Publications by authors named "Colleen J Thomas"

36 Publications

Environmental hotspots for antibiotic resistance genes.

Microbiologyopen 2021 Jun;10(3):e1197

Department of Physiology, Anatomy and Microbiology, School of Life Sciences, College of Science, Health and Engineering, La Trobe University, Bundoora, Vic, Australia.

Bacterial resistance toward broad-spectrum antibiotics has become a major concern in recent years. The threat posed by the infectious bacteria and the pace with which resistance determinants are transmitted needs to be deciphered. Soil and water contain unique and diverse microbial communities as well as pools of naturally occurring antibiotics resistant genes. Overuse of antibiotics along with poor sanitary practices expose these indigenous microbial communities to antibiotic resistance genes from other bacteria and accelerate the process of acquisition and dissemination. Clinical settings, where most antibiotics are prescribed, are hypothesized to serve as a major hotspot. The predisposition of the surrounding environments to a pool of antibiotic-resistant bacteria facilitates rapid antibiotic resistance among the indigenous microbiota in the soil, water, and clinical environments via horizontal gene transfer. This provides favorable conditions for the development of more multidrug-resistant pathogens. Limitations in detecting gene transfer mechanisms have likely left us underestimating the role played by the surrounding environmental hotspots in the emergence of multidrug-resistant bacteria. This review aims to identify the major drivers responsible for the spread of antibiotic resistance and hotspots responsible for the acquisition of antibiotic resistance genes.
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http://dx.doi.org/10.1002/mbo3.1197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123917PMC
June 2021

Twelve-Week Mediterranean Diet Intervention Increases Citrus Bioflavonoid Levels and Reduces Inflammation in People with Type 2 Diabetes Mellitus.

Nutrients 2021 Mar 30;13(4). Epub 2021 Mar 30.

Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne 3086, Australia.

The benefits of a Mediterranean Diet (MedDiet) in the management of diabetes have been reported, but the contribution of polyphenol-rich citrus fruit has not been studied widely. Here, we report the sub-study findings of a previously conducted MedDiet intervention clinical trial in patients with type 2 diabetes mellitus (T2DM), where we aimed to measure the diet intervention effects on plasma citrus bioflavonoids levels and biomarkers of inflammation and oxidative stress. We analysed plasma samples from 19 (of original 27) participants with T2DM who were randomly assigned to consume the MedDiet intervention or their usual diet for 12 weeks and then crossed over to the alternate diet. Compared with baseline, MedDiet significantly increased levels of the citrus bioflavonoids naringin, hesperitin and hesperidin (by 60%, 58% and 39%, respectively, < 0.05) and reduced plasma levels of the pro-inflammatory cytokine IL-6 (by 49%, = 0.016). Oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) decreased by 32.4% ( = 0.128). Usual diet did not induce these beneficial changes. The reduced inflammatory profile of T2DM participants may, in part, be attributed to the anti-inflammatory actions of citrus bioflavonoids. Together with indications of improved oxidative stress, these findings add to the scientific evidence base for beneficial consumption of citrus fruit in the MedDiet pattern.
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http://dx.doi.org/10.3390/nu13041133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065815PMC
March 2021

E-portfolios and Entrustable Professional Activities to support competency-based education in dietetics.

Nurs Health Sci 2021 Mar 28;23(1):148-156. Epub 2020 Sep 28.

Pro Vice Chancellor and Executive Dean College of Science, Health Engineering and Education Murdoch University and an Adjunct Professor of Dietetics, La Trobe University, Melbourne, Victoria, Australia.

The concept of Entrustable Professional Activities, recently pioneered in medical education, has emerged to support the implementation of competency-based education. Although competency-based frameworks are widely used in healthcare professional education to develop outcomes-based curricula, assessment of student competency in professional placement settings remains challenging. The novel concept of Entrustable Professional Activities together with established methods of competency assessment, namely e-portfolios and self-assessment, was implemented in the "[La Trobe University Dietetic program in 2015-2016. This study aimed to appraise the e-portfolio and evaluate the use of Entrustable Professional Activities to assess competence. A mixed-methods evaluation, using qualitative and quantitative surveys with follow-up structured consultations, was conducted with final year dietetics students and their supervisors. Dietetics students were comfortable with Entrustable Professional Activities and competency-based assessment, whereas supervisors preferred Entrustable Professional Activity based assessment. All stakeholders valued student self-assessment and the ongoing use of structured e-portfolios to develop and document competency. The use of structured e-portfolios, student self-assessment, and the emerging concept of Entrustable Professional Activities are useful tools to support dietetics student education in professional placement settings.
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http://dx.doi.org/10.1111/nhs.12774DOI Listing
March 2021

The Effect of High Polyphenol Extra Virgin Olive Oil on Blood Pressure and Arterial Stiffness in Healthy Australian Adults: A Randomized, Controlled, Cross-Over Study.

Nutrients 2020 Jul 29;12(8). Epub 2020 Jul 29.

Department of Dietetics, Nutrition and Sport, School of Allied Health, Human Services and Sport, La Trobe University, Melbourne 3086, Australia.

Extra virgin olive oil (EVOO) is suggested to be cardioprotective, partly due to its high phenolic content. We investigated the effect of extra virgin high polyphenol olive oil (HPOO) versus low polyphenol olive oil (LPOO) on blood pressure (BP) and arterial stiffness in healthy Australian adults. In a double-blind, randomized, controlled cross-over trial, 50 participants (age 38.5 ± 13.9 years, 66% female) were randomized to consume 60 mL/day of either HPOO (360 mg/kg polyphenols) or LPOO (86 mg/kg polyphenols) for three weeks. Following a two-week washout period, participants crossed over to consume the alternate oil. Anthropometric data, peripheral BP, central BP and arterial stiffness were measured at baseline and follow up. No significant differences were observed in the changes from baseline to follow up between the two treatments. However, a significant decrease in peripheral and central systolic BP (SBP) by 2.5 mmHg (95% CI: -4.7 to -0.3) and 2.7 mmHg (95% CI: -4.7 to -0.6), respectively, was observed after HPOO consumption. Neither olive oil changed diastolic BP (DBP) or measures of arterial stiffness. The reductions in SBP after HPOO consumption provide evidence for a potentially widely accessible dietary intervention to prevent cardiovascular disease in a multiethnic population. Longer intervention studies and/or higher doses of EVOO polyphenols are warranted to elucidate the potential effect on DBP and arterial stiffness.
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http://dx.doi.org/10.3390/nu12082272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468912PMC
July 2020

Effect of Lupin-Enriched Biscuits as Substitute Mid-Meal Snacks on Post-Prandial Interstitial Glucose Excursions in Post-Surgical Hospital Patients with Type 2 Diabetes.

Nutrients 2020 Apr 27;12(5). Epub 2020 Apr 27.

Department of Dietetics, Nutrition and Sport, School of Allied Health, Human Services and Sport, La Trobe University, Victoria 3086, Australia.

Hospital biscuit snacks offered to Type 2 Diabetes Mellitus (T2DM) patients may adversely affect glycaemic control. This study investigated the effect of lupin mid-meal biscuit snacks, compared to spelt or standard hospital biscuits, on interstitial glucose levels in post-operative T2DM inpatients. In a pilot cross-over pragmatic study, 20 patients (74 ± 12 years) consumed, in order, lupin biscuits (20% lupin), wholemeal spelt and standard plain sweet biscuits as mid-meal snacks (2 biscuits each for morning and afternoon tea) on three consecutive days. Continuous glucose monitoring, appetite perceptions and bowel motions were recorded. Glucose levels were not significantly different in the first 90 min after mid-meal biscuit consumption at morning and afternoon tea, irrespective of type. However, after consuming the lupin biscuits only, glucose levels were significantly ( < 0.001) reduced 90 min postprandially after dinner, indicating a potential second-meal effect. Patients also reported improved satiety after lupin biscuit consumption on day 1, compared to days 2 and 3 ( = 0.018). These findings suggest that lupin-enriched biscuits may improve both glycaemic control and satiety in hospitalised T2DM patients, potentially contributing to reduced length of stay. Larger controlled studies are warranted to confirm these findings and inform potential revision of hospital menu standards for T2DM patients.
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http://dx.doi.org/10.3390/nu12051239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281993PMC
April 2020

Ad libitum Mediterranean diet reduces subcutaneous but not visceral fat in patients with coronary heart disease: A randomised controlled pilot study.

Clin Nutr ESPEN 2019 08 14;32:61-69. Epub 2019 May 14.

Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, Victoria, 3086, Australia.

Background & Aims: The Mediterranean diet (MedDiet) is recognised to reduce risk of coronary heart disease (CHD), in part, via its anti-inflammatory and antioxidant properties, which may be mediated via effects on body fat distribution. Diet efficacy via these mechanisms is however unclear in patients with diagnosed CHD. This study aimed to determine: (1) the effect of ad libitum MedDiet versus low-fat diet intervention on adiposity, anti-inflammatory marker adiponectin, oxidative stress marker malondialdehyde (MDA) and traditional CVD risk markers, and (2) whether improvement in MedDiet adherence score in the pooled cohort was associated with these risk markers, in a pilot cohort of Australian patients post coronary event.

Methods: Participants (62 ± 9 years, 83% male) were randomised to 6-month ad libitum MedDiet (n = 34) or low-fat diet (n = 31). Pre- and post-intervention, dietary adherence, anthropometry, body composition (Dual-energy X-ray Absorptiometry) and venepuncture measures were conducted.

Results: The MedDiet group reduced subcutaneous adipose tissue (SAT) area compared to the low-fat diet group (12.5 cm more, p = 0.04) but not visceral adipose tissue or other body composition measures. In the pooled cohort, participants with greatest improvement in MedDiet adherence score had significantly lower waist circumference (-2.81 cm, p = 0.01) and SAT area (-27.1 cm, p = 0.04) compared to participants with no improvement in score at 6-months. There were no changes in adiponectin, MDA or other risk markers in the MedDiet compared to low-fat diet group, and no differences in 6-month levels between categories of improvement in MedDiet score (p > 0.05). Within the MedDiet group only, the proportion of participants taking beta-blocker medication reduced from baseline to 6-months (71% vs. 56%, p-trend = 0.007).

Conclusions: Adherence to 6-month ad libitum MedDiet reduced subcutaneous fat and waist circumference which discounts the misconception that this healthy but high fat diet leads to body fat gain. The effect of MedDiet on body fat distribution and consequent anti-inflammatory and antioxidant effects, as well as need for medications, in patients with CHD warrants exploration in larger studies. Clinically significant effects on these markers may require adjunct exercise and/or caloric restriction.

Trial Registration: ACTRN12616000156482.
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http://dx.doi.org/10.1016/j.clnesp.2019.05.001DOI Listing
August 2019

Effect of high polyphenol extra virgin olive oil on markers of cardiovascular disease risk in healthy Australian adults (OLIVAUS): A protocol for a double-blind randomised, controlled, cross-over study.

Nutr Diet 2020 11 17;77(5):523-528. Epub 2019 Apr 17.

Department of Dietetics, Nutrition and Sport, School of Allied Health, Human Services and Sport, College of Science, Melbourne, Victoria, Australia.

Background: Previous clinical studies have suggested that high polyphenol extra virgin olive oil (EVOO) provides a superior cardioprotective effect compared to low polyphenol olive oil. However, further studies are required to replicate these results in non-Mediterranean populations.

Aim: To investigate the effect of high polyphenol EVOO versus low polyphenol olive oil with known polyphenol composition on markers of cardiovascular disease risk in a healthy non-Mediterranean cohort.

Methods: In a double-blind randomised cross-over trial, the present study will examine the effect of high polyphenol EVOO versus low polyphenol olive oil in 50 healthy participants. Each intervention phase will be 3 weeks long with a 2-week washout period between each phase. Outcomes to be assessed include HDL cholesterol efflux, oxidised LDL, blood lipids, C-reactive protein, arterial stiffness, blood pressure and cognitive function. Dietary intake, physical activity levels and anthropometry will also be collected.

Discussion: Because of the rigorous trial design, novel and clinically relevant outcomes, the use of a well-characterised EVOO, and, in contrast to the current literature, the non-Mediterranean study population, the present study will provide a significant contribution to the understanding of the clinical importance of polyphenol intake in the Australian sociocultural context.
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http://dx.doi.org/10.1111/1747-0080.12531DOI Listing
November 2020

Australian patients with coronary heart disease achieve high adherence to 6-month Mediterranean diet intervention: preliminary results of the AUSMED Heart Trial.

Nutrition 2019 05 3;61:21-31. Epub 2018 Nov 3.

Department of Rehabilitation, Nutrition and Sport, School of Allied Health, La Trobe University, Melbourne, Victoria, Australia.

Objective: It is unclear whether the cardioprotective Mediterranean diet (MedDiet) can be adhered to in non-Mediterranean populations. The aim of this study was to report preliminary results on adherence to a 6-mo ad libitum MedDiet intervention in multiethnic Australian patients with coronary heart disease, including maintenance at 12 mo.

Methods: Participants (62 ± 9 y of age, 83% men) were randomized to the MedDiet (n = 34) or a low-fat diet (n = 31). Dietitian-led appointments occurred at 0, 3, and 6 mo with a follow-up phone review at 12 mo. Dietary intake was assessed via 7-d food diaries analyzed in FoodWorks8, and MedDiet adherence was measured by a validated 14-item questionnaire.

Results: In the pooled cohort, the MedDiet adherence score was low at baseline (5.2 ± 2.1 of 14), with only 6.2% achieving a high score (≥9). MedDiet participants significantly improved the MedDiet adherence score compared with low-fat diet participants after 6 mo (+4.8 ± 2.7 versus +1.2 ± 2 points, respectively; P < 0.001). MedDiet participants significantly increased intake of olive oil, nuts, tomato, yogurt, legumes, and seafood and decreased intake of processed meats and added sugars compared with low-fat diet participants (P < 0.05). Maintenance of the MedDiet at 12 mo was high with 78% of MedDiet participants maintaining an adherence score ≥9; however, mean adherence score decreased by 1 ± 1.9 point (P = 0.01) between 6 and 12 mo.

Conclusions: The MedDiet intervention in this pilot trial of Australian patients with coronary heart disease was well adhered to, improved diet quality, and could therefore provide a feasible alternative to a low-fat diet. Notably, improvement in adherence to the MedDiet was achieved through dietitian-led intervention and cross-cultural translation of dietary principles.
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http://dx.doi.org/10.1016/j.nut.2018.10.027DOI Listing
May 2019

The AUStralian MEDiterranean Diet Heart Trial (AUSMED Heart Trial): A randomized clinical trial in secondary prevention of coronary heart disease in a multiethnic Australian population: Study protocol.

Am Heart J 2018 09 24;203:4-11. Epub 2018 May 24.

Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Australia.

The Mediterranean diet was first characterized as a heart-protective diet in the 1960s. The significant cardioprotective effects of the Mediterranean diet in comparison to the standard-care low-fat diet have been established in the primary prevention of cardiovascular disease (CVD); however, there is insufficient evidence in secondary prevention research to influence the current standard of care. Opportunity exists to assess the Mediterranean diet as a therapeutic target for secondary CVD prevention within Australia's ethnoculturally diverse communities. The AUSMED Heart Trial is a multisite randomized controlled trial that will evaluate the efficacy of the Mediterranean diet for secondary prevention of CVD in the Australian health care setting. This trial aims to evaluate the effect of a 6-month Mediterranean diet intervention (delivered by dietitians) versus a "standard-care" low-fat diet in reducing the composite incidence of cardiovascular events at 12 months and at trial end in participants with documented evidence of a previous acute myocardial infarction at trial entry. The quality of the diet at baseline and follow-up will be assessed using comprehensive dietary questionnaires and diaries as well as relevant dietary biomarkers (such as urinary polyphenols and erythrocyte fatty acids). Cardiovascular risk markers, including novel measures of immune and inflammatory status, endothelial function, vascular compliance, platelet activity, and body composition, will be collected to explore possible mechanisms for treatment effect. Cost-effectiveness will also be estimated to support policy translation. We plan to recruit 1,032 participants (516 per arm) from cardiology clinics in major Australian hospitals in Melbourne, Adelaide, and Brisbane.
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http://dx.doi.org/10.1016/j.ahj.2018.05.010DOI Listing
September 2018

Improvement in dietary inflammatory index score after 6-month dietary intervention is associated with reduction in interleukin-6 in patients with coronary heart disease: The AUSMED heart trial.

Nutr Res 2018 07 25;55:108-121. Epub 2018 Apr 25.

Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, Victoria, Australia, 3086. Electronic address:

The Dietary Inflammatory Index (DII) was designed to measure the inflammatory potential of one's diet. Evidence from observational studies supports that a higher (ie, more pro-inflammatory) DII score is associated with inflammation and cardiometabolic diseases. We hypothesized that reduction in DII score would improve inflammatory cytokines. To test this hypothesis, we assessed data from a dietary intervention trial in patients with diagnosed coronary heart disease (CHD) to determine whether reduction in DII scores through healthy diets is linked to improvement in inflammatory and related cardiometabolic risk markers. Participants (n = 65, 83% male) were randomized to a Mediterranean diet or low-fat diet intervention for 6-months. Anthropometry, body composition and blood markers were measured and DII scores were calculated from 7-day food diaries. After 6-months, in participants who completed the intervention (n = 56), reduction in DII score correlated significantly with reduction in high sensitivity interleukin-6 (hs-IL-6) (r = 0.34, 95% CI 0.05, 0.56) and triglycerides (r = -0.30, 95% CI -0.51, -0.06) but not with C-reactive protein, adiponectin, glucose, body composition or anthropometry. The adjusted mean difference in hs-IL-6 and triglycerides between the highest and lowest tertiles of DII improvement was -0.47 pg/mL (95% CI 0.41, 1.10) and +0.30 mmol/L (95% CI 1.06, 1.59), respectively. The present study found that improvement in DII score through healthy diet intervention was linked with reduced levels of hs-IL-6, but also increased triglycerides, in adult Australian patients with CHD. Future research is warranted to investigate the impact of change in DII on cardiometabolic risk markers in larger cohorts, other disease populations or healthy subjects and with longer-term follow up.
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http://dx.doi.org/10.1016/j.nutres.2018.04.007DOI Listing
July 2018

Randomization to 6-month Mediterranean diet compared with a low-fat diet leads to improvement in Dietary Inflammatory Index scores in patients with coronary heart disease: the AUSMED Heart Trial.

Nutr Res 2018 07 14;55:94-107. Epub 2018 Apr 14.

Department of Rehabilitation, Nutrition and Sport, School of Allied Health, La Trobe University, Melbourne, Victoria, Australia, 3086. Electronic address:

A higher dietary inflammatory index (DII®) score is associated with inflammation and incidence of coronary heart disease (CHD). We hypothesized that a Mediterranean diet (MedDiet) intervention would reduce DII score. We assessed dietary data from a randomized controlled trial comparing 6-month MedDiet versus low-fat diet intervention, in patients with CHD. We aimed to determine the DII scores of the prescribed diets' model meal plans, followed by whether dietary intervention led to lower (i.e., more anti-inflammatory) DII scores and consequently lower high sensitivity C-reactive protein (hs-CRP) and interleukin-6 (hs-IL-6). DII scores were calculated from 7-day food diaries. The MedDiet meal plan had a markedly lower DII score than the low-fat diet meal plan (-4.55 vs. -0.33, respectively). In 56 participants who completed the trial (84% male, mean age 62 ± 9 years), the MedDiet group significantly reduced DII scores at 6 months (n = 27; -0.40 ± 3.14 to -1.74 ± 2.81, P = .008) and the low-fat diet group did not change (n = 29; -0.17 ± 2.27 to 0.05 ± 1.89, P = .65). There was a significant post-intervention adjusted difference in DII score between groups (compared to low-fat, MedDiet decreased by -1.69 DII points; P = .004). When compared to the low-fat diet, the MedDiet non-significantly reduced hs-IL-6 (-0.32 pg/mL, P = .29) and increased hs-CRP (+0.09 mg/L, P = .84). These findings demonstrated that MedDiet intervention significantly reduced DII scores compared to a low-fat diet. However, in this small cohort of patients with CHD this did not translate to a significant improvement in measured inflammatory markers. The effect of improvement in DII with MedDiet should be tested in larger intervention trials and observational cohorts.
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http://dx.doi.org/10.1016/j.nutres.2018.04.006DOI Listing
July 2018

The effect of high-polyphenol extra virgin olive oil on cardiovascular risk factors: A systematic review and meta-analysis.

Crit Rev Food Sci Nutr 2019 13;59(17):2772-2795. Epub 2018 Nov 13.

Department of Rehabilitation, Nutrition and Sport, School of Allied Health, College of Science, Health and Engineering, La Trobe University , Bundoora , Victoria , Australia.

The polyphenol fraction of extra-virgin olive oil may be partly responsible for its cardioprotective effects. The aim of this systematic review and meta-analysis was to evaluate the effect of high versus low polyphenol olive oil on cardiovascular disease (CVD) risk factors in clinical trials. In accordance with PRISMA guidelines, CINAHL, PubMed, Embase and Cochrane databases were systematically searched for relevant studies. Randomized controlled trials that investigated markers of CVD risk (e.g. outcomes related to cholesterol, inflammation, oxidative stress) were included. Risk of bias was assessed using the Jadad scale. A meta-analysis was conducted using clinical trial data with available CVD risk outcomes. Twenty-six studies were included. Compared to low polyphenol olive oil, high polyphenol olive oil significantly improved measures of malondialdehyde (MD: -0.07µmol/L [95%CI: -0.12, -0.02µmol/L]; I: 88%;  = 0.004), oxidized LDL (SMD: -0.44 [95%CI: -0.78, -0.10µmol/L]; I: 41%; P = 0.01), total cholesterol (MD 4.5 mg/dL [95%CI: -6.54, -2.39 mg/dL]; <0.0001) and HDL cholesterol (MD 2.37 mg/dL [95%CI: 0.41, 5.04 mg/dL];  = 0.02). Subgroup analyses and individual studies reported additional improvements in inflammatory markers and blood pressure. Most studies were rated as having low-to-moderate risk of bias. High polyphenol oils confer some CVD-risk reduction benefits; however, further studies with longer duration and in non-Mediterranean populations are required.
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http://dx.doi.org/10.1080/10408398.2018.1470491DOI Listing
February 2020

Adeno-Associated Virus Gene Therapy: Translational Progress and Future Prospects in the Treatment of Heart Failure.

Heart Lung Circ 2018 Nov 17;27(11):1285-1300. Epub 2018 Mar 17.

Baker Heart and Diabetes Institute, Melbourne, Vic, Australia; Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, Vic, Australia; Department of Diabetes, Central Clinical School, Monash University, Melbourne, Vic, Australia; Department of Physiology and Department of Medicine Alfred Hospital, Monash University, Melbourne, Vic, Australia. Electronic address:

Despite advances in treatment over the past decade, heart failure remains a significant public health burden and a leading cause of death in the developed world. Gene therapy provides a promising approach for preventing and reversing cardiac abnormalities, however, clinical application has shown limited success to date. A substantial effort is being invested into the development of recombinant adeno-associated viruses (AAVs) for cardiac gene therapy as AAV gene therapy offers a high safety profile and provides sustained and efficient transgene expression following a once-off administration. Due to the physiological, anatomical and genetic similarities between large animals and humans, preclinical studies using large animal models for AAV gene therapy are crucial stepping stones between the laboratory and the clinic. Many molecular targets selected to treat heart failure using AAV gene therapy have been chosen because of their potential to regulate and restore cardiac contractility. Other genes targeted with AAV are involved with regulating angiogenesis, beta-adrenergic sensitivity, inflammation, physiological signalling and metabolism. While significant progress continues to be made in the field of AAV cardiac gene therapy, challenges remain in overcoming host neutralising antibodies, improving AAV vector cardiac-transduction efficiency and selectivity, and optimising the dose, route and method of delivery.
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http://dx.doi.org/10.1016/j.hlc.2018.03.005DOI Listing
November 2018

Flavonols and Flavones - Protecting Against Myocardial Ischemia/Reperfusion Injury by Targeting Protein Kinases.

Curr Med Chem 2018 ;25(34):4402-4415

Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.

In acute myocardial infarction (AMI), the first line of treatment is to rapidly restore blood flow to the ischemic myocardium to limit infarct size. It is now well established that though clearly beneficial, the positive outcomes of this intervention are limited by injury in response to the reperfusion itself in addition to the prior ischemia. This process is described as reperfusion injury and is considered to contribute to the arrhythmias, microvascular dysfunction and impaired cardiac contractility that is observed even after the restoration of coronary blood flow. Thus an important, currently unmet, therapeutic challenge is to address the outcomes of this reperfusion injury. In this article, we review the evidence that flavonols and flavones may prove useful in preserving cardiac function after ischemia and reperfusion and consider the possible mechanisms, in particular, the inhibition of kinases, by which they may exert protection.
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http://dx.doi.org/10.2174/0929867325666180326161730DOI Listing
January 2019

Mediterranean-type diets and inflammatory markers in patients with coronary heart disease: a systematic review and meta-analysis.

Nutr Res 2018 02 21;50:10-24. Epub 2017 Oct 21.

Department of Rehabilitation, Nutrition and Sport, School of Allied Health, La Trobe University, Melbourne, Victoria, Australia, 3086. Electronic address:

The health benefits of a Mediterranean diet are thought to be mediated via its anti-inflammatory effects; however, the anti-inflammatory effect of this diet is unclear in patients who have already developed coronary heart disease (CHD). This systematic review and meta-analysis assessed the effect of Mediterranean-type diets on cytokines and adipokines in patients with CHD. An electronic search of the literature was conducted up to October 2016 using PubMed, Scopus, Web of Science, and Cochrane Library. Eleven of the 435 articles identified met eligibility criteria. Four observational studies reported significant inverse associations between Mediterranean-type diet scores and inflammatory cytokines. Five clinical trials (4 in non-Mediterranean countries) demonstrated nonsignificant reductions, and 2 trials conducted in Spain demonstrated significant reductions in C-reactive protein with a Mediterranean-type diet. Random effects meta-analysis of 4 controlled trials detected a nonsignificant difference in final mean value of C-reactive protein with Mediterranean-type diet vs low-fat diet. Despite promising findings from observational studies, this review demonstrated mostly nonsignificant effects of Mediterranean-type diet interventions on inflammatory cytokines and no effect in comparison to low-fat diets in controlled trials conducted primarily in Mediterranean populations. Therefore, randomized controlled trials of a traditional Mediterranean diet in non-Mediterranean populations and with multiple inflammatory biomarkers are needed in the high-risk CHD patient group.
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http://dx.doi.org/10.1016/j.nutres.2017.10.014DOI Listing
February 2018

ERp57 is protective against mutant SOD1-induced cellular pathology in amyotrophic lateral sclerosis.

Hum Mol Genet 2018 04;27(8):1311-1331

Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and mutations in superoxide dismutase 1 (SOD1) account for 20% of familial ALS cases. The aetiology of ALS remains unclear, but protein misfolding, endoplasmic reticulum (ER) stress and neuronal apoptosis are implicated. We previously established that protein disulphide isomerase (PDIA1) is protective against ER stress and apoptosis in neuronal cells expressing mutant SOD1, and recently mutations in PDIA1 and related PDI family member endoplasmic reticulum protein 57 (ERp57/PDIA3), were associated with ALS. Here, we examined whether ERp57 is also protective against mutant SOD1 or whether distinct specificity exists amongst individual PDI family members. Neuronal cells co-expressing SOD1 and ERp57 were examined for inclusion formation, ER stress, ubiquitin proteasome system (UPS) dysfunction and apoptosis. Over-expression of ERp57 inhibited inclusion formation, ER stress, UPS dysfunction and apoptosis, whereas silencing of ERp57 expression enhanced mutant SOD1 inclusion formation, ER stress and toxicity, indicating a protective role for ERp57 against SOD1 misfolding. ERp57 also inhibited the formation of mutant SOD1 inclusions and apoptosis in primary cortical neurons, thus confirming results obtained from cell lines. ERp57 partially co-localized with TAR DNA-binding protein-43 (TDP-43)-positive inclusions in spinal cords from sporadic ALS patients, thus linking ERp57 to protein misfolding in human sporadic disease. Our results therefore imply that ERp57 has a protective role against pathological events induced by mutant SOD1 and they link ERp57 to the misfolding of TDP-43. This study therefore has implications for the design of novel therapeutics based on the activities of the PDI family of proteins.
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http://dx.doi.org/10.1093/hmg/ddy041DOI Listing
April 2018

Symposium report on "Dynamic Methods For Improving Undergraduate Physiology Education": IUPS 38th World Congress.

Adv Physiol Educ 2017 12;41(4):560-564

Department of Morphology, Physiology and Basic Pathology, University of São Paulo , Ribeirão Preto, São Paulo , Brazil.

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http://dx.doi.org/10.1152/advan.00133.2017DOI Listing
December 2017

Endogenous Annexin-A1 Regulates Haematopoietic Stem Cell Mobilisation and Inflammatory Response Post Myocardial Infarction in Mice In Vivo.

Sci Rep 2017 11 30;7(1):16615. Epub 2017 Nov 30.

Baker Heart & Diabetes Institute, Melbourne, 3004, Australia.

Endogenous anti-inflammatory annexin-A1 (ANX-A1) plays an important role in preserving left ventricular (LV) viability and function after ischaemic insults in vitro, but its long-term cardioprotective actions in vivo are largely unknown. We tested the hypothesis that ANX-A1-deficiency exaggerates inflammation, haematopoietic stem progenitor cell (HSPC) activity and LV remodelling in response to myocardial ischaemia in vivo. Adult ANX - A1 mice subjected to coronary artery occlusion exhibited increased infarct size and LV macrophage content after 24-48 h reperfusion compared with wildtype (WT) counterparts. In addition, ANX - A1 mice exhibited greater expansion of HSPCs and altered pattern of HSPC mobilisation 8 days post-myocardial infarction, with increased circulating neutrophils and platelets, consistent with increased cardiac inflammation as a result of increased myeloid invading injured myocardium in response to MI. Furthermore, ANX - A1 mice exhibited significantly increased expression of LV pro-inflammatory and pro-fibrotic genes and collagen deposition after MI compared to WT counterparts. ANX-A1-deficiency increased cardiac necrosis, inflammation, hypertrophy and fibrosis following MI, accompanied by exaggerated HSPC activity and impaired macrophage phenotype. These findings suggest that endogenous ANX-A1 regulates mobilisation and differentiation of HSPCs. Limiting excessive monocyte/neutrophil production may limit LV damage in vivo. Our findings support further development of novel ANX-A1-based therapies to improve cardiac outcomes after MI.
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http://dx.doi.org/10.1038/s41598-017-16317-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709412PMC
November 2017

Sympathetic nervous response to ischemia-reperfusion injury in humans is altered with remote ischemic preconditioning.

Am J Physiol Heart Circ Physiol 2016 08 10;311(2):H364-70. Epub 2016 Jun 10.

Human Neurotransmitters Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.

Sympathetic neural activation may be detrimentally involved in tissue injury caused by ischemia-reperfusion (IR). We examined the effects of experimental IR in the forearm on sympathetic nerve response, finger reactive hyperemia, and oxidative stress, and the protection afforded by applying remote ischemic preconditioning (RIPC). Ischemia was induced in the forearm for 20 min in healthy volunteers. RIPC was induced by applying two cycles, 5 min each, of ischemia and reperfusion to the upper leg immediately before IR. We examined muscle sympathetic nerve activity (MSNA) in the contralateral leg using microneurography, finger reactive hyperemia [ischemic reactive hyperemia index (RHI)], erythrocyte production of reduced gluthathione (GSH), and plasma nitric oxide (NO) concentration. In controls (no RIPC; n = 15), IR increased MSNA in the early and late phase of ischemia (70% at 5 min; 101% at 15 min). In subjects who underwent RIPC (n = 15), the increase in MSNA was delayed to the late phase of ischemia and increased only by 40%. GSH increased during ischemia in the control group (P = 0.05), but not in those who underwent RIPC. Nitrate and nitrite concentration, taken as an index of NO availability, decreased during the reperfusion period in control individuals (P < 0.05), while no change was observed in those who underwent RIPC. Experimental IR did not affect RHI in the control condition, but a significant vasodilatory response occurred in the RIPC group (P < 0.05). RIPC attenuated ischemia-induced sympathetic activation, prevented the production of an erythrocyte marker of oxidative stress and the reduction of NO availability, and ameliorated RHI.
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http://dx.doi.org/10.1152/ajpheart.00369.2016DOI Listing
August 2016

Inhibition of miR-154 Protects Against Cardiac Dysfunction and Fibrosis in a Mouse Model of Pressure Overload.

Sci Rep 2016 Mar 1;6:22442. Epub 2016 Mar 1.

Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.

Expression of miR-154 is upregulated in the diseased heart and was previously shown to be upregulated in the lungs of patients with pulmonary fibrosis. However, the role of miR-154 in a model of sustained pressure overload-induced cardiac hypertrophy and fibrosis had not been assessed. To examine the role of miR-154 in the diseased heart, adult male mice were subjected to transverse aortic constriction for four weeks, and echocardiography was performed to confirm left ventricular hypertrophy and cardiac dysfunction. Mice were then subcutaneously administered a locked nucleic acid antimiR-154 or control over three consecutive days (25 mg/kg/day) and cardiac function was assessed 8 weeks later. Here, we demonstrate that therapeutic inhibition of miR-154 in mice with pathological hypertrophy was able to protect against cardiac dysfunction and attenuate adverse cardiac remodelling. The improved cardiac phenotype was associated with attenuation of heart and cardiomyocyte size, less cardiac fibrosis, lower expression of atrial and B-type natriuretic peptide genes, attenuation of profibrotic markers, and increased expression of p15 (a miR-154 target and cell cycle inhibitor). In summary, this study suggests that miR-154 may represent a novel target for the treatment of cardiac pathologies associated with cardiac fibrosis, hypertrophy and dysfunction.
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http://dx.doi.org/10.1038/srep22442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772383PMC
March 2016

The Unfolded Protein Response and the Role of Protein Disulfide Isomerase in Neurodegeneration.

Front Cell Dev Biol 2015 8;3:80. Epub 2016 Jan 8.

Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe UniversityMelbourne, VIC, Australia; Department of Biomedical Sciences, Faculty of Medicine and Human Science, Macquarie UniversitySydney, NSW, Australia.

The maintenance and regulation of proteostasis is a critical function for post-mitotic neurons and its dysregulation is increasingly implicated in neurodegenerative diseases. Despite having different clinical manifestations, these disorders share similar pathology; an accumulation of misfolded proteins in neurons and subsequent disruption to cellular proteostasis. The endoplasmic reticulum (ER) is an important component of proteostasis, and when the accumulation of misfolded proteins occurs within the ER, this disturbs ER homeostasis, giving rise to ER stress. This triggers the unfolded protein response (UPR), distinct signaling pathways that whilst initially protective, are pro-apoptotic if ER stress is prolonged. ER stress is increasingly implicated in neurodegenerative diseases, and emerging evidence highlights the complexity of the UPR in these disorders, with both protective and detrimental components being described. Protein Disulfide Isomerase (PDI) is an ER chaperone induced during ER stress that is responsible for the formation of disulfide bonds in proteins. Whilst initially considered to be protective, recent studies have revealed unconventional roles for PDI in neurodegenerative diseases, distinct from its normal function in the UPR and the ER, although these mechanisms remain poorly defined. However, specific aspects of PDI function may offer the potential to be exploited therapeutically in the future. This review will focus on the evidence linking ER stress and the UPR to neurodegenerative diseases, with particular emphasis on the emerging functions ascribed to PDI in these conditions.
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http://dx.doi.org/10.3389/fcell.2015.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705227PMC
January 2016

Evidence that the MEK/ERK but not the PI3K/Akt pathway is required for protection from myocardial ischemia-reperfusion injury by 3',4'-dihydroxyflavonol.

Eur J Pharmacol 2015 Jul 25;758:53-9. Epub 2015 Mar 25.

Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.

The novel pro-drug of 3'4'-dihydroxyflavonol, NP202, potently reduces myocardial infarct size resulting from ischemia-reperfusion (I/R) through mechanisms that remain to be fully defined. In this study, we investigated whether cardioprotection induced by NP202 depended on activation of the reperfusion injury survival kinase (RISK) pathways. We therefore examined the effects of PD98059 and LY294002, specific inhibitors of the MEK/ERK1/2 and PI3K/Akt pathways, respectively. In isolated cardiomyocytes, H2O2induced oxidative stress activated ERK1/2 and this was further enhanced by DiOHF, the active parent compound of NP202. Although oxidative stress did not stimulate Akt in cardiomyocytes, co-treatment with DiOHF substantially increased Akt phosphorylation. This suggests that DiOHF is a potent modulator of RISK pathways specifically in the context of stress stimulation. In anesthetised sheep, following 1h ischemia and 3h reperfusion, the contribution of the RISK pathways to NP202-mediated cardioprotection was determined by treating the animals with PD98059, LY294002 or vehicle prior to NP202 administration and reperfusion. Infarct size, as a percentage of the area-at-risk, was substantially reduced by NP202 (from 78±6 to 46±4%, P<0.05). Inhibition of MEK/ERK1/2 abolished the cardioprotective effects of NP202 (infarct size 81±4%), whereas inhibition of PI3K/Akt had no effect (infarct size 53±4%). Our combined cellular and animal studies indicate that NP202 potently protects against myocardial I/R injury through complex mechanisms that involved augmentation of MEK/ERK1/2 signaling, but not PI3K/Akt signaling.
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http://dx.doi.org/10.1016/j.ejphar.2015.03.054DOI Listing
July 2015

Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy.

FASEB J 2014 Dec 21;28(12):5097-110. Epub 2014 Aug 21.

Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;

Expression of microRNA-652 (miR-652) increases in the diseased heart, decreases in a setting of cardioprotection, and is inversely correlated with heart function. The aim of this study was to assess the therapeutic potential of inhibiting miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Mice were subjected to a sham operation or transverse aortic constriction (TAC) for 4 wk to induce hypertrophy and cardiac dysfunction, followed by administration of a locked nucleic acid (LNA)-antimiR-652 (miR-652 inhibitor) or LNA control. Cardiac function was assessed before and 8 wk post-treatment. Expression of miR-652 increased in hearts subjected to TAC compared to sham surgery (2.9-fold), and this was suppressed by ∼95% in LNA-antimiR-652-treated TAC mice. Inhibition of miR-652 improved cardiac function in TAC mice (fractional shortening:29±1% at 4 wk post-TAC compared to 35±1% post-treatment) and attenuated cardiac hypertrophy. Improvement in heart function was associated with reduced cardiac fibrosis, less apoptosis and B-type natriuretic peptide gene expression, and preserved angiogenesis. Mechanistically, we identified Jagged1 (a Notch1 ligand) as a novel direct target of miR-652. In summary, these studies provide the first evidence that silencing of miR-652 protects the heart against pathological remodeling and improves heart function.
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http://dx.doi.org/10.1096/fj.14-253856DOI Listing
December 2014

Cardioprotective 3',4'-dihydroxyflavonol attenuation of JNK and p38(MAPK) signalling involves CaMKII inhibition.

Biochem J 2013 Dec;456(2):149-61

*Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC 3010, Australia.

DiOHF (3',4'-dihydroxyflavonol) is cardioprotective against I/R (ischaemia/reperfusion) injury. The biological activities of flavonols are associated with kinase modulation to alter cell signalling. We thus investigated the effects of DiOHF on the activation of MAPKs (mitogen-activated protein kinases) that regulate the cardiac stress response. In an ovine model of I/R, JNK (c-Jun N-terminal kinase), p38(MAPK), ERK (extracellular-signal-regulated kinase) and Akt were activated, and NP202, a pro-drug of DiOHF, reduced infarct size and inhibited JNK and p38(MAPK) activation, whereas ERK and Akt phosphorylation were unaltered. Similarly, in cultured myoblasts, DiOHF pre-treatment preserved viability and inhibited activation of JNK and p38(MAPK), but not ERK in response to acute oxidative and chemotoxic stress. Furthermore, DiOHF prevented stress-activation of the direct upstream regulators MKK4/7 (MAPK kinase 4/7) and MKK3/6 respectively. We utilized small-molecule affinity purification and identified CaMKII (Ca(2+)/calmodulin-dependent protein kinase II) as a kinase targeted by DiOHF and demonstrated potent CaMKII inhibition by DiOHF in vitro. Moreover, the specific inhibition of CaMKII with KN-93, but not KN-92, prevented oxidative stress-induced activation of JNK and p38(MAPK). The present study indicates DiOHF inhibition of CaMKII and attenuation of MKK3/6→p38(MAPK) and MKK4/7→JNK signalling as a requirement for the protective effects of DiOHF against stress stimuli and myocardial I/R injury.
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http://dx.doi.org/10.1042/BJ20121538DOI Listing
December 2013

The effectiveness of separating theory and practicum as a conduit to learning physiology.

Adv Physiol Educ 2013 Jun;37(2):153-6

Department of Human Biosciences, La Trobe University, Bundoora, Victoria, Australia.

Many conventional science courses contain subjects embedded with laboratory-based activities. However, research on the benefits of positioning the practicals within the theory subject or developing them distinctly from the theory is largely absent. This report compared results in a physiology theory subject among three different cohorts of students: those taking the theory subject alone, those taking it concurrent with a physiology practicum subject, and those who previously took the subject when it had practicums embedded within the one subject. The path model shows that students taking both physiology theory and physiology practicum attained a significantly higher result in online tests compared with those who took the theory subject alone (P < 0.05) and that this translated to a significantly higher result in the end-of-semester examination. Similarly, students taking both physiology theory and the physiology practicum attained a significantly higher end-examination result compared with those who took the physiology subject in previous years when the practicums were embedded within the theory subject (P < 0.05). In both cases, this increase was largely attained in components that tested critical thinking and deep learning (short theory application questions and extended written questions). We conclude that students undertaking both physiology theory and the physiology practicum likely performed better in the theory subject due to better problem-solving skills and a more developed understanding of theoretical content. We suggest that consideration be given in all science curricula to the separation of theory and practicum by developing two subjects with clearly defined different learning outcomes.
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http://dx.doi.org/10.1152/advan.00161.2012DOI Listing
June 2013

Do prostanoids or nitric oxide mediate sensitization of the von Bezold-Jarisch reflex by B-type natriuretic peptide?

Clin Exp Pharmacol Physiol 2011 Jul;38(7):410-5

Florey Neuroscience Institutes, Parkville, Australia.

1. Cardiac natriuretic peptides act on cardiopulmonary chemoreceptor afferents to enhance the von Bezold-Jarisch reflex (BJR). Activity of the natriuretic peptide particulate guanylyl cyclase receptor is essential for full expression of the BJR. Whether natriuretic peptides act directly on cardiac afferents or they require another intermediate factor(s) for their effects on the BJR is unknown. Endogenous candidates tested as possible intermediates in the present study were prostanoids and nitric oxide (NO), plausible endogenous chemical mediators of cardiac chemoreflex activity. 2. Dose-dependent BJR bradycardia was evoked by the 5-HT(3) receptor agonist, phenylbiguanide (range 5-89 μg/kg), in conscious instrumented adult sheep (n = 6). The influence of B-type natriuretic peptide (BNP; the most potent of the natriuretic peptides) on the BJR was assessed before and after blockade of prostanoids (using indomethacin, 1 mg/kg per h i.v.) or nitric oxide (using N-nitro-l-arginine (NOLA), 3 mg/kg bolus, then 3 mg/kg per h infusion i.v.). 3. On their own, indomethacin and NOLA did not significantly alter the BJR, showing that prostanoids and NO are not essential endogenous mediators of the BJR. As shown in previous studies, BNP (10 pmol/kg per min i.v.) infusion enhanced the BJR by 85 ± 36%, P < 0.05. When the production of either prostanoids or nitric oxide was inhibited, BNP still enhanced the BJR. 4. The present study provides evidence that BNP does not require the activity or influence of prostaglandins or NO for its sensitising effects on the BJR. We propose that natriuretic peptides act directly on cardiac afferents, in synergy with 5-HT(3) agonists, to facilitate the BJR.
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http://dx.doi.org/10.1111/j.1440-1681.2011.05527.xDOI Listing
July 2011

Cardioprotection from ischaemia-reperfusion injury by a novel flavonol that reduces activation of p38 MAPK.

Eur J Pharmacol 2011 May 1;658(2-3):160-7. Epub 2011 Mar 1.

Howard Florey Institute, University of Melbourne, Victoria, Australia.

Oxidative stress, activation of intracellular protein kinases and cardiomyocyte apoptosis are known mediators of cardiac ischaemia/reperfusion injury. The sites at which NP202, a novel water soluble pro-drug of 3',4'-dihydroxyflavonol (DiOHF), acts in this cascade to cause cardioprotection are unknown. In this study we examined the ability of NP202 to reduce infarct size after a prolonged period of ischaemia and reperfusion. In addition, we tested whether NP202 inhibits pro-apoptotic signalling, apoptosis and inflammation following myocardial ischaemia and reperfusion. Sheep were anaesthetised, the heart exposed and the 2nd branch of the left anterior descending coronary artery isolated. The artery was occluded for 3h and, five minutes before 3h of reperfusion was commenced, sheep were treated with intravenous vehicle or NP202. At the end of reperfusion infarct size was measured and normal left ventricle, non-infarcted area-at-risk and infarcted myocardium were collected to identify polymorphonuclear leukocytes (PMN) or apoptotic cells (TUNEL-positive), or assessed for activation of mitogen-activated protein kinase (MAPK) pathways by Western blot analysis. Compared with vehicle treatment, NP202 reduced infarct size (-20 ± 4%, P<0.05) and decreased the number of PMNs and TUNEL-positive cells in the area-at-risk (-35 ± 16% and -52 ± 19%, respectively) and infarcted tissue (-57 ± 9 and -81 ± 5%, respectively, P<0.05). Furthermore, NP202 significantly reduced I/R-induced elevated p38 MAPK phosphorylation (by 67 ± 4%, P<0.05) in the area-at-risk zone. In conclusion, the novel aqueous flavonol NP202 provided significant cardioprotection from clinically relevant prolonged myocardial ischaemia when administered just before reperfusion. Efficacy of NP202 was also associated with reduced p38 MAPK activation, inflammation and apoptotic cell death.
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http://dx.doi.org/10.1016/j.ejphar.2011.02.041DOI Listing
May 2011

3',4'-Dihydroxyflavonol improves post-ischaemic coronary endothelial function following 7days reperfusion in sheep.

Eur J Pharmacol 2009 Dec 13;624(1-3):31-7. Epub 2009 Oct 13.

Howard Florey Institute, University of Melbourne, Victoria 3010, Australia.

3',4'-dihydroxyflavonol (DiOHF) is a potent antioxidant that reduces infarct size following myocardial ischaemia-reperfusion. Since oxidative stress induced by myocardial ischaemia-reperfusion impairs endothelium-dependent vasodilatation, we investigated whether DiOHF preserved coronary endothelial function following ischemia-reperfusion. One week after surgery conscious, instrumented sheep were subjected to 1h of myocardial ischaemia followed by 7 days reperfusion. Immediately before reperfusion, sheep were injected with DiOHF (2mg/kg iv, n=4) or vehicle (dimethyl sulphoxide, n=4). Coronary vascular responses to the endothelium-dependent vasodilator acetylcholine (ACh, 0.05-10.0 microg/kg/min iv), sodium nitroprusside and phenylephrine were determined. After ischaemia-reperfusion, dP/dt(max) decreased from 1511+/-93 to 1094+/-53 mmHg/s, P<0.05) at 24h in the vehicle group, but by 7 days had returned towards baseline (1347+/-91 mmHg/s). DiOHF prevented the fall in dP/dt(max). Coronary conductance (CC) was increased (+34+/-4%) by 10 microg/kg ACh given before ischaemia, but this vasodilatation was significantly reduced after 24h and 7 days of reperfusion (+7+/-2%, +15+/-2%, respectively, both P<0.05). DiOHF partially preserved the coronary vasodilator response to ACh after 24h reperfusion (basal 37+/-7%, 24h 18+/-5%), and after 7 days reperfusion the response had recovered (31+/-7%). DiOHF significantly decreased infarct size, expressed as a percentage of area-at-risk, by 40% after 7 days reperfusion (vehicle 80+/-7%, DiOHF 46+/-11%, P<0.05). A single administration of DiOHF, during ischaemia and just prior to reperfusion, reduced infarct size, preserved ventricular contractility and caused a sustained protection against coronary endothelial dysfunction, with all these beneficial actions being preserved for 7 days reperfusion.
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http://dx.doi.org/10.1016/j.ejphar.2009.10.001DOI Listing
December 2009
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