ORCID Profile
0000-0002-9230-9042
Current Organisation
University of Melbourne
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Publisher: Hindawi Limited
Date: 2010
DOI: 10.1155/2010/437809
Abstract: Hypercholesterolemia, homocysteine, oxidative stress, and hyperglycemia have been recognized as the major risk factors for atherogenesis. Their impact on the physiology and biochemistry of vascular cells has been widely demonstrated for the last century. However, the recent discovery of the role of epigenetics in human disease has opened up a new field in the study of atherogenic factors. Thus, epigenetic tags in endothelial, smooth muscle, and immune cells seem to be differentially affected by similar atherogenic stimuli. This paper summarizes some recent works on expression of histone-modifying enzymes and DNA methylation directly linked to the presence of risk factors that could lead to the development or prevention of the atherosclerotic process.
Publisher: Public Library of Science (PLoS)
Date: 21-02-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-07-2013
DOI: 10.1161/CIRCRESAHA.113.300689
Abstract: High-density lipoprotein cholesterol elevation via cholesteryl ester transfer protein (CETP) inhibition represents a novel therapy for atherosclerosis, which also may have relevance for type 2 diabetes mellitus. The current study assessed the effects of a CETP inhibitor on postprandial insulin, ex vivo insulin secretion, and cholesterol efflux from pancreatic β-cells. Healthy participants received a daily dose of CETP inhibitor (n=10) or placebo (n=15) for 14 days in a randomized double-blind study. Insulin secretion and cholesterol efflux from MIN6N8 β-cells were determined after incubation with treated plasma. CETP inhibition increased plasma high-density lipoprotein cholesterol, apolipoprotein AI, and postprandial insulin. MIN6N8 β-cells incubated with plasma from CETP inhibitor–treated in iduals (compared with placebo) exhibited an increase in both glucose-stimulated insulin secretion and cholesterol efflux over the 14-day treatment period. CETP inhibition increased postprandial insulin and promoted ex vivo β-cell glucose-stimulated insulin secretion, potentially via enhanced β-cell cholesterol efflux.
Publisher: Elsevier BV
Date: 05-2005
Publisher: Wiley
Date: 05-2005
Abstract: Relaxin decreases oxytocin-stimulated rat myometrial contractions in vitro. This study used pregnant relaxin-deficient (Rlx-/-) mice to investigate the interaction between relaxin, oxytocin receptor (OTR), and estrogen receptor (ER) expression in the myometrium. Myometrial OTRs were significantly decreased on gestation day 18.5 in Rlx-/- mice than in Rlx+/+ mice. An increase in ERalpha in Rlx+/+ mice at term was correlated with a decrease in ERbeta, which was not observed in Rlx-/- mice. Treatment of Rlx-/- mice with relaxin had no effect on OTR, LGR7, or ERalpha expression, but it caused a significant decrease in ERbetas.
Publisher: Bioscientifica
Date: 05-2005
DOI: 10.1530/REP.1.00505
Abstract: Mesotocin, an oxytocin-like peptide, is released in highest concentrations during parturition in macropodid marsupials. In late pregnant wallabies, uterine sensitivity to mesotocin increases markedly in the myometrium of the gravid uterus. This coincides with a significant increase in myometrial mesotocin receptor concentrations 3–4 days before term. To date, there is no information on mesotocin receptor gene expression in female wallaby reproductive tissues. This study aimed to examine mesotocin receptor gene expression in the uterus and ovaries of pregnant tammar wallabies, and to localise mesotocin receptors within the uterus. An RT-PCR strategy produced a consensus nucleotide sequence of 834 bp, which encoded 278 amino acids of transmembrane domains I to VI. This protein sequence has approximately 80% homology with the bovine and rat oxytocin receptor exon 2 region. Only one mesotocin receptor was detected in the tammar genome. The myometrium and mammary gland both expressed a 4.1 kb mesotocin receptor gene transcript. Myometrial mesotocin receptor gene expression increased on day 22 of the 26-day gestation and was significantly higher in the gravid than the non-gravid uterus in late pregnancy. This pattern of mesotocin receptor gene expression paralleled mesotocin receptor concentrations. Mesotocin binding sites were localised only to the myometrium, the highest densities being observed in the gravid uterus. Finally, this study showed high expression of mesotocin receptors in the corpus luteum. The pattern of luteal mesotocin receptor expression differed from the myometrium, with a decrease in mesotocin receptors occurring on the day of expected births.
Publisher: Frontiers Media SA
Date: 31-10-2015
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.METABOL.2016.03.002
Abstract: High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) can modulate glucose metabolism through multiple mechanisms. This study determined the effects of a novel bromodomain and extra-terminal (BET) inhibitor (RVX-208) and putative apoA-I inducer on lipid species contained within HDL (HDL lipidome) and glucose metabolism. Twenty unmedicated males with prediabetes received 100mg b.i.d. RVX-208 and placebo for 29-33days separated by a wash-out period in a randomized, cross-over design trial. Plasma HDL-cholesterol and apoA-I were assessed as well as lipoprotein particle size and distribution using NMR spectroscopy. An oral glucose tolerance test (OGTT) protocol with oral and infused stable isotope tracers was employed to assess postprandial plasma glucose, indices of insulin secretion and insulin sensitivity, glucose kinetics and lipolysis. Whole plasma and HDL lipid profiles were measured using mass spectrometry. RVX-208 treatment for 4weeks increased 6 sphingolipid and 4 phospholipid classes in the HDL lipidome (p≤0.05 versus placebo), but did not change conventional clinical lipid measures. The concentration of medium-sized HDL particles increased by 11% (P=0.01) and small-sized HDL particles decreased by 10% (P=0.04) after RVX-208 treatment. In response to a glucose load, after RVX-208 treatment, plasma glucose peaked at a similar level to placebo, but 30min later with a more sustained elevation (treatment effect, P=0.003). There was a reduction and delay in total (P=0.001) and oral (P=0.003) glucose rates of appearance in plasma and suppression of endogenous glucose production (P=0.014) after RVX-208 treatment. The rate of glucose disappearance was also lower following RVX-208 (P=0.016), with no effect on glucose oxidation or total glucose disposal. RVX-208 increased 10 lipid classes in the plasma HDL fraction, without altering the concentrations of either apoA-I or HDL-cholesterol (HDL-C). RVX-208 delayed and reduced oral glucose absorption and endogenous glucose production, with plasma glucose maintained via reduced peripheral glucose disposal. If sustained, these effects may protect against the development of type 2 diabetes.
Publisher: American Physiological Society
Date: 11-2011
DOI: 10.1152/AJPENDO.00114.2011
Abstract: Fetal growth restriction is associated with reduced pancreatic β-cell mass, contributing to impaired glucose tolerance and diabetes. Exercise training increases β-cell mass in animals with diabetes and has long-lasting metabolic benefits in rodents and humans. We studied the effect of exercise training on islet and β-cell morphology and plasma insulin and glucose, following an intraperitoneal glucose tolerance test (IPGTT) in juvenile and adult male Wistar-Kyoto rats born small. Bilateral uterine vessel ligation performed on day 18 of pregnancy resulted in Restricted offspring born small compared with sham-operated Controls and also sham-operated Reduced litter offspring that had their litter size reduced to five pups at birth. Restricted, Control, and Reduced litter offspring remained sedentary or underwent treadmill running from 5 to 9 or 20 to 24 wk of age. Early life exercise increased relative islet surface area and β-cell mass across all groups at 9 wk, partially restoring the 60–68% deficit ( P 0.05) in Restricted offspring. Remarkably, despite no further exercise training after 9 wk, β-cell mass was restored in Restricted at 24 wk, while sedentary littermates retained a 45% deficit ( P = 0.05) in relative β-cell mass. Later exercise training also restored Restricted β-cell mass to Control levels. In conclusion, early life exercise training in rats born small restored β-cell mass in adulthood and may have beneficial consequences for later metabolic health and disease.
Publisher: Elsevier BV
Date: 11-2016
Publisher: The Endocrine Society
Date: 10-2003
DOI: 10.1210/EN.2003-0548
Abstract: This study used relaxin (RLX) gene knockout mice (Rlx−/−) to investigate the effects of RLX on myometrial oxytocin receptor (OTR) and estrogen receptor (ER)-α gene expression in late gestation. We also characterized the temporal expression of the RLX receptor (LGR7) and demonstrated gene transcripts in the myometrium of Rlx+/+ and Rlx−/− mice. There was a significant (P & 0.05) decrease in myometrial LGR7 gene expression on d 17.5 and 18.5 post coitum (pc) compared with earlier stages of gestation, but no differences between Rlx+/+ and Rlx−/− mice. Myometrial OTR mRNA levels increased at the end of gestation in Rlx+/+ but not Rlx−/− mice. ERα gene expression was up-regulated on d 14.5 pc in Rlx+/+ mice, with mRNA levels remaining high throughout late gestation. In contrast, ERα mRNA levels were significantly lower in Rlx−/− mice on d 14.5 and 18.5 pc. These data show that the increases in myometrial OTR and ERα expression in late pregnant Rlx+/+ mice were attenuated in Rlx−/− mice. The effects of RLX on OTRs are probably mediated via activation of ERα. Finally, RLX receptor expression in the myometrium of Rlx−/− mice did not differ from wild-type mice, implying that RLX does not influence expression of its receptor.
Publisher: Wiley
Date: 04-2004
Publisher: Wiley
Date: 29-10-2012
DOI: 10.1111/J.1440-1681.2012.05732.X
Abstract: Being born preterm and/or small for gestational age are well-established risk factors for cardiometabolic disease in adulthood. Physical activity has the potential to mitigate against the detrimental cardiometabolic effects of low birth weight from two perspectives: (i) maternal exercise prior to and during pregnancy and (ii) exercise during childhood or adulthood for those born small or prematurely. Evidence from epidemiological birth cohort studies suggests that the effects of moderate-intensity physical activity during pregnancy on mean birth weight are small, but reduce the risk of either high or low birth weight infants. In contrast, vigorous and/or high-intensity exercise during pregnancy has been associated with reduced birth weight. In childhood and adolescence, exercise ability is compromised in extremely low birth weight in iduals (< 1000 g), but only marginally reduced in those of very low to low birth weight (1000-2500 g). Epidemiological studies show that the association between birth weight and metabolic disease is lost in physically fit in iduals and, consistently, that the association between low birth weight and metabolic syndrome is accentuated in unfit in iduals. Physical activity intervention studies indicate that most cardiometabolic risk factors respond to exercise in a protective manner, independent of birth weight. The mechanisms by which exercise may protect low birth weight in iduals include restoration of muscle mass, reduced adiposity and enhanced β-cell mass and function, as well as effects on both aerobic and anaerobic muscle metabolism, including substrate utilization and mitochondrial function. Vascular and cardiac adaptations are also likely important, but are less well studied.
Publisher: CRC Press
Date: 03-12-2010
DOI: 10.1201/B10449-10
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2007
Publisher: Springer Science and Business Media LLC
Date: 04-2009
Abstract: Uteroplacental insufficiency in the rat reduces maternal progesterone and impairs mammary function and pup milk intake, compromising postnatal growth. We determined whether progesterone administration to rat dams progesterone-deficient following uteroplacental insufficiency improves lactation and pup growth. Uteroplacental insufficiency (Restriction) or sham surgery (Control) was performed on day 18 of pregnancy in WKY rats. Pregnant dams were injected with progesterone or vehicle, and Control mothers with vehicle for three days and killed on day 20 of pregnancy or day 6 of lactation. Progesterone treatment in the Restricted group restored maternal progesterone with no effect on mammary Pgr mRNA expression. Uteroplacental insufficiency triggered early lactogenesis, with increased mammary Csn2, Lalba and Wap mRNA. Progesterone treatment following uteroplacental insufficiency increased mammary alveolar number and area. Pups from progesterone treated mothers had increased body weight when compared to Controls. Overall, maternal progesterone treatment following uteroplacental insufficiency improved postnatal growth by rescuing the mammary impairment.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-10-2017
DOI: 10.1126/SCITRANSLMED.AAM6084
Abstract: Protecting the heart after an acute coronary syndrome is a key therapeutic goal to support cardiac recovery and prevent progression to heart failure. A potential strategy is to target cardiac glucose metabolism at the early stages after ischemia when glycolysis is critical for myocyte survival. Building on our discovery that high-density lipoprotein (HDL) modulates skeletal muscle glucose metabolism, we now demonstrate that a single dose of reconstituted HDL (rHDL) delivered after myocardial ischemia increases cardiac glucose uptake, reduces infarct size, and improves cardiac remodeling in association with enhanced functional recovery in mice. These findings applied equally to metabolically normal and insulin-resistant mice. We further establish direct effects of HDL on cardiomyocyte glucose uptake, glycolysis, and glucose oxidation via the Akt signaling pathway within 15 min of reperfusion. These data support the use of infusible HDL preparations for management of acute coronary syndromes in the setting of primary percutaneous interventions.
Publisher: American Physiological Society
Date: 05-2008
DOI: 10.1152/AJPENDO.00037.2008
Abstract: Uteroplacental insufficiency has been shown to impair insulin action and glucose homeostasis in adult offspring and may act in part via altered mitochondrial biogenesis and lipid balance in skeletal muscle. Bilateral uterine vessel ligation to induce uteroplacental insufficiency in offspring (Restricted) or sham surgery was performed on day 18 of gestation in rats. To match the litter size of Restricted offspring, a separate cohort of sham litters had litter size reduced to five at birth (Reduced Litter), which also restricted postnatal growth. Remaining litters from sham mothers were unaltered (Control). Offspring were studied at 6 mo of age. In males, both Restricted and Reduced Litter offspring had reduced gastrocnemius PPARγ coactivator-1α (PGC-1α) mRNA and protein, and mitochondrial transcription factor A (mtTFA) and cytochrome oxidase (COX) III mRNA ( P 0.05), whereas only Restricted had reduced skeletal muscle COX IV mRNA and protein and glycogen ( P 0.05), despite unaltered glucose tolerance, homeostasis model assessment (HOMA) and intramuscular triglycerides. In females, only gastrocnemius mtTFA mRNA was lower in Reduced Litter offspring ( P 0.05). Furthermore, glucose tolerance was not altered in any female offspring, although HOMA and intramuscular triglycerides increased in Restricted offspring ( P 0.05). It is concluded that restriction of growth due to uteroplacental insufficiency alters skeletal muscle mitochondrial biogenesis and metabolic characteristics, such as glycogen and lipid levels, in a sex-specific manner in the adult rat in the absence of impaired glucose tolerance. Furthermore, an adverse postnatal environment induced by reducing litter size also restricts growth and alters skeletal muscle mitochondrial biogenesis and metabolic characteristics in the adult rat.
Publisher: Elsevier BV
Date: 07-2008
DOI: 10.1038/KI.2008.153
Abstract: Impaired growth in utero predicts a low nephron number and high blood pressure later in life as does slowed or accelerated growth after a normal birth weight. We measured the effects of early postnatal growth restriction, with or without prenatal growth restriction, on blood pressure and nephron number in male rat offspring. Bilateral uterine artery and vein ligation were performed to induce uteroplacental insufficiency (Restricted) on day 18 of pregnancy. Postnatal growth restriction was induced in a subset of sham operated control animals by reducing the number of pups at birth to that of the Restricted group (Reduced Litter). Compared to Controls, Restricted pups were born smaller while Reduced Litter pups weighed less by postnatal day 3 and both groups remained lighter throughout lactation. By 10 weeks of age all animals were of similar weight but the Reduced Litter rats had elevated blood pressure. At 22 weeks, Restricted but not Reduced Litter offspring were smaller and the blood pressure was increased in both groups. Restricted and Reduced Litter groups had fewer glomeruli and greater left ventricular mass than Controls. These results suggest that restriction of both perinatal and early postnatal growth increase blood pressure in male offspring. This study also demonstrates that the early postnatal period is a critical time for nephron endowment in the rat.
Publisher: The Endocrine Society
Date: 13-03-2008
DOI: 10.1210/EN.2008-0128
Abstract: Intrauterine growth restriction and accelerated postnatal growth predict increased risk of diabetes. Uteroplacental insufficiency in the rat restricts fetal growth but also impairs mammary development and postnatal growth. We used cross fostering to compare the influence of prenatal and postnatal nutritional restraint on adult glucose tolerance, insulin secretion, insulin sensitivity, and hypothalamic neuropeptide Y content in Wistar Kyoto rats at 6 months of age. Bilateral uterine vessel ligation (restricted) to induce uteroplacental insufficiency or sham surgery (control) was performed on d-18 gestation. Control, restricted, and reduced (reducing litter size of controls to match restricted) pups were cross fostered onto a control or restricted mother 1 d after birth. Restricted pups were born small compared with controls. Restricted males, but not females, remained lighter up to 6 months, regardless of postnatal environment. By 10 wk, restricted-on-restricted males ate more than controls. At 6 months restricted-on-restricted males had increased hypothalamic neuropeptide Y content compared with other groups, and together with reduced-on-restricted males had increased retroperitoneal fat weight (percent body weight) compared with control-on-controls. Restricted-on-restricted males had impaired glucose tolerance, reduced first-phase insulin secretion, but unaltered insulin sensitivity, compared with control-on-controls. In males, being born small and exposed to an impaired lactational environment adversely affects adult glucose tolerance and first-phase insulin secretion, but improving lactation partially ameliorates this condition. This study identifies early life as a target for intervention to prevent later diabetes after prenatal restraint.
Publisher: American Physiological Society
Date: 05-2012
DOI: 10.1152/AJPREGU.00030.2012
Abstract: A reduced complement of cardiomyocytes in early life can adversely affect life-long cardiac functional reserve. In the present study, using a cross-fostering approach in rats, we examined the contributions of the prenatal and postnatal environments in the programming of cardiomyocyte growth. Rat dams underwent either bilateral uterine vessel ligation (Restricted) or sham surgery (Control) on day 18 of gestation. One day after birth, Control and Restricted pups were cross-fostered onto Control (normal lactation) or Restricted (impaired lactation due to impaired mammary gland formation) mothers. In male offspring, genes involved in cardiomyocyte differentiation, proliferation, hypertrophy and apoptosis were examined at gestational day 20 and postnatal days 1 and 7 to assess effects on cardiomyocyte growth. At postnatal day 7 cardiomyocyte number was determined stereologically. Offspring were examined at age 6 mo for evidence of hypertension and pathological cardiac gene expression. There was an increase in Igf1 and Igf2 mRNA expression in hearts of Restricted pups at gestational day 20. At postnatal day 7, Agtr1a and Agtr1b mRNA expression as well as Bcl2 and Cmyc were elevated in all hearts from offspring that were prenatally or postnatally growth restricted. There was a significant reduction (−29%) in cardiomyocyte number in the Restricted-on-Restricted group. Importantly, this deficit was prevented by optimization of postnatal nutrition (in the Restricted-on-Control group). At 6 mo, blood pressure was significantly elevated in the Restricted-on-Restricted group, but there was no difference in expression of the cardiac hypertrophy, remodeling or angiogenic genes across groups. In conclusion, the findings reveal a critical developmental window, when cardiomyocytes are still proliferating, whereby improved neonatal nutrition has the capacity to restore cardiomyocyte number to normal levels. These findings are of particular relevance to the preterm infant who is born at a time when cardiomyocytes are immature and still iding.
Publisher: Cambridge University Press (CUP)
Date: 05-12-2012
Publisher: Elsevier BV
Date: 12-2010
Publisher: Wiley
Date: 06-2009
Publisher: AIP Publishing
Date: 15-06-2005
DOI: 10.1063/1.1946908
Abstract: The effect of increasing the number of quantum wells in a strain-compensated, multiquantum-well solar cell is investigated. It is found that as the well number is increased, dark current level close to the operating point rises linearly. Short-circuit current in the AM0 spectrum also rises linearly with the inclusion of more quantum wells. This allows the cell to maintain a constant open-circuit voltage irrespective of the number of wells grown. This is anticipated to have advantages when the cell is used as a replacement for the GaAs junction in the existing generation of tandem and triple-junction cells since current levels can be matched to the upper junction without detriment to the voltage performance. This result allows us to predict a tandem cell AM0 efficiency of 23.8% based on the 50-well cell.
Publisher: BMJ
Date: 03-11-2020
DOI: 10.1136/BJSPORTS-2020-102025
Abstract: Elite athletes are particularly susceptible to sleep inadequacies, characterised by habitual short sleep ( hours/night) and poor sleep quality (eg, sleep fragmentation). Athletic performance is reduced by a night or more without sleep, but the influence on performance of partial sleep restriction over 1–3 nights, a more real-world scenario, remains unclear. Studies investigating sleep in athletes often suffer from inadequate experimental control, a lack of females and questions concerning the validity of the chosen sleep assessment tools. Research only scratches the surface on how sleep influences athlete health. Studies in the wider population show that habitually sleeping hours/night increases susceptibility to respiratory infection. Fortunately, much is known about the salient risk factors for sleep inadequacy in athletes, enabling targeted interventions. For ex le, athlete sleep is influenced by sport-specific factors (relating to training, travel and competition) and non-sport factors (eg, female gender, stress and anxiety). This expert consensus culminates with a sleep toolbox for practitioners (eg, covering sleep education and screening) to mitigate these risk factors and optimise athlete sleep. A one-size-fits-all approach to athlete sleep recommendations (eg, 7–9 hours/night) is unlikely ideal for health and performance. We recommend an in idualised approach that should consider the athlete’s perceived sleep needs. Research is needed into the benefits of napping and sleep extension (eg, banking sleep).
No related grants have been discovered for Andrew Siebel.