Effects of epicatechin on cardiovascular function in middle-aged diet-induced obese rat models of metabolic syndrome.

The current study aimed to investigate the cardiovascular effects of epicatechin, a flavonoid found in green tea and cocoa, in attenuating complications associated with metabolic syndrome in diet-induced obese rats. Male Wistar-Kyoto (WKY) rats aged 16 weeks were fed either standard rat chow or given a high-fat-high-carbohydrate (HFHC) diet for 20 weeks. Epicatechin treatment (5 mg/kg/d) was administered to a subset of WKY rats commencing at week 8 of the 20 week HFHC feeding period. Body weights, food, water and energy intakes, blood pressure, heart rate and glucose tolerance were measured throughout the treatment period. Oxidative stress and inflammatory markers, lipid levels, cardiac collagen deposition, cardiac electrical function, aortic and mesenteric vessel reactivity were examined after the treatment. Twenty weeks of HFHC feeding in WKY rats resulted in the development of metabolic syndrome indicated by the presence of abdominal obesity, dyslipidaemia, glucose intolerance and increased blood pressure. Epicatechin treatment was found to enhance the oxidative stress status in HFHC groups through an increase in serum nitric oxide levels and a decrease in 8-isoprostane concentrations. Furthermore, WKY-HFHC rats displayed a decrease in IL-6 levels. The lipid profiles in HFHC groups showed improvement, with a decrease in LDL-cholesterol and TAG and an increase in HDL-cholesterol levels observed in WKY-HFHC rats. However, epicatechin was not effective in preventing weight gain, glucose intolerance or hypertension in HFHC fed rats. Overall, the results of this study suggest that epicatechin has the potential to improve the underlying mechanisms associated with metabolic syndrome in obese rats.

Repetitive mild traumatic brain injury-induced neurodegeneration and inflammation is attenuated by acetyl-L-carnitine in a preclinical model.

Repetitive mild traumatic brain injuries (rmTBI) may contribute to the development of neurodegenerative diseases through secondary injury pathways. Acetyl-L-carnitine (ALC) shows neuroprotection through anti-inflammatory effects and via regulation of neuronal synaptic plasticity by counteracting post-trauma excitotoxicity. This study aimed to investigate mechanisms implicated in the etiology of neurodegeneration in rmTBI mice treated with ALC. Adult male C57BL/6J mice were allocated to sham, rmTBI or ALC + rmTBI groups. 15 rmTBIs were administered across 23 days using a modified weight drop model. Neurological testing and spatial learning and memory assessments via the Morris Water Maze (MWM) were undertaken at 48 h and 3 months. RT-PCR analysis of the cortex and hippocampus was undertaken for MAPT, GFAP, AIF1, GRIA, CCL11, TDP43, and TNF genes. Gene expression in the cortex showed elevated mRNA levels of MAPT, TNF, and GFAP in the rmTBI group that were reduced by ALC treatment. In the hippocampus, mRNA expression was elevated for GRIA1 in the rmTBI group but not the ALC + rmTBI treatment group. ALC treatment showed protective effects against the deficits displayed in neurological testing and MWM assessment observed in the rmTBI group. While brain structures display differential vulnerability to insult as evidenced by location specific postimpact disruption of key genes, this study shows correlative mRNA neurodegeneration and functional impairment that was ameliorated by ALC treatment in several key genes. ALC may mitigate damage inflicted in the various secondary neurodegenerative cascades and contribute to functional protection following rmTBI.

Perindopril prevents development of obesity and hypertension in middle aged diet-induced obese rat models of metabolic syndrome.

AIMS: The therapeutic properties of anti-hypertensive medications that extend beyond blood pressure lowering have started to become important clinical targets in recent years. This study aimed to assess the cardioprotective effects of perindopril in attenuating complications associated with metabolic syndrome in diet induced obese rats. MAIN METHODS: Male Wistar-Kyoto (WKY) rats aged 16 weeks were fed either standard rat chow (SC) or given a high-fat-high-carbohydrate (HFHC) diet for 20 weeks. Perindopril treatment (1 mg/kg/day) was administered to a subset of WKY rats commencing at week 8 of the 20 week HFHC feeding period. Body weights, food, water and energy intakes, blood pressure, heart rate and glucose tolerance were measured throughout the treatment period. Oxidative stress and inflammatory markers, lipid levels, cardiac collagen deposition, vascular function, aortic and cardiac electrical function were examined after the treatment. KEY FINDINGS: WKY rats developed metabolic syndrome after 20 weeks of HFHC feeding, evidenced by the presence of abdominal obesity, dyslipidaemia, glucose intolerance and hypertension. Perindopril treatment prevented the development of obesity and hypertension in WKY-HFHC. Perindopril improved blood lipid profiles in HFHC rats with decreases in LDL cholesterol, triglycerides and total cholesterol. Type I collagen levels were decreased in WKY-HFHC rats along with decreases in left ventricle mass. Perindopril treated rats also showed improved cardiac electrical function indicated by decreases in action potential at 90 % of repolarisation in WKY-HFHC rats. SIGNIFICANCE: These results show that perindopril has a profound effect on preventing the development of metabolic syndrome in animals fed a HFHC diet.

Systematic Review of the Diagnostic and Clinical Utility of Salivary microRNAs in Traumatic Brain Injury (TBI).

Research in traumatic brain injury (TBI) is an urgent priority, as there are currently no TBI biomarkers to assess the severity of injury, to predict outcomes, and to monitor recovery. Small non-coding RNAs (sncRNAs) including microRNAs can be measured in saliva following TBI and have been investigated as potential diagnostic markers. The aim of this systematic review was to investigate the diagnostic or prognostic ability of microRNAs extracted from saliva in human subjects. PubMed, Embase, Scopus, PsycINFO and Web of Science were searched for studies that examined the association of saliva microRNAs in TBI. Original studies of any design involving diagnostic capacity of salivary microRNAs for TBI were selected for data extraction. Nine studies met inclusion criteria, with a heterogeneous population involving athletes and hospital patients, children and adults. The studies identified a total of 188 differentially expressed microRNAs, with 30 detected in multiple studies. MicroRNAs in multiple studies involved expression change bidirectionality. The study design and methods involved significant heterogeneity that precluded meta-analysis. Early data indicates salivary microRNAs may assist with TBI diagnosis. Further research with consistent methods and larger patient populations is required to evaluate the diagnostic and prognostic potential of saliva microRNAs.

Depression, anxiety, stress, and physical activity of Australian adults during COVID-19: A combined longitudinal and repeated cross-sectional study.

Background: The COVID-19 pandemic has led to a worsening of mental health and health behaviors. While physical activity is positively associated mental health, there is limited understanding of how mental health and physical activity evolve throughout the COVID-19 pandemic. This study aimed to examine changes in depression, anxiety and stress and physical activity, and associations between depression, anxiety, and stress with physical activity in Australian adults across three-time points during the COVID-19 pandemic. Materials and methods: This study collected both longitudinal and cross-sectional data at three-time points during the COVID-19 pandemic in Australia (i.e., April, July/August, and December 2020). Australians aged 18 years and over were invited to complete online surveys hosted on Qualtrics survey platform. Linear mixed models with random subject effect and general linear models were used to analyze the longitudinal and repeated cross-sectional data respectively. Results: The number of participants in cross-sectional surveys and longitudinal surveys was 1,877 and 849, respectively. There was an overall reduction between time 2 vs. time 3 in depression (d = 1.03, 95% CI = 0.20, 1.85), anxiety (d = 0.57, 95% CI = 0.02, 1.12), and stress (d = 1.13, 95% CI = 0.21, 2.04) scores but no significant differences in physical activity across three-time points. On average, participants who met the physical activity guidelines had lower depression (d = -2.08, 95% CI = -2.90, -1.26), anxiety (d = -0.88, 95% CI = -1.41, -0.34), and stress (d = -1.35, 95% CI = -2.13, -0.56) scores compared to those not meeting the guidelines. Conclusion: In the context of the ongoing COVID-19 pandemic, both governments and service providers should continue to provide the public with timely mental health support and promote the benefits of physical activity, as a cost-effective strategy to improve mental health and wellbeing.

The association of resilience with depression, anxiety, stress and physical activity during the COVID-19 pandemic.

BACKGROUND: COVID-19 has resulted in substantial global upheaval. Resilience is important in protecting wellbeing, however few studies have investigated changes in resilience over time, and associations between resilience with depression, anxiety, stress, and physical activity during the COVID-19 pandemic. METHODS: Online surveys were conducted to collect both longitudinal and cross-sectional data at three time points during 2020. Australian adults aged 18 years and over were invited to complete the online surveys. Measures include the six-item Brief Resilience Scale, the 21-item Depression, Anxiety and Stress Scale, and the Active Australia Survey which have eight items identifying the duration and frequency of walking, and moderate and vigorous physical activities (MVPA), over the past 7 days. General linear mixed models and general linear models were used in the analysis. RESULTS: In the longitudinal sample, adjusted differences (aDif) in resilience scores did not significantly change over time (time 2 vs. time 1 [aDif = - 0.02, 95% CI = - 0.08, 0.03], and time 3 vs. time 1 [aDif = < 0.01, 95% CI = - 0.07, 0.06]). On average, those engaging in at least 150 min of MVPA per week (aDif = 0.10, 95% CI = 0.04, 0.16), and having depression (aDif = 0.40, 95% CI = 0.33), anxiety (aDif = 0.34, 95% CI = 0.26, 0.41), and stress scores (aDif = 0.30, 95% CI = 0.23, 0.37) within the normal range had significantly higher resilience scores. The association between resilience and physical activity was independent of depression, anxiety, and stress levels. All results were similar for the cross-sectional sample. CONCLUSIONS: Resilience scores did not change significantly during the COVID-19 pandemic. However, there were significant associations between resilience with physical activity and psychological distress. This research helps inform future interventions to enhance or nurture resilience, particularly targeted at people identified as at risk of psychological distress.

How are COVID-19 knowledge and concern associated with practising preventive behaviours in Australian adults?

OBJECTIVE: This study investigated the association between COVID-19 prevention knowledge and concern and practising preventive behaviour in Australian adults. METHODS: Using an online survey, knowledge of Australian COVID-19 guidelines, concerns about pandemic impact, the practice of preventive behaviours, and sociodemographic variables (i.e. age, gender, information source) were measured. Bivariate analysis and linear regression models were used. RESULTS: A total of 1,491 participants (age 50.5 ±14.9 years, 32.3% males) completed the survey. Higher knowledge and concern scores were associated with a higher practice of preventive behaviour scores (ßs:0.47 & 0.08 respectively, p<0.001). Older adults (>65 years) and women had higher knowledge and practice scores compared to their counterparts. Being younger (<45 years) and male were associated with a lower practice score (ßs:-0.88 & -2.52, respectively, p<0.001). Referring to public and government sources as primary sources of information was associated with a higher practice score (ß:1.21, p<0.001). CONCLUSIONS: Government-run campaigns appear to be effective in promoting preventive practices and achieving a high knowledge of COVID-19 guidelines in Australian adults. Implications for public health: Public health strategies are required to promote the practice of preventive behaviour for COVID-19 (or future pandemics), especially among men and younger adults using social media, given their wide use of these sources.

Willingness to Vaccinate against COVID-19 Declines in Australia, Except in Lockdown Areas.

This study investigates changes in willingness to vaccinate against COVID-19 and the effect of the extended restrictions in metropolitan Victoria on this change. Longitudinal and repeated cross-sectional data were collected from online surveys distributed in April, between July and August, and December 2020. Australian adults who were ≥18 years old were recruited through email lists, social media networks, and paid Facebook advertisement. Willingness to vaccinate against COVID-19 was self-reported. The results showed that participants were more willing to vaccinate if the vaccine was safe at survey 1 (longitudinal: adjusted OR (aOR) = 1.88, 95%CI = 1.38, 2.56; cross-sectional: aOR = 3.73, 95%CI = 2.55, 5.45) and survey 2 (longitudinal: aOR = 1.54, 95%CI = 1.19, 2.00; cross-sectional: aOR = 2.48, 1.67, 3.67), compared to survey 3. The change in willingness to vaccinate if the vaccine was safe and effective was not significant for those in Metropolitan Victoria; but was for those living in other Australian locations at survey 1 (OR = 2.13, 95%CI = 1.64, 2.76) and survey 2 (OR = 1.62, 95%CI = 1.30, 2.01), compared to survey 3. Willingness to vaccinate even if a vaccine had not been proven safe decreased at survey 3 (OR = 2.02, 95%CI = 1.14, 3.57) for those living in Metropolitan Victoria. In conclusion willingness to vaccinate against COVID-19 decreased over time among Australians, except for those living in metropolitan Victoria, where an additional strict and prolonged lockdown was implemented around the time of survey 2. Either the experience of the lockdown, or the presence of the COVID-19 virus itself had a positive influence on participants' willingness to vaccinate, even if such a vaccine was not yet proven to be safe and effective.

Repetitive mild traumatic brain injury affects inflammation and excitotoxic mRNA expression at acute and chronic time-points.

The cumulative effect of mild traumatic brain injuries (mTBI) can result in chronic neurological damage, however the molecular mechanisms underpinning this detriment require further investigation. A closed head weight drop model that replicates the biomechanics and head acceleration forces of human mTBI was used to provide an exploration of the acute and chronic outcomes following single and repeated impacts. Adult male C57BL/6J mice were randomly assigned into one of four impact groups (control; one, five and 15 impacts) which were delivered over 23 days. Outcomes were assessed 48 hours and 3 months following the final mTBI. Hippocampal spatial learning and memory assessment revealed impaired performance in the 15-impact group compared with control in the acute phase that persisted at chronic measurement. mRNA analyses were performed on brain tissue samples of the cortex and hippocampus using quantitative RT-PCR. Eight genes were assessed, namely MAPT, GFAP, AIF1, GRIA1, CCL11, TARDBP, TNF, and NEFL, with expression changes observed based on location and follow-up duration. The cortex and hippocampus showed vulnerability to insult, displaying upregulation of key excitotoxicity and inflammation genes. Serum samples showed no difference between groups for proteins phosphorylated tau and GFAP. These data suggest that the cumulative effect of the impacts was sufficient to induce mTBI pathophysiology and clinical features. The genes investigated in this study provide opportunity for further investigation of mTBI-related neuropathology and may provide targets in the development of therapies that help mitigate the effects of mTBI.

Minocycline improves cognition and molecular measures of inflammation and neurodegeneration following repetitive mTBI.

OBJECTIVE: To compare the neuroprotective effects of minocycline treatment in a murine model of mTBI on measures of spatial learning and memory, neuroinflammation, excitotoxicity, and neurodegeneration. DESIGN: Adult male C57BL/6 J mice were randomly assigned into vehicle control, vehicle with repetitive mTBI, minocycline without mTBI, or minocycline with repetitive mTBI groups. METHODS: A validated mouse model of repetitive impact-induced rotational acceleration was used to deliver 15 mTBIs across 23 days. Cognition was assessed via Morris water maze (MWM) testing, and mRNA analysis investigated MAPT, GFAP, AIF1, GRIA1, TARDBP, TNF, and NEFL genes. Assessment was undertaken 48 h and 3 months following final mTBI. RESULTS: In the chronic phase of recovery, MWM testing revealed impairment in the vehicle mTBI group compared to unimpacted controls (p < .01) that was not present in the minocycline mTBI group, indicating chronic neuroprotection. mRNA analysis revealed AIF1 elevation in the acute cortex (p < .01) and chronic hippocampus (p < .01) of the vehicle mTBI group, with minocycline treatment leading to improved markers of microglial activation and inflammation in the chronic stage of recovery. CONCLUSIONS: These data suggest that minocycline treatment alleviated some mTBI pathophysiology and clinical features at chronic time-points.

As the Pandemic Progresses, How Does Willingness to Vaccinate against COVID-19 Evolve?

Controversy around the safety and efficacy of COVID-19 vaccines may lead to low vaccination rates. Survey data were collected in April and August 2020 from a total of 2343 Australian adults. A quarter (n = 575, 24%) completed both surveys. A generalized linear mixed model analysis was conducted to determine whether willingness to vaccinate changed in the repeated sample, and a multinominal logistic regression was conducted in all participants to determine whether willingness to vaccinate was associated with demographics, chronic disease, or media use. Willingness to vaccinate slightly decreased between April (87%) and August (85%) but this was not significant. Willingness to vaccinate was lower in people with a certificate or diploma (79%) compared to those with a Bachelor degree (87%), p < 0.01 and lower in infrequent users of traditional media (78%) compared to frequent users of traditional media (89%), p < 0.001. Women were more likely to be unsure if they would be willing to vaccinate (10%) compared to men (7%), p < 0.01. There were no associations between willingness to vaccinate and age, chronic disease, or social media use. Promotion of a COVID-19 vaccine should consider targeting women, and people with a certificate or diploma, via non-traditional media channels.

The effect of concentration, reconstitution solution and pH on the stability of a remifentanil hydrochloride and propofol admixture for simultaneous co-infusion.

BACKGROUND: There are scenarios where pre-mixing and infusing analgesic and anaesthetic agents as a single intravenous (IV) solution is highly desirable; however, it is important to ensure the agents are compatible when mixed. As such, the long-term stability of a remifentanil-propofol mixture, and means of improving this, were assessed across a range of remifentanil concentrations, diluents, and time points. METHODS: Remifentanil was reconstituted with ultrapure water, 0.9% saline, 20% saline, or 8.4% sodium bicarbonate solution (the latter two chosen for their pH characteristics, rather than their use in pharmaceutical reconstitution) and then mixed with propofol (1%) or further diluted with water to derive concentrations of 10-50 µg mL- 1. Remifentanil and propofol concentrations were determined initially and then periodically for up to 24 h using high performance liquid chromatography (HPLC). Mass spectrometry (MS) was used to detect degradation products in solutions containing 30 µg mL- 1 of remifentanil. Statistical analysis was performed using ANOVA and Student's t-test, with a significance value of 0.05. RESULTS: Isolated remifentanil (pH < 4) and propofol (pH 7.35) did not degrade significantly when reconstituted with water or saline solution over 24 h, while remifentanil reconstituted with sodium bicarbonate degraded significantly (P < 0.001, pH 8.65). Mixing with propofol substantially increased the pH of the mixture and resulted in significant remifentanil degradation for all reconstitution solutions used, while propofol remained stable (pH 6.50). The amount of degradation product detected in samples containing isolated remifentanil and a mixture of the drugs was proportional to the remifentanil degradation observed. CONCLUSIONS: Remifentanil stability is affected by both the reconstitution solution used and when mixed with propofol, with pH appearing to be a contributing factor to degradation. If the pH of the solution and concentration of remifentanil are correctly controlled, e.g. through the use of a more acidic diluent, an admixture of remifentanil and propofol may be useful clinically.

The Effect of High Storage Temperature on the Stability and Efficacy of Lyophilized Tenecteplase.

INTRODUCTION: Tenecteplase is a thrombolytic protein drug used by paramedics, emergency responders, and critical care medical personnel for the prehospital treatment of blood clotting diseases. Minimizing the time between symptom onset and the initiation of thrombolytic treatment is important for reducing mortality and improving patient outcomes. However, the structure of protein drug molecules makes them susceptible to physical and chemical degradation that could potentially result in considerable adverse effects. In locations that experience extreme temperatures, lyophilized tenecteplase transported in emergency service vehicles (ESVs) may be subjected to conditions that exceed the manufacturer's recommendations, particularly when access to the ambulance station is limited. STUDY OBJECTIVE: This study evaluated the impact of heat exposure (based on temperatures experienced in an emergency vehicle during summer in a regional Australian city) on the stability and efficacy of lyophilized tenecteplase. METHODS: Vials containing 50mg lyophilized tenecteplase were stored at 4.0°C (39.2°F), 35.5°C (95.9°F), or 44.9°C (112.8°F) for a continuous period of eight hours prior to reconstitution. Stability and efficacy were determined through assessment of: optical clarity and pH; analyte concentration using UV spectrometry; percent protein monomer and single chain protein using size-exclusion chromatography; and in vitro bioactivity using whole blood clot weight and fibrin degradation product (D-dimer) development. RESULTS: Heat treatment, particularly at 44.9°C, was found to have the greatest impact on tenecteplase solubility; the amount of protein monomer and single chain protein lost (suggesting structural vulnerability); and the capacity for clot lysis in the form of decreased D-dimer production. Meanwhile, storage at 4.0°C preserved tenecteplase stability and in vitro bioactivity. CONCLUSION: The findings indicate that, in its lyophilized form, even relatively short exposure to high temperature can negatively affect tenecteplase stability and pharmacological efficacy. It is therefore important that measures are implemented to ensure the storage temperature is kept below 30.0°C (86.0°F), as recommended by manufacturers, and that repeated refrigeration-heat cycling is avoided. This will ensure drug administration provides more replicable thrombolysis upon reaching critical care facilities.

Depression, Anxiety and Stress during COVID-19: Associations with Changes in Physical Activity, Sleep, Tobacco and Alcohol Use in Australian Adults.

The novel coronavirus (COVID-19) has enforced dramatic changes to daily living including economic and health impacts. Evidence for the impact of these changes on our physical and mental health and health behaviors is limited. We examined the associations between psychological distress and changes in selected health behaviors since the onset of COVID-19 in Australia. An online survey was distributed in April 2020 and included measures of depression, anxiety, stress, physical activity, sleep, alcohol intake and cigarette smoking. The survey was completed by 1491 adults (mean age 50.5 ± 14.9 years, 67% female). Negative change was reported for physical activity (48.9%), sleep (40.7%), alcohol (26.6%) and smoking (6.9%) since the onset of the COVID-19 pandemic. Significantly higher scores in one or more psychological distress states were found for females, and those not in a relationship, in the lowest income category, aged 18-45 years, or with a chronic illness. Negative changes in physical activity, sleep, smoking and alcohol intake were associated with higher depression, anxiety and stress symptoms. Health-promotion strategies directed at adopting or maintaining positive health-related behaviors should be utilized to address increases in psychological distress during the pandemic. Ongoing evaluation of the impact of lifestyle changes associated with the pandemic is needed.

Skeletal muscle - A bystander or influencer of metabolic syndrome?

BACKGROUND AND AIMS: Metabolic syndrome is the concurrent presentation of multiple cardiovascular risk factors, including obesity, insulin resistance, hyperglycemia, dyslipidemia and hypertension. It has been suggested that some of these risk factors can have detrimental effects on the skeletal muscle while others can be a direct result of skeletal muscle abnormalities, showing a two-way directionality in the pathogenesis of the condition. This review aims to explore this bidirectional correlation by discussing the impact of metabolic syndrome on skeletal muscle tissue in general and will also discuss ways in which skeletal muscle alterations may contribute to the pathogenesis of metabolic syndrome. METHODS: Literature searches were conducted with key words (e.g. metabolic syndrome, skeletal muscle, hyperglycemia) using PubMed, EBSCOhost, Science Direct and Google Scholar. All article types were included in the search. RESULTS: The pathological mechanisms associated with metabolic syndrome, such as hyperglycemia and inflammation, have been associated with changes in skeletal muscle fiber composition, metabolism, insulin sensitivity, mitochondrial function, and strength. Additionally, some skeletal muscle alterations, particularly mitochondrial dysfunction and insulin resistance, are suggested to contribute to the development of metabolic syndrome. For example, the suggested underlying mechanisms of sarcopenia development are also contributors to metabolic syndrome pathogenesis. CONCLUSION: Whilst numerous studies have identified a relationship between metabolic syndrome and skeletal muscle abnormalities, further investigation into the underlying mechanisms is needed to elucidate the best prevention and management strategies for these conditions.

Blood biomarkers for assessment of mild traumatic brain injury and chronic traumatic encephalopathy.

Mild traumatic brain injuries (mTBI) are prevalent and can result in significant debilitation. Current diagnostic methods have implicit limitations, with clinical assessment tools reliant on subjective self-reported symptoms or non-specific clinical observations, and commonly available imaging techniques lacking sufficient sensitivity to detect mTBI. A blood biomarker would provide a readily accessible detector of mTBI to meet the current measurement gap. Suitable options would provide objective and quantifiable information in diagnosing mTBI, in monitoring recovery, and in establishing a prognosis of resultant neurodegenerative disease, such as chronic traumatic encephalopathy (CTE). A biomarker would also assist in progressing research, providing suitable endpoints for testing therapeutic modalities and for further exploring mTBI pathophysiology. This review highlights the most promising blood-based protein candidates that are expressed in the central nervous system (CNS) and released into systemic circulation following mTBI. To date, neurofilament light (NF-L) may be the most suitable candidate for assessing neuronal damage, and glial fibrillary acidic protein (GFAP) for assessing astrocyte activation, although further work is required. Ultimately, the heterogeneity of cells in the brain and each marker's limitations may require a combination of biomarkers, and recent developments in microRNA (miRNA) markers of mTBI show promise and warrant further exploration.

Moderate-intensity physical activity reduces systemic inflammation and maintains cardiorespiratory function following chronic particulate matter2.5 exposure in rats.

AIMS: The purpose of the current study is to 1) examine the beneficial effects of moderate levels of physical activity (PA) on functional and biochemical markers of the cardiorespiratory system, 2) establish the detrimental effects of a single, daily particulate matter (PM) exposure event on cardiorespiratory function and 3) determine if exercising during daily PM exposure increases the deleterious effects caused by PM exposure due to increased inhalation of particulates on cardiorespiratory function. METHODS: Four groups of 16 rats were used: control (CON), PA, PM2.5 exposed and PA combined with PM2.5 exposure (PA + PM). Animals were purchased at 4 weeks old. However, both PA and PM exposure was initiated when the animals reached 8 weeks of age, for 8 weeks. RESULTS: PA alone did not alter body weight or blood pressure (BP) compared to control animals. However, there was a significant decrease in epididymal fat pad mass in the PA group. The PM exposed rats were hypertensive, showed increased systemic inflammation and oxidative stress, and had decreased spleen mass without pathological changes in the cardiac action potential or impaired vascular function. PA was able to decrease systemic inflammation in PM exposed animals, including a reduction in IL-6 serum levels, however, this did not translate to an improvement in BP or vascular reactivity. Smooth muscle relaxation in the trachea from the combination PA + PM group was not significantly different to CON and PA groups but was significantly higher than the PM group. CONCLUSIONS: The current study showed that while there is an increased cardiovascular disease (CVD) risk associated with PM exposure, engaging in PA during exposure events imposes no increased risk with exercise providing a protective mechanism against some of the biochemical signaling changes caused by inhaled PM.

Statins with different lipophilic indices exert distinct effects on skeletal, cardiac and vascular smooth muscle.

AIMS: Data concerning the influence of statin lipophilicity on the myotoxic and pleiotropic effects of statins is conflicting, and mechanistic head-to-head comparison studies evaluating this parameter are limited. In order to address the disparity, this mechanistic investigation aimed to assess the effects of two short-acting statins with different lipophilic indices on skeletal, cardiac and vascular smooth muscle physiology. MATERIALS AND METHODS: Young female Wistar rats were randomised to simvastatin (80 mg kg-1 day-1), pravastatin (160 mg kg-1 day-1) or control treatment groups. Changes in functional muscle performance were assessed, as well as mRNA levels of genes relating to atrophy, hypertrophy, mitochondrial function and/or oxidative stress. KEY FINDINGS: There were no significant differences in the mRNA profiles of isolated skeletal muscles amongst the treatment groups. In terms of skeleletal muscle performance, simvastatin reduced functionality but treatment with pravastatin significantly improved force production. Rodents given simvastatin demonstrated comparable myocardial integrity to the control group. Conversely, pravastatin reduced left ventricular action potential duration, diastolic stiffness and Mhc-ß expression. Pravastatin improved endothelium-dependent relaxation, particularly in muscular arteries, but this effect was absent in the simvastatin-treated rats. The responsiveness of isolated blood vessels to noradrenaline also differed between the statin groups. The findings of this study support that the effects of statins on skeletal, cardiac and vascular smooth muscle vary with their lipophilic indices. SIGNIFICANCE: The results of this work have important implications for elucidating the mechanisms responsible for the myotoxic and pleiotropic effects of statins.

Geranylgeraniol prevents statin-induced skeletal muscle fatigue without causing adverse effects in cardiac or vascular smooth muscle performance.

The administration of geranylgeranyl pyrophosphate (GGPP) (or its precursor, geranylgeraniol [GGOH]) has been shown by several in vitro studies to be capable of abrogating statin-induced myotoxicity. Nonetheless, the potential of GGPP repletion to prevent statin-associated muscle symptoms (SAMS) in vivo is yet to be investigated. Therefore, this study aimed to evaluate the ability of GGOH to prevent SAMS in rodents. Female Wistar rats (12 weeks of age) were randomised to 1 of 4 treatment groups: control, control with GGOH, simvastatin or simvastatin with GGOH. Ex vivo assessment of force production was conducted in skeletal muscles of varying fiber composition. Ex vivo left ventricular performance and blood vessel function was also assessed to determine if the administration of GGOH caused adverse changes in these parameters. Statin administration was associated with reduced force production in fast-twitch glycolytic muscle, but coadministration with GGOH completely abrogated this effect. Additionally, GGOH improved the performance of muscles not adversely affected by simvastatin (ie, those with a greater proportion of slow-twitch oxidative fibers), and increased force production in the control animals. Neither control nor statin-treated rodents given GGOH exhibited adverse changes in cardiac function. Vascular relaxation was also maintained following treatment with GGOH. The findings of this study demonstrate that GGOH can prevent statin-induced skeletal muscle fatigue in rodents without causing adverse changes in cardiovascular function. Further studies to elucidate the exact mechanisms underlying the effects observed in this investigation are warranted.