ORCID Profile
0000-0003-1545-0488
Current Organisation
University of Queensland
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Publisher: Bioscientifica
Date: 09-2013
DOI: 10.1530/REP-12-0508
Abstract: Endocannabinoids are a family of lipid signalling molecules. As with prostaglandins (PGs), endocannabinoids are derived from polyunsaturated fatty acids and affect cell function via receptor-mediated mechanisms. They also bind to PG receptors, although at a lower affinity. The endocannabinoid network is regulated in pregnancy from embryo development to labour onset. Even small changes in endocannabinoid exposure can retard embryo development and affect implantation success. There is now compelling evidence that aberrant expression of factors involved in the endocannabinoid pathway in the placenta and circulating lymphocytes results in spontaneous miscarriage and poor pregnancy outcomes. It is likely that competition between endocannabinoids, PGs and other similar lipids ultimately determines how phospholipid/fatty acid substrates are metabolised and, thus, the balance between the uterotonic and tocolytic activities. We, therefore, hypothesise that endocannabinoid profiles may be used as a biomarker to predict and/or identify spontaneous labour onset.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/850471
Abstract: Mammalian placentation is a vital facet of the development of a healthy and viable offspring. Throughout gestation the placenta changes to accommodate, provide for, and meet the demands of a growing fetus. Gestational gene expression is a crucial part of placenta development. The endocannabinoid pathway is activated in the placenta and decidual tissues throughout pregnancy and aberrant endocannabinoid signaling during the period of placental development has been associated with pregnancy disorders. In this study, the gene expression of eight endocannabinoid system enzymes was investigated throughout gestation. Rat placentae were obtained at E14.25, E15.25, E17.25, and E20, RNA was extracted, and microarray was performed. Gene expression of enzymes Faah, Mgll, Plcd4, Pld1, Nat1, Dagl α , and Ptgs2 was studied (cohort 1, microarray). Biological replication of the results was performed by qPCR (cohort 2). Four genes showed differential expression ( Mgll, Plcd4, Ptgs2, and Pld1 ), from mid to late gestation. Genes positively associated with gestational age were Ptgs2, Mgll, and Pld1 , while Plcd4 was downregulated. This is the first comprehensive study that has investigated endocannabinoid pathway gene expression during rat pregnancy. This study provides the framework for future studies that investigate the role of endocannabinoid system during pregnancy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2011
DOI: 10.1161/HYPERTENSIONAHA.110.166710
Abstract: Major interest surrounds how angiotensin II triggers cardiac hypertrophy via epidermal growth factor receptor transactivation. G protein–mediated transduction, angiotensin type 1 receptor phosphorylation at tyrosine 319, and β-arrestin–dependent scaffolding have been suggested, yet the mechanism remains controversial. We examined these pathways in the most reductionist model of cardiomyocyte growth, neonatal ventricular cardiomyocytes. Analysis with [ 32 P]-labeled cardiomyocytes, wild-type and [Y319A] angiotensin type 1 receptor immunoprecipitation and phosphorimaging, phosphopeptide analysis, and antiphosphotyrosine blotting provided no evidence for tyrosine phosphorylation at Y319 or indeed of the receptor, and mutation of Y319 (to A/F) did not prevent either epidermal growth factor receptor transactivation in COS-7 cells or cardiomyocyte hypertrophy. Instead, we demonstrate that transactivation and cardiomyocyte hypertrophy are completely abrogated by loss of G-protein coupling, whereas a constitutively active angiotensin type 1 receptor mutant was sufficient to trigger transactivation and growth in the absence of ligand. These results were supported by the failure of the β-arrestin–biased ligand SII angiotensin II to transactivate epidermal growth factor receptor or promote hypertrophy, whereas a β-arrestin–uncoupled receptor retained these properties. We also found angiotensin II–mediated cardiomyocyte hypertrophy to be attenuated by a disintegrin and metalloprotease inhibition. Thus, G-protein coupling, and not Y319 phosphorylation or β-arrestin scaffolding, is required for epidermal growth factor receptor transactivation and cardiomyocyte hypertrophy via the angiotensin type 1 receptor.
Publisher: Cambridge University Press (CUP)
Date: 2013
DOI: 10.1017/JNS.2013.36
Abstract: The high fat content in Western diets probably affects placental function during pregnancy with potential consequences for the offspring in the short and long term. The aim of the present study was to compare genome-wide placental gene expression between rat dams fed a high-fat diet (HFD) and those fed a control diet for 3 weeks before conception and during gestation. Gene expression was measured by microarray and pathway analysis was performed. Gene expression differences were replicated by real-time PCR and protein expression was assessed by Western blot analysis. Placental and fetal weights at E17.25 were not altered by exposure to the maternal HFD. Gene pathways targeting placental growth, blood supply and chemokine signalling were up-regulated in the placentae of dams fed the HFD. The up-regulation in messenger RNA expression for five genes Ptgs2 (fatty acid cyclo-oxidase 2 COX2), Limk1 (LIM domain kinase 1), Pla2g2a (phospholipase A2), Itga1 (integrin α-1) and Serpine1 was confirmed by real-time PCR. Placental protein expression for COX2 and LIMK was also increased in HFD-fed dams. In conclusion, maternal HFD feeding alters placental gene expression patterns of placental growth and blood supply and specifically increases the expression of genes involved in arachidonic acid and PG metabolism. These changes indicate a placental response to the altered maternal metabolic environment.
Publisher: Springer Science and Business Media LLC
Date: 11-2004
DOI: 10.1007/S00018-004-4244-3
Abstract: Activation of the type 1 angiotensin II receptor (AT(1)R) is associated with the aetiology of left ventricular hypertrophy, although the exact intracellular signalling mechanism(s) remain unclear. Transactivation of the epidermal growth factor receptor (EGFR) has emerged as a central mechanism by which the G protein-coupled AT(1)R, which lacks intrinsic tyrosine kinase activity, can stimulate the mitogen-activated protein kinase signalling pathways thought to mediate cardiac hypertrophy. Current studies support a model whereby AT(1)R-dependent transactivation of EGFRs on cardiomyocytes involves stimulation of membrane-bound metalloproteases, which in turn cleave EGFR ligands such as heparin-binding EGF from a plasma membrane-associated precursor. Numerous aspects of the 'triple membrane-passing signalling' paradigm of AT(1)R-induced EGFR transactivation remain to be characterised, including the identity of the specific metalloproteases involved, the intracellular mechanism for their activation and the exact EGFR subtypes required. Here we examine how 'hijacking' of the EGFR might explain the ability of the AT(1)R to elicit the temporally and qualitatively erse responses characteristic of the hypertrophic phenotype, and discuss the ramifications of delineating these pathways for the development of new therapeutic strategies to combat cardiac hypertrophy.
Publisher: Springer Science and Business Media LLC
Date: 02-2017
Abstract: The placenta plays an important role during pregnancy providing maternal blood supply from the uterus to the developing fetus. The structure and function of the placenta changes with gestation, as the fetus develops and its demands change. This study aims to elucidate changes in cytokine and chemokine gene expression throughout mid-to-late gestation in rat placenta. Sprague Dawley rats were time-mated, and placentae were obtained from 6 pregnant dams at 4 different gestational periods: E14.25, E15.25, E17.25, and E20. Changes in placental gene expression were measured by microarray analysis. Differentially expressed inflammatory genes were functionally categorized by pathway analysis. To validate the microarray results, a subset of genes was analyzed by quantitative real-time polymerase chain reaction (qPCR) in a validation cohort of 22 rats. Changes in messenger RNA (mRNA) expression of various cytokines, chemokines, and genes of the tumor growth factor β and tumor necrosis factor family were analyzed in rat placentae at E14.25, E15.25, E17.25, and E20. Forty-six genes were differentially expressed, and of these 21 genes had increased expression in late gestation (E20). The gestational age pattern of gene expression was confirmed by qPCR in the validation cohort. The observed acute, prelabor changes in the expression of these genes during gestation warrant further investigation to elucidate their role in pregnancy and parturition.
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/10799890600923187
Abstract: Angiotensin II (AngII) induces heart growth via cardiomyocyte hypertrophy, and central to this is the capacity of the type 1 AngII receptor (AT1R) to "transactivate" epidermal growth factor receptors (EGFRs)--a family with four main subtypes (HER1-4)--although the exact molecular mechanism remains unresolved. In this study, the pharmacological inhibition of AngII-stimulated ERK1/2 activation and cardiomyocyte hypertrophy by increasing concentrations of an EGFR inhibitor, AG1478, indicated that other EGFR subtypes, in addition to HER1, may be involved. We constructed expression vectors and adenoviruses expressing truncated mutant versions of HER1, HER2, and HER4 and determined their capacity to act as dominant-negative inhibitors when co-transfected with full-length EGFRs. It is surprising that adenoviral-mediated expression of these truncated EGFRs in cardiomyocytes led to paradoxical, ligand-independent increases in cardiomyocyte hypertrophy and unusual morphological changes. These results challenge our perception of AT1R-mediated EGFR transactivation and imply that truncated EGFRs may affect cell function through unconventional mechanisms.
Publisher: Wiley
Date: 29-09-2525
DOI: 10.1002/JCP.30487
Abstract: Epidermal growth factor (EGF) receptors (ErbB1–ErbB4) promote cardiac development and growth, although the specific EGF ligands and receptor isoforms involved in growth/repair versus pathology remain undefined. We challenged ventricular cardiomyocytes with EGF‐like ligands and observed that selective activation of ErbB4 (the receptor for neuregulin 1 [NRG1]), but not ErbB1 (the receptor for EGF, EGFR), stimulated hypertrophy. This lack of direct ErbB1‐mediated hypertrophy occurred despite robust activation of extracellular‐regulated kinase 1/2 (ERK) and protein kinase B. Hypertrophic responses to NRG1 were unaffected by the tyrosine kinase inhibitor (AG1478) at concentrations that are selective for ErbB1 over ErbB4. NRG1‐induced cardiomyocyte enlargement was suppressed by small interfering RNA (siRNA) knockdown of ErbB4 and ErbB2, whereas ERK phosphorylation was only suppressed by ErbB4 siRNA. Four ErbB4 isoforms exist (JM‐a/JM‐b and CYT‐1/CYT‐2), generated by alternative splicing, and their expression declines postnatally and following cardiac hypertrophy. Silencing of all four isoforms in cardiomyocytes, using an ErbB4 siRNA, abrogated NRG1‐induced hypertrophic promoter/reporter activity, which was rescued by coexpression of knockdown‐resistant versions of the ErbB4 isoforms. Thus, ErbB4 confers cardiomyocyte hypertrophy to NRG1, and all four ErbB4 isoforms possess the capacity to mediate this effect.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2015
Publisher: BMJ
Date: 10-2022
DOI: 10.1136/BMJOPEN-2022-064333
Abstract: Previous studies have identified associations between in idual reproductive factors and chronic disease risk among postmenopausal women. However, few have investigated the association of different markers of reproductive function, their interactions and risk factors of chronic disease among women approaching menopause. The Menarche-to-PreMenopause (M-PreM) Study aims to examine the relationship between reproductive factors across the reproductive lifespan and risk indicators for chronic disease among women in their early-to-mid-40s. The purpose of this cohort profile paper is to describe the rationale, study design and participant characteristics of the M-PreM Study. Women born in 1973–1978 who participated in the Australian Longitudinal Study on Women’s Health (ALSWH) were invited to undertake a clinical or self-administered assessment. A total of 1278 women were recruited from June 2019 to June 2021. The study measures included functional, cognitive and cardiometabolic tests, anthropometry, spirometry, respiratory health questionnaires, physical activity, sleep patterns, sex hormones, and cardiovascular and metabolic markers whereas blood and saliva s les were used for the analysis of genetic variants of genes associated with reproductive characteristics and chronic disease. The mean age of the clinic and self-assessed participants was 44.6 and 45.3 years, respectively. The menopausal status of participants was similar between the two arms of the study: 38%–41% premenopausal, 20% perimenopausal, and 36% took oral contraception or hormone replacement therapy. Approximately 80% of women had at least one child and participants reported experiencing pregnancy complications: preterm birth (8%–13% of pregnancies), gestational diabetes (10%) and gestational hypertension (10%–15%). The biomedical data collected in the M-PreM Study will be linked to existing ALSWH survey data on sociodemographic factors, health behaviour, reproductive function, and early life factors collected over the past 20 years and health administrative data. The association between reproductive factors and risk indicators of chronic disease will be analysed.
Publisher: Springer Science and Business Media LLC
Date: 28-01-2020
DOI: 10.1186/S12874-020-0904-8
Abstract: Use of generalized linear models with continuous, non-linear functions for age, period and cohort makes it possible to estimate these effects so they are interpretable, reliable and easily displayed graphically. To demonstrate the methods we use data on the prevalence of obesity among Australian women from two independent data sources obtained using different study designs. We used data from two long-running nationally representative studies: seven cross-sectional Australian National Health Surveys conducted between 1995 and 2017–18, each involving 6000–8000 women and the Australian Longitudinal Study on Women’s Health which started in 1996 and involves more than 57,000 women in four age cohorts who are re-surveyed at three-yearly intervals or annually. Age-period-cohort analysis was conducted using generalized linear models with splines to describe non-linear continuous effects. When analysed in the same way both data sets showed similar patterns. Prevalence of obesity increased with age until late middle age and then declined increased only slightly across surveys but increased steadily with birth year until the 1960s and then accelerated. The methods illustrated here make the estimation and visualisation of age, period and cohort effects accessible and interpretable. Regardless of how the data are collected (from repeated cross-sectional surveys or longitudinal cohort studies), it is clear that younger generations of Australian women are becoming heavier at younger ages. Analyses of trends in obesity should include cohort, in addition to age and period, effects in order to focus preventive strategies appropriately.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.EJOGRB.2013.12.032
Abstract: To determine the effect of lipopolysaccharide (LPS) on NF-κB gene expression and proinflammatory cytokine release from trophoblast cell models, JEG-3 and BeWo human choriocarcinoma cells. Serum-starved JEG-3 and BeWo cells were treated with LPS (from Escherichia coli serotype 0111:B4) for 24 or 48h. Cell culture medium was collected and assayed for interleukin (IL)-1β, IL-6, IL-8, and transforming necrosis factor (TNF)-α cytokine release using enzyme-linked immunosorbent assays. RNA was extracted from the cells and real-time PCR was performed to measure NF-κB mRNA expression. All results were analyzed by one-way analysis of variance tests followed by Sidak's post hoc analysis. p<0.05 was considered statistically significant. LPS triggered an inflammatory response in JEG-3 cells by inducing a 1.5-fold increase in NF-κB mRNA expression and TNF-α release (0μg/mL: 15.13±2.14, 1μg/mL: 14.94±0.75, 10μg/mL: 23.05±4.50, p<0.05) and a 2-fold elevation in IL-6 secretion (0μg/mL: 12.54±5.44, 1μg/mL: 25.54±0.91, 10μg/mL: 24.28±4.43, p<0.05). In contrast, BeWo cells were not as sensitive to LPS exposure NF-κB mRNA expression was unchanged between LPS-treated and control cells, whereas a small but significant 1.3-fold increase in TNF-α release was found (TNF-α: 15.45±1.53pg/mL, control: 12.24±1.00pg/mL, p<0.05). The inflammatory pathways in BeWo cells were found to be active given that treatment of these cells with IL-1β and TNF-α induced IL-6 secretion. Interestingly, 1μg/mL LPS appeared to decrease IL-6 and TNF-α release from BeWo cells. IL-1β and IL-8 secretion were not detected from either cell lines. LPS activates the NF-κB pathway in JEG-3 but not BeWo human choriocarcinoma cells and this may be the reason for their differential inflammatory response to LPS exposure.
Publisher: Wiley
Date: 21-04-2023
DOI: 10.1111/SMS.14363
Abstract: The associations between different types and contexts of stepping behaviors and cardiometabolic (CM) health markers are unclear. This study aimed to examine the associations of daily total, walking, stair, incidental and purposeful steps with cardiometabolic risk. A total of 943 women (mean age ± SD = 44.1 ± 1.6 years) from the Australian Longitudinal Study on Women's Health (ALSWH) were included in this cross‐sectional study. Daily total, walking, stair, incidental, and purposeful steps were measured using thigh‐worn accelerometry. Outcomes comprised of CM markers of adiposity, blood pressure, resting heart rate, lipids, glycaemia, and the composite CM score. We used generalized linear modeling and multiple linear regression to assess the associations. We observed that all stepping behaviors were beneficial to CM health, for ex le, compared to the lowest quartile (Q1), the change of the composite CM score across low to high quartile of purposeful steps was −0.12 (Q2, 95% CI: −0.41, 0.17), −0.16 (Q3, −0.46, 0.14), and −0.36 (Q4, −0.66, −0.05). Stair steps showed linear associations with blood pressure and adiposity biomarkers, for ex le, the change of quartile of waist circumference was −1.45 cm (Q2, −4.35, 1.44), −3.56 cm (Q3, −6.52, −0.60), and −7.08 cm (Q4, −10.31, −3.86). Peak 30‐min walking intensity showed independent association with adiposity biomarkers ( p linear 0.001 and p = 0.002 for waist circumference and BMI, respectively). Our study showed that all stepping forms were beneficial to CM health. Higher stair steps and peak 30‐min walking cadence were associated with a steep decline of adiposity biomarkers. Purposeful steps showed more consistent associations with CM biomarkers than incidental steps.
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.PLACENTA.2013.02.008
Abstract: Labour and delivery are processes associated with inflammation within intrauterine and cervical tissues. The mechanisms that induce labour-associated changes and, in particular, the role of microRNAs (miRNAs) remain to be elucidated. MiRNAs are small non-coding RNAs that repress gene expression via mRNA degradation and translational repression. Let-7 miRNAs are negatively regulated by RNA-binding protein, Lin28, and both function downstream of NF-κB signalling. In non-gestational tissues, let-7 and Lin28 reportedy function as negative and positive regulators of IL-6 expression. We hypothesised that labour-associated inflammation involves the downregulation of let-7 miRNAs and upregulation of Lin28 expression. To determine the expression of Lin28 protein and let-7 miRNA in human gestational tissue obtained before and after labour. Gestational tissues were collected from women at term by Caesarean section with and without labour and following normal vaginal delivery (n = 6 per group). Protein and RNA was extracted and Lin28 and let-7 miRNA expression was measured by Western blotting and real-time PCR. The data obtained established that let-7 miRNA and Lin28 display tissue-specific expression: Lin28 was strongly expressed in the placenta and choriodecidua, but not measurable in amnion and let-7b and -7c expression were significantly lower in choriodecidua compare to placenta and amnion, whereas the amnion expressed less let-7d and -7f than other tissues. While the expression of Lin28 protein and let-7 miRNA did not vary significantly with labour onset and delivery, changes in their bioactivity and impact on nuclear signalling pathways in human gestational tissues remain to be established.
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.PUPT.2005.04.005
Abstract: Tissue remodelling is an adaptive physiological event initiated by physical and/or hormonal stimuli and characterised by extracellular matrix modifications, inflammation, cellular hypertrophy, proliferation and/or apoptosis. Although its initial effects may be beneficial for the maintenance of organ function, it is evident that sustained remodelling processes can lead to pathological outcomes, such as fibrosis in asthma, and cardiac hypertrophy in heart failure. Our research is focussed upon cardiac hypertrophy and the significant contribution of the molecular pathway, termed 'the triple membrane-passing signalling' paradigm (TMPS), to this phenomenon. Cardiac hypertrophy describes the enlargement, but not proliferation, of cardiomyocytes in response to mechanical or hormonal factors to normalise cardiac output and accompanies other features of cardiac remodelling. As a major independent risk factor for heart failure, it is imperative that the molecular mechanisms that govern this phenotype are determined to identify possible therapeutic targets. This review will focus on the importance of matrix metalloproteases and epidermal growth factor receptors in the TMPS pathway and their potential as pharmacological targets for heart failure therapy. The evidence provided may have implications for pathological tissue remodelling in other organs.
Publisher: Human Kinetics
Date: 09-2023
Abstract: Objective : To investigate the association between physical activity accumulated from early (age 22–27 y) to mid (age 40–45 y) adulthood and resting heart rate at age 41–46 years in women. Methods : Data were from 479 participants in the 1973–1978 cohort of the Australian Longitudinal Study on Women’s Health. Participants reported physical activity every 3 years from age 22–27 years to 40–45 years. Linear regression models were used to investigate the associations of a cumulative physical activity score (average physical activity across 18 y up to 7 surveys) and changes in physical activity from age 22–33 years to 34–45 years with resting heart rate at age 41–46 years. Results : Average resting heart rate at age 41–46 years was 75 (SD: 11) beats per minute. An inverse nonlinear dose–response association between cumulative physical activity and resting heart rate was observed. Overall, accumulation of physical activity was associated with lower resting heart rate regardless of the age when physical activity was accumulated. Women in the highest tertile of physical activity at both age 22–33 years and 34–45 years had a resting heart rate, on average, 8 beats per minute lower (95% confidence interval, −11.42 to −4.69) than those consistently in the lowest tertile of physical activity. Conclusion : Accumulating physical activity, irrespective of timing, appears to provide cardiovascular health benefits for women before the transition to menopause.
Publisher: Public Library of Science (PLoS)
Date: 31-12-2013
No related grants have been discovered for Hsiu-Wen Chan.