Melbourne Medical School Collected Works - Research Publications
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ItemDefective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis(ELSEVIER, 2022-07-01)OBJECTIVES: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis. METHODS: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe-/-/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe-/- and Apoe-/-/Hmgcr KI mice. RESULTS: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe-/-/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe-/-/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe-/-/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs. CONCLUSIONS: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O-3O4 and PXL 770 for reducing atherosclerotic cardiovascular disease risks.
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ItemRoles of nutrition in muscle health of community-dwelling older adults: evidence-based expert consensus from Asian Working Group for Sarcopenia(WILEY, 2022-03-20)General muscle health declines with age, and in particular, sarcopenia-defined as progressive loss of muscle mass and strength/physical performance-is a growing issue in Asia with a rising population of community-dwelling older adults. Several guidelines have addressed early identification of sarcopenia and management, and although nutrition is central to treatment of sarcopenia, there are currently few guidelines that have examined this specifically in the Asian population. Therefore, the Asian Working Group for Sarcopenia established a special interest group (SIG) comprising seven experts across Asia and one from Australia, to develop an evidence-based expert consensus. A systematic literature search was conducted using MEDLINE on the topic of muscle health, from 2016 (inclusive) to July 2021, in Asia or with relevance to healthy, Asian community-dwelling older adults (≥60 years old). Several key topics were identified: (1) nutritional status: malnutrition and screening; (2) diet and dietary factors; (3) nutritional supplementation; (4) lifestyle interventions plus nutrition; and (5) outcomes and assessment. Clinical questions were developed around these topics, leading to 14 consensus statements. Consensus was achieved using the modified Delphi method with two rounds of voting. Moreover, the consensus addressed the impacts of COVID-19 on nutrition, muscle health, and sarcopenia in Asia. These statements encompass clinical expertise and knowledge across Asia and are aligned with findings in the current literature, to provide a practical framework for addressing muscle health in the community, with the overall aim to encourage and facilitate broader access to equitable care for this target population.
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ItemImproved sleep efficiency is associated with reduced cardio-metabolic risk: Findings from the MODERN trial(WILEY, 2021-06-02)Poor sleep increases cardio-metabolic risk, but limited information on the impact of sleep for the improvement of cardio-metabolic health exists. This analysis examined the impact of sleep on a health and lifestyle modification programme to reduce cardio-metabolic disease risk factors. Secondary analysis of the MODERN randomised controlled trial to reduce cardio-metabolic risk was undertaken at baseline and 24-month follow-up. Participants aged 40-70 years (n = 121) with three or more cardio-metabolic risk factors were randomised to a health and lifestyle modification intervention (n = 59) or usual care (n = 62), and underwent 7 day/night actigraphy to assess total sleep time, sleep efficiency (%), number of awakenings/night and physical activity levels. Blood pressure, blood lipid and glycaemic levels, anthropometric and diet measures were collected. The mean age was 59 ± 7 years and 37% were male. Baseline sleep measures were not different between groups. At the 24-month follow-up, both groups showed improvements in cardio-metabolic risk factors, albeit the change in blood pressure was greater in the intervention compared with the usual care group (systolic blood pressure: -11 versus -4 mmHg, p = .014). There were no differences between groups for diet, physical activity or sleep parameters. An increase in sleep efficiency was independently associated with lower systolic blood pressure (β = -2.117, p = .002) and higher high-density lipoprotein levels (β = 0.040, p = .033); an increase in total sleep time was associated with lower low-density lipoprotein levels (β = -0.003, p = .038) at 24 months. Overall, improvement in sleep quality over time was beneficial to reduce blood pressure and lipid levels. These findings highlight sleep as a potential target to reduce cardio-metabolic risk.
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ItemNo Preview AvailableEarly life infection and proinflammatory, atherogenic metabolomic and lipidomic profiles in infancy: a population-based cohort study.(eLife Sciences Publications, Ltd, 2022-05-10)Background: The risk of adult onset cardiovascular and metabolic (cardiometabolic) disease accrues from early life. Infection is ubiquitous in infancy and induces inflammation, a key cardiometabolic risk factor, but the relationship between infection, inflammation, and metabolic profiles in early childhood remains unexplored. We investigated relationships between infection and plasma metabolomic and lipidomic profiles at age 6 and 12 months, and mediation of these associations by inflammation. Methods: Matched infection, metabolomics, and lipidomics data were generated from 555 infants in a pre-birth longitudinal cohort. Infection data from birth to 12 months were parent-reported (total infections at age 1, 3, 6, 9, and 12 months), inflammation markers (high-sensitivity C-reactive protein [hsCRP]; glycoprotein acetyls [GlycA]) were quantified at 12 months. Metabolic profiles were 12-month plasma nuclear magnetic resonance metabolomics (228 metabolites) and liquid chromatography/mass spectrometry lipidomics (776 lipids). Associations were evaluated with multivariable linear regression models. In secondary analyses, corresponding inflammation and metabolic data from birth (serum) and 6-month (plasma) time points were used. Results: At 12 months, more frequent infant infections were associated with adverse metabolomic (elevated inflammation markers, triglycerides and phenylalanine, and lower high-density lipoprotein [HDL] cholesterol and apolipoprotein A1) and lipidomic profiles (elevated phosphatidylethanolamines and lower trihexosylceramides, dehydrocholesteryl esters, and plasmalogens). Similar, more marked, profiles were observed with higher GlycA, but not hsCRP. GlycA mediated a substantial proportion of the relationship between infection and metabolome/lipidome, with hsCRP generally mediating a lower proportion. Analogous relationships were observed between infection and 6-month inflammation, HDL cholesterol, and apolipoprotein A1. Conclusions: Infants with a greater infection burden in the first year of life had proinflammatory and proatherogenic plasma metabolomic/lipidomic profiles at 12 months of age that in adults are indicative of heightened risk of cardiovascular disease, obesity, and type 2 diabetes. These findings suggest potentially modifiable pathways linking early life infection and inflammation with subsequent cardiometabolic risk. Funding: The establishment work and infrastructure for the BIS was provided by the Murdoch Children's Research Institute (MCRI), Deakin University, and Barwon Health. Subsequent funding was secured from National Health and Medical Research Council of Australia (NHMRC), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women's Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Minderoo Foundation, the Ilhan Food Allergy Foundation, GMHBA, Vanguard Investments Australia Ltd, and the Percy Baxter Charitable Trust, Perpetual Trustees. In-kind support was provided by the Cotton On Foundation and CreativeForce. The study sponsors were not involved in the collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. Research at MCRI is supported by the Victorian Government's Operational Infrastructure Support Program. This work was also supported by NHMRC Senior Research Fellowships to ALP (1008396); DB (1064629); and RS (1045161) , NHMRC Investigator Grants to ALP (1110200) and DB (1175744), NHMRC-A*STAR project grant (1149047). TM is supported by an MCRI ECR Fellowship. SB is supported by the Dutch Research Council (452173113).
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ItemNo Preview AvailablePeripheral Oxygen Extraction and Exercise Limitation in Asymptomatic Patients with Diabetes Mellitus(EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC, 2021-06-16)Patients with diabetes mellitus (DM) frequently present reduced exercise capacity. We aimed to explore the extent to which peripheral extraction relates to exercise capacity in asymptomatic patients with DM. We prospectively enrolled 98 asymptomatic patients with type-2 DM (mean age of 59 ± 11 years and 56% male sex), and compared with 31 age, sex and body mass index-matched normoglycemic controls. Cardiopulmonary exercise testing with resting followed by stress echocardiography was performed. Exercise response was assessed using peak oxygen uptake (peak VO2) and ventilatory efficiency was measured using the slope of the relationship between minute ventilation and carbon dioxide production (VE/VCO2). Peripheral extraction was calculated as the ratio of VO2 to cardiac output. Cardiac function was evaluated using left ventricular longitudinal strain, E/e', and relative wall thickness. Among patients with DM, 26 patients (27%) presented reduced percent-predicted-peak VO2(<80%) and 18 (18%) presented abnormal VE/VCO2slope (>34). There was no significant difference in peak cardiac output; however, peripheral extraction was lower in patients with DM compared to controls. Higher peak E/e' (beta = -0.24, p = 0.004) was associated with lower peak VO2 along with age, sex and body mass index (R2 = 0.53). A cluster analysis found left ventricular longitudinal strain, E/e', relative wall thickness and peak VO2 in different clusters. In conclusion, impaired peripheral extraction may contribute to reduced peak VO2in asymptomatic patients with DM. Furthermore, a cluster analysis suggests that cardiopulmonary exercise testing and echocardiography may be complementary for defining subclinical heart failure in patients with DM.
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ItemNo Preview AvailableUltrasonic particles: An approach for targeted gene delivery(ELSEVIER, 2021-10-21)Gene therapy has been widely investigated for the treatment of genetic, acquired, and infectious diseases. Pioneering work utilized viral vectors; however, these are suspected of causing serious adverse events, resulting in the termination of several clinical trials. Non-viral vectors, such as lipid nanoparticles, have attracted significant interest, mainly due to their successful use in vaccines in the current COVID-19 pandemic. Although they allow safe delivery, they come with the disadvantage of off-target delivery. The application of ultrasound to ultrasound-sensitive particles allows for a direct, site-specific transfer of genetic materials into the organ/site of interest. This process, termed ultrasound-targeted gene delivery (UTGD), also increases cell membrane permeability and enhances gene uptake. This review focuses on the advances in ultrasound and the development of ultrasonic particles for UTGD across a range of diseases. Furthermore, we discuss the limitations and future perspectives of UTGD.
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ItemNo Preview AvailableMusculoskeletal Responses to Exercise Plus Nutrition in Men with Prostate Cancer on Androgen Deprivation: A 12-Month RCT(LIPPINCOTT WILLIAMS & WILKINS, 2021-10-01)PURPOSE: Androgen deprivation therapy (ADT) for prostate cancer has multiple adverse effects on musculoskeletal health. This 12-month randomized controlled trial aimed to assess the effects of multicomponent exercise training combined with whey protein, calcium and vitamin D supplementation on bone mineral density (BMD), structure and strength, body composition, muscle strength, and physical function in ADT-treated men. METHODS: Seventy ADT-treated men were randomized to exercise plus supplementation (Ex + Suppl; n = 34) or usual care (control; n = 36). Ex + Suppl involved thrice weekly progressive resistance training plus weight-bearing impact exercise with daily multinutrient supplementation. Primary outcomes were DXA hip and spine areal BMD. Secondary outcomes included the following: tibia and radius pQCT volumetric BMD, bone structure and strength, DXA body composition, pQCT muscle and fat cross-sectional area and muscle density, and muscle strength and physical function. RESULTS: Sixty men (86%) completed the study. Mean exercise and supplement adherence were 56% and 77%, respectively. There were no effects of the intervention on bone or body composition outcomes. Ex + Suppl improved leg muscle strength (net difference, (95% confidence interval, or CI), 14.5% (-0.2 to 29.2); P = 0.007) and dynamic mobility (four-square-step test time, -9.3% (-17.3 to -1.3), P = 0.014) relative to controls. Per-protocol analysis of adherent participants (≥66% exercise, ≥80% supplement) showed Ex + Suppl preserved femoral neck aBMD (1.9% (0.1 to 3.8), P = 0.026) and improved total body lean mass (1.0 kg (-0.23 to 2.22), P = 0.044) relative to controls. CONCLUSIONS: Exercise training combined with multinutrient supplementation had a limited effect on ameliorating the adverse musculoskeletal consequences of ADT, likely related to the modest intervention adherence.
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ItemNo Preview AvailableRisk Prediction Using Polygenic Risk Scores for Prevention of Stroke and Other Cardiovascular Diseases(LIPPINCOTT WILLIAMS & WILKINS, 2021-09-01)Early prediction of risk of cardiovascular disease (CVD), including stroke, is a cornerstone of disease prevention. Clinical risk scores have been widely used for predicting CVD risk from known risk factors. Most CVDs have a substantial genetic component, which also has been confirmed for stroke in recent gene discovery efforts. However, the role of genetics in prediction of risk of CVD, including stroke, has been limited to testing for highly penetrant monogenic disorders. In contrast, the importance of polygenic variation, the aggregated effect of many common genetic variants across the genome with individually small effects, has become more apparent in the last 5 to 10 years, and powerful polygenic risk scores for CVD have been developed. Here we review the current state of the field of polygenic risk scores for CVD including stroke, and their potential to improve CVD risk prediction. We present findings and lessons from diseases such as coronary artery disease as these will likely be useful to inform future research in stroke polygenic risk prediction.
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