ORCID Profile
0000-0002-0682-8760
Current Organisation
Macquarie University
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Biological Mathematics | Dynamical Systems in Applications | Applied Mathematics | Optical Properties of Materials | Nanotechnology | Biologically Active Molecules | Nanophotonics | Nanobiotechnology | Systems Biology | Optical Physics not elsewhere classified |
Cardiovascular System and Diseases | Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Physical Sciences | Scientific Instruments | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Mathematical Sciences | Expanding Knowledge in the Medical and Health Sciences | Expanding Knowledge in Technology
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.SCITOTENV.2022.156980
Abstract: Salmonellosis is a climate-sensitive gastroenteritis with over 92 million cases and over 50,000 deaths a year globally. Australia has high rates of salmonellosis compared with other industrialised nations. This study used a negative binomial time-series regression model to investigate the association between Australian salmonellosis notifications and monthly climate variables including El Niño Southern Oscillation (ENSO) and mean temperature anomaly from 1991 to 2019. Between 1991 and 2019 in Australia there were 275,753 salmonellosis notifications and the median annual rate for salmonellosis was 40.1 per 100,000 population. Salmonellosis notifications exhibited strong seasonality, reaching a peak in summer and a minimum in winter. There was an estimated increase of 3.4 % in salmonellosis cases nationally per 1 °C increase in monthly mean temperature anomaly (incidence rate ratio [IRR] of 1.034, 95 % confidence interval [CI]: 1.009, 1.059). Similar associations between salmonellosis and mean temperature anomaly were found for some states. Mean temperature anomaly exhibited an upward trend of 0.9 °C over the period 1991 to 2019. Additionally, a positive association was found between salmonellosis in Australia and ENSO whereby El Niño periods were associated with 7.9 % more salmonellosis cases compared to neutral periods (IRR 1.079, 95 % CI: 1.019, 1.143). A similar ENSO association was detected in the two eastern states of New South Wales and Queensland. This study suggests public health preventative measures to reduce salmonellosis could be enhanced in some regions during El Niño as well as during times of increased temperatures.
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.NANO.2017.06.012
Abstract: We utilized a plasma activated coating (PAC) to covalently bind the active component of high density lipoproteins (HDL), apolipoprotein (apo) A-I, to stainless steel (SS) surfaces. ApoA-I suppresses restenosis and thrombosis and may therefore improve SS stent biocompatibility. PAC-coated SS significantly increased the covalent attachment of apoA-I, compared to SS alone. In static and dynamic flow thrombosis assays, PAC+apoA-I inhibited thrombosis and reduced platelet activation marker p-selectin. PAC+apoA-I reduced smooth muscle cell attachment and proliferation, and augmented EC attachment to PAC. We then coated PAC onto murine SS stents and found it did not peel or delaminate following crimping/expansion. ApoA-I was immobilized onto PAC-SS stents and was retained as a monolayer when exposed to pulsatile flow in vivo in a murine stent model. In conclusion, ApoA-I immobilized on PAC withstands pulsatile flow in vivo and retains its bioactivity, exhibiting anti-thrombotic and anti-restenotic properties, demonstrating the potential to improve stent biocompatibility.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 11-09-2018
DOI: 10.1038/S41598-018-32016-X
Abstract: Diabetic vascular complications are associated with impaired ischaemia-driven angiogenesis. We recently found that reconstituted high-density lipoproteins (rHDL) rescue diabetes-impaired angiogenesis. microRNAs (miRNAs) regulate angiogenesis and are transported within HDL to sites of injury/repair. The role of miRNAs in the rescue of diabetes-impaired angiogenesis by rHDL is unknown. Using a miRNA array, we found that rHDL inhibits hsa-miR-181c-5p expression in vitro and using a hsa-miR-181c-5p mimic and antimiR identify a novel anti-angiogenic role for miR-181c-5p. miRNA expression was tracked over time post-hindlimb ischaemic induction in diabetic mice. Early post-ischaemia when angiogenesis is important, rHDL suppressed hindlimb mmu-miR-181c-5p. mmu-miR-181c-5p was not detected in the plasma or within HDL, suggesting rHDL specifically targets mmu-miR-181c-5p at the ischaemic site. Three known angiogenic miRNAs (mmu-miR-223-3p, mmu-miR-27b-3p, mmu-miR-92a-3p) were elevated in the HDL fraction of diabetic rHDL-infused mice early post-ischaemia. This was accompanied by a decrease in plasma levels. Only mmu-miR-223-3p levels were elevated in the hindlimb 3 days post-ischaemia, indicating that rHDL regulates mmu-miR-223-3p in a time-dependent and site-specific manner. The early regulation of miRNAs, particularly miR-181c-5p, may underpin the rescue of diabetes-impaired angiogenesis by rHDL and has implications for the treatment of diabetes-related vascular complications.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-11-2003
DOI: 10.1161/01.CIR.0000097119.57756.EF
Abstract: Background— Chemokines are important mediators of inflammatory cell recruitment that play a significant role in atherosclerosis. Fractalkine (CX 3 CL1) is an unusual membrane-bound chemokine that mediates chemotaxis through the CX 3 CR1 receptor. Recently, functional polymorphisms in the human CX3CR1 gene have been described that are associated with coronary artery disease. Methods and Results— We investigated the expression of the CX 3 C chemokine fractalkine and its receptor CX 3 CR1 in human coronary artery plaques by immunocytometry. We show that a subset of mononuclear cells expresses high levels of fractalkine in human coronary atherosclerotic plaques and that smooth muscle cells within the neointima express the fractalkine receptor CX 3 CR1. There is a positive correlation between the number of fractalkine-expressing cells and the number of CX 3 CR1-positive cells in human atherosclerotic plaques ( r =0.70, n=15 plaques). Furthermore, we demonstrate that cultured vascular smooth muscle cells express the CX 3 CR1 receptor and undergo chemotaxis to fractalkine that can be inhibited by G protein inactivation by pertussis toxin. Conclusions— These results suggest that in human atherosclerosis, fractalkine, rather than mediating inflammatory cell recruitment, can act as a mediator of smooth muscle cell migration.
Publisher: Elsevier BV
Date: 2021
DOI: 10.1016/J.JCMG.2021.03.028
Abstract: The majority of coronary atherothrombotic events presenting as myocardial infarction (MI) occur as a result of plaque rupture or erosion. Understanding the evolution from a stable plaque into a life-threatening, high-risk plaque is required for advancing clinical approaches to predict atherothrombotic events, and better treat coronary atherosclerosis. Unfortunately, none of the coronary imaging approaches used in clinical practice can reliably predict which plaques will cause an MI. Currently used imaging techniques mostly identify morphological features of plaques, but are not capable of detecting essential molecular characteristics known to be important drivers of future risk. To address this challenge, engineers, scientists, and clinicians have been working hand-in-hand to advance a variety of multimodality intravascular imaging techniques, whereby 2 or more complementary modalities are integrated into the same imaging catheter. Some of these have already been tested in early clinical studies, with other next-generation techniques also in development. This review examines these emerging hybrid intracoronary imaging techniques and discusses their strengths, limitations, and potential for clinical translation from both an engineering and clinical perspective.
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.ATHEROSCLEROSIS.2013.11.068
Abstract: Carnosine has been shown to modulate triglyceride and glycation levels in cell and animal systems. In this study we investigated whether prolonged supplementation with carnosine inhibits atherosclerosis and markers of lesion stability in hyperglycaemic and hyperlipidaemic mice. Streptozotocin-induced diabetic apo E(-/-) mice were maintained for 20 weeks, post-induction of diabetes. Half of the animals received carnosine (2g/L) in their drinking water. Diabetes was confirmed by significant increases in blood glucose and glycated haemoglobin, plasma triglyceride and total cholesterol levels, brachiocephalic artery and aortic sinus plaque area and lower body mass. Prolonged carnosine supplementation resulted in a significant (∼20-fold) increase in plasma carnosine levels, and a significant (∼23%) lowering of triglyceride levels in the carnosine-supplemented groups regardless of glycaemic status. Supplementation did not affect glycaemic status, blood cholesterol levels or loss of body mass. In the diabetic mice, carnosine supplementation did not diminish measured plaque area, but reduced the area of plaque occupied by extracellular lipid (∼60%) and increased both macrophage numbers (∼70%) and plaque collagen content (∼50%). The area occupied by α-actin-positive smooth muscle cells was not significantly increased. These data indicate that in a well-established model of diabetes-associated atherosclerosis, prolonged carnosine supplementation enhances plasma levels, and has novel and significant effects on atherosclerotic lesion lipid, collagen and macrophage levels. These data are consistent with greater lesion stability, a key goal in treatment of existing cardiovascular disease. Carnosine supplementation may therefore be of benefit in lowering triglyceride levels and suppressing plaque instability in diabetes-associated atherosclerosis.
Publisher: Wiley
Date: 17-01-2018
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.ENVRES.2022.113762
Abstract: Allergic rhinitis affects half a billion people globally, including a fifth of the Australian population. As the foremost outdoor allergen source, ambient grass pollen exposure is likely to be altered by climate change. The AusPollen Partnership aimed to standardize pollen monitoring and examine broad-scale biogeographical and meteorological factors influencing interannual variation in seasonality of grass pollen aerobiology in Australia. Daily airborne grass and other pollen concentrations in four eastern Australian cities separated by over 1700 km, were simultaneously monitored using Hirst-style s lers following the Australian Interim Pollen and Spore Monitoring Standard and Protocols over four seasons from 2016 to 2020. The grass seasonal pollen integral was determined. Gridded rainfall, temperature, and satellite-derived grassland sources up to 100 km from the monitoring site were analysed. The complexity of grass pollen seasons was related to latitude with multiple major summer-autumn peaks in Brisbane, major spring and minor summer peaks in Sydney and Canberra, and single major spring peaks occurring in Melbourne. The subtropical site of Brisbane showed a higher proportion of grass out of total pollen than more temperate sites. The magnitude of the grass seasonal pollen integral was correlated with pasture greenness, rainfall and number of days over 30 °C, preceding and within the season, up to 100 km radii from monitoring sites. Interannual fluctuations in Australian grass pollen season magnitude are strongly influenced by regional biogeography and both pre- and in-season weather. This first continental scale, Southern Hemisphere standardized aerobiology dataset forms the basis to track shifts in pollen seasonality, bio ersity and impacts on allergic respiratory diseases.
Publisher: MDPI AG
Date: 13-12-2019
DOI: 10.3390/JCM8122199
Abstract: Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Atherosclerosis develops over several decades and is mediated by a complex interplay of cellular mechanisms that drive a chronic inflammatory milieu and cell-to-cell interactions between endothelial cells, smooth muscle cells and macrophages that promote plaque development and progression. While there has been significant therapeutic advancement, there remains a gap where novel therapeutic approaches can complement current therapies to provide a holistic approach for treating atherosclerosis to orchestrate the regulation of complex signalling networks across multiple cell types and different stages of disease progression. MicroRNAs (miRNAs) are emerging as important post-transcriptional regulators of a suite of molecular signalling pathways and pathophysiological cellular effects. Furthermore, circulating miRNAs have emerged as a new class of disease biomarkers to better inform clinical diagnosis and provide new avenues for personalised therapies. This review focusses on recent insights into the potential role of miRNAs both as therapeutic targets in the regulation of the most influential processes that govern atherosclerosis and as clinical biomarkers that may be reflective of disease severity, highlighting the potential theranostic (therapeutic and diagnostic) properties of miRNAs in the management of cardiovascular disease.
Publisher: Wiley
Date: 25-10-2022
DOI: 10.5694/MJA2.51742
Abstract: The MJA-Lancet Countdown on health and climate change in Australia was established in 2017 and produced its first national assessment in 2018 and annual updates in 2019, 2020 and 2021. It examines five broad domains: climate change impacts, exposures and vulnerability adaptation, planning and resilience for health mitigation actions and health co-benefits economics and finance and public and political engagement. In this, the fifth year of the MJA-Lancet Countdown, we track progress on an extensive suite of indicators across these five domains, accessing and presenting the latest data and further refining and developing our analyses. Within just two years, Australia has experienced two unprecedented national catastrophes - the 2019-2020 summer heatwaves and bushfires and the 2021-2022 torrential rains and flooding. Such events are costing lives and displacing tens of thousands of people. Further, our analysis shows that there are clear signs that Australia's health emergency management capacity substantially decreased in 2021. We find some signs of progress with respect to health and climate change. The states continue to lead the way in health and climate change adaptation planning, with the Victorian plan being published in early 2022. At the national level, we note progress in health and climate change research funding by the National Health and Medical Research Council. We now also see an acceleration in the uptake of electric vehicles and continued uptake of and employment in renewable energy. However, we also find Australia's transition to renewables and zero carbon remains unacceptably slow, and the Australian Government's continuing failure to produce a national climate change and health adaptation plan places the health and lives of Australians at unnecessary risk today, which does not bode well for the future.
Publisher: Wiley
Date: 20-10-2021
DOI: 10.5694/MJA2.51302
Publisher: Informa UK Limited
Date: 14-05-2023
Publisher: Springer Science and Business Media LLC
Date: 29-07-2016
Publisher: The Endocrine Society
Date: 18-10-2016
DOI: 10.1210/EN.2016-1301
Abstract: Increasing evidence indicates that androgens regulate ischemia-induced neovascularization. However, the role of genomic androgen action mediated by androgen receptor (AR), a ligand-activated nuclear transcription factor, remains poorly understood. Using an AR knockout (KO) mouse strain that contains a transcriptionally inactive AR (AR
Publisher: Elsevier BV
Date: 10-2022
Publisher: Wiley
Date: 13-11-2019
DOI: 10.5694/MJA2.50405
Abstract: The MJA-Lancet Countdown on health and climate change was established in 2017 and produced its first Australian national assessment in 2018. It examined 41 indicators across five broad domains: climate change impacts, exposures and vulnerability adaptation, planning and resilience for health mitigation actions and health co-benefits economics and finance and public and political engagement. It found that, overall, Australia is vulnerable to the impacts of climate change on health, and that policy inaction in this regard threatens Australian lives. In this report we present the 2019 update. We track progress on health and climate change in Australia across the same five broad domains and many of the same indicators as in 2018. A number of new indicators are introduced this year, including one focused on wildfire exposure, and another on engagement in health and climate change in the corporate sector. Several of the previously reported indicators are not included this year, either due to their discontinuation by the parent project, the Lancet Countdown, or because insufficient new data were available for us to meaningfully provide an update to the indicator. In a year marked by an Australian federal election in which climate change featured prominently, we find mixed progress on health and climate change in this country. There has been progress in renewable energy generation, including substantial employment increases in this sector. There has also been some progress at state and local government level. However, there continues to be no engagement on health and climate change in the Australian federal Parliament, and Australia performs poorly across many of the indicators in comparison to other developed countries for ex le, it is one of the world's largest net exporters of coal and its electricity generation from low carbon sources is low. We also find significantly increasing exposure of Australians to heatwaves and, in most states and territories, continuing elevated suicide rates at higher temperatures. We conclude that Australia remains at significant risk of declines in health due to climate change, and that substantial and sustained national action is urgently required in order to prevent this.
Publisher: Springer Science and Business Media LLC
Date: 08-02-2019
DOI: 10.1038/S41598-019-39123-3
Abstract: Nitric oxide (NO) is a key regulator of endothelial cell and vascular function. The direct measurement of NO is challenging due to its short half-life, and as such surrogate measurements are typically used to approximate its relative concentrations. Here we demonstrate that ruthenium-based [Ru(bpy) 2 (dabpy)] 2+ is a potent sensor for NO in its irreversible, NO-bound active form, [Ru(bpy) 2 (T-bpy)] 2+ . Using spectrophotometry we established the sensor’s ability to detect and measure soluble NO in a concentration-dependent manner in cell-free media. Endothelial cells cultured with acetylcholine or hydrogen peroxide to induce endogenous NO production showed modest increases of 7.3 ± 7.1% and 36.3 ± 25.0% respectively in fluorescence signal from baseline state, while addition of exogenous NO increased their fluorescence by 5.2-fold. The changes in fluorescence signal were proportionate and comparable against conventional NO assays. Rabbit blood s les immediately exposed to [Ru(bpy) 2 (dabpy)] 2+ displayed 8-fold higher mean fluorescence, relative to blood without sensor. Approximately 14% of the observed signal was NO/NO adduct-specific. Optimal readings were obtained when sensor was added to freshly collected blood, remaining stable during subsequent freeze-thaw cycles. Clinical studies are now required to test the utility of [Ru(bpy) 2 (dabpy)] 2+ as a sensor to detect changes in NO from human blood s les in cardiovascular health and disease.
Publisher: Springer Science and Business Media LLC
Date: 04-03-2019
DOI: 10.1007/S00484-019-01689-Y
Abstract: Temperature and crime is one of the most extreme relationships between the atmospheric environment and human behaviour, yet our knowledge about it is primarily based on Northern Hemisphere research. This study used both temporal and spatial models to investigate the relationship between temperature and crime in New South Wales (NSW), Australia, using an 11-year data set. Results suggested that assault and theft counts were significantly higher in summer than winter (17.8 and 3.7%, respectively), while fraud counts were not significantly different. Using linear and quadratic terms for maximum daily temperature, a linear regression model indicated that daily assault counts significantly increased with rising temperature and the rate of increase slowed as temperatures exceeded 30 °C. Theft counts significantly increased with rising temperature then declined as temperatures exceeded 30°C. Again, there was no evidence of a relationship between temperature and frequency of fraud count. Spatial modelling revealed that 96% of local government areas (LGAs) in NSW had a higher summer assault rate than winter. The findings of this study provide an empirical foundation for understanding crime-temperature relationships in Australia.
Publisher: Portland Press Ltd.
Date: 13-06-2016
DOI: 10.1042/CS20160090
Abstract: Inflammasome activation, with subsequent release of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, has recently been implicated in atherosclerosis-associated inflammation. This study aims to assess in acute coronary syndrome (ACS) patients (1) inflammasome activation in circulating monocytes and (2) whether short-term oral colchicine, a recognized anti-inflammatory agent that has been shown to be cardio-protective in clinical studies, might acutely suppress inflammasome-dependent inflammation. ACS patients (n=21) were randomized to oral colchicine (1 mg followed by 0.5 mg 1 h later) or no treatment, and compared with untreated healthy controls (n=9). Peripheral venous blood was s led pre- (day 1) and 24 h post- (day 2) treatment. Monocytes were cultured and stimulated with ATP. Analysis of key inflammasome markers was performed by ELISA. IL-1β secretion increased by 580.4% (P& .01) in ACS patients compared with controls but only with ATP stimulation. Untreated ACS patients secreted significantly higher levels of IL-18 compared with healthy controls independent of ATP stimulation (P& .05). Colchicine treatment in ACS patients markedly reduced intracellular and secreted levels of IL-1β compared with pre-treatment levels (P& .05 for both), as well as significantly reducing pro-caspase-1 mRNA levels by 57.7% and secreted caspase-1 protein levels by 30.2% compared with untreated patients (P& .05 for both). Monocytes from ACS patients are ‘primed’ to secrete inflammasome-related cytokines and short-term colchicine acutely and markedly suppresses monocyte caspase-1 activity, thereby reducing monocyte secretion of IL-1β.
Publisher: Public Library of Science (PLoS)
Date: 29-05-2014
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.NUMECD.2022.01.019
Abstract: Although overweight and obesity are associated with increased risk of atrial fibrillation (AF), the underlying mechanisms are not well characterised. Recent data suggest that this link may be partly due to abnormal adipose tissue-derived cytokines or adipokines. However, this relationship is not well clarified. To evaluate the association between adipokines and AF in a systematic review and meta-analysis. PubMed, Embase, and Web of Science Core Collection were searched from inception through 1 Adipokines, principally adiponectin, apelin, and resistin, are associated with the risk of atrial fibrillation. However, the association is not seen after multivariate adjustment, likely reflecting the lack of statistical power. Future research should investigate these relationships in larger prospective cohorts and how they can refine AF monitoring strategies. CRD42020208879.
Publisher: American Diabetes Association
Date: 13-02-2017
DOI: 10.2337/DB17-ER04B
Publisher: Elsevier BV
Date: 02-2015
Publisher: Elsevier BV
Date: 04-2021
Publisher: MDPI AG
Date: 28-06-2018
DOI: 10.3390/IJMS19071903
Publisher: Springer Science and Business Media LLC
Date: 13-05-2019
DOI: 10.1038/S41598-019-43765-8
Abstract: The cellular origins of vasa vasorum are ill-defined and may involve circulating or local progenitor cells. We previously discovered that murine aortic adventitia contains Sca-1 + CD45 + progenitors that produce macrophages. Here we investigated whether they are also vasculogenic. In aortas of C57BL/6 mice, Sca-1 + CD45 + cells were localised to adventitia and lacked surface expression of endothelial markers ( % for CD31, CD144, TIE-2). In contrast, they did show expression of CD31, CD144, TIE-2 and VEGFR2 in atherosclerotic ApoE −/− aortas. Although Sca-1 + CD45 + cells from C57BL/6 aorta did not express CD31, they formed CD31 + colonies in endothelial differentiation media and produced interconnecting vascular-like cords in Matrigel that contained both endothelial cells and a small population of macrophages, which were located at branch points. Transfer of aortic Sca-1 + CD45 + cells generated endothelial cells and neovessels de novo in a hindlimb model of ischaemia and resulted in a 50% increase in perfusion compared to cell-free control. Similarly, their injection into the carotid adventitia of ApoE −/− mice produced donor-derived adventitial and peri-adventitial microvessels after atherogenic diet, suggestive of newly formed vasa vasorum. These findings show that beyond its content of macrophage progenitors, adventitial Sca-1 + CD45 + cells are also vasculogenic and may be a source of vasa vasorum during atherogenesis.
Publisher: American Diabetes Association
Date: 16-01-2014
DOI: 10.2337/DB13-0417
Abstract: Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose–mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose–induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.
Publisher: Elsevier BV
Date: 02-2021
Publisher: American Chemical Society (ACS)
Date: 18-02-2011
DOI: 10.1021/AC102845Y
Abstract: Androgenic steroids marketed online as nutraceuticals are a growing concern in sport doping. The inability of conventional mass spectrometry (MS)-based techniques to detect structurally novel androgens has led to the development of in vitro androgen bioassays to identify such designer androgens by their bioactivity. The objective of this study was to determine the androgenic bioactivity of novel steroidal compounds isolated from nutraceuticals using both yeast and mammalian cell-based androgen bioassays. We developed two new in vitro androgen bioassays by stably transfecting HEK293 and HuH7 cells with the human androgen receptor (hAR) expression plasmid together with a novel reporter gene vector (enhancer/ARE/SEAP). The yeast β-galactosidase androgen bioassay was used for comparison. Our new bioassay featuring the enhancer/ARE/SEAP construct (-S) displayed simpler assay format and higher specificity with lower sensitivity compared with the commonly used mouse mammary tumour virus (MMTV)-luciferase. The relative potencies (RP), defined as [EC(50)] of testosterone/[EC(50)] of steroid, of nutraceutical extracts in the yeast, HEK293-S, and HuH7-S, were 34, 333, and 80,000 for Hemapolin 208, 250, and 80 for Furazadrol 0.38, 10, and 106 for Oxyguno 2.7, 0.28, and 15 for Trena and 4.5, 0.1, and 0.4 for Formadrol, respectively. The wide discrepancies in rank RP of these compounds was reconciled into a consistent potency ranking when the cells were treated with meclofenamic acid, a nonselective inhibitor of steroid metabolizing enzymes. These findings indicate that steroids extracted from nutraceuticals can be converted in vitro into more or less potent androgens in mammalian but not in yeast cells. We conclude that the putative androgenic bioactivity of a new compound may depend on the bioassay cellular format and that mammalian cell bioassays may have an added benefit in screening for proandrogens but sacrifice specificity for sensitivity in quantitation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2018
DOI: 10.1161/ATVBAHA.118.310788
Abstract: Revascularization because of coronary artery disease is commonly achieved by percutaneous coronary intervention with stent deployment. Refinement in interventional techniques, major improvements in stent design (particularly drug-eluting stents), and adjunctive pharmacotherapy with dual antiplatelet regimens have led to marked reductions in the overall rates of stent failure. However, even with the advancements made in the latest generation of drug-eluting stents, unresolved biological problems persist including delayed re-endothelialization and neoatherosclerosis, which can promote late expansion of the neointima and late stent thrombosis. Novel strategies are still needed beyond what is currently available to specifically address the pathobiological processes that underpin the residual risk for adverse clinical events. This review focuses on the emerging evidence that HDL (high-density lipoproteins) and its main apo (apolipoprotein), apoA-I, exhibit multiple vascular biological functions that are associated with an improvement in stent biocompatibility. HDL/apoA-I have recently been shown to inhibit in-stent restenosis in animal models of stenting and suppress smooth muscle cell proliferation in in vitro studies. Reconstituted HDL also promotes endothelial cell migration, endothelial progenitor cell mobilization, and re-endothelialization. Furthermore, reconstituted HDL decreases platelet activation and HDL cholesterol is inversely associated with the risk of thrombosis. Finally, reconstituted HDL/apoA-I suppresses key inflammatory mechanisms that initiate in-stent neoatherosclerosis and can efflux cholesterol from plaque macrophages, an important function of HDLs that prevents plaque progression. These unique multifunctional effects of HDL/apoA-I suggest that, if translated appropriately, have the potential to improve stent biocompatibility. This may provide an alternate and more efficacious therapeutic pathway for the translation of HDL.
Publisher: University of California Press
Date: 2020
DOI: 10.1525/ELEMENTA.423
Abstract: Terrestrial air-surface exchange of mercury (Hg) forms an important component of the global Hg cycle, with drivers varying across spatial and temporal scales. These drivers include substrate properties, atmospheric chemistry, and meteorological factors. Vegetation uptake represents the dominant pathway of atmospheric Hg deposition to terrestrial surfaces. This study investigated the drivers of net ecosystem exchange of gaseous elemental mercury (Hg0) across multiple seasons in order to gain an understanding of the influence of vegetation and other environmental parameters on the Hg0 air-surface exchange. Measurements were made continuously using a micrometeorological aerodynamic flux gradient method at a low-vegetated background site in south-eastern Australia, over 14 months. Mean Hg fluxes and atmospheric concentrations across the entire study period were 0.002 ng m–2 h–1 (SD ± 14.23 ng m2 h–1) and 0.68 ng m–3 (SD ± 0.22 ng m–3), respectively. Variability was observed across seasons, with the highest average rate of emissions occurring in austral summer (December, January, February) (0.69 ng m–2 h–1) and the highest rate of deposition observed in autumn (March, April, May) (–0.50 ng m–2 h–1). Vegetation uptake dominated Hg flux during the winter and spring when meteorological conditions were cold and light levels were low. This is supported by CO2 flux data, with a daytime winter mean of 0.80 µmol m–2 h–1 and a spring daytime mean of 1.54 µmol m–2 h–1. Summer Hg fluxes were dominantly emission due to higher solar radiation and temperature. Climatic conditions at Oakdale allowed plant production to occur year-round, however the hot dry conditions observed in the warmer months increased evasion, allowing this site to be a small net source of Hg0 to the atmosphere.
Publisher: American Chemical Society (ACS)
Date: 08-05-2019
DOI: 10.1021/ACS.CHEMRESTOX.9B00044
Abstract: During inflammation, myeloperoxidase released from activated phagocytes generates the highly reactive oxidant hypochlorous acid (HOCl). This oxidant plays an important role in the immune response but can also promote tissue damage and has been strongly linked with the development of numerous inflammatory diseases. HOCl reacts with cellular DNA forming chlorinated nucleobases, which induce strand breaks, mutations, and cross-links. Although it has been shown that chlorinated nucleosides are present within inflammatory pathologies and diseased tissue, whether or not these species are biomarkers formed as a byproduct of chronic inflammation or play a role in the disease progression has not been ascertained. In this study, we show that exposure of J774A.1 macrophage-like cells to chlorinated ribose and deoxyribose nucleosides results in the incorporation of 5-chloro-cytidine (5ClC), 8-chloro-adenosine (8ClA), and 8-chloro-guanosine (8ClG) into the cellular RNA and 5-chloro-deoxycytidine (5CldC) but not 8-chloro-deoxyguanosine (8CldG) or 8-chloro-deoxyadenosine (8CldA) into cellular DNA. Evidence was obtained for the clearance of 5ClC from the RNA, with a loss of 8ClA and 8ClG observed to a lesser extent, whereas an increase in the level of 5CldC in DNA was seen on further incubation of treated cells in the absence of chlorinated nucleosides. Importantly, exposure of the macrophages to chlorinated nucleosides, particularly 8ClG and 5ClC, resulted in the increased expression of interleukin-1β, and other pro-inflammatory cytokines and chemokines. With 5ClC, this inflammatory response was associated with the increased nuclear translocation of the NF-κB subunit, p65, rather than inflammasome activation. This alteration in gene expression appeared to be unrelated to the extent of incorporation of the chlorinated nucleosides into RNA or DNA and was not associated with any significant changes in cell viability or proliferation. Taken together, these results highlight a potential biological role for chlorinated nucleosides to promote inflammatory disease, in addition to their utility as biomarkers.
Publisher: Wiley
Date: 20-12-2017
Publisher: Portland Press Ltd.
Date: 31-07-2018
DOI: 10.1042/BSR20180563
Abstract: Chronic wounds are a major complication in patients with cardiovascular diseases. Cell therapies have shown potential to stimulate wound healing, but clinical trials using adult stem cells have been tempered by limited numbers of cells and invasive procurement procedures. Induced pluripotent stem cells (iPSCs) have several advantages of other cell types, for ex le they can be generated in abundance from patients’ somatic cells (autologous) or those from a matched donor. iPSCs can be efficiently differentiated to functional endothelial cells (iPSC-ECs). Here, we used a murine excisional wound model to test the pro-angiogenic properties of iPSC-ECs in wound healing. Two full-thickness wounds were made on the dorsum of NOD-SCID mice and splinted. iPSC-ECs (5 × 105) were topically applied to one wound, with the other serving as a control. Treatment with iPSC-ECs significantly increased wound perfusion and accelerated wound closure. Expression of endothelial cell (EC) surface marker, platelet endothelial cell adhesion molecule (PECAM-1) (CD31), and pro-angiogenic EC receptor, Tie1, mRNA was up-regulated in iPSC-EC treated wounds at 7 days post-wounding. Histological analysis of wound sections showed increased capillary density in iPSC-EC wounds at days 7 and 14 post-wounding, and increased collagen content at day 14. Anti-GFP fluorescence confirmed presence of iPSC-ECs in the wounds. Bioluminescent imaging (BLI) showed progressive decline of iPSC-ECs over time, suggesting that iPSC-ECs are acting primarily through short-term paracrine effects. These results highlight the pro-regenerative effects of iPSC-ECs and demonstrate that they are a promising potential therapy for intractable wounds.
Publisher: Springer Science and Business Media LLC
Date: 06-05-2021
DOI: 10.1038/S41598-021-89191-7
Abstract: Type 2 diabetes mellitus (T2DM) increases cardiac inflammation which promotes the development of cardiac fibrosis. We sought to determine the impact of circadian disruption on the induction of hyperglycaemia, inflammation and cardiac fibrosis. Methods: Psammomys obesus ( P. obesus ) were exposed to neutral (12 h light:12 h dark) or short (5 h light:19 h dark) photoperiods and fed a low energy (LE) or high energy (HE) diet for 8 or 20 weeks. To determine daily rhythmicity, P. obesus were euthanised at 2, 8, 14, and 20 h after ‘lights on’. Results: P. obesus exposed to a short photoperiod for 8 and 20 weeks had impaired glucose tolerance following oral glucose tolerance testing, compared to a neutral photoperiod exposure. This occurred with both LE and HE diets but was more pronounced with the HE diet. Short photoperiod exposure also increased myocardial perivascular fibrosis after 20 weeks on LE (51%, P 0.05) and HE (44%, P 0.05) diets, when compared to groups with neutral photoperiod exposure. Short photoperiod exposure caused elevations in mRNA levels of hypertrophy gene Nppa (atrial natriuretic peptide) and hypertrophy transcription factors Gata4 and Mef2c in myocardial tissue after 8 weeks. Conclusion: Exposure to a short photoperiod causes impaired glucose tolerance in P. obesus that is exacerbated with HE diet and is accompanied by an induction in myocardial perivascular fibrosis.
Publisher: Elsevier BV
Date: 06-2018
Publisher: Elsevier BV
Date: 05-2022
Publisher: American Chemical Society (ACS)
Date: 13-10-2020
Publisher: Elsevier BV
Date: 11-2015
Publisher: Public Library of Science (PLoS)
Date: 29-03-2017
Publisher: Springer Science and Business Media LLC
Date: 02-03-2021
DOI: 10.1007/S00125-021-05414-6
Abstract: Diabetes is a major burden on Australia's Indigenous population, with high rates of disease and vascular complications. Diabetic vascular complications are associated with impaired ischaemia-driven angiogenesis. MicroRNAs (miRNAs) are key players in the regulation of angiogenesis. HDL-cholesterol (HDL-c) levels are inversely associated with the risk of developing diabetic complications and HDL can carry miRNAs. HDL-miRNA profiles differ in disease states and may present as biomarkers with the capacity to act as bioactive signalling molecules. Recent studies have demonstrated that HDL becomes dysfunctional in a diabetic environment, losing its vasculo-protective effects and becoming more pro-atherogenic. We sought to determine whether HDL-associated miRNA profiles and HDL functionality were predictive of the severity of diabetic vascular complications in Australia's Indigenous population. HDL was isolated from plasma s les from Indigenous participants without diabetes ('Healthy'), with type 2 diabetes mellitus ('T2DM') and with diabetes-associated macrovascular complications (specifically peripheral artery disease, 'T2DM+Comp'). To assess HDL angiogenic capacity, human coronary artery endothelial cells were treated with PBS, reconstituted HDL (rHDL, positive control) or isolated HDL and then exposed to high-glucose (25 mmol/l) conditions. The expression levels of two anti-angiogenic miRNAs (miR-181c-5p and miR-223-3p) and one pro-angiogenic miRNA (miR-27b-3p) were measured in the HDL fraction, plasma and treated human coronary artery endothelial cells by quantitative real-time PCR. In vitro endothelial tubule formation was assessed using the Matrigel tubulogenesis assay. Strikingly, we found that the levels of the anti-angiogenic miRNA miR-181c-5p were 14-fold higher (1454 ± 1346%) in the HDL from Aboriginal people with diabetic complications compared with both the Healthy (100 ± 121%, p < 0.05) and T2DM (82 ± 77%, p < 0.05) groups. Interestingly, we observed a positive correlation between HDL-associated miR-181c-5p levels and disease severity (p = 0.0020). Under high-glucose conditions, cells treated with rHDL, Healthy HDL and T2DM HDL had increased numbers of tubules (rHDL: 136 ± 8%, p < 0.01 Healthy HDL: 128 ± 6%, p < 0.01 T2DM HDL: 124 ± 5%, p < 0.05) and branch points (rHDL: 138 ± 8%, p < 0.001 Healthy HDL: 128 ± 6%, p < 0.01 T2DM HDL: 127 ± 5%, p < 0.01) concomitant with elevations in mRNA levels of the key hypoxia angiogenic transcription factor HIF1A (rHDL: 140 ± 10%, p < 0.01 Healthy HDL: 136 ± 8%, p < 0.01 T2DM HDL: 133 ± 9%, p < 0.05). However, this increase in angiogenic capacity was not observed in cells treated with T2DM + Comp HDL (tubule numbers: 113 ± 6%, p = 0.32 branch points: 113 ± 5%, p = 0.28 HIF1A: 117 ± 6%, p = 0.43), which could be attributed to the increase in cellular miR-181c-5p levels (T2DM + Comp HDL: 136 ± 7% vs PBS: 100 ± 9%, p < 0.05). In conclusion, HDL from Aboriginal people with diabetic complications had reduced angiogenic capacity. This impairment is associated with an increase in the expression of anti-angiogenic miR-181c-5p. These findings provide the rationale for a new way to better inform clinical diagnosis of disease severity with the potential to incorporate targeted, personalised HDL-miRNA intervention therapies to prevent further development of, or to reverse, diabetic vascular complications in Australian Aboriginal people.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: AMPCo
Date: 29-11-2018
DOI: 10.5694/MJA18.00789
Abstract: Climate plays an important role in human health and it is well established that climate change can have very significant impacts in this regard. In partnership with The Lancet and the MJA, we present the inaugural Australian Countdown assessment of progress on climate change and health. This comprehensive assessment examines 41 indicators across five broad sections: climate change impacts, exposures and vulnerability adaptation, planning and resilience for health mitigation actions and health co-benefits economics and finance and public and political engagement. These indicators and the methods used for each are largely consistent with those of the Lancet Countdown global assessment published in October 2017, but with an Australian focus. Significant developments include the addition of a new indicator on mental health. Overall, we find that Australia is vulnerable to the impacts of climate change on health, and that policy inaction in this regard threatens Australian lives. In a number of respects, Australia has gone backwards and now lags behind other high income countries such as Germany and the United Kingdom. Ex les include the persistence of a very high carbon-intensive energy system in Australia, and its slow transition to renewables and low carbon electricity generation. However, we also find some ex les of good progress, such as heatwave response planning. Given the overall poor state of progress on climate change and health in Australia, this country now has an enormous opportunity to take action and protect human health and lives. Australia has the technical knowhow and intellect to do this, and our annual updates of this assessment will track Australia's engagement with and progress on this vitally important issue.
Publisher: Frontiers Media SA
Date: 13-08-2021
DOI: 10.3389/FPHAR.2021.718679
Abstract: Diabetes mellitus is estimated to affect up to 700 million people by the year 2045, contributing to an immense health and economic burden. People living with diabetes have a higher risk of developing numerous debilitating vascular complications, leading to an increased need for medical care, a reduced quality of life and increased risk of early death. Current treatments are not satisfactory for many patients who suffer from impaired angiogenesis in response to ischaemia, increasing their risk of ischaemic cardiovascular conditions. These vascular pathologies are characterised by endothelial dysfunction and abnormal angiogenesis, amongst a host of impaired signaling pathways. Therapeutic stimulation of angiogenesis holds promise for the treatment of diabetic vascular complications that stem from impaired ischaemic responses. However, despite significant effort and research, there are no established therapies that directly stimulate angiogenesis to improve ischaemic complications such as ischaemic heart disease and peripheral artery disease, highlighting the immense unmet need. However, despite significant effort and research, there are no established therapies that directly stimulate angiogenesis in a clinical setting, highlighting the immense unmet need. MicroRNAs (miRNAs) are emerging as powerful targets for multifaceted diseases including diabetes and cardiovascular disease. This review highlights the potential role of microRNAs as therapeutic targets for rescuing diabetes-impaired angiogenesis, with a specific focus on miR-181c, which we have previously identified as an important angiogenic regulator. Here we summarise the pathways currently known to be regulated by miR-181c, which include the classical angiogenesis pathways that are dysregulated in diabetes, mitochondrial function and axonal guidance, and describe how these relate both directly and indirectly to angiogenesis. The pleiotropic actions of miR-181c across multiple key angiogenic signaling pathways and critical cellular processes highlight its therapeutic potential as a novel target for treating diabetic vascular complications.
Publisher: Oxford University Press (OUP)
Date: 20-03-2020
DOI: 10.1093/CVR/CVAA072
Abstract: While the advent of drug-eluting stents has been clinically effective in substantially reducing the rates of major stent-related adverse events compared with bare metal stents, vascular biological problems such as neointimal hyperplasia, delayed re-endothelialization, late stent thrombosis are not eliminated and, increasingly, neoatherosclerosis is the underlying mechanism for very late stent failure. Further understanding regarding the mechanisms underlying the biological responses to stent deployment is therefore required so that new and improved therapies can be developed. This review will discuss the accumulating evidence that the chemokines, small inflammatory proteins, play a role in each key biological process of stent biocompatibility. It will address the chemokine system in its specialized roles in regulating the multiple facets of vascular biocompatibility including neointimal hyperplasia, endothelial progenitor cell (EPC) mobilization and re-endothelialization after vascular injury, platelet activation and thrombosis, as well as neoatherosclerosis. The evidence in this review suggests that chemokine-targeting strategies may be effective in controlling the pathobiological processes that lead to stent failure. Preclinical studies provide evidence that inhibition of specific chemokines and/or broad-spectrum inhibition of the CC-chemokine class prevents neointimal hyperplasia, reduces thrombosis and suppresses the development of neoatherosclerosis. In contrast, however, to these apparent deleterious effects of chemokines on stent biocompatibility, the CXC chemokine, CXCL12, is essential for the mobilization and recruitment of EPCs that make important contributions to re-endothelialization post-stent deployment. This suggests that future chemokine inhibition strategies would need to be correctly targeted so that all key stent biocompatibility areas could be addressed, without compromising important adaptive biological responses.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Wiley
Date: 05-2021
DOI: 10.1111/IMJ.15327
Abstract: Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease. New clinical practice recommendations are presented to assist practitioners in enhancing the care of all patients with FH. Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. Management is under‐pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non‐cholesterol risk factors and appropriate use of low‐density lipoprotein (LDL)‐cholesterol‐lowering therapies including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The recommendations need to be utilised using judicious clinical judgement and shared decision‐making with patients and families. New government‐funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of the recommendations. However, a comprehensive implementation science and practice strategy is required to ensure that the guidance translates into benefit for all families with FH.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2018
DOI: 10.1161/ATVBAHA.118.307026
Abstract: Considerable evidence from preclinical and population studies suggests that HDLs (high-density lipoproteins) possess atheroprotective properties. Reports from HDL infusion studies in animals and early clinical imaging trials reported evidence of plaque regression. These findings have stimulated further interest in developing new agents targeting HDL. However, the results of more recent imaging studies in the setting of high-intensity statin use have been disappointing. As the concept of plaque changes with HDL therapeutics evolves and imaging technology to evaluate these effects advances, there will become increasing opportunity to determine the effects of HDL agents on atherosclerotic plaque (Graphic Abstract).
Publisher: Wiley
Date: 15-01-2022
Publisher: MDPI AG
Date: 21-05-2020
DOI: 10.3390/IJMS21103633
Abstract: Diabetes mellitus affects millions of people worldwide and is associated with devastating vascular complications. A number of these complications, such as impaired wound healing and poor coronary collateral circulation, are characterised by impaired ischaemia-driven angiogenesis. There is increasing evidence that high-density lipoproteins (HDL) can rescue diabetes-impaired angiogenesis through a number of mechanisms, including the modulation of endothelial cell metabolic reprogramming. Endothelial cell metabolic reprogramming in response to tissue ischaemia is a driver of angiogenesis and is dysregulated by diabetes. Specifically, diabetes impairs pathways that allow endothelial cells to upregulate glycolysis in response to hypoxia adequately and impairs suppression of mitochondrial respiration. HDL rescues the impairment of the central hypoxia signalling pathway, which regulates these metabolic changes, and this may underpin several of its known pro-angiogenic effects. This review discusses the current understanding of endothelial cell metabolism and how diabetes leads to its dysregulation whilst examining the various positive effects of HDL on endothelial cell function.
Publisher: Public Library of Science (PLoS)
Date: 21-11-2017
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.ATHEROSCLEROSIS.2011.04.001
Abstract: Mimetic peptides of apolipoprotein A-I (apoA-I) present a new strategy for promoting the biological activity of high density lipoproteins (HDL). This study aimed to compare the anti-inflammatory effects of ETC-642, a new apoA-I mimetic peptide, with discoidal reconstituted HDL (rHDL). New Zealand White rabbits (n=42) received daily infusions of saline, rHDL or discoidal complexes of an hipathic peptide, ETC-642 (1-30 mg/kg), prior to insertion of non-occlusive carotid collars. Human coronary artery endothelial cells (HCAECs) were pre-incubated with ETC-642 or rHDL before TNF-α stimulation. Monocyte adhesion was investigated by pre-incubating HCAECs with rHDL or ETC-642, stimulating with TNF-α and incubating with THP-1 monocytes. Infusion of ETC-642 resulted in dose-dependent reductions of collar-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the artery wall (p<0.05). Pre-incubation of HCAECs with ETC-642 and rHDL reduced TNF-α-induced THP-1 monocyte adhesion (p<0.01). Furthermore, ETC-642 and rHDL treatment reduced TNF-α induced mRNA levels of inflammatory markers VCAM-1, fractalkine, MCP-1 and the p65 subunit of NF-κB (p<0.05). These studies demonstrate that ETC-642 exhibits anti-inflammatory properties that are comparable to apoA-I both in vivo and in vitro and that these effects are mediated via the NF-κB signaling pathway.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Springer Science and Business Media LLC
Date: 06-09-2016
Publisher: MDPI AG
Date: 20-03-2022
DOI: 10.3390/IJMS23063363
Abstract: Peripheral arterial disease (PAD) is characterised by accelerated arterial calcification and impairment in angiogenesis. Studies implicate vascular calcification as a contributor to PAD, but the mechanisms remain unclear. We aimed to determine the effect of calcification on ischaemia-driven angiogenesis. Human coronary artery endothelial cells (ECs) were treated with calcification medium (CM: CaCl2 2.7 mM, Na2PO4 2.0 mM) for 24 h and exposed to normoxia (5% CO2) or hypoxia (1.2% O2 5% CO2 balanced with N2). In normoxia, CM significantly inhibited tubule formation and migration and upregulated calcification markers of ALP, BMP2, and Runx2. CM elevated levels of calcification-protective gene OPG, demonstrating a compensatory mechanism by ECs. CM failed to induce pro-angiogenic regulators VEGFA and HIF-1α in hypoxia and further suppressed the phosphorylation of endothelial nitric oxide synthase (eNOS) that is essential for vascular function. In vivo, osteoprotegerin-deficient mice (OPG−/−), a calcification model, were subjected to hind-limb ischaemia (HLI) surgery. OPG−/− mice displayed elevated serum alkaline phosphatase (ALP) activity compared to wild-type controls. OPG−/− mice experienced striking reductions in blood-flow reperfusion in both 8-week-old and 6-month-old mice post-HLI. This coincided with significant impairment in tissue ischaemia and reduced limb function as assessed by clinical scoring (Tarlov). This study demonstrated for the first time that a pro-calcific environment is detrimental to ischaemia-driven angiogenesis. The degree of calcification in patients with PAD can often be a limiting factor with the use of standard therapies. These highly novel findings require further studies for full elucidation of the mechanisms involved and have implications for the development of therapies to suppress calcification in PAD.
Publisher: Elsevier BV
Date: 03-2021
Publisher: MDPI AG
Date: 27-07-2022
DOI: 10.3390/BIOMEDICINES10081807
Abstract: Macrophage-derived nitric oxide (NO) plays a critical role in atherosclerosis and presents as a potential biomarker. We assessed the uptake, distribution, and NO detection capacity of an irreversible, ruthenium-based, fluorescent NO sensor (Ru-NO) in macrophages, plasma, and atherosclerotic plaques. In vitro, incubation of Ru-NO with human THP1 monocytes and THP1-PMA macrophages caused robust uptake, detected by Ru-NO fluorescence using mass-cytometry, confocal microscopy, and flow cytometry. THP1-PMA macrophages had higher Ru-NO uptake (+13%, p 0.05) than THP1 monocytes with increased Ru-NO fluorescence following lipopolysaccharide stimulation (+14%, p 0.05). In mice, intraperitoneal infusion of Ru-NO found Ru-NO uptake was greater in peritoneal CD11b+F4/80+ macrophages (+61%, p 0.01) than CD11b+F4/80− monocytes. Infusion of Ru-NO into Apoe−/− mice fed high-cholesterol diet (HCD) revealed Ru-NO fluorescence co-localised with atherosclerotic plaque macrophages. When Ru-NO was added ex vivo to aortic cell suspensions from Apoe−/− mice, macrophage-specific uptake of Ru-NO was demonstrated. Ru-NO was added ex vivo to tail-vein blood s les collected monthly from Apoe−/− mice on HCD or chow. The plasma Ru-NO fluorescence signal was higher in HCD than chow-fed mice after 12 weeks (37.9%, p 0.05). Finally, Ru-NO was added to plasma from patients (N = 50) following clinically-indicated angiograms. There was lower Ru-NO fluorescence from plasma from patients with myocardial infarction (−30.7%, p 0.01) than those with stable coronary atherosclerosis. In conclusion, Ru-NO is internalised by macrophages in vitro, ex vivo, and in vivo, can be detected in atherosclerotic plaques, and generates measurable changes in fluorescence in murine and human plasma. Ru-NO displays promising utility as a sensor of atherosclerosis.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2020
DOI: 10.1038/S41377-020-00365-W
Abstract: Preclinical and clinical diagnostics increasingly rely on techniques to visualize internal organs at high resolution via endoscopes. Miniaturized endoscopic probes are necessary for imaging small luminal or delicate organs without causing trauma to tissue. However, current fabrication methods limit the imaging performance of highly miniaturized probes, restricting their widespread application. To overcome this limitation, we developed a novel ultrathin probe fabrication technique that utilizes 3D microprinting to reliably create side-facing freeform micro-optics ( µm diameter) on single-mode fibers. Using this technique, we built a fully functional ultrathin aberration-corrected optical coherence tomography probe. This is the smallest freeform 3D imaging probe yet reported, with a diameter of 0.457 mm, including the catheter sheath. We demonstrated image quality and mechanical flexibility by imaging atherosclerotic human and mouse arteries. The ability to provide microstructural information with the smallest optical coherence tomography catheter opens a gateway for novel minimally invasive applications in disease.
Publisher: MDPI AG
Date: 08-11-2016
DOI: 10.3390/IJMS17111856
Publisher: MDPI AG
Date: 18-10-2018
DOI: 10.3390/IJMS19103217
Abstract: Wound healing is a multistep process with four overlapping but distinct stages: hemostasis, inflammation, proliferation, and remodeling. An alteration at any stage may lead to the development of chronic non-healing wounds or excessive scar formation. Impaired wound healing presents a significant health and economic burden to millions of in iduals worldwide, with diabetes mellitus and aging being major risk factors. Ongoing understanding of the mechanisms that underly wound healing is required for the development of new and improved therapies that increase repair. Chemokines are key regulators of the wound healing process. They are involved in the promotion and inhibition of angiogenesis and the recruitment of inflammatory cells, which release growth factors and cytokines to facilitate the wound healing process. Preclinical research studies in mice show that the administration of CCL2, CCL21, CXCL12, and a CXCR4 antagonist as well as broad-spectrum inhibition of the CC-chemokine class improve the wound healing process. The focus of this review is to highlight the contributions of chemokines during each stage of wound healing and to discuss the related molecular pathologies in complex and chronic non-healing wounds. We explore the therapeutic potential of targeting chemokines as a novel approach to overcome the debilitating effects of impaired wound healing.
Publisher: Wiley
Date: 03-2022
Abstract: Multimodal microendoscopes enable co‐located structural and molecular measurements in vivo, thus providing useful insights into the pathological changes associated with disease. However, different optical imaging modalities often have conflicting optical requirements for optimal lens design. For ex le, a high numerical aperture (NA) lens is needed to realize high‐sensitivity fluorescence measurements. In contrast, optical coherence tomography (OCT) demands a low NA to achieve a large depth of focus. These competing requirements present a significant challenge in the design and fabrication of miniaturized imaging probes that are capable of supporting high‐quality multiple modalities simultaneously. An optical design is demonstrated which uses two‐photon 3D printing to create a miniaturized lens that is simultaneously optimized for these conflicting imaging modalities. The lens‐in‐lens design contains distinct but connected optical surfaces that separately address the needs of both fluorescence and OCT imaging within a lens of 330 µm diameter. This design shows an improvement in fluorescence sensitivity of x in contrast to more conventional fiber‐optic design approaches. This lens‐in‐lens is then integrated into an intravascular catheter probe with a diameter of 520 µm. The first simultaneous intravascular OCT and fluorescence imaging of a mouse artery in vivo is reported.
Publisher: MDPI AG
Date: 26-07-2019
DOI: 10.3390/JCM8081109
Abstract: Atherosclerotic coronary artery disease (CAD) results from build-up of cholesterol-rich plaques in the walls of the coronary arteries and is a leading cause of death. Inflammation is central to atherosclerosis. Uncontrolled inflammation makes coronary plaques “unstable” and vulnerable to rupture or erosion, leading to thrombosis and myocardial infarction (MI). As multiple inflamed plaques often co-exist in the coronary system, patients are at risk of repeated atherothrombotic cardiovascular events after MI, with rates of 10–12% at one year and 18–20% at three years. This is largely because current therapies for CAD, such as lipid-lowering statins, do not adequately control plaque inflammation. New anti-atherosclerotic agents are therefore needed, especially those that better target inflammation. The recent positive results for the anti-interleukin-1-beta (IL-1β) monoclonal antibody, Canakinumab, in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) clinical trial has provided a major stimulant to the field. It highlights that not only is inflammation important from a pathogenic and risk prediction perspective in CAD, but that reducing inflammation can be beneficial. The challenge is now to find the best strategies to achieve this in real-world practice. This review outlines the role that inflammation plays in atherosclerosis and provides an update on anti-inflammatory therapies currently being investigated to target atherosclerosis.
Publisher: AMPCo
Date: 02-12-2020
DOI: 10.5694/MJA2.50869
Publisher: Oxford University Press (OUP)
Date: 10-03-2015
DOI: 10.1093/CVR/CVV104
Abstract: Angiogenesis is important for postnatal physiological processes including tissue neovascularization in response to an ischaemic injury. Conversely, uncontrolled inflammatory-driven angiogenesis can accelerate atherosclerotic plaque and tumour growth. Angiogenesis-associated diseases are highly prevalent globally, with cardiovascular-related disorders and cancer being the leading causes of mortality worldwide. A vast amount of research has been conducted on the vasculoprotective effects of high-density lipoproteins (HDLs) and while current HDL-raising therapies to date have not yielded the desired benefits clinically, its role in angiogenesis is yet to be fully elucidated. Epidemiological studies report positive correlations between elevated HDL levels and improved prognosis in both ischaemia- and inflammatory-driven pathologies, in which angiogenesis plays a key role. This review focuses on current evidence from epidemiological and prospective studies, coupled with animal models and mechanistic studies that highlight the ability of HDL to conditionally regulate angiogenesis.
Publisher: Environmental Health Perspectives
Date: 08-2005
DOI: 10.1289/EHP.7724
Abstract: The increase in asthma incidence, prevalence, and morbidity over recent decades presents a significant challenge to public health. Pollen is an important trigger of some types of asthma, and both pollen quantity and season depend on climatic and meteorologic variables. Over the same period as the global rise in asthma, there have been considerable increases in atmospheric carbon dioxide concentration and global average surface temperature. We hypothesize anthropogenic climate change as a plausible contributor to the rise in asthma. Greater concentrations of carbon dioxide and higher temperatures may increase pollen quantity and induce longer pollen seasons. Pollen allergenicity can also increase as a result of these changes in climate. Exposure in early life to a more allergenic environment may also provoke the development of other atopic conditions, such as eczema and allergic rhinitis. Although the etiology of asthma is complex, the recent global rise in asthma could be an early health effect of anthropogenic climate change.
Publisher: American Meteorological Society
Date: 02-2020
Abstract: In November 2016, an unprecedented epidemic thunderstorm asthma event in Victoria, Australia, resulted in many thousands of people developing breathing difficulties in a very short period of time, including 10 deaths, and created extreme demand across the Victorian health services. To better prepare for future events, a pilot forecasting system for epidemic thunderstorm asthma (ETSA) risk has been developed for Victoria. The system uses a categorical risk-based approach, combining operational forecasting of gusty winds in severe thunderstorms with statistical forecasts of high ambient grass pollen concentrations, which together generate the risk of epidemic thunderstorm asthma. This pilot system provides the first routine daily epidemic thunderstorm asthma risk forecasting service in the world that covers a wide area, and integrates into the health, ambulance, and emergency management sector. Epidemic thunderstorm asthma events have historically occurred infrequently, and no event of similar magnitude has impacted the Victorian health system since. However, during the first three years of the pilot, 2017–19, two high asthma presentation events and four moderate asthma presentation events were identified from public hospital emergency department records. The ETSA risk forecasts showed skill in discriminating between days with and without health impacts. However, even with hindsight of the actual weather and airborne grass pollen conditions, some high asthma presentation events occurred in districts that were assessed as low risk for ETSA, reflecting the challenge of predicting this unusual phenomenon.
Publisher: Oxford University Press (OUP)
Date: 13-10-2022
DOI: 10.1093/IJE/DYAC197
Publisher: Wiley
Date: 10-2019
Abstract: M3 is a broad‐spectrum chemokine‐binding protein that inactivates inflammatory chemokines, including CCL2, CCL5, and CX 3 CL1. The aim of this study was to compare whether M3 could inhibit angiogenesis driven by inflammation or ischemia. Here, apolipoprotein E –/– mice were injected with adenoviral M3 (AdM3) or control adenoviral green fluorescent protein (AdGFP) 3 d prior to stimulating angiogenesis using 2 established models that distinctly represent inflammatory or ischemia‐driven angiogenesis, namely the periarterial femoral cuff and hind limb ischemia. AdM3 reduced intimal thickening, adventitial capillary density, and macrophage accumulation in femoral arteries 21 d after periarterial femoral cuff placement compared with AdGFP‐treated mice ( P 0.05). AdM3 also reduced mRNA expression of proangiogenic VEGF, inflammatory markers IL‐6 and IL‐1β, and vascular smooth muscle cell (VSMC)‐activated synthetic markers Krüppel‐like family of transcription factor 4 (KLF4) and platelet‐derived growth factor receptor β (PDGFRβ) in the inflammatory cuff model. In contrast, capillary density, VSMC content, blood flow perfusion, and VEGF gene expression were unaltered between groups in skeletal muscle following hind limb ischemia. In vitro , AdM3 significantly reduced human microvascular endothelial cell 1 proliferation, migration, and tubule formation by ~17, 71.3, and 8.7% ( P 0.05) in macrophage‐conditioned medium associating with reduced VEGF and hypoxia‐inducible factor 1α mRNA but not in hypoxia (1% O 2 ). Compared with AdGFP, AdM3 also inhibited VSMC proliferation and migration and reduced mRNA expression of KLF4 and PDGFRβ under inflammatory conditions. In contrast, AdM3 had no effect on VSMC processes in response to hypoxia in vitro. Our findings show that broad‐spectrum inhibition of inflammatory chemokines by M3 inhibits inflammatory‐driven but not ischemia‐driven angiogenesis, presenting a novel strategy for the treatment of diseases associated with inflammatory‐driven angiogenesis.—Ravindran, D., Cartland, S. P., Bursill, C. A., Kavurma, M. M. Broad‐spectrum chemokine inhibition blocks inflammation‐induced angiogenesis, but preserves ischemia‐driven angiogenesis. FASEB J. 33, 13423–13434 (2019). www.fasebj.org
Publisher: MDPI AG
Date: 13-01-2017
DOI: 10.3390/IJMS18010155
Publisher: Wiley
Date: 20-05-2017
DOI: 10.1002/JOC.4770
Publisher: MDPI AG
Date: 13-12-2019
DOI: 10.3390/IJMS20246291
Abstract: Dysfunctional adipose tissue phenotype underpins type 2 diabetes mellitus (T2DM) development. The disruption of circadian rhythms contributes to T2DM development. We investigated the effects of high-energy diet and photoperiod length on visceral and subcutaneous adipose tissue phenotype. Psammomys obesus sand rats exposed to neutral (12 light:12 dark) or short (5 light:19 dark) photoperiod were fed a low- (LE) or high- (HE) energy diet. The HE diet and/or short photoperiod reduced subcutaneous expression of adipocyte differentiation/function markers C/ebpα, Pparδ, Pparγ and Adipoq. Visceral Pparα levels were elevated in the 5:19HE group however, the HE diet and/or short photoperiod decreased visceral Pparγ and Adipoq expression. 5:19HE animals had elevated Ucp1 yet lower Pgc-1α levels. The HE diet increased visceral Tgf-β1, Ccl2 and Cd68 levels, suggestive of a pro-inflammatory state. Daily visceral rhythms of these genes were affected by a short photoperiod and/or HE diet. The 12:12HE, 5:19LE or 5:19HE animals had a higher proportion of larger adipocytes, indicating increased adipocyte hypertrophy. Collectively, the HE diet and/or shorter light exposure drives a dysfunctional adipose tissue phenotype. Daily rhythms are affected by a short photoperiod and HE diet in a site-specific manner. These findings provide mechanistic insight on the influence of disrupted circadian rhythms and HE diet on adipose tissue phenotype.
Publisher: American Chemical Society (ACS)
Date: 05-10-2001
DOI: 10.1021/JF010275D
Abstract: Green tea from Camellia sinensis lowers plasma cholesterol in animal models of hypercholesterolemia. The aim of this study was to determine the effects of green tea on the expression of the hepatic low-density lipoprotein (LDL) receptor, a cell surface protein involved in the control of plasma cholesterol. Incubating human HepG2 liver cells in culture with green tea increased both LDL receptor binding activity and protein. An ethyl acetate extract of green tea, containing 70% (w/w) catechins, also increased the LDL receptor binding activity, protein, and mRNA, indicating that (1) the effect was at the level of gene transcription and that (2) the catechins were the active constituents. The mechanism by which green tea up-regulated the LDL receptor was then investigated. Green tea decreased the cell cholesterol concentration (-30%) and increased the conversion of the sterol-regulated element binding protein (SREBP-1) from the inactive precursor form to the active transcription-factor form. Consistent with this, the mRNA of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis, was also increased by green tea. In conclusion, green tea up-regulated the LDL receptor in HepG2 cells. The effect was most likely mediated through SREBP-1 in response to a decrease in the intracellular cholesterol concentration. The LDL receptor may therefore play a role in the hypocholesterolemic effect of green tea in vivo.
Publisher: Springer Science and Business Media LLC
Date: 05-04-2019
Publisher: MyJove Corporation
Date: 28-05-2013
DOI: 10.3791/50265
Publisher: Springer Science and Business Media LLC
Date: 14-11-2017
Publisher: SAGE Publications
Date: 26-06-2021
Abstract: Hotter weather is associated with aggressive crime. However, it is not well known if similar relationships apply to online aggression. This study uses anger counts derived from Twitter posts (tweets) and assault counts in New South Wales, Australia, to investigate if they share a similar relationship with temperature, and to determine if online anger is a predictor of assault. Results indicated that the relationships were largely inverse—assault counts were higher in summer than winter, while angry tweet counts were lower. As daily maximum temperatures rose, assault counts increased while angry tweet counts decreased. Angry tweet counts were inversely associated with assaults, with an increase in tweets signaling decreasing assaults. There are several plausible explanations for the dissimilarities including the impact of temperature on behavior, socio-demographic differences, and data collection methods. The findings of this study add to the growing literature in social media emotion and its relationship with temperature.
Publisher: Wiley
Date: 10-09-2013
DOI: 10.1096/FJ.13-233874
Abstract: Increasing evidence suggests that high-density lipoproteins (HDLs) promote hypoxia-induced angiogenesis. The hypoxia-inducible factor 1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway is important in hypoxia and is modulated post-translationally by prolyl hydroxylases (PHD1-PHD3) and E3 ubiquitin ligases (Siah1 and Siah2). We aimed to elucidate the mechanisms by which HDLs augment hypoxia-induced angiogenesis. Preincubation (16 h) of human coronary artery endothelial cells with reconstituted high-density lipoprotein (rHDL) containing apolipoprotein A-I (apoA-I) and phosphatidylcholine (20 μM, final apoA-I concentration), before hypoxia, increased Siah1 (58%) and Siah2 (88%) mRNA levels and suppressed PHD2 (32%) and PHD3 (45%) protein levels compared with hypoxia-induced control levels. After Siah1/2 small interfering RNA knockdown, rHDL was unable to suppress PHD2/3 and failed to induce HIF-1α, VEGF, and tubulogenesis in hypoxia. Inhibition of the upstream phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway also abrogated the effects of rHDL. Furthermore, knockdown of the scavenger receptor SR-BI attenuated rHDL-induced elevations in Siah1/2 and tubulogenesis in hypoxia, indicating that SR-BI plays a key role. Finally, the importance of VEGF in mediating the ability of rHDL to drive hypoxia-induced angiogenesis was confirmed using a VEGF-neutralizing antibody. In summary, rHDL augments the HIF-1α/VEGF pathway via SR-BI and modulation of the post-translational regulators of HIF-1α (PI3K/Siahs/PHDs). HDL-induced augmentation of angiogenesis in hypoxia may have implications for therapeutic modulation of ischemic injury.
Publisher: American Diabetes Association
Date: 09-06-2016
DOI: 10.2337/DB15-1668
Abstract: Disordered neovascularization and impaired wound healing are important contributors to diabetic vascular complications. We recently showed that high-density lipoproteins (HDLs) enhance ischemia-mediated neovascularization, and mounting evidence suggests HDL have antidiabetic properties. We therefore hypothesized that HDL rescue diabetes-impaired neovascularization. Streptozotocin-induced diabetic mice had reduced blood flow recovery and neovessel formation in a hindlimb ischemia model compared with nondiabetic mice. Reconstituted HDL (rHDL) infusions in diabetic mice restored blood flow recovery and capillary density to nondiabetic levels. Topical rHDL application rescued diabetes-impaired wound closure, wound angiogenesis, and capillary density. In vitro, rHDL increased key mediators involved in hypoxia-inducible factor-1α (HIF-1α) stabilization, including the phosphoinositide 3-kinase/Akt pathway, Siah1, and Siah2, and suppressed the prolyl hydroxylases (PHD) 2 and PHD3. rHDL rescued high glucose–induced impairment of tubulogenesis and vascular endothelial growth factor (VEGF) A protein production, a finding associated with enhanced phosphorylation of proangiogenic mediators VEGF receptor 2 and endothelial nitric oxide synthase. Siah1/2 small interfering RNA knockdown confirmed the importance of HIF-1α stability in mediating rHDL action. Lentiviral short hairpin RNA knockdown of scavenger receptor class B type I (SR-BI) in vitro and SR-BI−/− diabetic mice in vivo attenuated rHDL rescue of diabetes-impaired angiogenesis, indicating a key role for SR-BI. These findings provide a greater understanding of the vascular biological effects of HDL, with potential therapeutic implications for diabetic vascular complications.
Publisher: Springer Science and Business Media LLC
Date: 30-11-2011
Abstract: High-density lipoproteins (HDL) and their main apolipoprotein, apoA-I, exhibit anti-inflammatory properties. The development of peptides that mimic HDL apolipoproteins offers a promising strategy to reduce inflammatory disease. This study aimed to compare the anti-inflammatory effects of ETC-642, an apoA-I mimetic peptide, with that of discoidal reconstituted HDL (rHDL), consisting of full-length apoA-I complexed with phosphatidylcholine, in rabbits with chronic vascular inflammation. New Zealand White rabbits (n = 10/group) were placed on chow supplemented with 0.2% (w/w) cholesterol for 6-weeks. The animals received two infusions of saline, rHDL (8 mg/kg apoA-I) or ETC-642 (30 mg/kg peptide) on the third and fifth days of the final week. The infusions of rHDL and ETC-642 were able to significantly reduce cholesterol-induced expression of intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the thoracic aorta (p 0.05). When isolated rabbit HDL was pre-incubated with human coronary artery endothelial cells (HCAECs), prior to stimulation with TNF-α, it was found that HDL from ETC-642 treated rabbits were more effective at inhibiting the TNF-α-induced increase in ICAM-1, VCAM-1 and p65 than HDL isolated from saline treated rabbits (p 0.05). There were, however, no changes in HDL lipid composition between treatment groups. Infusion of ETC-642 causes anti-inflammatory effects that are comparable to rHDL in an animal model of chronic vascular inflammation and highlights that apoA-I mimetic peptides present a viable strategy for the treatment of inflammatory disease.
Publisher: Public Library of Science (PLoS)
Date: 09-03-2016
Publisher: MDPI AG
Date: 05-06-2018
DOI: 10.3390/IJMS19061680
Publisher: AME Publishing Company
Date: 08-2019
Publisher: Wiley
Date: 19-10-2021
DOI: 10.1002/MED.21736
Abstract: Nitric oxide (NO) is a ubiquitous, volatile, cellular signaling molecule that operates across a wide physiological concentration range (pM–µM) in different tissues. It is a highly diffusible messenger and intermediate in various metabolic pathways. NO plays a pivotal role in maintaining optimum cardiovascular function, particularly by regulating vascular tone and blood flow. This review highlights the need for accurate, real‐time bioimaging of NO in clinical diagnostic, therapeutic, monitoring, and theranostic applications within the cardiovascular system. We summarize electrochemical, optical, and nanoscale sensors that allow measurement and imaging of NO, both directly and indirectly via surrogate measurements. The physical properties of NO render it difficult to accurately measure in tissues using direct methods. There are also significant limitations associated with the NO metabolites used as surrogates to indirectly estimate NO levels. All these factors added to significant variability in the measurement of NO using available methodology have led to a lack of sensors and imaging techniques of clinical applicability in relevant vascular pathologies such as atherosclerosis and ischemic heart disease. Challenges in applying current methods to biomedical and clinical translational research, including the wide physiological range of NO and limitations due to the characteristics and toxicity of the sensors are discussed, as are potential targets and modifications for future studies. The development of biocompatible nanoscale sensors for use in combination with existing clinical imaging modalities provides a feasible opportunity for bioimaging NO within the cardiovascular system.
Publisher: Elsevier BV
Date: 11-2015
Publisher: American Diabetes Association
Date: 14-02-2019
DOI: 10.2337/DB17-0926
Abstract: Fenofibrate, a peroxisome proliferator–activated receptor α (PPARα) agonist, reduces lower limb utations in patients with type 2 diabetes. The mechanism is, however, unknown. In this study, we demonstrate that fenofibrate markedly attenuates diabetes-related impairment of ischemia-mediated angiogenesis. In a murine model of hindlimb ischemia, daily oral fenofibrate treatment restored diabetes-impaired blood flow recovery, foot movement, hindlimb capillary density, vessel diameter, and vascular endothelial growth factor signaling to nondiabetic levels in both wild-type and PPARα-knockout mice, indicating that these fenofibrate effects are largely PPARα independent. In vitro, fenofibric acid (FFA) rescued high glucose–induced (25 mmol/L) impairment of endothelial cell migration, tubulogenesis, and survival in a PPARα-independent manner. Interestingly, fenofibrate in vivo and FFA in vitro reversed high glucose–induced expression of thioredoxin-interacting protein (TXNIP), an exquisitely glucose-inducible gene previously identified as a critical mediator of diabetes-related impairment in neovascularization. Conversely, adenoviral overexpression of TXNIP abrogated the restorative effects of FFA on high glucose–impaired endothelial cell function in vitro, indicating that the effects of FFA are mediated by TXNIP. We conclude that fenofibrate rescues diabetic impairment in ischemia-mediated angiogenesis, in large part, by PPARα-independent regulation of TXNIP. These findings may therefore explain the reduction in utations seen in patients with diabetes treated with fenofibrate.
Publisher: Public Library of Science (PLoS)
Date: 10-03-2017
Publisher: Oxford University Press (OUP)
Date: 15-10-2013
DOI: 10.1093/CVR/CVT234
Abstract: High-density lipoproteins (HDL) exert striking anti-inflammatory effects and emerging evidence suggests that they may augment ischaemia-mediated neovascularization. We sought to determine whether HDL conditionally regulates angiogenesis, depending on the pathophysiological context by (i) inhibiting inflammation-induced angiogenesis, but also (ii) enhancing ischaemia-mediated angiogenesis. Intravenously delivered apolipoprotein (apo) A-I attenuated neovascularization in the murine femoral collar model of inflammation-induced angiogenesis, compared with phosphate-buffered saline infused C57BL6/J mice (58%), P < 0.05. Conversely, apoA-I delivery augmented neovessel formation (75%) and enhanced blood perfusion (45%) in the murine hindlimb ischaemia model, P < 0.05. Reconstituted HDL (rHDL) was tested on key angiogenic cell functions in vitro. rHDL inhibited human coronary artery endothelial cell migration (37.9 and 76.9%), proliferation (15.7 and 40.4%), and tubulogenesis on matrigel (52 and 98.7%) when exposed to two inflammatory stimuli: tumour necrosis factor-α (TNF-α) and macrophage-conditioned media (MCM). In contrast, rHDL significantly augmented hypoxia-stimulated migration (36.9%), proliferation (135%), and tubulogenesis (22.9%), P < 0.05. Western blot and RT-PCR analyses revealed that these ergent actions of rHDL were associated with conditional regulation of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and VEGF receptor 2, which were attenuated in response to TNF-α (40.4, 41.0, and 33.2%) and MCM (72.5, 30.7, and 69.5%), but augmented by rHDL in hypoxia (39.8, 152.6, and 15.7%%), all P < 0.05. HDL differentially regulates angiogenesis dependent upon the pathophysiological setting, characterized by suppression of inflammation-associated angiogenesis, and conversely, by the enhancement of hypoxia-mediated angiogenesis. This has significant implications for therapeutic modulation of neovascularization.
Publisher: Springer Science and Business Media LLC
Date: 03-03-2015
DOI: 10.1007/S00285-015-0864-5
Abstract: We present here a mathematical model describing the primary mechanisms that drive the early stages of atherosclerosis. This involves the interactions between modified low density lipoprotein (LDL), monocytes/macrophages, cytokines and foam cells. This model suggests that there is an initial inflammatory phase associated with atherosclerotic lesion development and a longer, quasi-static process of plaque development inside the arterial wall that follows the initial transient. We will show results that show how different LDL concentrations in the blood stream and different immune responses can affect the development of a plaque. Through numerical bifurcation analysis, we show the existence of a fold bifurcation when the flux of LDL from the blood is sufficiently high. By analysing the model presented in this paper, we gain a greater insight into this inflammatory response qualitatively and quantitatively.
Publisher: Elsevier BV
Date: 08-2018
Publisher: Elsevier BV
Date: 05-2015
Publisher: Springer Science and Business Media LLC
Date: 29-09-2017
Publisher: Elsevier BV
Date: 10-2019
Publisher: Springer Science and Business Media LLC
Date: 18-07-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-08-2015
Abstract: Interleukin ( IL )‐1β, IL ‐18, and downstream IL ‐6 are key inflammatory cytokines in the pathogenesis of coronary artery disease. Colchicine is believed to block the NLRP 3 inflammasome, a cytosolic complex responsible for the production of IL ‐1β and IL ‐18. In vivo effects of colchicine on cardiac cytokine release have not been previously studied. This study aimed to (1) assess the local cardiac production of inflammatory cytokines in patients with acute coronary syndromes ( ACS ), stable coronary artery disease and in controls and (2) determine whether acute administration of colchicine inhibits their production. Forty ACS patients, 33 with stable coronary artery disease, and 10 controls, were included. ACS and stable coronary artery disease patients were randomized to oral colchicine treatment (1 mg followed by 0.5 mg 1 hour later) or no colchicine, 6 to 24 hours prior to cardiac catheterization. Blood s les from the coronary sinus, aortic root (arterial), and lower right atrium (venous) were collected and tested for IL ‐1β, IL ‐18, and IL ‐6 using ELISA . In ACS patients, coronary sinus levels of IL ‐1β, IL ‐18, and IL ‐6 were significantly higher than arterial and venous levels ( P =0.017, .001 and .001, respectively). Transcoronary (coronary sinus‐arterial) gradients for IL ‐1β, IL ‐18, and IL ‐6 were highest in ACS patients and lowest in controls ( P =0.077, 0.033, and 0.014, respectively). Colchicine administration significantly reduced transcoronary gradients of all 3 cytokines in ACS patients by 40% to 88% ( P =0.028, 0.032, and 0.032, for IL ‐1β, IL ‐18, and IL ‐6, respectively). ACS patients exhibit increased local cardiac production of inflammatory cytokines. Short‐term colchicine administration rapidly and significantly reduces levels of these cytokines.
Start Date: 2016
End Date: 03-2019
Amount: $342,200.00
Funder: Australian Research Council
View Funded ActivityStart Date: 10-2014
End Date: 12-2020
Amount: $23,000,000.00
Funder: Australian Research Council
View Funded Activity