%0 Journal Article %~ PubMed %A Ng, Ethan %A Lu, Yaxin %A Hambly, Brett %A Jelinek, Herbert F %A Yu, Bing %A Matthews, Slade %A McLachlan, Craig S %T Angiotensin-converting enzyme gene DD genotype is associated with increased systolic blood pressure in an Australian Rural Type 2 Diabetic Cohort. %B Hypertension Research %D 2013 %C United Kingdom %I Nature Publishing Group %V 36 %N 4 %P 381-382 %@ 1348-4214 %X %Z FOR Codes: 110201 %0 Journal Article %A Buljan, Vlado %A Holsinger, Damian %A Hambly, Brett %A Banati, Richard %A Ivanova, E.P. %T Intrinsic microtubule GTP-cap dynamics in semi-confined systems: kinetochore-microtubule interface %B Journal of Biological Physics %D 2013 %C Netherlands %I Springer Netherlands %V 39 %N 1 %P 81-98 %@ 1573-0689 %X %Z FOR Codes: 110902 %0 Journal Article %~ PubMed %A Ko, Hung T %A Yin, Jian L %A Wyburn, Kate %A Wu, Huiling %A Eris, Josette M %A Hambly, Brett D %A Chadban, Steven J %T Sirolimus reduces vasculopathy but exacerbates proteinuria in association with inhibition of VEGF and VEGFR in a rat kidney model of chronic allograft dysfunction. %B Nephrology, Dialysis, Transplantation %D 2013 %C United Kingdom %I Oxford University Press %V 28 %N 2 %P 327-336 %@ 1460-2385 %X %Z FOR Codes: 110708 %0 Journal Article %A Buljan, Vlado %A Holsinger, Damian %A Brown, Daniel %A Bohorquez-Florez, J. J. %A Hambly, Brett %A Delikatny, E. J. %A Ivanova, E. P. %A Banati, Richard %T Spinodal decomposition and the emergence of dissipative transient periodic spatio-temporal patterns in acentrosomal microtubule multitudes of different morphology %B Chaos %D 2013 %C United States %I American Institute of Physics %V 23 %N 2 %P 023120 %@ 1089-7682 %X %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Wu, Buchu %A Hu, Ke %A Li, Shu %A Zhu, Jing %A Gu, Liying %A Shen, Haoran %A Hambly, Brett D %A Bao, Shisan %A Di, Wen %T Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer. %B Oncology Reports %D 2012 %C Greece %I Spandidos Publications %V 27 %N 1 %P 101-108 %@ 1791-2431 %X Dihydroartiminisin (DHA), the active component of a Chinese herb (Artemisia annua), has been utilised as an anti-malarial drug since ancient China. DHA has also been shown to inhibit proliferation of cancer in vitro. However, the capacity of DHA to inhibit the development of ovarian cancer is still unclear. The adhesion, invasion, and migration of human ovarian cancer cell line (HO8910PM) was determined following DHA treatment in vitro, using Matrigel coated plate, transwell membrane chamber, and wound healing models, respectively. A mouse ovarian cancer model was established by orthotopic inoculation of HO8910PM cell line in nude mice. The growth and metastasis in vivo was determined 8 weeks post-implantation in response to DHA treatment. The expression of phosphorylated focal adhesion kinase (pFAK) and matrix metalloproteinases (MMP-2 and MMP-9) was evaluated using Western blotting. The expression of Von Willebrand factor (vWF) and infiltration of macrophages were determined, using immunohistochemistry. DHA inhibits ovarian cancer cell proliferation, adhesion, migration and invasion in vitro in a dose-dependent manner, consistent with decreased expression of pFAK and MMP-2, but not MMP-9. DHA inhibited metastasis significantly in vivo, associated with reduced vWF expression and macrophage infiltration. In conclusion, DHA inhibits the development of ovarian cancer, in part via down-regulating pFAK, MMP-2, vWF and macrophage infiltration. %Z FOR Codes: 111201 %0 Journal Article %~ PubMed %A Yao, Mu %A Xie, Chanlu %A Constantine, Maryrose %A Hua, Sheng %A Hambly, Brett D %A Jardine, Greg %A Sved, Paul %A Dong, Qihan %T How can food extracts consumed in the Mediterranean and East Asia suppress prostate cancer proliferation? %B British Journal of Nutrition %D 2012 %C United Kingdom %I Cambridge University Press %V 108 %N 3 %P 424-430 %@ 0007-1145 %X We have developed a blend of food extracts commonly consumed in the Mediterranean and East Asia, named blueberry punch (BBP), with the ultimate aim to formulate a chemoprevention strategy to inhibit prostate cancer progression in men on active surveillance protocol. We demonstrated previously that BBP inhibited prostate cancer cell proliferation in vitro and in vivo. The purpose of this study was to determine the molecular mechanism responsible for the suppression of prostate cancer cell proliferation by BBP. Treatment of lymph node-metastasised prostate cancer cells (LNCaP) and bone-metastasised prostate cancer cells (PC-3 and MDA-PCa-2b) with BBP (up to 0??8??%) for 72??h increased the percentage of cells at the G0/G1 phase and decreased those at the S and G2/M phases. The finding was supported by the reduction in the percentage of Ki-67-positive cells and of DNA synthesis measured by the incorporation of 5-ethynyl-2''-deoxyuridine. Concomitantly, BBP treatment decreased the protein levels of phosphorylated retinoblastoma, cyclin D1 and E, cyclin-dependent kinase (CDK) 4 and 2, and pre-replication complex (CDC6 and MCM7) in LNCaP and PC-3 cells, whereas CDK inhibitor p27 was elevated in these cell lines. In conclusion, BBP exerts its anti-proliferative effect on prostate cancer cells by modulating the expression and phosphorylation of multiple regulatory proteins essential for cell proliferation. %Z FOR Codes: 601 111204 %0 Journal Article %~ PubMed %A Tavakoli, Nasim Nik %A Harris, Angie K %A Sullivan, David R %A Hambly, Brett D %A Bao, Shisan %T Interferon-γ deficiency reduces neointimal formation in a model of endoluminal endothelial injury combined with atherogenic diet. %B International Journal of Molecular Medicine %D 2012 %C Greece %I Spandidos Publications %V 30 %N 3 %P 545-552 %@ 1791-244X %X Interferon (IFN)-?? has been implicated in restenosis, however its precise role in the pathophysiology of neointimal formation following angioplasty is unclear, as it has been shown to both promote and inhibit neointimal formation. Dietary-induced hypercholesterolemia enhances injury-mediated neointimal formation, associated with increased systemic inflammation and serum IFN-??. This study examined the effect of IFN-?? gene deficiency (-/-) on neointimal formation in a mouse model of endothelial injury combined with an atherogenic diet. Neointimal formation was induced via endoluminal endothelial injury of the common iliac arteries of IFN-??-/- and wild-type (WT) C57Bl/6 mice. Histopathological analysis of the arteries was performed at 3 and 6 weeks post-surgery. IFN-??-/- mice demonstrated a significant reduction in neointimal formation at the 3???week time point, compared to their WT counterpart. No significant differences in plasma lipid profile and the extent of re-endothelialization were detected between IFN-??-/- and WT mice, suggesting that the effect of IFN-?? on neointimal formation is due to injury-mediated vessel neointimal responses. In support of the histopathological findings, immunohistochemical analysis revealed a significant reduction in vessel infiltrating macrophages, and neointimal PDGF-B expression, vascular smooth muscle cell composition and cellular proliferation in the IFN-??-/- mice, in comparison to their corresponding WT group at the 3-week time point. In conclusion, the IFN????????mediated pathway plays an important role in inflammatory responses and proliferative effects following injury, suggesting that modulation of the IFN-?? pathway would be beneficial in controlling neointimal formation and restenosis. %Z FOR Codes: 110201 %0 Journal Article %~ PubMed %A Wu, Buchu %A Li, Shu %A Sheng, Lili %A Zhu, Jing %A Gu, Liying %A Shen, Haoran %A La, Duanduan %A Hambly, Brett D %A Bao, Shisan %A Di, Wen %T Metformin inhibits the development and metastasis of ovarian cancer. %B Oncology Reports %D 2012 %C Greece %I Spandidos Publications %V 28 %N 3 %P 903-908 %@ 1791-2431 %X The aim of this study was to investigate the role of metformin in the regulation of development and metastasis of ovarian carcinoma cell lines in vitro and ovarian cancer in a nude mouse model in vivo. The effects of metformin on the ability of two high-metastatic potential human ovarian cancer cell lines (SKOV3 and HO8910-PM) to adhere, invade and migrate in vitro were observed by means of a cell adhesion test, cell invasion test and cell migration test. The size and number of the inoculated and metastatic tumours in vivo in a nude mouse were determined following intraperitoneal injection of metformin. Furthermore, the extent of angiogenesis (vWF) and macrophage infiltration in the tumour were determined. Proliferation, migration, invasion and adhesion of ovarian cancer cells were significantly inhibited (P<0.05) in a dose-dependent manner in vitro. In addition, metformin inhibited hepatic, intestinal and lung metastasis (P<0.05), with no weight loss in vivo, consistent with decreased expression of vWF and macrophage infiltration. Our data suggest that metformin inhibits the development and metastasis of ovarian cancer by reducing cellular-ECM interactions, neovascularisation and macrophage infiltration. %Z FOR Codes: 111201 %0 Journal Article %~ PubMed %A Cordwell, Stuart J %A Edwards, Alistair V G %A Liddy, Kiersten A %A Moshkanbaryans, Lia %A Solis, Nestor %A Parker, Benjamin L %A Yong, Andy S C %A Wong, Clement %A Kritharides, Leonard %A Hambly, Brett D %A White, Melanie Y %T Release of tissue-specific proteins into coronary perfusate as a model for biomarker discovery in myocardial ischemia / reperfusion injury. %B Journal of Proteome Research %D 2012 %C United States %I American Chemical Society %V 11 %N 4 %P 2114-2126 %@ 1535-3893 %X Diagnosis of acute coronary syndromes is based on protein biomarkers, such as the cardiac troponins (cTnI/cTnT) and creatine kinase (CK-MB) that are released into the circulation. Biomarker discovery is focused on identifying very low abundance tissue-derived analytes from within albumin-rich plasma, in which the wide dynamic range of the native protein complement hinders classical proteomic investigations. We employed an ex vivo rabbit model of myocardial ischemia / reperfusion (I/R) injury using Langendorff buffer perfusion. Non-recirculating perfusate was collected over a temporal profile of 60 minutes reperfusion following brief, reversible ischemia (15 minutes; 15I/60R) for comparison with irreversible I/R (60I/60R). Perfusate proteins were separated using two-dimensional gel electrophoresis (2-DE) and identified by mass spectrometry (MS), revealing 26 tissue-specific proteins released during reperfusion post-15I. Proteins released during irreversible I/R (60I/60R) were profiled using gel-based (2-DE and one-dimensional gel electrophoresis coupled to liquid chromatography and tandem mass spectrometry; geLC-MS) and gel-free (LC/MS-MS) methods. A total of 192 tissue-specific proteins were identified during reperfusion post-60I. Identified proteins included those previously associated with I/R (myoglobin, CK-MB, cTnI and cTnT), in addition to examples currently under investigation in large cohort studies (heart-type fatty acid binding protein; FABPH). The post-ischemic release profile of a novel cardiac-specific protein, cysteine and glycine-rich protein 3 (Csrp3; cardiac LIM domain protein) was validated by Western blot analysis. We also identified Csrp3 in serum from 6 of 8 patients post-reperfusion following acute myocardial infarction. These studies indicate that animal modeling of biomarker release using ex vivo buffer perfused tissue to limit the presence of obfuscating plasma proteins may identify candidates for further study in humans. %Z FOR Codes: 1102 1101 %0 Conference Proceedings %A Ng, Ethan %A Hambly, Brett %A Matthews, Slade %A McLachlan, Craig S %A Jelinek, Herbert F %T WEKA machine learning classification in identifying autonomic dysfunction parameters associated with ACE insertion/deletion genotypes %B International Conference: Biomedical Engineering %D 2012 %C Innsbruck, Austria Feb 15-17 %I ACTA Press %V %N %P %@ %E Simsik, D %E Hamza, MH %X %Z FOR Codes: 90302 %0 Journal Article %~ PubMed %A Parker, Benjamin L %A Palmisano, Giuseppe %A Edwards, Alistair V G %A White, Melanie Y %A Engholm-Keller, Kasper %A Lee, Albert %A Scott, Nichollas E %A Kolarich, Daniel %A Hambly, Brett D %A Packer, Nicolle H %A Larsen, Martin R %A Cordwell, Stuart J %T Quantitative N-linked glycoproteomics of myocardial ischemia / reperfusion injury reveals early remodeling in the extracellular environment. %B Molecular & Cellular Proteomics %D 2011 %C United States %I American Society for Biochemistry and Molecular Bi %V 10 %N 8 %P M110.006833 %@ 1535-9484 %X Extracellular and cell surface proteins are generally modified with N-linked glycans and glycopeptide enrichment is an attractive tool to analyze these proteins. The role of N-linked glycoproteins in cardiovascular disease, particularly ischemia and reperfusion injury, is poorly understood. Observation of glycopeptides by mass spectrometry is challenging due to the presence of abundant, nonglycosylated analytes, and robust methods for purification are essential. We employed digestion with multiple proteases to increase glycoproteome coverage coupled with parallel glycopeptide enrichments using hydrazide capture, titanium dioxide, and hydrophilic interaction liquid chromatography with and without an ion-pairing agent. Glycosylated peptides were treated with PNGase F and analyzed by liquid chromatography-MS/MS. This allowed the identification of 1556 nonredundant N-linked glycosylation sites, representing 972 protein groups from ex vivo rat left ventricular myocardium. False positive "glycosylations" were observed on 44 peptides containing a deamidated Asn-Asp in the N-linked sequon by analysis of samples without PNGase F treatment. We used quantitation via isobaric tags for relative and absolute quantitation (iTRAQ) and validation with dimethyl labeling to analyze changes in glycoproteins from tissue following prolonged ischemia and reperfusion (40 mins ischemia and 20 mins reperfusion) indicative of myocardial infarction. The iTRAQ approach revealed 80 of 437 glycopeptides with altered abundance, while dimethyl labeling confirmed 46 of these and revealed an additional 62 significant changes. These were mainly from predicted extracellular matrix and basement membrane proteins that are implicated in cardiac remodeling. Analysis of N-glycans released from myocardial proteins suggest that the observed changes were not due to significant alterations in N-glycan structures. Altered proteins included the collagen-laminin-integrin complexes and collagen assembly enzymes, cadherins, mast cell proteases, proliferation-associated secreted protein acidic and rich in cysteine, and microfibril-associated proteins. The data suggest that cardiac remodeling is initiated earlier during reperfusion than previously hypothesized. %Z FOR Codes: 110106 %0 Journal Article %~ PubMed %A Singh, Jaskirat %A Xie, Chanlu %A Yao, Mu %A Hua, Sheng %A Vignarajan, Soma %A Jardine, Greg %A Hambly, Brett D %A Sved, Paul %A Dong, Qihan %T Food extracts consumed in Mediterranean countries and East Asia reduce protein concentrations of androgen receptor, phospho-protein kinase B, and phospho-cytosolic phospholipase A(2)alpha in human prostate cancer cells. %B Journal of Nutrition %D 2010 %C United States %I American Society for Nutrition %V 140 %N 4 %P 786-791 %@ 1541-6100 %X Active surveillance is an emerging management option for the rising number of men with low-grade, clinically localized prostate cancer. However, 30-40% of men on active surveillance will progress to high-grade disease over 5 y. With the ultimate aim of developing a food-based chemoprevention strategy to retard cancer progression in these otherwise healthy men, we have developed a blend of food extracts commonly consumed in Mediterranean countries and East Asia. The effect of the food extracts known as Blueberry Punch (BBP) on prostate cancer cell growth and key signaling pathways were examined in vitro and in vivo. BBP reduced prostate cancer cell growth in a dose-dependent manner (0.08-2.5%) at 72 h in vitro due to the reduction in cell proliferation and viability. Prostate cancer cell xenograft-bearing mice, administered 10% BBP in drinking water for 2 wk, had a 25% reduction in tumor volume compared with the control (water only). In vitro, BBP reduced protein concentrations in 3 signaling pathways necessary for the proliferation and survival of prostate cancer cells, namely androgen receptor, phospho-protein kinase B/protein kinase B, and phospho-cytosolic phospholipase A(2)alpha. The downstream effectors of these pathways, including prostate-specific antigen and glycogen synthase kinase 3beta, were also reduced. Thus, this palatable food supplement is a potential candidate for testing in clinical trials and may ultimately prove effective in retarding the progression of low-grade, early-stage prostate cancer in men managed by active surveillance. %Z FOR Codes: 111201 %0 Journal Article %~ PubMed %A Fang, Y %A Shen, J %A Yao, M %A Beagley, K W %A Hambly, B D %A Bao, S %T Granulocyte-macrophage colony-stimulating factor enhances wound healing in diabetes via upregulation of proinflammatory cytokines. %B The British journal of dermatology %D 2010 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 162 %N 3 %P 478-86 %@ 1365-2133 %X Chronic ulceration, especially in diabetes, remains a substantial clinical problem. Exogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) is efficacious in the treatment of chronic wound healing in both animal models and patients, but its role in diabetic wounds remains to be explored. Objectives Using a diabetic mouse model, to investigate the role of GM-CSF in wound healing. %Z FOR Codes: 1103 %0 Journal Article %~ PubMed %A McLachlan, Craig S %A Ocsan, Ryan %A Spence, Ian %A Hambly, Brett %A Matthews, Slade %A Wang, Lexin %A Jelinek, Herbert F %T Increased total heart rate variability and enhanced cardiac vagal autonomic activity in healthy humans with sinus bradycardia. %B Baylor University Medical Center Proceedings %D 2010 %C United States %I Baylor University Medical Center %V 23 %N 4 %P 368-370 %@ 0899-8280 %X Sinus bradycardia can be defined as a sinus rhythm with a resting heart rate of 60 beats per minute or less. While it is assumed that increased autonomic parasympathetic activity is associated with sinus bradycardia, such an association has yet to be proven. The aims of this study were to compute a number of heart rate variability (HRV) parameters in healthy individuals with sinus bradycardia and determine whether there was a significant vagal component to sinus bradycardia. Forty-three healthy adults with normal sinus rhythm and 25 healthy adults with sinus bradycardia had an electrocardiogram recorded for 20 minutes, from which HRV indices were calculated. Results showed significant increases in SDNN (standard deviation of NN intervals) (P < 0.05), RMSDD (square root of the mean squared differences of successive NN intervals) (P < 0.05), and DFA32 (detrended fluctuation analysis) (P < 0.05) in bradycardic subjects compared with subjects with normal sinus rhythm. There were no significant differences in sympathetic frequency domain indices between the two groups. In conclusion, there were significant increases in total heart variability and increased parasympathetic drive in subjects with bradycardia. Clinically, bradycardia is likely to be cardioprotective in aging populations based upon these HRV findings. %Z FOR Codes: 110201 %0 Journal Article %~ PubMed %A Hardy, Jayne %A Hambly, Brett %A Ko, Hongda %A Wyburn, Kate %A Eris, Josette %A Yin, Jianlin %T Stimulation of Mesangial Cells by Angiotensin II and Lipopolysaccharide Increases Expression of Interleukin-18, but Not IL-18 Receptor. %B Nephron. Experimental nephrology %D 2010 %C Switzerland, United %I S. Karger AG %V 116 %N 4 %P e63-71 %@ 1660-2129 %X Mesangial cell (MC) hyperplasia is associated with several kidney diseases. Experimental studies confirm upregulation of IL-18 in glomerular disease and renal allograft rejection. We evaluated whether MCs express IL-18 and IL-18 receptor-?? (IL-18R??) with and without stimulation by LPS, AngII and PDGF. %Z FOR Codes: 110312 %0 Journal Article %~ PubMed %A Harris, Angie K %A Shen, Jie %A Radford, Jane %A Bao, Shisan %A Hambly, Brett D %T GM-CSF deficiency delays neointima formation in a normolipidemic mouse model of endoluminal endothelial damage. %B Immunology and cell biology %D 2009 %C United Kingdom %I Nature Publishing Group %V 87 %N 2 %P 122-30 %@ 1440-1711 %X Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been implicated in atherogenesis and has been shown to have both pro- and antiatherogenic properties. Neointimal thickening is a prominent feature of early atherogenesis. This study aimed to examine the role of GM-CSF in neointimal formation induced by endothelial injury using a GM-CSF(-/-) mouse model. Neointimal thickening was induced by endothelial damage in the common iliac arteries of normolipidemic C57Bl/6 (wild-type) and GM-CSF(-/-) mice. Arteries were collected weekly for 3-7 weeks following surgery. A significant delay in neointimal formation in the GM-CSF(-/-) compared with wild-type mice was detected by morphometric analysis of the intimal area. Neointimal size was approximately 10% smaller in GM-CSF(-/-) mice at 4-6 weeks post-surgery, compared with wild-type mice. The neointima was composed predominantly of smooth muscle cells and there was no difference in the extent of endothelial cell coverage between the wild-type and GM-CSF(-/-) mice. Using immunohistochemistry, reduced macrophages (F4/80(+) cells), proliferating cells (proliferating cell nuclear antigen (PCNA)(+) cells) and platelet-derived growth factor-B were detected within the arteries of GM-CSF(-/-) mice compared with wild types at 4 weeks post-surgery. GM-CSF(-/-) mice had reduced connective tissue within the neointima compared with wild types at 5 weeks post-surgery, determined by trichrome staining. We conclude that GM-CSF deficiency reduces neointimal formation in a normolipidemic model, primarily due to reduced macrophage recruitment. %Z FOR Codes: 110299 %0 Journal Article %~ PubMed %A Zhang, Xinyuan %A Bao, Shisan %A Hambly, Brett D %A Gillies, Mark C %T Vascular endothelial growth factor-A: A multifunctional molecular player in diabetic retinopathy. %B The international journal of biochemistry & cell biology %D 2009 %C United Kingdom %I Pergamon %V 41 %N 12 %P 2368-71 %@ 1357-2725 %X Vascular endothelial growth factor-A (VEGF-A), first described as "vascular permeability factor", is a critical molecule in the pathogenesis of diabetic retinopathy at several levels. Previous studies have outlined the importance of VEGF-A in mediating vascular pathology in both experimental models and clinical diabetic retinopathy, which are characterized by retinal vascular leakage, preretinal neovascularisation and neuronal degeneration. Paradoxically, recent reports have emphasized the potential neurotrophic effects of VEGF-A on the quiescent vasculature, as well as its direct and indirect protective effects on retinal neurons. VEGF-A has also been identified as an important signalling regulator in the normal central nervous system. Consequently, anti-VEGF therapy for diabetic retinopathy has become a controversal issue. This review outlines recently developed concepts relating to the role of VEGF-A in the pathogenesis of diabetic retinopathy, with particular emphasis on its implications for clinical practice. %Z FOR Codes: 111301 %0 Book Section %A Stefani, M %A Tsubakihara, M %A Allen, PD %A Macdonald, PS %A dos Remedios, Cristobal %T Actin and its binding proteins in heart failure %B Actin-binding proteins and disease %D 2008 %C United Kingdom %I Springer %V %N %P 318-334 %@ 978-0-387-71747-0 %E Dos Remedios, Cristobal %E Chhabra, Deepak %X %Z FOR Codes: 1101 %0 Journal Article %~ PubMed %A Eng, Pei Chia %A Chua, Wendy Chen-Nee %A Suk Peng Chew, Valerie %A Wong, Peter Tsun Hon %A Yin, Jian Lin %A Hambly, Brett %A McLachlan, Craig Steven %T Chronic angiotensin-converting enzyme inhibition up-regulates mouse kidney growth arrest specific-6 protein and the AXL subfamily of receptor tyrosine kinases. %B Journal of the Renin-angiotensin-Aldosterone System %D 2008 %C United Kingdom %I Sage Publications Ltd. %V 9 %N 4 %P 238-241 %@ 1470-3203 %X INTRODUCTION: Growth arrest specific-6 (GAS-6), a vitamin K-dependent protein, is a potential mediator in progressive and chronic renal disease, specifically as a mediator of abnormal mesangial cell proliferation. Nitric oxide and angiotensin II affect mesangial cell proliferation. However, an association between nitric oxide synthase or angiotensin II on GAS-6 expression in the kidney has not previously been examined. Thus, our aim was to examine the effects of antihypertensive angiotensin-converting enzyme inhibitors and chronic nitric oxide synthase inhibition on the kidney expression of GAS-6 and its receptors AXL, MER and RSE. METHODS: Four groups of adult male C57BL/6J mice were studied: group 1, untreated controls (tap water for six weeks); group 2, treated orally with a nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 0.325 mg/ml for six weeks); group 3, treated orally with captopril (0.6875 mg/ml for six weeks); group 4, co-treated orally with L-NAME and captopril (same doses for six weeks). At the end of the study, kidneys were placed in fixative and processed to paraffin for immunohistochemical staining. RESULTS: GAS-6 and its receptors were not present in control and L-NAME-treated mice. Positive GAS-6 staining was detectable only in those mice receiving some form of chronic dosing with captopril, whether they were treated with captopril only or with captopril and L-NAME. Immunohistochemical detection across cases for MER and RSE was rare, whereas AXL-positive staining in the kidney mirrored GAS-6 staining/expression. The staining of GAS6 and AXL was predominantly localised to the renal tubular cells. CONCLUSIONS: These findings suggest that GAS-6 may not be a final common pathway for nitric oxide synthase inhibition-induced renal disease. Renal tubular GAS-6 expression following captopril treatment was unexpected and could be beneficial in preventing tubular atrophy following the onset of persistent systemic hypertension. %Z FOR Codes: 111599 %0 Journal Article %~ PubMed %A Ko, Hungta %A Hambly, Brett D %A Eris, Josette M %A Levidiotis, Vicki %A Wyburn, Kate %A Wu, Huiling %A Chadban, Steve J %A Yin, Jian L %T Dentritic cell derived IL-18 production is inhibited by rapamycin and sanglifehrin A, but not cyclosporine A. %B Transplant immunology %D 2008 %C Netherlands %I Elsevier BV %V 20 %N 0 %P 99-105 %@ 0966-3274 %X Interleukin-18 (IL-18), a product of dendritic cells (DC), is a pro-inflammatory cytokine involved in the pathogenesis of allograft rejection, vascular disease, arthritis and diabetes. Rapamycin (Rapa) is an immunosuppressant that inhibits T cell mTOR kinase activation. In contrast, Sanglifehrin A (SFA), is a cyclophilin-binding immunosuppressant that does not act on calcineurin phosphatases but appears to inhibit IL-2-dependent T cell proliferation. Rapa and SFA exert some immunosuppressive effects on DC by inhibiting IL-12 production, although their effects on DC have not been investigated as comprehensively as those on T cells. We aimed to determine the impact of these drugs on DC IL-18 synthesis in vivo and in vitro. We found in vivo that LPS-stimulated OX62(+) DC produced significantly more IL-18 mRNA, compared to OX62(+) DC depleted splenocytes (p<0.01) and non-LPS-stimulated OX62(+) DC (p<0.01). OX62(+)CD4(+) and OX62(+)CD4(-) cells produced similar amounts of IL-18 mRNA. Rapa and SFA, but not CsA, significantly inhibited IL-18 production from OX62(+) DC in vitro, in a dose-dependent manner (p<0.05). In vivo IL-18 production was also inhibited by Rapa and SFA in splenic OX62(+) DC (p<0.01). Finally, inhibition of IL-18 production by Rapa and SFA was independent of the FK506 or cyclophilin pathways, respectively. In conclusion, Rapa and SFA, but not CsA, block IL-18 production and this novel Rapa blockade effect on IL-18 may contribute to the ability of Rapa to inhibit chronic allograft nephropathy and restenosis. %Z FOR Codes: 110708 %0 Journal Article %~ PubMed %A Wu, Huiling %A Craft, Melissa L %A Wang, Peng %A Wyburn, Kate R %A Chen, Gang %A Ma, Jin %A Hambly, Brett %A Chadban, Steven J %T IL-18 Contributes to Renal Damage after Ischemia-Reperfusion. %B Journal of the American Society of Nephrology : JASN %D 2008 %C United States %I Lippincott Williams & Wilkins %V 19 %N 12 %P 2331-41 %@ 1046-6673 %X IL-18 is a proinflammatory cytokine produced by macrophages and other cell types present in the kidney during ischemia-reperfusion injury (IRI), but its role in this injury is unknown. Here, compared with wild-type mice, IL-18(-/-) mice subjected to kidney IRI demonstrated better kidney function, less tubular damage, reduced accumulation of neutrophils and macrophages, and decreased expression of proinflammatory molecules that are downstream of IL-18. For determination of the relative contributions of leukocytes and parenchymal cells to IL-18 production and subsequent kidney damage during IRI, bone marrow-chimeric mice were generated. Wild-type mice engrafted with IL-18(-/-) hemopoietic cells showed less kidney dysfunction and tubular damage than IL-18(-/-) mice engrafted with wild-type bone marrow. In vitro, macrophages produced IL-18 mRNA and protein in response to ischemia. These data suggest bone marrow-derived cells are the key contributors to IL-18-mediated effects of renal IRI. Finally, similar to IL-18(-/-) mice, pretreatment of wild-type mice with IL-18-binding protein was renoprotective in this model of IRI. In conclusion, IL-18, derived primarily from cells of bone marrow origin, contributes to the renal damage observed during IRI. IL-18-binding protein may have potential as a renoprotective therapy. %Z FOR Codes: 110707 110312 %0 Book Section %A Hambly, Brett %A Oakley, Cecily E %A Fajer, Piotr G %T Protein Comparative Sequence Analysis and Computer Modeling %B Clinical Bioinformatics %D 2008 %C New Jersey, USA %I Humana Press Inc. %V %N %P 245-256 %@ 9781588297914 %E Trent, Ronald %X %Z FOR Codes: 111602 %0 Journal Article %~ PubMed %A Hambly, Brett D %A Oakley, Cecily E %A Fajer, Piotr G %T Protein comparative sequence analysis and computer modeling. %B Methods in molecular medicine %D 2008 %C United States %I Humana Press %V 141 %N %P 245-256 %@ 1543-1894 %X A problem frequently encountered by the biological scientist is the identification of a previously unknown gene or protein sequence, where there are few or no clues as to the biochemical function, ligand specificity, gene regulation, protein-protein interactions, tissue specificity, cellular localization, developmental phase of activity, or biological role. Through the process of bioinformatics there are now many approaches for predicting answers to at least some of these questions, often then allowing the design of more insightful experiments to characterize more definitively the new protein. %Z FOR Codes: 110199 %0 Journal Article %~ Isi %A Harris, AK %A Bao, S %A Hambly, BD %A Prabhu, KV %T Absence of toll-like receptor 4 increases macrophage population and collagen content in an endothelial denudation mouse model of neointimal proliferation %B ATHEROSCLEROSIS SUPPLEMENTS %D 2007 %C Ireland %I Elsevier Ireland Ltd %V 8 %N %P 229-229 %@ 1567-5688 %X %Z FOR Codes: %0 Journal Article %~ Isi %A Fajer, P %A Kekic, M %A Hambly, BD %A Hwang, JM %A Oakley, C %A Brown, L %T F-actin binding to the N-terminal region of cardiac myosin binding protein-C %B BIOPHYSICAL JOURNAL %D 2007 %C US %I Biophysical Society %V Supp %N %P 489A-489A %@ 1542-0086 %X %Z FOR Codes: 110106 %0 Journal Article %~ PubMed %A Tavakoli, Nasim Nik %A Hambly, Brett D %A Sullivan, David R %A Bao, Shisan %T Forkhead box protein 3: Essential immune regulatory role. %B The international journal of biochemistry & cell biology %D 2007 %C United Kingdom %I Pergamon %V 40 %N 0 %P 2369-73 %@ 1357-2725 %X CD4+CD25+ regulatory T (Treg) cells play a crucial role in maintaining self-tolerance and preventing autoimmune disease. The transcription factor forkhead box protein 3 (Foxp3) has been identified as a molecular marker for Treg cells. Foxp3 is highly expressed in lymphoid tissue and several signalling pathways influence its expression. It plays an essential role in the development and function of Treg cells. Mutations in Foxp3 are responsible for the scurfy (sf) mutant mouse, and for autoimmune human diseases including the X-linked fatal "immune dysregulation, polyendocrinopathy, enteropathy, X-linked" (IPEX), autoimmune colitis and rheumatoid arthritis. Recent studies have also revealed an important and novel anti-atherogenic role for Treg cells and consequently for Foxp3. These data open up potential novel therapeutic avenues for the management of atherosclerosis. %Z FOR Codes: 110704 %0 Journal Article %~ Isi %A Fang, Y %A Bao, S %A Hambly, BD %A Gong, SJ %A Xu, YH %T Impaired cutaneous wound healing in granulocyte/macrophage colony-stimulating factor knockout mice %B BRITISH JOURNAL OF DERMATOLOGY %D 2007 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 157 %N 3 %P 458-465 %@ 0007-0963 %X %Z FOR Codes: 110702 %0 Journal Article %~ Isi %A Bao, S %A Hambly, BD %A Harris, AK %A Tavakoli, NN %T Interferon-gamma contributes to neointimal proliferation following arterial angioplasty in a mouse model %B ATHEROSCLEROSIS SUPPLEMENTS %D 2007 %C Ireland %I Elsevier Ireland Ltd %V 8 %N %P 65-66 %@ %X %Z FOR Codes: %0 Journal Article %~ PubMed %A Oakley, Cecily E %A Chamoun, Jean %A Brown, Louise J %A Hambly, Brett D %T Myosin binding protein-C: Enigmatic regulator of cardiac contraction. %B The international journal of biochemistry & cell biology %D 2007 %C United Kingdom %I Pergamon %V 39 %N 12 %P 2161-6 %@ 1357-2725 %X Myosin binding protein C (MyBPC) is a sarcomeric protein whose role in sarcomere structure and regulation of contraction is currently under investigation. It is a member of the immunoglobulin superfamily and is found in the C-zone of the A-band of the sarcomere. The elongated structure of MyBPC is composed of a series of immunoglobulin and fibronectin domains, with the C-terminal domains binding to the myosin thick filament and the N-terminal domains interacting with the myosin subfragment-2 (S2) neck region and possibly the actin thin filament. The functions of MyBPC are to stabilise the sarcomere structure and to regulate contraction. When phosphorylated near its N-terminus, MyBPC no longer binds myosin-S2, causing an increase in the ordering of the myosin heads, ATPase activity, F(max) and Ca(2+) sensitivity of contraction. Mutations in MyBPC have been found to cause familial hypertrophic cardiomyopathy (FHC) and changes in MyBPC phosphorylation have been linked to cardiac ischaemia-reperfusion injury. %Z FOR Codes: