrolysis, 71 aromatic compounds were quantified in plasma and urine at 2 and 5 h, respectively, after flavonoid ingestion. Plasma concentrations of different aromatic compounds ranged widely, from 0.01 to 10 mmol/L, with variation among volunteers. None of the aromatic compounds was significantly elevated in plasma 2 h after consumption of either flavonoid compared with water placebo. This indicates that flavonoid-derived aromatic compounds are not responsible for the acute physiological effects reported within 2 h in previous human intervention studies involving flavonoids or flavonoid-rich food consumption. These effects are more likely due to absorption of the intact flavonoid. Our urine analysis suggested that urinary 4-ethylphenol, benzoic acid, and 4-ethylbenzoic acid may be potential biomarkers of quercetin intake and 1,3,5-trimethoxybenzene, 4-O-methylgallic acid, 3-O-methylgallic acid, and gallic acid may be potential markers of epigallocatechin gallate intake. Potential biomarkers of (-)-epicatechin were not identified. These urinary biomarkers may provide an accurate indication of flavonoid exposure. © 2009 American Society for Nutrition.</p>
profiling
humans
metabolite
intake
flavonoid
biomarkers
identify
approach
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/33
oai:ro.uow.edu.au:ihmri-1043
2013-08-09T00:25:30Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Role of ATP-binding cassette transporters in brain lipid transport and neurological disease
Kim, Woojin Scott
Shannon Weickert, Cynthia
Garner, Brett
Journal Article
2008-01-01T08:00:00Z
<p>Kim, W., Shannon Weickert, C. & Garner, B. (2008). Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. Journal of Neurochemistry, 104 (5), 1145-1166.</p>
10.1111/j.1471-4159.2007.05099.x
<p>The brain is lipid-rich compared to other organs and although previous studies have highlighted the importance of ATP-binding cassette (ABC) transporters in the regulation of lipid transport across membranes in peripheral tissues, very little is known regarding ABC transporter function in the CNS. In this study, we bring together recent literature focusing on potential roles for ABC transporters in brain lipid transport and, where appropriate, identify possible links between ABC transporters, lipid transport and neurological disease. Of the 48 transcriptionally active ABC transporters in the human genome, we have focused on 13 transporters (ABCA1, ABCA2, ABCA3, ABCA4, ABCA7 and ABCA8; ABCB1 and ABCB4; ABCD1 and ABCD2; ABCG1, ABCG2, and ABCG4) for which there is evidence suggesting they may contribute in some way to brain lipid transport or homeostasis. The transporters are discussed in terms of their location within brain regions and brain cell types and, where possible, in terms of their known functions and established or proposed association with human neurological diseases. Specific examples of novel treatment strategies for diseases, such as Alzheimer’s disease and X-linked adrenoleukodystrophy that are based on modulation of ABC transporter function are discussed and we also examine possible functions for specific ABC transporters in human brain development.</p>
disease
transporters
neurological
cassette
binding
atp
role
transport
lipid
brain
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/28
oai:ro.uow.edu.au:ihmri-1047
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Allantoin in human plasma, serum, and nasal-lining fluids as a biomarker of oxidative stress: Avoiding artifacts and establishing real in vivo concentrations
Gruber, Jan
Tang, Soon Yew
Jenner, Andrew M
Mudway, Ian
Blomberg, Anders
Behndig, Annelie
Kasiman, Katherine
Lee, Chung-Yung J
Seet, Raymond C S
zhang, wenxia
Chen, Christopher
Kelly, Frank J
Halliwell, Barry
Journal Article
2009-01-01T08:00:00Z
Gruber, J., Tang, S. Yew., Jenner, A. M., Mudway, I., Blomberg, A., Behndig, A., Kasiman, K., Lee, C. J., Seet, R. C S., zhang, w., Chen, C., Kelly, F. J. & Halliwell, B. (2009). Allantoin in human plasma, serum, and nasal-lining fluids as a biomarker of oxidative stress: Avoiding artifacts and establishing real in vivo concentrations. Antioxidants and Redox Signaling, 11 (8), 1767-1776.
10.1089/ars.2008.2364
Urate is the terminal product of purine metabolism in primates, including humans. Urate is also an efficient scavenger of oxidizing species and is thought to be an important antioxidant in human body fluids. Allantoin, the major oxidation product of urate, has been suggested as a candidate biomarker of oxidative stress because it is not produced metabolically. Although urate is converted to allantoin under strongly alkaline pH, such conditions have been used in the past to facilitate extraction of allantoin. We evolved a method for the determination of allantoin concentrations in human plasma and serum by gas chromatography-mass spectrometry without such artifact. With this method, we show that alkaline conditions do indeed cause breakdown of urate, leading to significant overestimation of allantoin concentration in human samples. By using our alternative method, serum samples from 98 volunteers were analyzed, and allantoin levels were found to be significantly lower than was previously reported. The in vivo utility and sensitivity of our method was further evaluated in human nasal-lining fluids. We were able to demonstrate an ozone-induced increase in allantoin, in the absence of increases in either ascorbate or glutathione oxidation products. © Copyright 2009, Mary Ann Liebert, Inc. 2009.
concentrations
human
vivo
allantoin
real
establishing
artifacts
avoiding
stress
oxidative
biomarker
fluids
lining
nasal
serum
plasma
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/32
oai:ro.uow.edu.au:ihmri-1057
2012-09-06T23:32:57Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Isolation and characterization of neural crest progenitors from adult dorsal root ganglia
Li, Hong-yun
Say, Evonne Hwee Min
Zhou, Xin-Fu
Journal Article
2007-01-01T08:00:00Z
<p>Li, H., Say, E. Hwee Min. & Zhou, X. (2007). Isolation and characterization of neural crest progenitors from adult dorsal root ganglia. Stem Cells, 25 (8), 2053-2065.</p>
10.1634/stemcells.2007-0080
<p>After peripheral nerve injury, the number of sensory neurons in the adult dorsal root ganglia (DRG) is initially reduced but recovers to a normal level several months later. The mechanisms underlying the neuronal recovery after injury are not clear. Here, we showed that in the DRG explant culture, a subpopulation of cells that emigrated out from adult rat DRG expressed nestin and p75 neurotrophin receptor and formed clusters and spheres. They differentiated into neurons, glia, and smooth muscle cells in the presence or absence of serum and formed secondary and tertiary neurospheres in cloning assays. Molecular expression analysis demonstrated the characteristics of neural crest progenitors and their potential for neuronal differentiation by expressing a set of well-defined genes related to adult stem cells niches and neuronal fate decision. Under the influence of neurotrophic factors, some of these progenitors gave rise to neuropeptide-expressing cells and protein zero-expressing Schwann cells. In a 5-bromo-2′-deoxyuridine chasing study, we showed that these progenitors likely originate from satellite glial cells. Our study suggests that a subpopulation of glia in adult DRG is likely to be progenitors for neurons and glia and may play a role in neurogenesis after nerve injury. ©AlphaMed Press.</p>
progenitors
dorsal
root
isolation
ganglia
adult
crest
characterization
neural
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/42
oai:ro.uow.edu.au:ihmri-1065
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Endogenous 24(S),25-epoxycholesterol fine-tunes acute control of cellular cholesterol homeostasis
Wong, Jenny
Quinn, C M
Gelissen, I C
Brown, A
Journal Article
2008-01-01T08:00:00Z
Wong, J., Quinn, C., Gelissen, I. & Brown, A. (2008). Endogenous 24(S),25-epoxycholesterol fine-tunes acute control of cellular cholesterol homeostasis. Journal of Biological Chemistry, 283 (2), 700-707.
10.1074/jbc.M706416200
Certain oxysterols, when added to cultured cells, are potent regulators of cholesterol homeostasis, decreasing cholesterol synthesis and uptake and increasing cholesterol efflux. However, very little is known about whether or not endogenous oxysterol( s) plays a significant role in cholesterol homeostasis. 24(S),25-Epoxycholesterol (24,25EC) is unique among oxysterols in that it is produced in a shunt of the mevalonate pathway which also produces cholesterol. We investigated the role of endogenously produced 24,25EC using a novel strategy of overexpressing the enzyme 2,3-oxidosqualene cyclase in Chinese hamster ovary cells to selectively inhibit the synthesis of this oxysterol. First, loss of 24,25EC decreased expression of the LXR target gene, ABCA1, substantiating its role as an endogenous ligand for LXR. Second, loss of 24,25EC increased acute cholesterol synthesis, which was rationalized by a concomitant increase in HMG-CoA reductase gene expression at the level of SREBP-2 processing. Therefore, in the absence of 24,25EC, fine-tuning of the acute regulation of cholesterol homeostasis is lost, supporting the hypothesis that 24,25EC functions to protect the cell against the accumulation of newly synthesized cholesterol. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.
24
25
epoxycholesterol
fine
endogenous
tunes
cholesterol
acute
control
cellular
homeostasis
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/50
oai:ro.uow.edu.au:ihmri-1071
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Glycosphingolipid accumulation inhibits cholesterol efflux via the ABCA1/apolipoprotein A-I pathway: 1-Phenyl-2-decanoylamino-3-morpholino-1- propanol is a novel cholesterol efflux accelerator
Glaros, Elias N
Kim, W B
Quinn, C M
Wong, Jenny
Gelissen, I C
Jessup, W
Garner, Brett
Journal Article
2005-01-01T08:00:00Z
Glaros, E. N., Kim, W. B., Quinn, C., Wong, J., Gelissen, I., Jessup, W. & Garner, B. (2005). Glycosphingolipid accumulation inhibits cholesterol efflux via the ABCA1/apolipoprotein A-I pathway: 1-Phenyl-2-decanoylamino-3-morpholino-1- propanol is a novel cholesterol efflux accelerator. Journal of Biological Chemistry, 280 (26), 24515-24523.
10.1074/jbc.M413862200
Cellular glycosphingolipid (GSL) storage is known to promote cholesterol accumulation. Although physical interactions between GSLs and cholesterol are thought to cause intracellular cholesterol "trapping," it is not known whether cholesterol homeostatic mechanisms are also impaired under these conditions. ApoA-I-mediated cholesterol efflux via ABCA1 (ATP-binding cassette transporter A1) is a key regulator of cellular cholesterol balance. Here, we show that apoA-I-mediated cholesterol efflux was inhibited (by up to 53% over 8 h) when fibroblasts were treated with lactosylceramide or the glucocerebrosidase inhibitor conduritol B epoxide. Furthermore, apoA-I-mediated cholesterol efflux from fibroblasts derived from patients with genetic GSL storage diseases (Fabry disease, Sandhoff disease, and GM1 gangliosidosis) was impaired compared with control cells. Conversely, apoA-I-mediated cholesterol efflux from fibroblasts and cholesterol-loaded macrophage foam cells was dose-dependently stimulated (by up to 6-fold over 8 h) by the GSL synthesis inhibitor 1-phenyl-2-decanoylamino- 3-morpholino-1-propanol (PDMP). Unexpectedly, a structurally unrelated GSL synthesis inhibitor, N-butyldeoxynojirimycin, was unable to stimulate apoA-I-mediated cholesterol efflux despite achieving similar GSL depletion. PDMP was found to up-regulate ABCA1 mRNA and protein expression, thereby identifying a contributing mechanism for the observed acceleration of cholesterol efflux to apoA-I. This study reveals a novel defect in cellular cholesterol homeostasis induced by GSL storage and identifies PDMP as a new agent for enhancing cholesterol efflux via the ABCA1/apoA-I pathway. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.
accumulation
inhibits
cholesterol
efflux
via
abca1
apolipoprotein
i
pathway
1
phenyl
2
glycosphingolipid
decanoylamino
accelerator
3
morpholino
propanol
novel
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/56
oai:ro.uow.edu.au:ihmri-1072
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Expression and regulation of sterol 27-hydroxylase (CYP27A1) in human macrophages: a role for RXR and PPARγ ligands
Quinn, C M
Jessup, W
Wong, Jenny
Kritharides, L
Brown, A
Journal Article
2005-01-01T08:00:00Z
Quinn, C., Jessup, W., Wong, J., Kritharides, L. & Brown, A. (2005). Expression and regulation of sterol 27-hydroxylase (CYP27A1) in human macrophages: a role for RXR and PPARγ ligands. Biochemical Journal, 385 (3), 823-830.
10.1042/BJ20041776
CYP27A1 (sterol 27-hydroxylase) catalyses an important sterol elimination pathway in the human macrophage, and consequently may protect against atherosclerosis. We studied the expression and regulation of CYP27A1 in a human macrophage-like cell-line, THP-1, and primary HMDMs (human monocyte-derived macrophages). In both macrophage cell types, we found that CYP27A1 expression is independent of cellular cholesterol levels and of LXR (liver X receptor)-dependent control of transcription. However, the RXR (retinoid X receptor) ligand, 9-cis-retinoic acid, upregulates CYP27A1 expression. Of the RXR heterodimeric partners tested, PPAR (peroxisome-proliferator-activated receptor) γ ligands significantly increased CYP27A1 mRNA levels. Its reversal by a PPARγ antagonist demonstrated the specificity of this effect. Interestingly, HMDMs express markedly higher levels of CYP27A1 than THP-1 macrophages, and this difference was reflected in both protein levels and enzyme activities between the two cell types. In conclusion, stimulation of CYP27A1 by PPARγ may represent a key previously unrecognized mechanism by which PPARγ protects against atherosclerosis.
pparγ
cyp27a1
hydroxylase
27
sterol
regulation
expression
ligands
rxr
role
macrophages
human
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/57
oai:ro.uow.edu.au:ihmri-1068
2013-08-09T01:08:41Z
publication:journal_articles
publication:grants
publication:smh
publication:ihmri
publication:document_types
Changes in alternative brain-derived neurotrophic factor transcript expression in the developing human prefrontal cortex
Wong, Jenny
Webster, Maree J.
Cassano, Hope
Weickert, Cynthia S.
Journal Article
2009-01-01T08:00:00Z
<p>Wong, J., Webster, M. J., Cassano, H. & Weickert, C. S. (2009). Changes in alternative brain-derived neurotrophic factor transcript expression in the developing human prefrontal cortex. European Journal of Neuroscience, 29 (7), 1311-1322.</p>
10.1111/j.1460-9568.2009.06669.x
<p>In this study, we determined when and through which promoter brain-derived neurotrophic factor (BDNF) transcription is regulated during the protracted period of human frontal cortex development. Using quantitative real-time polymerase chain reaction, we examined the expression of the four most abundant alternative 5′ exons of the BDNF gene (exons I, II, IV, and VI) in RNA extracted from the prefrontal cortex. We found that expression of transcripts I-IX and VI-IX was highest during infancy, whereas that of transcript II-IX was lowest just after birth, slowly increasing to reach a peak in toddlers. Transcript IV-IX was significantly upregulated within the first year of life, and was maintained at this level until school age. Quantification of BDNF protein revealed that levels followed a similar developmental pattern as transcript IV-IX. In situ hybridization of mRNA in cortical sections showed the highest expression in layers V and VI for all four BDNF transcripts, whereas moderate expression was observed in layers II and III. Interestingly, although low expression of BDNF was observed in cortical layer IV, this BDNF mRNA low-zone decreased in prominence with age and showed an increase in neuronal mRNA localization. In summary, our findings show that dynamic regulation of BDNF expression occurs through differential use of alternative promoters during the development of the human prefrontal cortex, particularly in the younger age groups, when the prefrontal cortex is more plastic. © 2009 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.</p>
NHMRC/568884
<a href="http://purl.org/au-research/grants/NHMRC/568884">http://purl.org/au-research/grants/NHMRC/568884</a>
alternative
cortex
brain
prefrontal
derived
changes
neurotrophic
factor
transcript
expression
developing
human
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/53
oai:ro.uow.edu.au:ihmri-1064
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
OSBP-related protein 8 (ORP8) suppresses ABCA1 expression and cholesterol efflux from macrophages
Yan, D
Mayranpaa, M I
Wong, Jenny
Perttila, J
Lehto, M
Jauhiainen, M
Kovanen, P T
Enholm, C
Brown, A
Olkkonen, V M
Journal Article
2008-01-01T08:00:00Z
Yan, D., Mayranpaa, M., Wong, J., Perttila, J., Lehto, M., Jauhiainen, M., Kovanen, P., Enholm, C., Brown, A. & Olkkonen, V. (2008). OSBP-related protein 8 (ORP8) suppresses ABCA1 expression and cholesterol efflux from macrophages. Journal of Biological Chemistry, 283 (1), 332-340.
10.1074/jbc.M705313200
ORP8 is a previously unexplored member of the family of
oxysterol-binding protein-related proteins (ORP). We now
report the expression pattern, the subcellular distribution, and
data on the ligand binding properties and the physiological
function of ORP8. ORP8 is localized in the endoplasmic reticulum
(ER) via its C-terminal transmembrane span and binds
25-hydroxycholesterol, identifying it as a new ER oxysterolbinding
protein. ORP8 is expressed at highest levels in macrophages,
liver, spleen, kidney, and brain. Immunohistochemical
analysis revealed ORP8 in the shoulder regions of human coronary
atherosclerotic lesions, where it is present in CD68()
macrophages. In advanced lesions the ORP8mRNAwas up-regulated
2.7-fold as compared with healthy coronary artery wall.
Silencing of ORP8 by RNA interference in THP-1 macrophages
increased the expression of ATP binding cassette transporter
A1 (ABCA1) and concomitantly cholesterol efflux to lipidfree
apolipoprotein A-I but had no significant effect on
ABCG1 expression or cholesterol efflux to spherical high
density lipoprotein HDL2. Experiments employing an ABCA1
promoter-luciferase reporter confirmed that ORP8 silencing
enhances ABCA1 transcription. The silencing effect was partially
attenuated by mutation of the DR4 element in the
ABCA1 promoter and synergized with that of the liver X
receptor agonist T0901317. Furthermore, inactivation of the
E-box in the promoter synergized with ORP8 silencing, suggesting
that the suppressive effect of ORP8 involves both the
liver X receptor and the E-box functions. Our data identify
ORP8 as a negative regulator of ABCA1 expression and macrophage
cholesterol efflux. ORP8 may, thus, modulate the
development of atherosclerosis
efflux
expression
abca1
suppresses
orp8
8
protein
related
osbp
macrophages
cholesterol
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/49
oai:ro.uow.edu.au:ihmri-1067
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia
Shannon Weickert, Cynthia
Miranda-Angulo, A L
Wong, Jenny
Perlman, W R
Ward, S E
Radhakrishna, V
Straub, R E
Weinberger, D R
Kleinman, J E
Journal Article
2008-01-01T08:00:00Z
Shannon Weickert, C., Miranda-Angulo, A., Wong, J., Perlman, W., Ward, S., Radhakrishna, V., Straub, R., Weinberger, D. & Kleinman, J. (2008). Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia. Human Molecular Genetics, 17 (15), 2293-2309.
10.1093/hmg/ddn130
Estrogen modifies human emotion and cognition and impacts symptoms of schizophrenia. We hypothesized that the variation in the estrogen receptor alpha (ESR1) gene and cortical ESR1 mRNA is associated with schizophrenia. In a small case-control genetic association analysis of postmortem brain tissue, genotype CC (rs2234693) and haplotypes containing the C allele of a single-nucleotide polymorphism (SNP) in intron1 (PvuII) were more frequent in African American schizophrenics (P = 0.01-0.001). In a follow-up family-based association analysis, we found overtransmission of PvuII allele C and a PvuII C-containing haplotype (P = 0.01-0.03) to African American and Caucasian patients with schizophrenia. Schizophrenics with the 'at risk' PvuII genotype had lower ESR1 mRNA levels in the frontal cortex. Eighteen ESR1 splice variants and decreased frequencies of the wild-type ESR1 mRNA were detected in schizophrenia. In one patient, a unique ESR1 transcript with a genomic insert encoding a premature stop codon and a truncated ESR1 protein lacking most of the estrogen binding domain was the only transcript detected. Using a luciferase assay, we found that mRNA encoding a truncated ESR1 significantly attenuates gene expression at estrogen-response elements demonstrating a dominant negative function. An intron 6 SNP [rs2273207(G)] was associated with an ESR1 splice variant missing exon seven. The T allele of another intron 6 SNP was part of a 3′ haplotype less common in schizophrenia [rs2273206(T), rs2273207(G), rs2228480(G)]. Thus, the variation in the ESR1 gene is associated with schizophrenia and the mechanism of this association may involve alternative gene regulation and transcript processing. © The Author 2008. Published by Oxford University Press. All rights reserved.
variants
risk
alpha
receptor
gene
schizophrenia
estrogen
its
mrna
contribute
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/52
oai:ro.uow.edu.au:ihmri-1066
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Involvement of Akt in ER-to-Golgi transport of SCAP/SREBP: A link between a key cell proliferative pathway and membrane synthesis
Du, X
Kristiana, Ika
Wong, Jenny
Brown, A
Journal Article
2006-01-01T08:00:00Z
Du, X., Kristiana, I., Wong, J. & Brown, A. (2006). Involvement of Akt in ER-to-Golgi transport of SCAP/SREBP: A link between a key cell proliferative pathway and membrane synthesis. Molecular Biology of the Cell, 17 (6), 2735-2745.
10.1091/mbc.E05-11-1094
Akt is a critical regulator of cell growth, proliferation, and survival that is activated by phosphatidylinositol 3-kinase (PI3K). We investigated the effect of PI3K inhibition on activation of sterol regulatory element binding protein-2 (SREBP-2), a master regulator of cholesterol homeostasis. SREBP-2 processing increased in response to various cholesterol depletion approaches (including statin treatment) and this increase was blunted by treatment with a potent and specific inhibitor of PI3K, LY294002, or when a plasmid encoding a dominant-negative form of Akt (DN-Akt) was expressed. LY294002 also suppressed SREBP-2 processing induced by insulin-like growth factor-1. Furthermore, LY294002 treatment down-regulated SREBP-2 or -1c gene targets and decreased cholesterol and fatty acid synthesis. Fluorescence microscopy studies indicated that LY294002 disrupts transport of the SREBP escort protein, SCAP, from the endoplasmic reticulum to the Golgi. This disruption was also shown by immunofluorescence staining when DN-Akt was expressed. Taken together, our studies indicate that the PI3K/Akt pathway is involved in SREBP-2 transport to the Golgi, contributing to the control of SREBP-2 activation. Our results provide a crucial mechanistic link between the SREBP and PI3K/Akt pathways that may be reconciled teleologically because synthesis of new membrane is an absolute requirement for cell growth and proliferation. © 2006 by The American Society for Cell Biology.
involvement
pathway
proliferative
cell
key
between
link
srebp
scap
transport
golgi
er
synthesis
akt
membrane
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/51
oai:ro.uow.edu.au:ihmri-1050
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Elevation of oxidative-damage biomarkers during aging in F2 hybrid mice: Protection by chronic oral intake of resveratrol
Wong, Yee Ting
Gruber, Jan
Jenner, Andrew M
Ng, Mary Pei-Ern
Ruan, Runsheng
Tay, Francis Eng Hock
Journal Article
2009-01-01T08:00:00Z
Wong, Y. Ting., Gruber, J., Jenner, A. M., Ng, M. Pei-Ern., Ruan, R. & Tay, F. Eng Hock. (2009). Elevation of oxidative-damage biomarkers during aging in F2 hybrid mice: Protection by chronic oral intake of resveratrol. Free Radical Biology and Medicine, 46 (6), 799-809.
10.1016/j.freeradbiomed.2008.12.016
Resveratrol (RSV), a naturally occurring phytoalexin that can be found in red wine, berries, and peanuts, has been shown to extend both mean and maximum life span in model organisms. RSV has also been reported to shift the physiology of middle-aged mice on a high-calorie diet toward that of mice on a standard diet. These beneficial effects of RSV have been suggested to resemble caloric restriction. Our study in F2 four-way cross-hybrid mice was the first to evaluate the effects of aging and long-term RSV treatment (14.09 ± 3.4 mg/L in drinking water for 6 or 12 months) on biomarkers of oxidative damage to DNA, 8-hydroxy-2′-deoxyguanosine (8OHdG); lipid, 8-iso-prostaglandin2α (8-iso-PGF2α); and protein, protein carbonyl content (PCC). There was a significant age-dependent accumulation of oxidative damage to DNA, lipid, and protein as well as a clear increase in urine 8-iso-PGF2α levels in the majority of mouse tissues. Rates of age-dependent increases in damage biomarkers varied between tissues. Chronic RSV treatment elevated total RSV plasma levels and reduced the observed age-dependent accumulation of (1) 8OHdG in liver and heart, (2) 8-iso-PGF2α in heart and urine, and (3) PCC in liver and kidney. However, a 12-month RSV intake resulted in significant elevation of 8-iso-PGF2α and PCC in kidney. Our studies demonstrate that RSV treatment consistently attenuated oxidative damage in tissues where age-related oxidative damage accumulation was prominent, but also suggested that chronic RSV treatment may induce nephrotoxicity. © 2008
damage
oxidative
elevation
oral
chronic
protection
mice
hybrid
f2
aging
during
resveratrol
biomarkers
intake
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/35
oai:ro.uow.edu.au:ihmri-1051
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Elevated oxidative stress, iron accumulation around microvessels and increased 4-hyroxynonenal immunostaining in zone 1 of the liver acinus in hypercholesterolemic rabbits
Ong, Wei-Yi
Jenner, Andrew M
Pan, Ning
Ong, Choon-Nam
Halliwell, Barry
Journal Article
2009-01-01T08:00:00Z
Ong, W., Jenner, A. M., Pan, N., Ong, C. & Halliwell, B. (2009). Elevated oxidative stress, iron accumulation around microvessels and increased 4-hyroxynonenal immunostaining in zone 1 of the liver acinus in hypercholesterolemic rabbits. Free Radical Research, 43 (3), 241-249.
10.1080/10715760802691455
Rabbits were fed a diet containing 1% cholesterol for 8 weeks and the levels of iron and oxidized lipids in liver analysed using atomic absorption spectroscopy and gas chromatography-mass spectrometry. A non-significant trend to an increase in iron level, but significant increases in the lipid peroxidation products, F2-isoprostanes and the cholesterol oxidation products 7 beta hydroxycholesterol, 7 ketocholesterol and cholesterol 5,6-alpha epoxide were detected in the liver of the cholesterol-fed rabbits. Histological analysis showed greater accumulation of lipids by Sudan red labelling in hepatocytes of zone I than zones II and III of the liver acinus. The increase in lipids coincided with an increase in iron staining in macrophages around liver microvessels and increased immunostaining to melanotransferrin and the lipid peroxidation product, 4-hydroxynonenal (4-HNE), in zone 1. The results are suggestive of microvascular damage associated with iron accumulation and oxidative stress in the liver during hypercholesterolemia.
immunostaining
microvessels
around
accumulation
iron
stress
oxidative
elevated
acinus
liver
1
zone
hyroxynonenal
4
rabbits
increased
hypercholesterolemic
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/36
oai:ro.uow.edu.au:ihmri-1053
2012-09-06T23:35:40Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Measurement of F2-isoprostanes, hydroxyeicosatetraenoic products, and oxysterols from a single plasma sample
Lee, C-Y J
Huang, Shizhen
Jenner, Andrew M
Halliwell, Barry
Journal Article
2008-01-01T08:00:00Z
<p>Lee, C., Huang, S., Jenner, A. M. & Halliwell, B. (2008). Measurement of F2-isoprostanes, hydroxyeicosatetraenoic products, and oxysterols from a single plasma sample. Free Radical Biology and Medicine, 44 (7), 1314-1322.</p>
10.1016/j.freeradbiomed.2007.12.026
<p>Oxidized lipids such as F2-isoprostanes (F2-IsoPs), hydroxyeicosatetraenoic acid products (HETEs), and cholesterol oxidation products (COPs) are widely believed to be involved in multiple diseases. Usually, each product is measured individually in separate blood samples. In this study we describe a method allowing us to measure F2-IsoPs, HETEs, COPs, and arachidonate using a single sample. Plasma (1 ml) samples from healthy volunteers were diluted with heavy isotopic standards, hydrolyzed in alkali with organic solvent, and then subjected to anionic-exchange solid-phase extraction (SPE). After the SPE column was washed, hexane and hexane/ethyl acetate portions were collected and combined for COPs measurement. Thereafter the column was loaded with hexane/ethanol/acetic acid and fractions were collected for total F2-IsoPs, total HETEs, and arachidonate measurement. All compounds in the eluates were measured by gas chromatography-mass spectrometry. The efficiency of SPE and reproducibility for all compounds measured were high. Levels of total F2-IsoPs (0.45 ± 0.26 ng/ml (n = 157)), total HETEs (34.06 ± 16.35 ng/ml (n = 21)), total arachidonate (68.36 ± 24.45 μg/ml (n = 33)), and COPs (7-ketocholesterol, 12.25 ± 6.56 ng / ml; 7β-hydroxycholesterol, 6.32 ± 3.46 ng / ml; 7α-hydroxycholesterol, 15.06 ± 7.06 ng/ml; 24-hydroxycholesterol, 41.39 ± 18.22 ng/ml; and 27-hydroxycholesterol, 29.08 ± 16.79 ng/ml (n = 26)) were recorded in healthy subjects (age range 20 to 66 years; average male to female ratio 1:1). © 2007 Elsevier Inc. All rights reserved.</p>
f2
isoprostanes
plasma
measurement
hydroxyeicosatetraenoic
sample
products
oxysterols
single
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/38
oai:ro.uow.edu.au:ihmri-1054
2012-09-06T23:55:03Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Zinc supplementation inhibits lipid peroxidation and the development of atherosclerosis in rabbits fed a high cholesterol diet
Jenner, Andrew M
Ren, M
Rajendran, Reshmi
Ning, Pan
Huat, B
Watt, Frank
Halliwell, Barry
Journal Article
2007-01-01T08:00:00Z
<p>Jenner, A. M., Ren, M., Rajendran, R., Ning, P., Huat, B., Watt, F. & Halliwell, B. (2007). Zinc supplementation inhibits lipid peroxidation and the development of atherosclerosis in rabbits fed a high cholesterol diet. Free Radical Biology and Medicine, 42 (4), 559-566.</p>
10.1016/j.freeradbiomed.2006.11.024
<p>Developing atherosclerotic lesions in hypercholesterolemic rabbits are depleted in zinc, while iron accumulates. This study examined the influence of zinc supplementation on the development of atherosclerosis and used isotope dilution gas chromatography-mass spectrometry techniques to measure biomarkers of oxidative lipid damage in atherosclerotic rabbit aorta. Our previous method for F2-isoprostane measurement was adapted to include the quantitation of cholesterol oxidation products in the same sample. Two groups of New Zealand white rabbits were fed a high cholesterol (1% w/w) diet and one group was also supplemented with zinc (1 g/kg) for 8 weeks. Controls were fed a normal diet. Zinc supplementation did not significantly alter the increase in total plasma cholesterol levels observed in animals fed high cholesterol. However, in cholesterol-fed animals zinc supplementation significantly reduced the accumulation of total cholesterol levels in aorta which was accompanied by a significant reduction in average aortic lesion cross-sectional areas of the animals. Elevated levels of cholesterol oxidation products (5,6-α and β cholesterol epoxides, 7β-hydroxycholesterol, 7-ketocholesterol) in aorta and total F2-isoprostanes in plasma and aorta of rabbits fed a cholesterol diet were significantly decreased by zinc supplementation. Our data indicate that zinc has an antiatherogenic effect, possibly due to a reduction in iron-catalyzed free radical reactions. © 2006 Elsevier Inc. All rights reserved.</p>
cholesterol
high
fed
rabbits
supplementation
atherosclerosis
zinc
development
peroxidation
lipid
inhibits
diet
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/39
oai:ro.uow.edu.au:ihmri-1055
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
The identification of antioxidants in dark soy sauce
Wang, Huansong
Jenner, Andrew M
Lee, Chung-Yung J
Shui, Guanghou
Tang, Soon Yew
Whiteman, Matthew
Wenk, Markus R
Halliwell, Barry
Journal Article
2007-01-01T08:00:00Z
Wang, H., Jenner, A. M., Lee, C. J., Shui, G., Tang, S. Yew., Whiteman, M., Wenk, M. R. & Halliwell, B. (2007). The identification of antioxidants in dark soy sauce. Free Radical Research, 41 (4), 479-488.
10.1080/10715760601110871
Soy sauce is a traditional fermented seasoning in Asian countries, that has high antioxidant activity in vitro and some antioxidant activity in vivo. We attempted to identify the major antioxidants present, using the 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay as a guide. 3-Hydroxy-2-methyl-4H-pyran-4-one (maltol) was one of several active compounds found in an ethyl acetate extract of dark soy sauce (DSS) and was present at millimolar concentrations in DSS. However, most of the antioxidant activity was present in colored fractions, two of which (CP1 and CP2) were obtained by gel filtration chromatography. Their structural characteristics based on nuclear magnetic resonance (NMR) and electrospray-ionization time-of-flight mass spectrometry (ESI-TOF-MS) analysis suggest that carbohydrate-containing pigments such as melanoidins are the major contributors to the high antioxidant capacity of DSS.
soy
dark
antioxidants
identification
sauce
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/40
oai:ro.uow.edu.au:ihmri-1056
2012-09-06T23:37:38Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Potential conversion of adult clavicle-derived chondrocytes into neural lineage cells in vitro
Li, Hongyun
Zhou, Xin-Fu
Journal Article
2008-01-01T08:00:00Z
<p>Li, H. & Zhou, X. (2008). Potential conversion of adult clavicle-derived chondrocytes into neural lineage cells in vitro. Journal of Cellular Physiology, 214 (3), 630-644.</p>
10.1002/jcp.21251
<p>Neural stem cells (NSC) can be isolated from a variety of adult tissues and become a valuable cell source for the repair of peripheral and central nervous diseases. However, their origin and identity remain controversial because of possible de-differentiation/transdifferentiation or contaminations by hematopoietic stem cells (HSCs) or mesenchymal stem cells (MSCs). We hypothesize that the commonly used NSC culture medium can induce committed cartilage chondrocytes to de-differentiate and/or trans-differentiate into neural cell lineages. Using a biological isolation and purification method with explants culture, we here show that adult rat clavicle cartilage chondrocytes migrate out from tissue blocks, form sphere-like structures, possess the capability of self-renewal, express nestin and p75NTR, markers for neural crest progenitors, and differentiate into neurons, glia, and smooth muscle cells. Comparing with adult cartilage, the spherical-forming neural crest cell-like cells downregulate the chondrocytic marker genes, including collagen II, collagen X, and sox9, as well as neural-lineage repressors/silencers REST and coREST, but upregulate a set of well-defined genes related to neural crest cells and pro-neural potential. Nerve growth factor (NGF) and glial growth factor (GGF) increase glial and neuronal differentiation, respectively. These results suggest that chondrocytes derived from adult clavicle cartilage can become neural crest stem-like cells and acquire neuronal phenotypes in vitro. The possible de-differentiation/trans-differentiation mechanisms underlying the conversion were discussed. © 2007 Wiley-Liss, Inc.</p>
adult
conversion
potential
derived
clavicle
chondrocytes
lineage
vitro
neural
cells
into
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/41
oai:ro.uow.edu.au:ihmri-1061
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
SREBP-2 positively regulates transcription of the cholesterol efflux gene, ABCA1, by generating oxysterol ligands for LXR
Wong, Jenny
Quinn, C M
Brown, A
Journal Article
2006-01-01T08:00:00Z
Wong, J., Quinn, C. & Brown, A. (2006). SREBP-2 positively regulates transcription of the cholesterol efflux gene, ABCA1, by generating oxysterol ligands for LXR. Biochemical Journal, 400 (3), 485-491.
10.1042/BJ20060914
Cholesterol accumulation and removal are regulated by two different transcription factors. SREBP-2 (sterol-regulatory-element-binding protein-2) is best known to up-regulate genes involved in cholesterol biosynthesis and uptake, whereas LXR (liver X receptor) is best known for up-regulating cholesterol efflux genes. An important cholesterol efflux gene that is regulated by LXR is the ATP-binding cassette transporter, ABCA1 (ATP-binding cassette transporter-A1). We have previously shown that statin treatment down-regulated ABCA1 expression in human macrophages, probably by inhibiting synthesis of the LXR ligand 24(S),25-epoxycholesterol. However, it was subsequently reported that ABCA1 expression is down-regulated by SREBP-2 through binding of SREBP-2 to an E-box element in ABCA1's proximal promoter. As statin treatment induces SREBP-2 activation, this may provide an alternative explanation for the statin-mediated down-regulation of ABCAl. In the present study, we employed a set of CHO (Chinese-hamster ovary) mutant cell lines to investigate the role of SREBP-2 in the regulation of ABCA1. We observed increased ABCA1 mRNA levels in SREBP-2-overexpressing cells and decreased levels in cells lacking a functional SREBP-2 pathway, which were restored when the SREBP-2 pathway was reinstated. Moreover, ABCA1 gene expression was positively associated with synthesis of 24(S),25-epoxycholesterol in these cell lines. In studies using a human ABCA1 promoter reporter assay, mutation of the E-box motif had a similar response as the wild-type construct to either statin treatment or addition of 24(S),25-epoxycholesterol. By contrast, these responses were completely ablated when the DR4 element to which LXR binds was mutated. These results support the idea that 24(S),25-epoxycholesterol and statin treatment influence ABCA1 transcription via supply of an LXR ligand and not through an SREBP-2/E-box-related mechanism. In addition, our results indicate a critical role of SREBP-2 as a positive regulator of ABCA1 gene expression by enabling the generation of oxysterol ligands for LXR. © 2006 Biochemical Society.
oxysterol
generating
abca1
gene
efflux
cholesterol
transcription
regulates
positively
ligands
2
lxr
srebp
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/46
oai:ro.uow.edu.au:ihmri-1062
2013-08-09T00:10:37Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Primary human astrocytes produce 24(S),25-epoxycholesterol with implications for brain cholesterol homeostasis
Wong, Jenny
Quinn, Carmel M.
Guillemin, Gilles
Brown, Andrew J.
Journal Article
2007-01-01T08:00:00Z
<p>Wong, J., Quinn, C. M., Guillemin, G. & Brown, A. J. (2007). Primary human astrocytes produce 24(S),25-epoxycholesterol with implications for brain cholesterol homeostasis. Journal of Neurochemistry, 103 (5), 1764-1773.</p>
10.1111/j.1471-4159.2007.04913.x
<p>Cholesterol is an essential component of the CNS and its metabolism in the brain has been implicated in various neurodegenerative diseases. The oxysterol produced from cholesterol, 24(S)-hydroxycholesterol, is known to be an important regulator of brain cholesterol homeostasis. In this study, we focussed on another oxysterol, 24(S),25-epoxycholesterol (24,25EC), which has not been studied before in a neurological context. 24,25EC is unique in that it is synthesized in a shunt in the mevalonate pathway, parallel to cholesterol and utilizing the same enzymes. Considering that all the cholesterol present in the brain is derived from de novo synthesis, we investigated whether or not primary human neurons and astrocytes can produce 24,25EC. We found that astrocytes produced more 24,25EC than neurons under basal conditions, but both cell types had the capacity to synthesize this oxysterol when the enzyme 2,3-oxidosqualene cyclase was partially inhibited. Furthermore, both added 24,25EC and stimulated cellular production of 24,25EC (by partial inhibition of 2,3-oxidosqualene cyclase) modulated expression of key cholesterol-homeostatic genes regulated by the liver X receptor and the sterol regulatory element-binding protein-2. Moreover, we found that 24,25EC synthesized in astrocytes can be taken up by neurons and exert downstream effects on gene regulation. In summary, we have identified 24,25EC as a novel neurosterol which plays a likely role in brain cholesterol homeostasis. © 2007 The Authors</p>
implications
brain
cholesterol
homeostasis
astrocytes
produce
24
25
human
epoxycholesterol
primary
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/47
oai:ro.uow.edu.au:ihmri-1063
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Synthesis of the oxysterol, 24(S), 25-epoxycholesterol, parallels cholesterol production and may protect against cellular accumulation of newly-synthesized cholesterol
Wong, Jenny
Quinn, Carmel M
Brown, Andrew J
Journal Article
2007-01-01T08:00:00Z
Wong, J., Quinn, C. M. & Brown, A. J. (2007). Synthesis of the oxysterol, 24(S), 25-epoxycholesterol, parallels cholesterol production and may protect against cellular accumulation of newly-synthesized cholesterol. Lipids in Health and Disease, 6 (N/A), 1-12.
10.1186/1476-511X-6-10
Aim. The effects of 24(S),25-epoxycholesterol (24,25EC) on aspects of cholesterol homeostasis is well-documented. When added to cells, 24,25EC decreases cholesterol synthesis and up-regulates cholesterol efflux genes, including ABCA1. Synthesis of 24,25EC occurs in a shunt of the mevalonate pathway which also produces cholesterol. Therefore, 24,25EC synthesis should be subject to the same negative feedback regulation as cholesterol synthesis. To date, no role has been ascribed to 24,25EC in light of the fact that increased accumulation of cholesterol should decrease formation of this oxysterol through feedback inhibition. This leads to the intriguing paradox: why inhibit production of an apparently important regulator of cholesterol homeostasis when it is needed most?. Methods. We used a combination of pharmacological and genetic approaches in Chinese Hamster Ovary cell-lines to investigate this paradox. Endogenous synthesis of 24,25EC was manipulated using partial inhibition of the enzyme, Oxidosqualene Cyclase. Changes in cholesterol and 24,25EC synthesis were determined using metabolic labelling with [1- 14C]-acetate, thin-layer chromatography and phosphorimaging. Transcriptional effects mediated via SREBP and LXR were analysed by luciferase reporter assays. Results. We showed that cholesterol addition to cells lead to a rapid and preferential inhibition of 24,25EC synthesis. Addition of 24,25EC resulted in parallel inhibition of 24,25EC and cholesterol synthesis. Furthermore, we used a variety of approaches to examine the relationship between cholesterol and 24,25EC synthesis, including cell-lines with different rates of cholesterol synthesis, varying cholesterol synthetic rates by pre-treatment with a statin, or lipoprotein cholesterol loading of macrophages. In all cases, we showed that 24,25EC synthesis faithfully tracked cholesterol synthesis. Moreover, changes in 24,25EC synthesis exerted downstream effects, reducing SREBP transcriptional activity whilst increasing ABCA1 and LXR transcriptional activity. Conclusion. Our results show that 24,25EC synthesis parallels cholesterol synthesis, consistent with this oxysterol functioning as a safety valve to protect against the accumulation of newly-synthesised cholesterol (as opposed to exogenously-derived cholesterol). Considering that 24,25EC is capable of being produced in all cholesterogenic cells, we propose that production of 24,25EC may represent a ubiquitous defence mechanism. © 2007 Wong et al; licensee BioMed Central Ltd.
cellular
accumulation
newly
synthesized
24
25
epoxycholesterol
parallels
cholesterol
production
oxysterol
may
synthesis
protect
against
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/48
oai:ro.uow.edu.au:ihmri-1069
2013-08-09T00:22:02Z
publication:journal_articles
publication:grants
publication:smh
publication:ihmri
publication:document_types
Apolipoprotein-D expression is increased during development and maturation of the human prefrontal cortex
Kim, Woojin S.
Wong, Jenny
Weickert, Cynthia Shannon
Webster, Maree J.
Bahn, Sabine
Garner, Brett
Journal Article
2009-01-01T08:00:00Z
<p>Kim, W. s., Wong, J., Weickert, C. Shannon ., Webster, M. J., Bahn, S. & Garner, B. (2009). Apolipoprotein-D expression is increased during development and maturation of the human prefrontal cortex. Journal of Neurochemistry, 109 (4), 1053-1066.</p>
10.1111/j.1471-4159.2009.06031.x
<p>Apolipoprotein D (apoD) is a lipid binding protein expressed in the brain where its function is largely unknown. Based on changes in lipid metabolism and deposition that occur in the human brain during postnatal development, we investigated changes in apoD expression in the prefrontal cortex in 69 normal cases ranging in age from 40 days to 49 years utilizing gene microarray, quantitative PCR and western blotting methods. In contrast to the high expression of apolipoprotein E (APOE), low-density lipoprotein receptor-related protein 8 (LRP8) and 3-hydroxy-3-methyl-glutaryl-CoA reducatase (HMGCR) (genes that play a role in lipid-related pathways in brain development) early in life, apoD expression was low in neonates and increased in expression throughout life resulting in six- to eight-fold higher levels at the mRNA and protein levels in adults. Recent studies suggest that apoD has a novel antioxidant function in the brain and we found that the increased apoD expression throughout development and into adulthood was correlated with the expression of antioxidant genes superoxide dismutase 1 (SOD1) and glutathione peroxidase 3 (GPX3) as well as proteins that were modified by the lipid peroxidation end-product 4-hydroxynonenal. These studies reveal that apoD expression is increased throughout life in the human prefrontal cortex and that this is correlated with genetic and biochemical markers of oxidative stress. © 2009 International Society for Neurochemistry.</p>
NHMRC/568884
<a href="http://purl.org/au-research/grants/NHMRC/568884">http://purl.org/au-research/grants/NHMRC/568884</a>
cortex
during
development
maturation
human
apolipoprotein
expression
prefrontal
increased
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/54
oai:ro.uow.edu.au:ihmri-1070
2011-11-14T02:48:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
The effect of statins on ABCA1 and ABCG1 expression in human macrophages is influenced by cellular cholesterol levels and extent of differentiation
Wong, Jenny
Quinn, C M
Gelissen, I C
Jessup, W
Brown, A
Journal Article
2008-01-01T08:00:00Z
Wong, J., Quinn, C., Gelissen, I., Jessup, W. & Brown, A. (2008). The effect of statins on ABCA1 and ABCG1 expression in human macrophages is influenced by cellular cholesterol levels and extent of differentiation. Atherosclerosis, 196 (1), 180-189.
10.1016/j.atherosclerosis.2007.03.030
macrophages
influenced
cellular
cholesterol
levels
effect
statins
abca1
abcg1
extent
expression
differentiation
human
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/55
oai:ro.uow.edu.au:ihmri-1074
2011-11-28T04:18:15Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
The kynurenine pathway and inflammation in amyotrophic lateral sclerosis
Chen, Yiquan
Stankovic, Roger
Cullen, Karen M
Meininger, Vincent
Garner, Brett
Coggan, Sarah
Grant, Ross
Brew, Bruce J
Guillemin, Gilles J
Journal Article
2010-01-01T08:00:00Z
Chen, Y., Stankovic, R., Cullen, K., Meininger, V., Garner, B., Coggan, S., Grant, R., Brew, B. & Guillemin, G. (2010). The kynurenine pathway and inflammation in amyotrophic lateral sclerosis. Neurotoxicity research, 18 (2), 132-142.
10.1007/s12640-009-9129-7
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease of unknown pathogenesis. The kynurenine pathway (KP), activated during neuroinflammation, is emerging as a possible contributory factor in ALS. The KP is the major route for tryptophan (TRP) catabolism. The intermediates generated can be either neurotoxic, such as quinolinic acid (QUIN), or neuroprotective, such as picolinic acid (PIC), an important endogenous chelator. The first and inducible enzyme of the pathway is indoleamine 2,3-dioxygenase (IDO). The present study aimed to characterize the expression of the KP in cerebrospinal fluid (CSF), serum and central nervous system (CNS) tissue of ALS patients. Using high performance liquid chromatography, we analysed the levels of TRP and kynurenine (KYN), and, with gas chromatography/mass spectrometry, the levels of PIC and QUIN, in the CSF and serum of ALS patients and control subjects. Immunohistochemistry was employed to determine the expression of QUIN, IDO and human leukocyte antigen-DR (HLA-DR) in sections of brain and spinal cord from ALS patients. There were significantly increased levels of CSF and serum TRP (P < 0.0001), KYN (P < 0.0001) and QUIN (P < 0.05) and decreased levels of serum PIC (P < 0.05) in ALS samples. There was a significant increase in activated microglia expressing HLA-DR (P < 0.0001) and increased neuronal and microglial expression of IDO and QUIN in ALS motor cortex and spinal cord. We show the presence of neuroinflammation in ALS and provide the first strong evidence for the involvement of the KP in ALS. These data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which may be amenable to inhibitors of the KP.
inflammation
lateral
amyotrophic
sclerosis
kynurenine
pathway
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/59
oai:ro.uow.edu.au:ihmri-1076
2011-11-28T04:18:15Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Oxidative damage in mitochondrial DNA is not extensive
Lim, Kok Seong
Jeyaseelan, Kandiah
Whiteman, Matthew
Jenner, Andrew M
Halliwell, Barry
Journal Article
2005-01-01T08:00:00Z
Lim, K. Seong., Jeyaseelan, K., Whiteman, M., Jenner, A. M. & Halliwell, B. (2005). Oxidative damage in mitochondrial DNA is not extensive. Annals of the New York Academy of Sciences, 1042 210-220.
10.1196/annals.1338.023
Since 1988 several research groups have reported greater levels of oxidative damage in mitochondrial DNA than in nuclear DNA, while others have suggested that the greater damage in mtDNA might be due to artifactual oxidation. The popular theory that mtDNA is more heavily damaged in vivo than nDNA does not stand on firm ground. Using an improved GC-MS method and pure mtDNA, our analyses revealed that the damage level in mtDNA is not higher, and may be somewhat lower, than that in nDNA. © 2005 New York Academy of Sciences.
oxidative
extensive
damage
not
mitochondrial
dna
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/61
oai:ro.uow.edu.au:ihmri-1080
2012-09-06T23:48:24Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
The effect of APOE genotype on brain levels of oxysterols in young and old human APOE ε2,ε3 and ε4 knock-in mice
Jenner, Andrew M
Lim, W L F
Ng, M P E
Wenk, M R
Shui, G
Sharman, M J
Gandy, S E
Martins, R N
Journal Article
2010-01-01T08:00:00Z
<p>Jenner, A. M., Lim, W., Ng, M., Wenk, M., Shui, G., Sharman, M., Gandy, S. & Martins, R. (2010). The effect of APOE genotype on brain levels of oxysterols in young and old human APOE ε2,ε3 and ε4 knock-in mice. Neuroscience, 169 (1), 109-115.</p>
10.1016/j.neuroscience.2010.04.026
<p>Despite apolipoprotein E's important role in cholesterol transport and metabolism in the brain as well as its influence on Alzheimer's disease, the impact of the human APOE genotype on cholesterol metabolism in brain has not been fully examined. This study was carried out to investigate APOE genotype effects on oxysterols measured. In this study the measurement of cholesterol and several oxysterols in the brains of human APOE ε2, ε3 and ε4 knock-in mice at 8 weeks and 1 year of age using gas chromatography mass spectrometry (GC-MS) demonstrated no APOE genotype or age effect on total brain cholesterol and the oxysterol 24-hydroxycholesterol. The level of 27-hydroxycholesterol was elevated in 1 year old animals for all APOE genotypes. Interestingly, lathosterol an indicator of cholesterol synthesis was significantly reduced in the 1 year old animals for all APOE genotypes. APOE ε4 expressing mice exhibited statistically lower levels of lathosterol compared to APOE ε2 in both the young and old mice. Oxidized cholesterol metabolites were significantly lower in APOE ε2 mice compared to other genotypes at 8 weeks old. Although minimal differences were observed between APOE E3 and E4 knock-in (KI) mice, these findings indicate that there are some clear APOE genotype specific effects on brain cholesterol synthesis and associated metabolic pathways, particularly in APOE ε2 KI mice. © 2010 IBRO.</p>
ε2
ε3
ε4
brain
levels
oxysterols
young
old
human
genotype
effect
knock
mice
apoe
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/65
oai:ro.uow.edu.au:ihmri-1079
2012-09-06T23:14:38Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Changes in brain cholesterol metabolome after excitotoxicity
Ong, Wei-Yi
Kim, Ji-Hyun
He, Xin
Chen, Peng
Farooqui, Akhlaq A
Jenner, Andrew M
Journal Article
2010-01-01T08:00:00Z
<p>Ong, W., Kim, J., He, X., Chen, P., Farooqui, A. & Jenner, A. M. (2010). Changes in brain cholesterol metabolome after excitotoxicity. Molecular Neurobiology: a review journal, 41 (2-3), 299-313.</p>
10.1007/s12035-010-8099-3
<p>Excitotoxicity due to excess stimulation of glutamate receptors in neurons is accompanied by increased Ca2+ influx, stimulation of Ca 2+-dependent enzymes, ATP depletion, increase in lipid peroxidation products, and loss of glutathione. These changes resemble neurochemical alterations in acute neuronal injury (stroke, spinal cord injury, and traumatic brain injury) and chronic neurodegenerative diseases such as Alzheimer's disease. Intracerebroventricular injection of the potent glutamate analog kainate in rats results in increased cholesterol concentration in the hippocampus at short to medium time intervals, i.e., 3 days-1 week post-injection, as detected by gas chromatography-mass spectrometry in the lesioned hippocampus. This is accompanied by an early increase in levels of cholesterol biosynthetic precursors and increases in both enzymatically derived oxysterols such as 24-hydroxycholesterol and cholesterol oxidation products (COPs) generated by reactive oxygen species, including cholesterol epoxides and 7-ketocholesterol. In contrast to COPs, no change in concentration of the neurosteroid pregnenolone was found after KA injury. Cholesterol and COPs significantly increase exocytosis in cultured PC12 cells and neurons, and both oxysterols and COPs are able to induce cytotoxic and apoptotic injuries in different cell types, including neurons. Together, the findings suggest that increased cholesterol and COPs after KA excitotoxicity could themselves lead to disturbed neuronal ion homeostasis, increased neurotransmitter release, and propagation of excitotoxicity. © 2010 Springer Science+Business Media, LLC.</p>
after
metabolome
excitotoxicity
cholesterol
changes
brain
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/64
oai:ro.uow.edu.au:ihmri-1084
2013-05-10T00:03:04Z
publication:journal_articles
publication:grants
publication:smh
publication:ihmri
publication:document_types
Promoter specific alterations of brain-derived neurotrophic factor mRNA in schizophrenia
Wong, Jenny
Hyde, T M
Cassano, H L
Deep-Soboslay, A
Kleinman, J E
Shannon Weickert, Cynthia
Journal Article
2010-01-01T08:00:00Z
<p>Wong, J., Hyde, T., Cassano, H., Deep-Soboslay, A., Kleinman, J. & Shannon Weickert, C. (2010). Promoter specific alterations of brain-derived neurotrophic factor mRNA in schizophrenia. Neuroscience, 169 (3), 1071-1084.</p>
10.1016/j.neuroscience.2010.05.037
<p>The brain-derivedneurotrophicfactor (BDNF) gene contains multiple 5′ promoters which generate alternate transcripts. Previously, we found that pan-BDNF mRNA and protein are reduced in the dorsolateral prefrontal cortex (DLPFC) from patients with schizophrenia. In this study, we determined which of the four most abundant and best characterized BDNF alternate transcripts, I-IX, II-IX, IV-IX, and VI-IX are altered in schizophrenia. Using a cohort from the NIMH, USA, we found that BDNF II-IX mRNA was significantly reduced in the DLPFC of patients with schizophrenia, and we replicated this finding using a second cohort from Sydney, Australia. Moreover, we show that BDNF protein expression [including prepro (∼32 kDa), pro (∼28 kDa) and mature (∼14 kDa) BDNF] is reduced in the DLPFC of patients with schizophrenia. We next determined the regional specificity of the BDNF mRNA reduction by measuring BDNF transcripts in the parietal cortex and hippocampus and found no significant changes. The effect of antipsychotics on BDNF alternate transcript expression was also examined and we found no relationship between BDNF mRNA expression and antipsychotic use. As schizophrenic patients are often prescribed antidepressants which can up-regulate expression of BDNF, we investigated the relationship between antidepressant treatment and BDNF transcript expression. All four BDNF transcripts were significantly up-regulated in schizophrenic patients treated with antidepressants. Moreover, we found significant reductions in BDNF transcripts II-IX and IV-IX in the parietal cortex and VI-IX in the hippocampus of patients with schizophrenia who did not have a history of treatment with antidepressants. This suggests that down-regulation of at least one out of four major BDNF transcripts occurs in various brain regions of patients with schizophrenia, particularly in the DLPFC which appears to have the most robust BDNF deficit in schizophrenia.</p>
NHMRC/568884
<a href="http://purl.org/au-research/grants/NHMRC/568884">http://purl.org/au-research/grants/NHMRC/568884</a>
derived
factor
mrna
neurotrophic
promoter
alterations
brain
specific
schizophrenia
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/69
oai:ro.uow.edu.au:ihmri-1073
2013-06-05T04:37:57Z
publication:journal_articles
publication:grants
publication:smh
publication:ihmri
publication:document_types
Vascular pharmacotherapy and dementia
Piguet, Oliver
Garner, Brett
Journal Article
2010-01-01T08:00:00Z
<p>Piguet, O. & Garner, B. (2010). Vascular pharmacotherapy and dementia. Current Vascular Pharmacology, 8 (1), 44-50.</p>
10.2174/157016110790226705
<p>The incidence of dementia is increasing dramatically with the ageing population. Increasing evidence indicates that vascular disease is associated with cognitive decline and with the most common form of dementia, Alzheimer's disease (AD). Cardiovascular risk factors such as hyperlipidaemia, hypertension and type 2 diabetes have attracted attention as potential targets in the prevention of dementia. The present review aims to provide a concise overview of the recent advances linking vascular disease with dementia (with a particular focus on AD) and to examine the evidence for efficacy, where possible, for utilising vascular pharmacotherapy as a treatment option for dementia. © 2010 Bentham Science Publishers Ltd.</p>
NHMRC/568651
<a href="http://purl.org/au-research/grants/NHMRC/568651">http://purl.org/au-research/grants/NHMRC/568651</a>
pharmacotherapy
dementia
vascular
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/58
oai:ro.uow.edu.au:ihmri-1075
2011-11-28T04:18:15Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Impact of 27-hydroxycholesterol on amyloid-beta peptide production and ATP-binding cassette transporter expression in primary human neurons
Scott, Kim W
Chan, S L
Hill, A F
Guillemin, G J
Garner, B
Journal Article
2009-01-01T08:00:00Z
Scott, K., Chan, S., Hill, A., Guillemin, G. & Garner, B. (2009). Impact of 27-hydroxycholesterol on amyloid-beta peptide production and ATP-binding cassette transporter expression in primary human neurons. Journal of Alzheimer's Disease, 16 (1), 121-131.
Cholesterol is an integral component of neuronal membranes and recent evidence has shown that it regulates amyloid-β protein precursor processing to form amyloid-β peptides, which are a major constituent of cerebral amyloid plaques associated with Alzheimer's disease. 27-Hydroxycholesterol (27OHC) is synthesized from cholesterol via sterol 27-hydroxylase (CYP27A1) in the brain and, unlike cholesterol, can cross into the brain through the blood brain barrier from the circulation. Previous studies point toward a potential role for 27OHC in the regulation of neuronal amyloid-β peptide generation, however, this has not been investigated in primary human neurons. Here we show that 27OHC significantly reduced amyloid-β peptide detected in cell culture supernatants from primary human neurons. We also show that 27OHC does not affect α-, β- or γ-secretase activity but does upregulate the liver X receptor (LXR) responsive genes ABCA1, ABCG1 and APOE. These data suggest that 27OHC-mediated reduction in extracellular amyloid-β peptide levels is potentially due to its action as an LXR ligand. © 2009 - IOS Press and the authors. All rights reserved.
peptide
amyloid
neurons
hydroxycholesterol
human
27
impact
primary
expression
transporter
cassette
binding
atp
production
beta
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/60
oai:ro.uow.edu.au:ihmri-1078
2014-02-21T00:01:59Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Toward consensus in the analysis of urinary 8-oxo-7,8-dihydro-2′- deoxyguanosine as a noninvasive biomarker of oxidative stress
Evans, M D
Olinski, R
Loft, S
Cooke, M S
Rossner, Jr P
Sram, R
Henriksen, T
Poulsen, H E
Weimann, Allan
Barbieri, A
Sabatini, L
Violante, F
Kino, S
Ochi, T
Sakai, K
Takeuchi, M
Kasai, H
Meerman, J H N
Gackowski, D
Rozalski, R
Siomek, A
Halliwell, Barry
Jenner, Andrew M
Wang, H
Cerda, C
Saez, G
Haghdoost, S
Svoboda, P
Hu, C-W
Chao, M-R
Peng, K-Y
Shih, W-C
Wu, K-Y
Orhan, H
Istanbullu, N S
Mistry, V
Farmer, P B
Sandhu, J
Singh, R
Cortez, C
Su, Y
Santella, R M
Lambert, P
Smith, R
Journal Article
2010-01-01T08:00:00Z
<p>Evans, M., Olinski, R., Loft, S., cooke, M., Rossner, J., Sram, R., Henriksen, T., Poulsen, H., Weimann, A., Barbieri, A., Sabatini, L., Violante, F., Kino, S., Ochi, T., Sakai, K., Takeuchi, M., Kasai, H., Meerman, J., Gackowski, D., Rozalski, R., Siomek, A., Halliwell, B., Jenner, A. M., Wang, H., Cerda, C., Saez, G., Haghdoost, S., Svoboda, P., Hu, C., Chao, M., Peng, K., Shih, W., Wu, K., Orhan, H., Istanbullu, N., Mistry, V., Farmer, P., Sandhu, J., Singh, R., Cortez, C., Su, Y., Santella, R., Lambert, P. & Smith, R. (2010). Toward consensus in the analysis of urinary 8-oxo-7,8-dihydro-2′- deoxyguanosine as a noninvasive biomarker of oxidative stress. FASEB Journal, 24 (4), 1249-1260.</p>
10.1096/fj.09-147124
<p>Of the DNA-derived biomarkers of oxidative stress, urinary 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) is the most frequently measured. However, there is significant discrepancy between chromatographic and immunoassay approaches, and intratechnique agreement among all available chromatography-based assays and ELISAs is yet to be established. This is a significant obstacle to their use in large molecular epidemiological studies. To evaluate the accuracy of intra/intertechnique and interlaboratory measurements, samples of phosphate buffered saline and urine, spiked with different concentrations of 8-oxoG, together with a series of urine samples from healthy individuals were distributed to ESCULA members. All laboratories received identical samples, including 2 negative controls that contained no added 8-oxodG. Data were returned from 17 laboratories, representing 20 methods, broadly classified as mass spectrometric (MS), electrochemical detection (EC), or enzyme-linked immunosorbant assay (ELISA). Overall, there was good within-technique agreement, with the majority of laboratories' results lying within 1 SD of their consensus mean. However, ELISA showed more within-technique variation than did the chromatographic techniques and, for the urine samples, reported higher values. Bland-Altman plots revealed good agreement between MS and EC methods but concentration-dependent deviation for ELISA. All methods ranked urine samples according to concentration similarly. Creatinine levels are routinely used as a correction factor for urine concentration, and therefore we also conducted an interlaboratory comparison of methods for urinary creatinine determination, in which the vast majority of values lay within 1 SD of the consensus value, irrespective of the analysis procedure. This study reveals greater consensus than previously expected, although concern remains over ELISA. © FASEB.</p>
7
oxidative
oxo
8
urinary
analysis
consensus
toward
biomarker
noninvasive
deoxyguanosine
2
dihydro
stress
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/63
oai:ro.uow.edu.au:ihmri-1081
2011-11-28T04:18:15Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
ProBDNF inhibits infiltration of ED1+ macrophages after spinal cord injury
Wong, Ira
Liao, Hong
Bai, Xianshu
Zaknic, Antony
Zhong, Jinhua
Guan, Yue
Li, Hongyun
Wang, Yan-Jiang
Zhou, Xin-Fu
Journal Article
2010-01-01T08:00:00Z
Wong, I., Liao, H., Bai, X., Zaknic, A., Zhong, J., Guan, Y., Li, H., Wang, Y. & Zhou, X. (2010). ProBDNF inhibits infiltration of ED1+ macrophages after spinal cord injury. Brain, Behavior, and Immunity, 24 (4), 585-597.
10.1016/j.bbi.2010.01.001
The central nervous system (CNS) does not regenerate partly due to the slow clearance of debris from the degenerated myelin sheath by Wallerian degeneration. The mechanism underlying the inefficiency in myelin clearance is not clear. Here we showed that endogenous proBDNF may inhibit the infiltration of ED1+ inflammatory cells afterspinalcordinjury. Afterinjury, proBDNF and its receptors sortilin and p75NTR are expressed in the spinalcord as determined by Western blots and immunocytochemistry. ProBDNF and mature BDNF were released from macrophagesin vitro. Macrophagesin vivo (ED1+) and isolated in vitro (CD11b+) express moderate levels of proBDNF, sortilin and p75NTR. ProBDNF suppressed the migration of isolated macrophagesin vitro and the antibody to proBDNF enhanced the migration. Suppression of proBDNFin vivo by administering the antiserum to the prodomain of BDNF afterspinalcordinjury (SCI) increased the infiltration of macrophages and increased number of neurons in the injured cord. BBB tests showed that the treatment of the antibody to proBDNF improved the functional recovery afterspinalcordinjury. Our data suggest that proBDNF is a suppressing factor for macrophage migration and infiltration and may play a detrimental role after SCI.
probdnf
macrophages
after
spinal
cord
inhibits
infiltration
injury
ed1
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/66
oai:ro.uow.edu.au:ihmri-1085
2012-09-06T23:29:20Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Imaging of single cells and tissue using MeV ions
Watt, F
Bettiol, A A
Kan, J. A van
Ynsa, M D
Minqin, Ren
Rajendran, R
Huifang, Cui
Fwu-Shen, Shen
Jenner, A M
Journal Article
2009-01-01T08:00:00Z
<p>Watt, F., Bettiol, A. A., Kan, J. van., Ynsa, M. D., Minqin, R., Rajendran, R., Huifang, C., Fwu-Shen, S. & Jenner, A. M. (2009). Imaging of single cells and tissue using MeV ions. Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms, 267 (12-13), 2113-2116.</p>
10.1016/j.nimb.2009.03.069
<p>With the attainment of sub-100 nm high energy (MeV) ion beams, comes the opportunity to image cells and tissue at nano-dimensions. The advantage of MeV ion imaging is that the ions will penetrate whole cells, or relatively thick tissue sections, without any significant loss of resolution. In this paper, we demonstrate that whole cells (cultured N2A neuroblastoma cells ATCC) and tissue sections (rabbit pancreas tissue) can be imaged at sub-100 nm resolutions using scanning transmission ion microscopy (STIM), and that sub-cellular structural details can be identified. In addition to STIM imaging we have also demonstrated for the first time, that sub-cellular proton induced fluorescence imaging (on cultured N2A neuroblastoma cells ATCC) can also be carried out at resolutions of 200 nm, compared with 300-400 nm resolutions achieved by conventional optical fluorescence imaging. The combination of both techniques offers a potentially powerful tool in the quest for elucidating cell function, particularly when it should be possible in the near future to image down to sub-50 nm. © 2009 Elsevier B.V. All rights reserved.</p>
mev
tissue
imaging
cells
ions
single
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/70
oai:ro.uow.edu.au:ihmri-1096
2011-12-06T02:50:00Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Remating in Drosophila melanogaster: an examination of the trading-up and intrinsic male-quality hypotheses
Byrne, Phillip G
Rice, W R
Journal Article
2005-01-01T08:00:00Z
Byrne, P. G. & Rice, W. R. (2005). Remating in Drosophila melanogaster: an examination of the trading-up and intrinsic male-quality hypotheses. Journal of Evolutionary Biology, 18 (5), 1324-1331.
10.1111/j.1420-9101.2005.00918.x
Female Drosophila melanogaster remate more frequently than necessary to ensure fertilization. We tested whether polyandrous females gain genetic benefits for their offspring by (1) selecting secondary sires of higher genetic-quality than original partners or (2) because post-copulatory mechanisms bias fertilizations towards genetically superior males. We screened 119 hemiclones of males for lifetime fitness then selected eight hemiclones (four of extreme high fitness and four of extreme low fitness) and mated them to virgin females. Females were then given the opportunity to remate with males of benchmark-genetic quality and their propensity to remate (fidelity) and sperm displacement scored. A female's fidelity and her level of sperm displacement varied depending on which hemiclone she mated first, but not on male-genetic quality. These findings indicate that female remating and sperm displacement are strongly influenced by male genotype, but provide no evidence that these traits contribute to adaptive female choice to obtain superior genes for offspring. © 2005 European Society for Evolutionary Biology.
trading
examination
hypotheses
melanogaster
quality
drosophila
remating
male
intrinsic
up
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/81
oai:ro.uow.edu.au:ihmri-1087
2014-04-09T08:43:06Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Hormone induction of gamete release and In-vitro fertilization in the critically endangered corroboree frog
Byrne, Phillip G
Silla, A J
Journal Article
2010-01-01T08:00:00Z
<p>Byrne, P. G. & Silla, A. (2010). Hormone induction of gamete release and In-vitro fertilization in the critically endangered corroboree frog. Reproductive Biology and Endocrinology, 8 (144), 1-13.</p>
10.1186/1477-7827-8-144
<p>Background: Conservation Breeding Programs (CBP's) are playing an important role in the protection of critically endangered anuran amphibians, but for many species recruitment is not successful enough to maintain captive populations, or provide individuals for release. In response, there has been an increasing focus on the use of Assisted Reproductive Technologies (ART), including the administration of reproductive hormones to induce gamete release followed by in vitro fertilisation. The objective of this study was to test the efficacy of two exogenous hormones to induce gamete release, for the purpose of conducting in vitro fertilisation (IVF), in one of Australia's most critically endangered frog species, Pseudophryne corroboree.Methods: Male frogs were administered a single dose of either human chorionic gonadotropin (hCG) or luteinizing hormone-releasing hormone (LHRHa), while female frogs received both a priming and ovulatory dose of LHRHa. Spermiation responses were evaluated at 3, 7, 12, 24, 36, 48, 60 and 72 h post hormone administration (PA), and sperm number and viability were quantified using fluorescent microscopy. Ovulation responses were evaluated by stripping females every 12 h PA for 5 days. Once gametes were obtained, IVF was attempted by combining spermic urine with oocytes in a dilute solution of simplified amphibian ringer (SAR).Results: Administration of both hCG and LHRHa induced approximately 80% of males to release sperm over 72 h. Peak sperm release occurred at 12 h PA for hCG treated males and 36 h PA for LHRHa treated males. On average, LHRHa treated males released a significantly higher total number of live sperm, and a higher concentration of sperm, over a longer period. In female frogs, administration of LHRHa induced approximately 30% of individuals to release eggs. On average, eggs were released between 24 and 48 h PA, with a peak in egg release at 36 h PA. IVF resulted in a moderate percentage (54.72%) of eggs being fertilised, however all resultant embryos failed prior to gastrulation.Conclusions: Hormone treatment successfully induced spermiation and ovulation in P. corroboree, but refinement of gamete induction and IVF techniques will be required before ART protocols can be used to routinely propagate this species. © 2010 Byrne and Silla; licensee BioMed Central Ltd</p>
frog
fertilization
corroboree
vitro
release
gamete
induction
hormone
endangered
critically
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/72
oai:ro.uow.edu.au:ihmri-1092
2011-12-06T02:50:00Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Microsatellite markers in the endangered Australian northern corroboree frog, Pseudophryne pengilleyi (Anura: Myobatrachidae) and amplification in other Pseudophryne species
Morgan, M J
Byrne, Phillip G
Hayes, C M
Keogh, J S
Journal Article
2008-01-01T08:00:00Z
Morgan, M., Byrne, P. G., Hayes, C. & Keogh, J. (2008). Microsatellite markers in the endangered Australian northern corroboree frog, Pseudophryne pengilleyi (Anura: Myobatrachidae) and amplification in other Pseudophryne species. Conservation Genetics, 9 (5), 1315-1317.
10.1007/s10592-007-9468-y
Seven microsatellite primer pairs were isolated and characterized in the endangered Australian northern corroboree frog (Pseudophryne pengilleyi). All seven were polymorphic (2-14 alleles) and displayed high heterozygosity (0.036-0.964) in 28 sampled individuals. We also tested the microsatellites on two closely related species. Four were polymorphic in the southern corroboree frog (P. corroboree) and Bibron's toadlet (P. bibronii). These primers will be useful in studies of conservation genetics and mating systems in Pseudophryne species. © 2007 Springer Science+Business Media B.V
australian
northern
corroboree
microsatellite
frog
endangered
markers
amplification
myobatrachidae
species
anura
other
pengilleyi
pseudophryne
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/77
oai:ro.uow.edu.au:ihmri-1093
2011-12-06T02:50:00Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Terrestrial toadlets use chemosignals to recognise conspecifics, locate mates and strategically adjust calling behaviour
Byrne, Phillip G
Keogh, J Scott
Journal Article
2007-01-01T08:00:00Z
Byrne, P. G. & Keogh, J. Scott. (2007). Terrestrial toadlets use chemosignals to recognise conspecifics, locate mates and strategically adjust calling behaviour. Animal Behaviour, 74 (5), 1155-1162.
10.1016/j.anbehav.2006.10.033
Among anuran amphibians evidence for chemical communication is scarce. We carried out three experiments to evaluate whether chemosignals influence the sexual behaviour of an Australian terrestrial toadlet, Pseudophryne bibronii. Substrate choice trials (experiment 1) revealed that females preferred to associate with substrate marked by either sex rather than an unmarked substrate and that males preferred substrate marked by females, but avoided substrate marked by other males. These results suggest that the odour of both sexes functions as a sexual attractant and that male odour may also function to repel potential male competitors. In experiment 2 we assessed whether females use male chemosignals during mate location by making gravid females navigate a two-choice Y-maze to reach calling males. Almost invariably, females followed a path outlined with male gland secretions. This result indicates that male chemosignals combined with acoustic signals improve the ability of females to find nest sites. In experiment 3 we tested whether conspecific odour influences the callingbehaviour of nesting males. Female odour stimulated a twofold increase in advertisement calling and male odour stimulated a switch to territorial calling. These findings indicate that nesting males use conspecific odour as a cue for regulating investment in acoustic courtship and territory defence. Our results advance a small body of evidence to suggest that anurans use chemosignals to identify and locate potential mates and provide the first demonstration that odour can influence anuran callingbehaviour.
locate
terrestrial
mates
strategically
adjust
chemosignals
calling
conspecifics
behaviour
recognise
toadlets
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/78
oai:ro.uow.edu.au:ihmri-1086
2013-05-10T00:31:32Z
publication:journal_articles
publication:grants
publication:smh
publication:ihmri
publication:document_types
Transcriptional interaction of an estrogen receptor splice variant and ErbB4 suggests convergence in gene susceptibility pathways in schizophrenia
Wong, Jenny
Weickert, Cynthia Shannon
Journal Article
2009-01-01T08:00:00Z
<p>Wong, J. & Weickert, C. Shannon . (2009). Transcriptional interaction of an estrogen receptor splice variant and ErbB4 suggests convergence in gene susceptibility pathways in schizophrenia. Journal of Biological Chemistry, 284 (28), 18824-18832.</p>
10.1074/jbc.M109.013243
<p>Mounting evidence from clinical and basic research suggests that estrogen signaling may be altered in the brains of people with schizophrenia. Previously, we found that DNA sequence variation in the estrogen receptor (ER) α gene, lower ERα mRNA levels, and/or blunted ERα signaling is associated with schizophrenia. In this study, we asked whether the naturally occurring truncated ERα isoform, Δ7, which acts as a dominant negative, can attenuate gene expression induced by the wildtype (WT) receptor in an estrogen-dependent manner in neuronal (SHSY5Y) and non-neuronal (CHOK1 and HeLa) cells. In addition, we determined the extent to which ERα interacts with NRG1-ErbB4, a leading schizophrenia susceptibility pathway. Reductions in the transcriptionally active form of ErbB4 comprising the intracytoplasmic domain (ErbB4-ICD) have been found in schizophrenia, and we hypothesized that ERα and ErbB4 may converge to control gene expression. In the present study, we show that truncated Δ7-ERα attenuates WT-ERα-driven gene expression across a wide range of estrogen concentrations in cells that express functional ERα at base line or upon co-transfection of full-length ERα. Furthermore, we find that ErbB4-ICD can potentiate the transcriptional activity of WTERα at EREs in two cell lines and that this potentiation effect is abolished by the presence of Δ7-ERα. Immunofluorescence microscopy revealed nuclear co-localization of WT-ERα, Δ7-ERα, and ErbB4-ICD, whereas immunoprecipitation assays showed direct interaction. Our findings demonstrate convergence between ERα and ErbB4-ICD in the transcriptional control of ERα-target gene expression and suggest that this may represent a convergent pathway that may be disrupted in schizophrenia. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.</p>
NHMRC/568884
<a href="http://purl.org/au-research/grants/NHMRC/568884">http://purl.org/au-research/grants/NHMRC/568884</a>
schizophrenia
receptor
pathways
splice
variant
transcriptional
erbb4
suggests
convergence
interaction
gene
estrogen
susceptibility
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/71
oai:ro.uow.edu.au:ihmri-1088
2014-04-09T08:43:12Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Extreme sequential polyandry insures gainst nest failure in a frog
Byrne, Phillip G
Keogh, J Scott
Journal Article
2009-01-01T08:00:00Z
<p>Byrne, P. G. & Keogh, J. Scott. (2009). Extreme sequential polyandry insures gainst nest failure in a frog. Proceedings of the Royal Society B: Biological Sciences, 276 (1654), 115-120.</p>
10.1098/rspb.2008.0794
<p>Sequential polyandry may evolve as an insurance mechanism to reduce the risk of choosing a mate that is infertile, closely related, genetically inferior or incompatible, but polyandry also might insure against nest failure in unpredictable environments. Most animals are oviparous, and in species where males provide nest sites whose quality varies substantially and unpredictably, polyandrous females might insure offspring success by distributing their eggs across multiple nests. Here, we test this hypothesis in a wild population of an Australian terrestrial toadlet, a polyandrous species, where males construct nests and remain with broods. We found that females partitioned their eggs across the nests of two to eight males and that more polyandrous females gained a significant increase in mean offspring survivorship. Our results provide evidence for the most extreme case of sequential polyandry yet discovered in a vertebrate and also suggest that insurance against nest failure might favour the evolution of polyandry. We propose that insurance against nest failure might be widespread among oviparous taxa and provide an important explanation for the prevalence of sequential polyandry in nature. © 2008 The Royal Society.</p>
nest
failure
insures
frog
extreme
sequential
gainst
polyandry
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/73
oai:ro.uow.edu.au:ihmri-1089
2011-12-06T02:50:00Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Effect of a refuge from persistent male courtship in the Drosophila laboratory environment
Byrne, Phillip G
Rice, W R
Rice, G R
Journal Article
2008-01-01T08:00:00Z
Byrne, P. G., Rice, W. & Rice, G. (2008). Effect of a refuge from persistent male courtship in the Drosophila laboratory environment. Integrative and Comparative Biology, 48 (2), E1-E7.
10.1093/icb/icn001
The Drosophila melanogaster laboratory model has been used extensively in studies of sexual conflict because during the process of courtship and mating, males impose several costs upon females (e.g., reduced fecundity). One important difference between the laboratory and the wild is that females in the laboratory lack a spatial refuge from persistent male courtship. Here, we describe two experiments that examine the potential consequences of a spatial refuge for females. In the first experiment, we examined the influence of a spatial refuge on mating rate of females, and in the second one we examined its influence on females' lifetime fecundity. We found that females mated about 25% less often when a spatial refuge was available, but that the absence of a spatial refuge did not substantially increase the level of male-induced harm to females (i.e., sexual conflict). © The Author 2008. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved.
persistent
environment
refuge
laboratory
effect
drosophila
courtship
male
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/74
oai:ro.uow.edu.au:ihmri-1091
2014-04-09T08:43:19Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Simultaneous polyandry increases fertilisation success in an African foam-nesting tree frog
Byrne, Phillip G
Whiting, M J
Journal Article
2008-01-01T08:00:00Z
<p>Byrne, P. G. & Whiting, M. (2008). Simultaneous polyandry increases fertilisation success in an African foam-nesting tree frog. Animal Behaviour, 76 (4), 1157-1164.</p>
10.1016/j.anbehav.2008.05.019
<p>In many animals females mate with multiple males during a single breeding season (polyandry), but the benefits of this mating system remain poorly understood. One hypothesis is that polyandry ensures the fertilization of a female’s ova (fertilization insurance hypothesis). We tested the fertilization insurance hypothesis in a natural population of African foam-nesting treefrogs, Chiromantis xerampelina, a species lacking male contest competition and in which females routinely mate with multiple males. We observed matings involving from one to 12 males and found that fertilization success was positively correlated with the number of mating males, but was unaffected by variance in clutch size or ambient temperature. Variance in fertilization success was also unrelated to the body size ratio of mating pairs. Critically, females that mated with more males also produced more tadpoles. These findings provide the first evidence that polyandry can benefit female frogs by increasing fertilization success and offspring production. We propose that fertilization insurance may account for the high incidence of simultaneous polyandry in frog species that use foam nests during breeding</p>
frog
nesting
success
fertilisation
increases
polyandry
foam
tree
african
simultaneous
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/76
oai:ro.uow.edu.au:ihmri-1094
2011-12-06T02:50:00Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Assessing sexual conflict in the Drosophila melanogaster laboratory model system
Rice, William R
Stewart, Andrew D
Morrow, Edward H
Linder, Jodell E
Orteiza, Nicole
Byrne, Phillip G
Journal Article
2006-01-01T08:00:00Z
Rice, W. R., Stewart, A. D., Morrow, E. H., Linder, J. E., Orteiza, N. & Byrne, P. G. (2006). Assessing sexual conflict in the Drosophila melanogaster laboratory model system. Philosphical Transactions of the Royal Society B: Biological Sciences, 361 (1466), 287-299.
10.1098/rstb.2005.1787
We describe a graphical model of interlocus coevolution used to distinguish between the interlocus sexual conflict that leads to sexually antagonistic coevolution, and the intrinsic conflict over mating rate that is an integral part of traditional models of sexual selection. We next distinguish the 'laboratory island' approach from the study of both inbred lines and laboratory populations that are newly derived from nature, discuss why we consider it to be one of the most fitting forms of laboratory analysis to study interlocus sexual conflict, and then describe four experiments using this approach with Drosophila melanogaster. The first experiment evaluates the efficacy of the laboratory model system to study interlocus sexual conflict by comparing remating rates of females when they are, or are not, provided with a spatial refuge from persistent male courtship. The second experiment tests for a lag-load in males that is due to adaptations that have accumulated in females, which diminish male-induced harm while simultaneously interfering with a male's ability to compete in the context of sexual selection. The third and fourth experiments test for a lag-load in females owing to direct costs from their interactions with males, and for the capacity for indirect benefits to compensate for these direct costs. © 2006 The Royal Society.
conflict
drosophila
assessing
melanogaster
system
laboratory
sexual
model
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/79
oai:ro.uow.edu.au:ihmri-1095
2011-12-06T02:50:00Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Evidence for adaptive male-mate choice in the fruit fly Drosophila melanogaster
Byrne, Phillip G
Rice, William R
Journal Article
2006-01-01T08:00:00Z
Byrne, P. G. & Rice, W. R. (2006). Evidence for adaptive male-mate choice in the fruit fly Drosophila melanogaster. Proceedings of the Royal Society B: Biological Sciences, 273 (1589), 917-922.
10.1098/rspb.2005.3372
Theory predicts that males will benefit when they bias their mating effort towards females of higher reproductive potential, and that this discrimination will increase as males become more resource limited. We conducted a series of experiments to test these predictions in a laboratory population of the fruitfly, Drosophila melanogaster. In this species, courtship and copulation have significant costs to males, and females vary greatly in fecundity, which is positively associated with body size. When given a simultaneous choice between small and large virgin females, males preferentially mated with larger, more fecund, females. Moreover, after males had recently mated they showed a stronger preference for larger females. These results suggest that male D. melanogaster adaptively allocate their mating effort in response to variation in female quality and provide some of the first support for the theoretical prediction that male stringency in mate choice increases as resources become more limiting. © 2006 The Royal Society.
fly
drosophila
choice
melanogaster
fruit
mate
male
adaptive
evidence
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/80
oai:ro.uow.edu.au:ihmri-1097
2011-12-06T02:50:00Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Assessing the potential for an ongoing arms race within and between the sexes: selection and heritable variation
Friberg, Urban
Lew, Timothy A
Byrne, Phillip G
Rice, William R
Journal Article
2005-01-01T08:00:00Z
Friberg, U., Lew, T. A., Byrne, P. G. & Rice, W. R. (2005). Assessing the potential for an ongoing arms race within and between the sexes: selection and heritable variation. Evolution, 59 (7), 1540-1551.
10.1554/05-069
In promiscuous species, sexual selection generates two opposing male traits: offense (acquiring new mates and supplanting stored sperm) and defense (enforcing fidelity on one's mates and preventing sperm displacement when this fails). Coevolution between these traits requires both additive genetic variation and associated natural selection. Previous work with Drosophila melanogaster found autosomal genetic variation for these traits among inbred lines from a mixture of populations, but only nonheritable genetic variation was found within a single outbred population. These results do not support ongoing antagonistic coevolution between offense and defense, nor between either of these male traits and female reproductive characters. Here we use a new method (hemiclonal analysis) to study genomewide genetic variation in a large outbred laboratory population of D. melanogaster. Hemiclonal analysis estimates the additive genetic variation among random, genomewide haplotypes taken from a large, outbred, locally adapted laboratory population and determines the direction of the selection gradient on this variation. In contrast to earlier studies, we found low but biologically significant heritable variation for defensive and offensive offspring production as well as all their components (P1, fidelity, P2, and remating). Genetic correlations between these traits were substantially different from those reported for inbred lines. A positive genetic correlation was found between defense and offense, demonstrating that some shared genes influence both traits. In addition to this common variation, evidence for unique genetic variation for each trait was also found, supporting an ongoing coevolutionary arms race between defense and offense. Reproductive conflict between males can strongly influence female fitness. Correspondingly, we found genetic variation in both defense and offense that affected female fitness. No evidence was found for intersexual conflict in the context of male defense, but we found substantial intersexual conflict in the context of male offensive sperm competitive ability. These results indicate that conflict between competing males also promotes an associated arms race between the sexes. © 2005 The Society for the Study of Evolution. All rights reserved.
potential
ongoing
arms
assessing
within
variation
between
sexes
race
selection
heritable
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/82
oai:ro.uow.edu.au:ihmri-1114
2013-03-11T03:05:16Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Chronic exposure to U18666A is associated with oxidative stress in cultured murine cortical neurons
Koh, Chor
Whiteman, Matthew
Li, Qiao-Xin
Halliwell, Barry
Jenner, Andrew
Wong, Boon
Laughton, Katrina
Wenk, Markus
Masters, Colin
Beart, Philip
Bernard, Ora
Cheung, Nam
Journal Article
2006-01-01T08:00:00Z
<p>Koh, C., Whiteman, M., Li, Q., Halliwell, B., Jenner, A., Wong, B., Laughton, K., Wenk, M., Masters, C., Beart, P., Bernard, O. & Cheung, N. (2006). Chronic exposure to U18666A is associated with oxidative stress in cultured murine cortical neurons. Journal of Neurochemistry, 98 (4), 1278-1289.</p>
10.1111/j.1471-4159.2006.03958.x
<p>Findings that antioxidant treatment may be beneficial in Alzheimer's disease indicate that oxidative stress is an important factor in its pathogenesis. Studies have also suggested that cholesterol imbalance in the brain might be related to the development of neurological disorders. Previously, we have reported that U18666A, a cholesterol transport-inhibiting agent, leads to apoptosis and intracellular cholesterol accumulation in primary cortical neurons. In this study, we found that neuronal apoptosis mediated by U18666A is associated with oxidative stress in the treated cortical neurons. Cortical neurons treated with U18666A also showed decreased secretion and increased intraneuronal accumulation of β-amyloid. The association of neuronal apoptosis with oxidative stress and Aβ accumulation may provide clues to the pathogenesis of Alzheimer's disease, as well as the role oxidative stress plays in other neurodegenerative diseases.</p>
stress
oxidative
associated
u18666a
exposure
chronic
cortical
neurons
murine
cultured
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/99
oai:ro.uow.edu.au:ihmri-1111
2013-03-11T03:03:32Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Potential artifacts in the measurement of DNA deamination
Lim, Kok
Huang, Shan
Jenner, Andrew
Wang, Huansong
Tang, Soon Y
Halliwell, Barry
Journal Article
2006-01-01T08:00:00Z
<p>Lim, K., Huang, S., Jenner, A., Wang, H., Tang, S. Y. & Halliwell, B. (2006). Potential artifacts in the measurement of DNA deamination. Free Radical Biology and Medicine, 40 (11), 1939-1948.</p>
10.1016/j.freeradbiomed.2006.01.030
<p>Attack on DNA by some reactive nitrogen species results in deamination of adenine and guanine, leading to the formation of hypoxanthine and xanthine, respectively. Published levels of these products in cellular DNA have varied widely. Although these two deamination products are often measured by GC-MS analysis, the procedure of acid hydrolysis to release DNA bases for derivatization poses a risk of artifactual deamination of the DNA. In this study, we demonstrated the artifactual formation of these two deamination products during acid hydrolysis and hence developed a method for detecting and measuring 2′-deoxyinosine, the nucleoside of hypoxanthine. Our assay for 2′-deoxyinosine employs nuclease P1 and alkaline phosphatase to achieve release of the nucleosides from DNA, followed by HPLC prepurification with subsequent GC-MS analysis of the nucleosides. This assay detected an increase in the levels of 2′-deoxyinosine in DNA when commercial salmon testis DNA was treated with nitrous acid. We also used it to measure levels in various rat tissues of both normal and endotoxin-treated rats, but could not find increased 2′-deoxyinosine formation in tissues even though <sup>·</sup>NO production was substantially increased.</p>
measurement
dna
artifacts
deamination
potential
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/96
oai:ro.uow.edu.au:ihmri-1115
2013-04-09T02:34:07Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Quantitative gas chromatography mass spectrometric analysis of 2'-deoxyinosine in tissue DNA
Lim, Kok
Jenner, Andrew
Halliwell, Barry
Journal Article
2006-01-01T08:00:00Z
<p>Lim, K., Jenner, A. & Halliwell, B. (2006). Quantitative gas chromatography mass spectrometric analysis of 2'-deoxyinosine in tissue DNA. Nature Protocols, 1 (4), 1995-2002.</p>
10.1038/nprot.2006.301
<p>Several studies examining DNA deamination have published levels of 2′-deoxyinosine that illustrated a large variation between studies. Most of them are the result of artifactual DNA deamination that occurs during the process of sample preparation, particularly acid hydrolysis. This protocol for measurement of 2′-deoxyinosine describes the use of nuclease P1 and alkaline phosphatase to achieve release of nucleosides from DNA, followed by HPLC prepurification with subsequent gas chromatography–mass spectrometry analysis of the nucleosides. It has been used in the measurement of the levels of 2′-deoxyinosine in DNA of commercial sources and DNA from cells and animal tissues, and gives values ranging from 3 to 7 2′-deoxyinosine per 10<sup>6</sup> 2-deoxyadenosine. This protocol should take approximately 7 days to complete.</p>
gas
quantitative
deoxyinosine
2
analysis
spectrometric
mass
dna
chromatography
tissue
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/100
oai:ro.uow.edu.au:ihmri-1116
2013-04-15T00:30:28Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Effect of tea phenolics and their aromatic fecal bacterial metabolites on intestinal microbiota
Lee, Hui
Jenner, Andrew
Low, Chin S
Lee, Yuan K
Journal Article
2006-01-01T08:00:00Z
<p>Lee, H., Jenner, A., Low, C. S. & Lee, Y. K. (2006). Effect of tea phenolics and their aromatic fecal bacterial metabolites on intestinal microbiota. Research in Microbiology, 157 (9), 876-884.</p>
10.1016/j.resmic.2006.07.004
<p>Tea is rich in polyphenols and other phenolics that have been widely reported to have beneficial health effects. However, dietary polyphenols are not completely absorbed from the gastrointestinal tract and are metabolized by the gut microflora so that they and their metabolites may accumulate to exert physiological effects. In this study, we investigated the influence of the phenolic components of a tea extract and their aromatic metabolites upon bacterial growth. Fecal homogenates containing bacteria significantly catalyzed tea phenolics, including epicatechin, catechin, 3-O-methyl gallic acid, gallic acid and caffeic acid to generate aromatic metabolites dependent on bacterial species. Different strains of intestinal bacteria had varying degrees of growth sensitivity to tea phenolics and metabolites. Growth of certain pathogenic bacteria such as <em>Clostridium perfringens, Clostridium difficile</em> and <em>Bacteroides</em> spp. was significantly repressed by tea phenolics and their derivatives, while commensal anaerobes like <em>Clostridium</em> spp., <em>Bifidobacterium</em> spp. and probiotics such as <em>Lactobacillus</em> sp. were less severely affected. This indicates that tea phenolics exert significant effects on the intestinal environment by modulation of the intestinal bacterial population, probably by acting as metabolic prebiotics. Our observations provide further evidence for the importance of colonic bacteria in the metabolism, absorption and potential activity of phenolics in human health and disease. The bioactivity of different phenolics may play an important role in the maintenance of gastrointestinal health.</p>
metabolites
bacterial
fecal
aromatic
their
phenolics
tea
microbiota
intestinal
effect
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/101
oai:ro.uow.edu.au:ihmri-1117
2013-08-08T23:56:01Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Changes in cholesterol biosynthetic and transport pathways after excitotoxicity
Kim, Ji-Hyun
Jittiwat, Jinatta
Ong, Wei-Yi
Farooqui, Akhlaq A.
Jenner, Andrew M.
Journal Article
2010-01-01T08:00:00Z
<p>Kim, J., Jittiwat, J., Ong, W., Farooqui, A. & Jenner, A. M. (2010). Changes in cholesterol biosynthetic and transport pathways after excitotoxicity. Journal of Neurochemistry, 112 (1), 34-41.</p>
10.1111/j.1471-4159.2009.06449.x
<p>The present study was carried out to elucidate changes in the gene expression and activity of cholesterol biosynthetic enzymes and transporters in the rat hippocampus after kainate excitotoxicity. Significantly increased cholesterol level was detected in the degenerating hippocampus, reaching double normal levels at 1 week after kainate injury. RT-PCR analyses of hippocampal homogenates showed significantly decreased mRNA expression of the transcription factor controlling cholesterol biosynthesis SREBP-2, and the rate-controlling enzyme HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase at all time points after kainate injection; and decreased lanosterol synthase and CYP51 at 1 and 2 weeks post-kainate injection respectively. GC-MS analyses showed a significant increase in cholesterol biosynthetic precursors lanosterol, desmosterol and 7-dehydrocholesterol at 1 day after kainate injection presumably reflecting biosysnthesis in injured neurons, and significant decreases in precursors at 1 and 2 weeks post-kainate injection, at time of gliosis in the degenerating hippocampus. Levels of cholesterol autooxidation including 7 ketocholesterol and cholesterol epoxides were elevated in the kainate lesioned hippocampus. Furthermore, loss of expression of the cholesterol transporter, ABCA1 was detected in neurons, but increased expression in astrocytes was detected after kainate lesions. The results suggest that increased cholesterol biosynthesis and loss of ABCA1 expression in injured neurons might result in increase in cholesterol in the degenerating hippocampus. The increased cholesterol might predispose to increased formation of cholesterol oxidation products which have been shown to be toxic to neurons. © 2009 International Society for Neurochemistry.</p>
cholesterol
biosynthetic
changes
transport
excitotoxicity
pathways
after
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/102
oai:ro.uow.edu.au:ihmri-1098
2011-12-09T00:48:09Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Health promotion by flavonoids, tocopherols, tocotrienols, and other phenols: direct or indirect effects? Antioxidant or not?
Halliwell, Barry
Rafter, J J
Jenner, Andrew M
Journal Article
2005-01-01T08:00:00Z
<p>Halliwell, B., Rafter, J. & Jenner, A. M. (2005). Health promotion by flavonoids, tocopherols, tocotrienols, and other phenols: direct or indirect effects? Antioxidant or not?. The American Journal of Clinical Nutrition, 81 (1), 268S-276S.</p>
<p>Foods and beverages rich in phenolic compounds, especially flavonoids, have often been associated with decreased risk of developing several diseases. However, it remains unclear whether this protective effect is attributable to the phenols or to other agents in the diet. Alleged health-promoting effects of flavonoids are usually attributed to their powerful antioxidant activities, but evidence for in vivo antioxidant effects of flavonoids is confusing and equivocal. This may be because maximal plasma concentrations, even after extensive flavonoid intake, may be low (insufficient to exert significant systemic antioxidant effects) and because flavonoid metabolites tend to have decreased antioxidant activity. Reports of substantial increases in plasma total antioxidant activity after flavonoid intake must be interpreted with caution; findings may be attributable to changes in urate concentrations. However, phenols might exert direct effects within the gastrointestinal tract, because of the high concentrations present. These effects could include binding of prooxidant iron, scavenging of reactive nitrogen, chlorine, and oxygen species, and perhaps inhibition of cyclooxygenases and lipoxygenases. Our measurements of flavonoids and other phenols in human fecal water are consistent with this concept. We argue that tocopherols and tocotrienols may also exert direct beneficial effects in the gastrointestinal tract and that their return to the gastrointestinal tract by the liver through the bile may be physiologically advantageous.</p>
other
tocotrienols
tocopherols
flavonoids
promotion
health
effects
indirect
direct
not
phenols
antioxidant
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/83
oai:ro.uow.edu.au:ihmri-1110
2013-03-11T03:01:04Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Cautions in the use of biomarkers of oxidative damage; the vascular and antioxidant effects of dark soy sauce in humans
Lee, Chung-Yung
Isaac, Helen
Wang, Huansong
Huang, Shan
Long, Lee-Hua
Jenner, Andrew
Kelly, Ronan
Halliwell, Barry
Journal Article
2006-01-01T08:00:00Z
<p>Lee, C., Isaac, H., Wang, H., Huang, S., Long, L., Jenner, A., Kelly, R. & Halliwell, B. (2006). Cautions in the use of biomarkers of oxidative damage; the vascular and antioxidant effects of dark soy sauce in humans. Biochemical and Biophysical Research Communications, 344 (3), 906-911.</p>
10.1016/j.bbrc.2006.03.217
<p>Dark soy sauce (DSS) is a powerful antioxidant in vitro. We investigated whether this effect could occur in vivo and improve vascular function. Healthy human subjects were given DSS or placebo meals in a randomized, crossover study. Blood and urine were sampled before and 1, 2, 3, and 4 h after the meal for F<sub>2</sub>-isoprostanes (total, free, and esterified) and 8OHdG measurements. Blood pressure, vascular augmentation index (AIx), and heart rate (HR) were also measured. Plasma total F<sub>2</sub>-isoprostanes significantly decreased 3 h after placebo and the decrease was greater for DSS. Plasma free and esterified F<sub>2</sub>-isoprostanes were also significantly decreased after DSS. Both placebo and DSS meals increased urinary F<sub>2</sub>-isoprostanes at 1 h but not thereafter, and lowered urinary 8OHdG levels, DBP and AIx, and increased HR. We conclude that DSS decreases lipid peroxidation in vivo. However, oxidative damage biomarkers changed after the placebo meal, a phenomenon to consider when designing interventional studies.</p>
humans
soy
dark
effects
sauce
antioxidant
oxidative
vascular
biomarkers
damage
cautions
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/95
oai:ro.uow.edu.au:ihmri-1112
2013-04-12T05:21:28Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Lovastatin modulates increased cholesterol and oxysterol levels and has a neuroprotective effect on rat hippocampal neurons after kainate injury
He, Xin
Jenner, Andrew
Ong, Wei-Yi
Farooqui, Akhlaq A
Patel, Shutish C
Journal Article
2006-01-01T08:00:00Z
<p>He, X., Jenner, A., Ong, W., Farooqui, A. A. & Patel, S. C. (2006). Lovastatin modulates increased cholesterol and oxysterol levels and has a neuroprotective effect on rat hippocampal neurons after kainate injury. Journal of Neuropathology and Experimental Neurology, 65 (7), 652-663.</p>
10.1097/01.jnen.0000225906.82428.69
<p>This study was carried out to elucidate the effect of a brain-permeable statin (lovastatin) on cholesterol and oxysterol levels of the hippocampus after neuronal injury induced by the excitotoxin, kainic acid. Increased immunolabeling to cholesterol and the oxysterol biosynthetic enzyme, cholesterol 24-hydroxylase, was observed in the rat hippocampus after kainate lesions. This was accompanied by increased levels of cholesterol, 24-hydroxycholesterol (product of cholesterol 24-hydroxylase enzymatic activity), and 7-ketocholesterol in homogenates of the degenerating hippocampus as detected by gas chromatography/mass spectrometry. Hippocampi from rats or organotypic slices that had been treated with kainate plus lovastatin showed significantly lower levels of cholesterol, 24-hydroxycholesterol, and 7-ketocholesterol compared with those that had been treated with kainate only. Lovastatin also modulated hippocampal neuronal loss after kainate treatment in vivo and in vitro. The level of 24-hydroxycholesterol detected in vivo after kainate treatment (>50 μM) was found to be neurotoxic in hippocampal slice cultures. These results suggest that brain-permeable statins such as lovastatin could have a neuroprotective effect by limiting the levels of oxysterol in brain areas undergoing neurodegeneration.</p>
injury
has
kainate
levels
oxysterol
cholesterol
increased
modulates
lovastatin
after
neurons
hippocampal
rat
effect
neuroprotective
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/97
oai:ro.uow.edu.au:ihmri-1113
2013-03-11T03:04:25Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Zinc supplementation decreases the development of atherosclerosis in rabbits
Ren, Minqin
Rajendran, Reshmi
Ning, Pan
Kwong Huat, Benny
Nam, Ong
Watt, Frank
Jenner, Andrew
Halliwell, Barry
Journal Article
2006-01-01T08:00:00Z
<p>Ren, M., Rajendran, R., Ning, P., Kwong Huat, B., Nam, O., Watt, F., Jenner, A. & Halliwell, B. (2006). Zinc supplementation decreases the development of atherosclerosis in rabbits. Free Radical Biology and Medicine, 41 (2), 222-225.</p>
10.1016/j.freeradbiomed.2006.03.017
<p>Developing atherosclerotic plaques in cholesterol-fed rabbits are enriched in iron but depleted in zinc. In order to examine further the role of zinc, New Zealand White rabbits were fed a high-cholesterol 1% (w/w) diet with zinc (1 g/kg) supplementation for 8 weeks. After the 8-week period, the average atherosclerotic lesion cross-sectional areas in the aortas of the animals fed with the zinc supplement were significantly decreased (1.0 mm<sup>2</sup>) compared with lesion areas of the animals fed only on the high-cholesterol diet (3.1 mm<sup>2</sup>). Using nuclear microscopy, a technique for mapping and measuring trace elements in tissue sections, lesion zinc levels (24 ppm) were observed to be unchanged in the zinc-fed rabbits compared to controls. However, average lesion Fe levels in the zinc-fed group were measured at 32 ppm, whereas in the control group the average Fe levels were significantly higher at 43 ppm (<em>P</em> = 0.03). Our data support the concept that zinc may have an antiatherogenic effect by decreasing iron levels in the lesion, possibly leading to inhibition of iron-catalyzed free radical reactions.</p>
atherosclerosis
development
rabbits
decreases
zinc
supplementation
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/98
oai:ro.uow.edu.au:ihmri-1123
2011-12-13T00:54:29Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: An orally active anti-cancer drug waiting for its call-of-duty?
Matthews, Hayden
Ranson, Marie
Kelso, Michael J
Journal Article
2011-01-01T08:00:00Z
Matthews, H., Ranson, M. & Kelso, M. J. (2011). Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: An orally active anti-cancer drug waiting for its call-of-duty?. International Journal of Cancer, 129 (9), 2051-2061.
10.1002/ijc.26156
Amiloride.HCl is clinically used as an oral potassium-sparing diuretic, but multiple studies in biochemical, cellular and animal models have shown that the drug also possesses anti-tumour and anti-metastasis activities. The additional effects appear to arise through inhibition of two discrete targets: (i) the sodium-hydrogen exchanger 1 (NHE1), a membrane protein responsible for the characteristically low extracellular pH of tumours and (ii) the urokinase-type plasminogen activator (uPA), a serine protease mediator of cell migration, invasion and metastasis and well-known marker of poor prognosis in cancer. This mini-review summarises for the first time the reported anti-tumour/metastasis effects of amiloride in experimental models, discusses the putative molecular mechanisms responsible for these effects and concludes by commenting on the pros and cons of trialling amiloride or one of its structural analogues as potential new anti-tumour/metastasis drugs. © 2011 UICC.
amiloride
orally
active
cancer
drug
waiting
its
call
duty
potassium
effects
sparing
metastasis
tumour
anti
diuretic
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/108
oai:ro.uow.edu.au:ihmri-1125
2011-12-20T00:42:28Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Editorial: The Plasminogen Activation System in Pathology: Use in Prognosis and Therapy
Ranson, Marie
Journal Article
2011-01-01T08:00:00Z
Ranson, M. (2011). Editorial: The Plasminogen Activation System in Pathology: Use in Prognosis and Therapy. Current Drug Targets, 12 (11), 1-2.
10.2174/138945011797635894
activation
plasminogen
pathology
system
editorial
therapy
prognosis
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/110
oai:ro.uow.edu.au:ihmri-1124
2011-12-20T00:42:28Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Dependence on Endocytic Receptor Binding via a Minimal Binding Motif Underlies the Differential Prognostic Profiles of SerpinE1 and SerpinB2 in Cancer
Cochran, Blake J
Croucher, David
Lobov, Sergei A
Saunders, Darren
Ranson, Marie
Journal Article
2011-01-01T08:00:00Z
Cochran, B. J., Croucher, D., Lobov, S. A., Saunders, D. & Ranson, M. (2011). Dependence on Endocytic Receptor Binding via a Minimal Binding Motif Underlies the Differential Prognostic Profiles of SerpinE1 and SerpinB2 in Cancer. The Journal of Biological Chemistry, 286 (27), 24467-24475.
10.1074/jbc.M111.225706
Tumor overexpression of urokinase-type plasminogen activator (uPA) and its specific inhibitor SerpinE1 (plasminogen activator inhibitor type-1) correlates with poor prognosis and increased metastatic potential. Conversely, tumor expression of uPA and another specific inhibitor, SerpinB2 (plasminogen activator inhibitor type-2), are associated with favorable outcome and relapse-free survival. It is not known how overexpression of these uPA inhibitors results in such disparate outcomes. A possible explanation may be related to the presence of a proposed low density lipoprotein receptor (LDLR)-binding motif in SerpinE1 responsible for mitogenic signaling via ERK that is absent in SerpinB2. We now show that complementation of such a LDLR-binding motif in SerpinB2 by mutagenesis of two key residues enabled high affinity binding to very LDLR (VLDLR). Furthermore, the VLDLR-binding SerpinB2 form behaved in a manner indistinguishable from SerpinE1 in terms of enhanced uPA-SerpinB2 complex endocytosis and subsequent ERK phosphorylation and cell proliferation; that is, the introduction of the LDLR-binding motif to SerpinB2 was necessary and sufficient to allow it to acquire characteristics of SerpinE1 associated with malignancy. In conclusion, this study defines the structural elements underlying the distinct interactions of SerpinE1 versus SerpinB2 with endocytic receptors and how differential VLDLR binding impacts on downstream cellular behavior. This has clear relevance to understanding the paradoxical disease outcomes associated with overexpression of these serpins in cancer
serpinb2
serpine1
profiles
prognostic
differential
underlies
motif
cancer
minimal
dependence
via
binding
receptor
endocytic
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/109
oai:ro.uow.edu.au:ihmri-1126
2011-12-21T03:31:36Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Codon usage roles in human papillomavirus
Zhao, Kongnan
Chen, Jiezhong
Journal Article
2011-01-01T08:00:00Z
Zhao, K. & Chen, J. (2011). Codon usage roles in human papillomavirus. Reviews in Medical Virology, 21 (6), 397-411.
10.1002/rmv.707
Human papillomavirus (HPV) genomes, similar to other virus genomes, frequently have a G+C content significantly different from their host species. The HPV genomes show a strong codon usage bias to 18 codons, with 14 showing T at the third position amongst degenerately encoded amino acids. The codon usage pattern in HPV genome plays an important role, which regulates low or non-translational expression of the viral capsid genes and results in very weak protein expression of oncogenes in a wide range of mammalian cells. Codon modification has been proved to be a powerful technology to overcome the translational blockage and weak expression of both HPV capsid genes and oncogenes
in different expression systems. Furthermore, keratinocytes are the host cells of HPV infection; the codon usage in HPV capsid genes matches available aminoacyl-tRNAs in differentiated keratinocytes to modulate their protein expression. HPV DNA vaccines with codon optimization have been shown to have higher immunogenicity and induce both strong cellular and humoral responses in animal models, which may be a promising form of therapeutic HPV vaccines.
codon
roles
papillomavirus
human
usage
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/111
oai:ro.uow.edu.au:ihmri-1128
2013-05-10T00:01:11Z
publication:journal_articles
publication:grants
publication:smh
publication:ihmri
publication:document_types
Full length TrkB potentiates estrogen receptor alpha mediated transcription suggesting convergence of susceptibility pathways in schizophrenia
Wong, Jenny
Woon, H G
Shannon Weickert, Cynthia
Journal Article
2011-01-01T08:00:00Z
<p>Wong, J., Woon, H. & Shannon Weickert, C. (2011). Full length TrkB potentiates estrogen receptor alpha mediated transcription suggesting convergence of susceptibility pathways in schizophrenia. Molecular and Cellular Neuroscience, 46 (1), 67-78.</p>
10.1016/j.mcn.2010.08.007
<p>In this study, we determined if estrogen receptor alpha (ERα) can interact with the full length tropomyosin receptor kinase B (TrkB-TK+), both of which are implicated in schizophrenia pathogenesis. Using neuronal (SHSY5Y) and non-neuronal (CHOK1) cell-lines, we showed that TrkB-TK+ can increase transcription at estrogen response elements (EREs) with and without exogenous estrogen treatment. In the presence of estrogen, TrkB-TK+ further potentiated the effect of estrogen stimulation on ERα-mediated transcription. This synergistic effect of TrkB-TK+ on ERα-mediated transcription was not due to direct effects of TrkB-TK+ in the nucleus, but occurred through cytoplasmic signaling of TrkB-TK+ via the MAPK/ERK pathway to phosphorylate ERα, leading to an induction in ERα-mediated transcription. When we examined the PI3K/AKT pathway, we found that PI3K/AKT activity constitutively inhibited baseline transcription at EREs. Furthermore, we showed that signaling via PI3K/AKT inhibited TrkB-TK+-dependent transcriptional potentiation at EREs. Our findings suggest that TrkB-TK+-linked second messenger signaling pathways can reciprocally regulate ERα-mediated transcription at EREs. Considering that both ERα and TrkB-TK+ expression are reduced in schizophrenia, our findings suggest that dysfunction in TrkB-TK+ signaling may occur upstream of, or in conjunction with a dysfunction in ERα, and that transcriptional regulation by ERα may be decreased by reductions in TrkB-TK+. © 2010.</p>
NHMRC/568884
<a href="http://purl.org/au-research/grants/NHMRC/568884">http://purl.org/au-research/grants/NHMRC/568884</a>
mediated
alpha
receptor
estrogen
potentiates
trkb
suggesting
convergence
transcription
susceptibility
length
full
schizophrenia
pathways
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/113
oai:ro.uow.edu.au:ihmri-1127
2011-12-21T03:31:36Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Forty Years Later and the Role of Plasminogen Activator Inhibitor Type 2/SERPINB2 Is Still an Enigma
Lee, Jodi A
Cochran, Blake J
Lobov, Sergei A
Ranson, Marie
Journal Article
2011-01-01T08:00:00Z
Lee, J. A., Cochran, B. J., Lobov, S. A. & Ranson, M. (2011). Forty Years Later and the Role of Plasminogen Activator Inhibitor Type 2/SERPINB2 Is Still an Enigma. Seminars in Thrombosis and Hemostasis, 37 (4), 395-407.
10.1055/s-0031-1276589
Plasminogen activator inhibitor (PAI)-2 expression is acutely upregulated in pregnancy, inflammation, infection, and other pathophysiological conditions. Circumstances that prevent PAI-2 upregulation are associated with chronic pathology. Altogether this strongly suggests that PAI-2 is one of the many proteins that maintain homeostasis during damage or stress. However, several functions ranging from a classical serpin to various intracellular roles have been ascribed to PAI-2 and, because none of these have been definitively proven in vivo, to this day its precise role or roles remains an enigma. This review readdresses the evidence supporting a role for PAI-2 in fibrinolysis and proteolysis within extracellular environments and includes a review of the many potential intracellular functions attributed to PAI-2.
still
serpinb2
2
type
inhibitor
activator
enigma
plasminogen
forty
role
later
years
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/112
oai:ro.uow.edu.au:ihmri-1129
2012-01-03T01:00:57Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Molecular competition between plasminogen activator inhibitors type -1 and -2 for urokinase: implications for cellular proteolysis and adhesion in cancer
Lobov, Sergei
Ranson, Marie
Journal Article
2011-01-01T08:00:00Z
Lobov, S. & Ranson, M. (2011). Molecular competition between plasminogen activator inhibitors type -1 and -2 for urokinase: implications for cellular proteolysis and adhesion in cancer. Cancer Letters, 303 (2), 118-127.
10.1016/j.canlet.2011.01.018
Up-regulation of the urokinase plasminogen activation (uPA) system leads to increased
cancer invasion and metastasis. Plasminogen activator inhibitors type-1 (PAI-1/SERPINE1)
and type-2 (PAI-2/SERPINB2) have similar uPA inhibitory properties yet PAI-1 promotes
cell invasion by modulating cell adhesion and migration. High tumour PAI-2 levels are
associated with improved prognoses. Herein we show that PAI-2 is capable of inhibiting
uPA in the presence of PAI-1, particularly on adherent cells in the presence of vitronectin.
This suggests that elevated levels of PAI-2 in the tumour microenvironment could outcompete
PAI-1 for uPA inhibition through its inhibitory serpin function. However, PAI-1 modulated
cell adhesion in a largely uPA-independent manner consequently PAI-2 could not
counteract the effects of PAI-1 on adhesion/migration. Thus studies aimed at further characterising
the interplay between PAI-1 and PAI-2 on uPA-dependent pro-invasive processes
are warranted.
type
cancer
adhesion
inhibitors
cellular
implications
activator
plasminogen
urokinase
between
competition
molecular
proteolysis
2
1
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/114
oai:ro.uow.edu.au:ihmri-1130
2014-10-15T22:44:32Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Small molecule antagonists of the urokinase (uPA): urokinase receptor (uPAR) interaction with high reported potencies show only weak effects in cell-based competition assays employing the native uPAR ligand
De Souza, Melissa
Matthews, Hayden
Lee, Jodi A
Ranson, Marie
Kelso, Michael J
Journal Article
2011-01-01T08:00:00Z
<p>De Souza, M., Matthews, H., Lee, J. A., Ranson, M. & Kelso, M. J. (2011). Small molecule antagonists of the urokinase (uPA): urokinase receptor (uPAR) interaction with high reported potencies show only weak effects in cell-based competition assays employing the native uPAR ligand. Bioorganic and Medicinal Chemistry, 19 (8), 2549-2556.</p>
10.1016/j.bmc.2011.03.016
<p>Binding of the urokinase-type plasminogen activator (uPA) to its cell-surface-bound receptor uPAR and upregulation of the plasminogen activation system (PAS) correlates with increased metastasis and poor prognosis in several tumour types. Disruptors of the uPA:uPAR interaction represent promising anti-tumour/metastasis agents and several approaches have been explored for this purpose, including the use of small molecule antagonists. Two highly potent non-peptidic antagonists 1 and 2 (IC50 1 = 0.8 nM, IC50 2 = 33 nM) from the patent literature were reportedly identified using competition assays employing radiolabelled uPAR-binding uPA fragments and appeared as useful pharmacological tools for studying the PAS. Before proceeding to such studies, confirmation was sought that 1 and 2 retained their potencies in physiologically relevant cell-based competition assays employing uPAR's native binding partner high molecular weight uPA (HMW-uPA). This study describes a new solution phase synthesis of 1, a mixed solid/solution phase synthesis of 2 and reports the activities of 1 and 2 in semi-quantitative competition flow cytometry assays and quantitative cell-based uPA activity assays that employed HMW-uPA as the competing ligand. The flow cytometry experiments revealed that high concentrations of 2 (10-100 μM) are required to compete with HMW-uPA for uPAR binding and that 1 shows no antagonist effects at 100 μM. The cell-based enzyme activity assays similarly revealed that 1 and 2 are poor inhibitors of cell surface-bound HMW-uPA activity (IC50 >100 μM for 1 and 2). The report highlights the dangers of identifying false-positive lead uPAR antagonists from competition assays employing labelled competing ligands other than the native HMW-uPA. © 2011 Elsevier Ltd. All rights reserved.</p>
small
molecule
antagonists
urokinase
upa
receptor
upar
interaction
high
reported
potencies
show
only
native
weak
ligand
effects
cell
competition
assays
employing
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/115
oai:ro.uow.edu.au:medpapers-1154
2013-04-16T05:34:49Z
publication:journal_articles
publication:smh
publication:medpapers
publication:ihmri
publication:document_types
Nutritional supplementation for older people
Lambert, Matt A
Potter, Jan M
McMurdo, Marion ET
Journal Article
10.1017/S0959259810000262
2010-01-01T08:00:00Z
Nutritional
supplementation
for
older
people
<p>Lambert, M. A., Potter, J. M. & McMurdo, M. E.. (2010). Nutritional supplementation for older people. Reviews in Clinical Gerontology, 20 (4), 317-326.</p>
<p>Malnutrition is common in older people and is associated with a number of adverse outcomes. We review the evidence for the effectiveness of nutritional supplementation for older people in the community, in institutional care and following discharge from hospital. Studies in these settings are scarce, often include only small numbers of participants and are of variable quality. The interventions used are heterogeneous and difficult to directly compare. Oral nutritional supplements (sip feeds), dietary fortification, educational programmes, exercise, flavour enhancement and meal setting have all been studied. Evidence for use of oral nutritional supplements as sip feeds in undernourished community-dwelling and institutionalized older people and in those discharged from hospital is currently insufficient to recommend routine use. Flavour enhancement and more sociable meal environments may be beneficial. Further, more methodologically robust research is needed to clarify the effect of these interventions.</p>
Medicine and Health Sciences
https://ro.uow.edu.au/medpapers/150
oai:ro.uow.edu.au:hbspapers-2815
2013-10-23T01:07:35Z
publication:journal_articles
publication:smh
publication:ihmri
publication:hbspapers
publication:document_types
Intraluminal pressure readings during the establishment of a positive 'tamponade test' in the management of postpartum haemorrhage
Georgiou, Christos
Journal Article
10.1111/j.1471-0528.2009.02436.x
2010-01-01T08:00:00Z
Intraluminal
pressure
readings
during
establishment
positive
tamponade
test
management
postpartum
haemorrhage
<p>Georgiou, C. (2010). Intraluminal pressure readings during the establishment of a positive 'tamponade test' in the management of postpartum haemorrhage. BJOG: an International Journal of Obstetrics and Gynaecology, 117 (3), 295-303.</p>
<p><strong>Objective</strong> To investigate the proposed mechanism by which intrauterine balloons achieve their tamponade effect of creating an ‘intrauterine pressure that is greater than the systemic arterial pressure’.</p>
<p><strong>Design</strong> To determine the intraluminal pressures within a Bakri balloon during the establishment of a positive ‘tamponade test’ in the management of postpartum haemorrhage. To correlate these intraluminal pressures with contemporaneous readings of blood pressure recordings as documented from the operating theatre anaesthetic charts.</p>
<p><strong>Setting</strong> An obstetric unit (approximately 2400 births) in Wollongong, New South Wales, Australia.</p>
<p><strong>Sample</strong> Two women in whom first-line uterotonics were unsuccessful and who required a Bakri balloon to control postpartum haemorrhage secondary to an atonic uterus.</p>
<p><strong>Methods</strong> A DigiMano (Netech Corporation, Farmingdale, NY, USA) pressure recorder was attached via a three-way tap to a Bakri balloon. Anaesthetic charts of the two cases were reviewed retrospectively.</p>
<p><strong>Main outcome measures</strong> Intraluminal pressure readings were recorded after each 50-ml aliquot of normal saline had been insufflated into the balloon whilst the next aliquot was being prepared.</p>
<p><strong>Results</strong> There is a curvilinear relationship between the intraluminal pressure and the balloon volume. The pressure does not exceed the systolic blood pressure of the patient at the time of establishment of a positive tamponade test.</p>
<p><strong>Conclusions</strong> The intraluminal pressure within the tamponade balloon does not exceed the systolic blood pressure of the patient when a positive tamponade test is established.</p>
Arts and Humanities
Life Sciences
Medicine and Health Sciences
Social and Behavioral Sciences
https://ro.uow.edu.au/hbspapers/1762
oai:ro.uow.edu.au:ihmri-1151
2012-07-13T07:48:00Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Overcoming original antigenic sin to generate new CD8 T cell IFN-y responses in an antigen-experienced host
Liu, Xiaosong
Leggatt, Graham R
Frazer, Ian H
Thomas, Ranjeny
Dyer, Joanne
Fernando, Germain J P
Zhong, Jie
Journal Article
2006-01-01T08:00:00Z
Liu, X., Dyer, J., Leggatt, G. R., Fernando, G. J P., Zhong, J., Thomas, R. & Frazer, I. H. (2006). Overcoming original antigenic sin to generate new CD8 T cell IFN-y responses in an antigen-experienced host. Journal of Immunology, 177 (5), 2873-2879.
The failure to mount effective immunity to virus variants in a previously virus-infected host is known as original antigenic sin. We have previously shown that prior immunity to a virus capsid protein inhibits induction by immunization of an IFN-?? CD8+ T cell response to an epitope linked to the capsid protein. We now demonstrate that capsid protein-primed CD4+ T cells secrete IL-10 in response to capsid protein presented by dendritic cells, and deviate CD8+ T cells responding to a linked MHC class I-restricted epitope to reduce IFN-?? production. Neutralizing IL-10 while delivering further linked epitope, either in vitro or in vivo, restores induction by immunization of an Ag-specific IFN-?? response to the epitope. This finding demonstrates a strategy for overcoming inhibition of MHC class I epitopes upon immunization of a host already primed to Ag, which may facilitate immunotherapy for chronic viral infection or cancer. Copyright ?? 2006 by The American Association of Immunologists, Inc.
Overcoming
original
antigenic
sin
generate
CD8
cell
IFN
responses
antigen
experienced
host
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/136
oai:ro.uow.edu.au:scipapers-7418
2012-07-25T04:54:04Z
publication:journal_articles
publication:smh
publication:scipapers
publication:ihmri
publication:cmmb
publication:science
publication:document_types
Attenuation of the lysosomal death pathway by lysosomal cholesterol accumulation
Garner, Brett
Brown, A
Appelqvist, Hanna
Nilsson, C
Kagedal, K
Ollinger, K
Journal Article
10.1016/j.ajpath.2010.10.030
2011-01-01T08:00:00Z
Attenuation
lysosomal
death
pathway
lysosomal
cholesterol
accumulation
CMMB
Appelqvist, H., Nilsson, C., Garner, B., Brown, A. J., Kagedal, K. & Ollinger, K. (2011). Attenuation of the lysosomal death pathway by lysosomal cholesterol accumulation. American Journal of Pathology, 178 (2), 629-639.
In the past decade, lysosomal membrane permeabilization (LMP) has emerged as a significant component of cell death signaling. The mechanisms by which lysosomal stability is regulated are not yet fully understood, but changes in the lysosomal membrane lipid composition have been suggested to be involved. Our aim was to investigate the importance of cholesterol in the regulation of lysosomal membrane permeability and its potential impact on apoptosis. Treatment of normal human fibroblasts with U18666A, an amphiphilic drug that inhibits cholesterol transport and causes accumulation of cholesterol in lysosomes, rescued cells from lysosome-dependent cell death induced by the lysosomotropic detergent O-methyl-serine dodecylamide hydrochloride (MSDH), staurosporine (STS), or cisplatin. LMP was decreased by pretreating cells with U18666A, and there was a linear relationship between the cholesterol content of lysosomes and their resistance to permeabilization induced by MSDH. U18666A did not induce changes in expression or localization of 70-kDa heat shock proteins (Hsp70) or antiapoptotic Bcl-2 proteins known to protect the lysosomal membrane. Induction of autophagy also was excluded as a contributor to the protective mechanism. By using Chinese hamster ovary (CHO) cells with lysosomal cholesterol overload due to a mutation in the cholesterol transporting protein Niemann-Pick type C1 (NPC1), the relationship between lysosomal cholesterol accumulation and protection from lysosome-dependent cell death was confirmed. Cholesterol accumulation in lysosomes attenuates apoptosis by increasing lysosomal membrane stability. Copyright C 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Life Sciences
Physical Sciences and Mathematics
Social and Behavioral Sciences
https://ro.uow.edu.au/scipapers/4076
oai:ro.uow.edu.au:ihmri-1162
2013-05-09T23:46:07Z
publication:journal_articles
publication:grants
publication:smh
publication:ihmri
publication:document_types
Amyloid beta selectively modulates neuronal TrkB alternative transcript expression with implications for Alzheimer's disease
Wong, J
Higgins, M
Halliday, G
Garner, B
Journal Article
2012-01-01T08:00:00Z
<p>Wong, J., Higgins, M., Halliday, G. & Garner, B. (2012). Amyloid beta selectively modulates neuronal TrkB alternative transcript expression with implications for Alzheimer's disease. Neuroscience, 210 (N/A), 363-374.</p>
10.1016/j.neuroscience.2012.02.037
<p>Dysregulation in brain-derived neurotrophic factor (BDNF)/full-length TrkB (TrkB-TK+) signaling is implicated in promoting neurodegeneration in Alzheimer's disease (AD). BDNF/TrkB-TK+ signaling can be modulated by the presence of truncated TrkB isoforms (TrkB-TK-, TrkB-Shc). All TrkB isoforms are encoded by different alternative transcripts. In this study, we assessed if expression of the three main TrkB alternative transcripts, TrkB-TK+, TrkB-TK-, and TrkB-Shc are altered in AD. Using a cohort of control and AD brains (n=29), we surveyed the hippocampus, temporal cortex, occipital cortex, and cerebellum and found specific increases in TrkB-Shc, a neuron-specific transcript, in the AD hippocampus. No significant changes were detected in TrkB-TK+ and TrkB-TK- transcript levels in AD in any brain region examined. Corresponding changes in truncated TrkB protein levels were found in the hippocampus, although a significant increase in the temporal cortex was also observed. Our findings suggested that neuron-specific changes in TrkB may be occurring in AD; thus, we determined whether TrkB-Shc expression could be modulated by amyloid beta 1-42 (Aβ 42). We found increased TrkB-Shc mRNA levels in differentiated SHSY5Y neuronal cell-lines exposed to fibril-containing Aβ 42 preparations. When we assessed the cellular impact of increased TrkB-Shc, we found co-localization between TrkB-Shc and TrkB-TK+. Interestingly, TrkB-Shc overexpression selectively attenuated BDNF/TrkB-TK+-mediated signaling via the mitogen-activated protein kinase kinase (MEK) pathway, but not the protein kinase B pathway. In AD, MEK signaling is increased in vulnerable neurons and linked to abnormal phosphorylation of cytoskeletal proteins. Altogether, our findings suggest that elevated TrkB-Shc expression in AD may function as a compensatory response in neurons in AD to promote survival.</p>
NHMRC/568884
<a href="http://purl.org/au-research/grants/NHMRC/568884">http://purl.org/au-research/grants/NHMRC/568884</a>
expression
alzheimer
transcript
alternative
trkb
neuronal
modulates
selectively
beta
amyloid
implications
disease
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/147
oai:ro.uow.edu.au:ihmri-1163
2015-03-08T21:37:17Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Recent peritonitis associates with mortality among patients treated with peritoneal dialysis
Boudville, Neil
Kemp, Anna
Clayton, Philip
Lim, Wai
Badve, Sunil V
Hawley, Carmel M
McDonald, Stephen P
Wiggins, Kathryn J
Bannister, Kym M
Brown, Fiona G
Johnson, David W
Journal Article
2012-01-01T08:00:00Z
<p>Boudville, N., Kemp, A., Clayton, P., Lim, W., Badve, S. V., Hawley, C. M., McDonald, S. P., Wiggins, K. J., Bannister, K. M., Brown, F. C. & Johnson, D. W. (2012). Recent peritonitis associates with mortality among patients treated with peritoneal dialysis. Journal of the American Society of Nephrology, 23 (8), 1398-1405.</p>
10.1681/ASN.2011121135
<p>Peritonitis is a major complication of peritoneal dialysis, but the relationship between peritonitis and mortality among these patients is not well understood. In this case-crossover study, we included the 1316 patients who received peritoneal dialysis in Australia and New Zealand from May 2004 through December 2009 and either died on peritoneal dialysis or within 30 days of transfer to hemodialysis. Each patient served as his or her own control. The mean age was 70 years, and the mean time receiving peritoneal dialysis was 3 years. In total, there were 1446 reported episodes of peritonitis with 27% of patients having ≥2 episodes. Compared with the rest of the year, there were significantly increased odds of peritonitis during the 120 days before death, although themagnitude of this association wasmuch greater during the 30 days before death. Compared with a 30-day window 6 months before death, the odds for peritonitis was six-fold higher during the 30 days immediately before death (odds ratio, 6.2; 95% confidence interval, 4.4–8.7). In conclusion, peritonitis significantly associates with mortality in peritoneal dialysis patients. The increased odds extend up to 120 days after an episode of peritonitis but themagnitude is greater during the initial 30 days.</p>
dialysis
peritonitis
peritoneal
recent
treated
patients
among
mortality
associates
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/148
oai:ro.uow.edu.au:ihmri-1165
2012-09-19T05:48:14Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Glucose-6-phosphate stimulatioin of human muscle glycogen synthase phosphate
Okubo, Masamichi
Bogardus, Clifton
Lillioja, S
Mott, David M
Journal Article
1988-01-01T08:00:00Z
<p>Okubo, M., Bogardus, C., Lillioja, S. & Mott, D. 1988, 'Glucose-6-phosphate stimulatioin of human muscle glycogen synthase phosphate', Metabolism: Clinical and Experimental, vol. 37, no. 12, pp. 1171-1176.</p>
<p>The influence of glucose-&phosphate (glucose-6-P) on skeletal muscle glycogen eynthase phosphatase was examined in normal glucose-tolerant Southwest American Indians. Phosphatase was stimulated with physiological concentrations of glucose-6-P and inhibited by ATP (5 mmol/L) and glycogen (0.1%). Phosphatase activity was measured before and after insulin infusion using the euglycemic clamp technique. Although glycogen synthase fractional activity increased in all subjects, this increase was not related to a change in phosphatase activity in the absence or presence of glucose-6-P. These results suggest that glycogen synthase phosphatase from human muscle can be regulated by physiological concentrations of glucose-6-P, ATP, and glycogen, and that insulin does not alter glucose-6-P stimulation of the enzyme in normal subjects.</p>
human
glycogen
muscle
glucose
6
synthase
phosphate
stimulatioin
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/150
oai:ro.uow.edu.au:ihmri-1164
2012-09-19T04:33:28Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Two cases of thyroid carcinoma that were not stimulated by recombinant human thyotropin
Depczynski, Barbara
Lillioja, Stephen
Journal Article
2004-01-01T08:00:00Z
Depczynski, B. & Lillioja, S. 2004, 'Two cases of thyroid carcinoma that were not stimulated by recombinant human thyotropin', Journal of Clinical Endocrinology & Metabolism, vol. 89, no. 9, pp. 4772-4772.
recombinant
stimulated
not
were
thyotropin
that
human
carcinoma
thyroid
cases
two
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/149
oai:ro.uow.edu.au:ihmri-1168
2012-09-19T04:33:28Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Recent epidemiological contributions to the pathogenesis and etiology of non-insulin dependent diabetes
Bennett, P
Bogardus, C
Knowler, W C
Lillioja, Stephen
Journal Article
1987-01-01T08:00:00Z
Bennett, P., Bogardus, C., Knowler, W. C. & Lillioja, S. 1987, 'Recent epidemiological contributions to the pathogenesis and etiology of non-insulin dependent diabetes', Journal of Medical Association of Thailand, vol. 70, no. Suppl 2, pp. 5-11.
insulin
epidemiological
dependent
diabetes
recent
contributions
non
pathogenesis
etiology
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/153
oai:ro.uow.edu.au:ihmri-1169
2012-09-19T05:36:32Z
publication:journal_articles
publication:smh
publication:ihmri
publication:document_types
Relationships between plasma lipoprotein concentrations and insulin action in an obese hyperinsulinemic population
Abbott, W
Lillioja, Stephen
Young, A
Zawadzki, J K
Yki-Jarvinen, H
Christin, L
Howard, B
Journal Article
1987-01-01T08:00:00Z
<p>Abbott, W., Lillioja, S., Young, A., Zawadzki, J. K., Yki-Jarvinen, H., Christin, L. & Howard, B. 1987, 'Relationships between plasma lipoprotein concentrations and insulin action in an obese hyperinsulinemic population', Diabetes, vol. 36, no. 8, pp. 897-904.</p>
<p>Relationships have been observed between lipoprotein concentrations and insulin action. These relationships may be important in explaining the association of insulin resistance and abnormalities of lipoprotein metabolism found in obesity, diabetes, and hypertriglyceridemia. We have measured plasma lipoprotein concentrations and indices of insulin action in 85 men and 56 women, all of whom were normolipidemic and had normal glucose tolerance. The subjects were obese Southwestern American Indians (body mass index 34 +/- 1). Insulin action was measured via the hyperinsulinemic clamp with simultaneous indirect calorimetry. Triglyceride concentrations were inversely related to rates of total insulin-mediated glucose disposal (in men and women, respectively, r = -.37, P less than .01; r = -.24, P less than .10), glucose storage (r = -.31, P less than .01; r = -.25, P less than .10), increase in glucose oxidation (r = -.29, P less than .01; r = -.24, P less than .10), and, in men only, suppression of endogenous glucose production (r = -.32, P less than .01). High-density lipoprotein (HDL) cholesterol concentration was positively related to rates of total insulin-mediated glucose disposal (r = .35, P less than .01; r = .33, P less than .05), increase in carbohydrate oxidation (r = .40, P less than .001; r = .39, P less than .001), suppression of endogenous glucose production (r = .24, P less than .05; r = .29, P less than .05), and, in men only, glucose storage (r = .35, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)</p>
lipoprotein
concentrations
insulin
action
between
obese
relationships
hyperinsulinemic
population
plasma
Medicine and Health Sciences
https://ro.uow.edu.au/ihmri/154
1538834/qualified-dublin-core/100//