The impact of lipopolysaccharide on cerebrovascular function and cognition resulting from obesity-induced gut dysbiosis.

Obesity is a worldwide epidemic coinciding with a concomitant increase in the incidence of neurodegenerative diseases, particularly dementia. Obesity is characterised by increased adiposity, chronic low-grade systemic inflammation, and oxidative stress, which promote endothelial dysfunction. Endothelial dysfunction reduces cerebrovascular function leading to reduced cerebral blood flow and, eventually, cognitive decline, thus predisposing to a neurodegenerative disease. Obesity is also characterised by gut dysbiosis and a subsequent increase in the lipopolysaccharide which increasingly activates toll-like receptor 4 (TLR4) and further promotes chronic low-grade systemic inflammation. This also disrupts the crosstalk within the gut-brain axis, thus influencing the functions of the central nervous system, including cognition. However, the mechanisms by which obesity-related increases in oxidative stress, inflammation and endothelial dysfunction are driven by, or associated with, increased systemic lipopolysaccharide leading to reduced cerebrovascular function and cognition, beyond normal ageing, have not been elucidated. Hence, this review examines how increased concentrations of lipopolysaccharide and the subsequent increased TLR4 activation observed in obesity exacerbate the development of obesity-induced reductions in cerebrovascular function and cognition.

Differences in total cognition and cerebrovascular function in female breast cancer survivors and cancer-free women.

Reduced cognition is often reported by breast cancer patients and survivors, but the mechanisms for this decline are yet to be determined. We compared the differences in cerebrovascular function and cognition in breast cancer survivors (n = 15) and cancer-free women (n = 15) matched by age and body mass index. Participants undertook anthropometric, mood, cardiovascular, exercise performance, strength, cerebrovascular, and cognitive measurements. Transcranial Doppler ultrasound was used to measure the cerebrovascular responsiveness (CVR) to physiological (hypercapnia; 5% carbon dioxide) and psychological stimuli. Breast cancer survivors had a lower CVR to hypercapnia (21.5 ± 12.8 vs 66.0 ± 20.9%, P < 0.001), CVR to cognitive stimuli (15.1 ± 1.5 vs 23.7 ± 9.0%, P < 0.001) and total composite cognitive score (100 ± 12 vs. 113 ± 7, P = 0.003) than cancer-free women. These parameters remained statistically different between the groups following adjustments for covariates using an analysis of co-variance. We observed significant correlations between multiple measures and exercise capacity the only variable positively correlated to all primary measures (CVR to hypercapnia, r = 0.492, P = 0.007; CVR to cognitive stimuli r = 0.555, P = 0.003; and total composite cognitive score, r = 0.625, P < 0.001). In this study, breast cancer survivors had lower cerebrovascular and cognitive function than age-matched cancer-free women, which may be attributable to the effects of cancer and cancer treatment on brain health.

Biomarkers to measure respiratory muscle damage following inspiratory pressure threshold loading in healthy young men.

Elevated respiratory muscle work is encountered during strenuous exercise, acute and chronic respiratory disorders, and during inspiratory pressure threshold loading (ITL). ITL can induce respiratory muscle damage, evidenced by increases in fast and slow skeletal troponin-I (sTnI). However, other blood markers of muscle damage have not been measured. We investigated respiratory muscle damage following ITL using a skeletal muscle damage biomarkers panel. Seven healthy men (33 ± 2 yr) undertook 60 min of ITL at a resistance equivalent to ∼0% (Sham ITL) and 70% of their maximal inspiratory pressure 2 wk apart. Serum was collected before and at 1, 24, and 48 h after each ITL session. Creatine kinase muscle-type (CKM), myoglobin, fatty acid-binding protein-3 (FABP3), myosin light chain-3, and fast and slow sTnI were measured. Two-way ANOVA revealed time × load interaction effects (P < 0.05) for CKM, slow and fast sTnI. All of these were higher for 70% compared with Sham ITL. CKM was higher at 1 and 24 h, fast sTnI at 1 h, whereas slow sTnI was higher at 48 h. There were main effects of time (P < 0.01) for FABP3 and myoglobin, but no time × load interaction effects. Hence, CKM and fast sTnI could be used to assess respiratory muscle damage immediately (1 h), whereas CKM and slow sTnI could be used to assess respiratory muscle damage 24 and 48 h following conditions that elevate inspiratory muscle work. The specificity of these markers for different time points needs further exploration in other protocols that cause elevated inspiratory muscle work.NEW & NOTEWORTHY We investigated inspiratory pressure threshold loading-induced respiratory muscle damage using a skeletal muscle damage biomarkers panel. Our investigation showed that creatine kinase muscle-type, and fast skeletal troponin I could be used to assess respiratory muscle damage immediately (1 h), whereas creatine kinase muscle-type, and slow skeletal troponin I could be used to assess respiratory muscle damage 24 and 48 h following conditions that cause elevated inspiratory muscle work.

Capsaicin: A Potential Treatment to Improve Cerebrovascular Function and Cognition in Obesity and Ageing.

Impaired cognition is the primary symptom of dementia, which can lead to functional disability and reduced quality of life among an increasingly ageing population. Ageing is associated with increased oxidative stress, chronic low-grade systemic inflammation, and endothelial dysfunction, which reduces cerebrovascular function leading to cognitive decline. Chronic low-grade systemic inflammatory conditions, such as obesity, exacerbate this decline beyond normal ageing and predispose individuals to neurodegenerative diseases, such as dementia. Capsaicin, the major pungent molecule of chilli, has recently demonstrated improvements in cognition in animal models via activation of the transient receptor potential vanilloid channel 1 (TRPV1). Capsaicin-induced TRPV1 activation reduces adiposity, chronic low-grade systemic inflammation, and oxidative stress, as well as improves endothelial function, all of which are associated with cerebrovascular function and cognition. This review examines the current literature on capsaicin and Capsimax, a capsaicin supplement associated with reduced gastrointestinal irritation compared to capsaicin. Acute and chronic capsaicin treatment can improve cognition in animals. However, studies adequately assessing the effects of capsaicin on cerebrovascular function, and cognition in humans do not exist. Capsimax may be a potentially safe therapeutic intervention for future clinical trials testing the effects of capsaicin on cerebrovascular function and cognition.

The benefits of regular aerobic exercise training on cerebrovascular function and cognition in older adults.

We compared the differences in cerebrovascular and cognitive function between 13 aerobic exercise trained, older adults and 13 age-, height- and sex-matched sedentary, untrained controls. We determined whether other measures accounted for differences in cerebrovascular and cognitive function between these groups and examined the associations between these functions. Participants undertook anthropometric, mood, cardiovascular, exercise performance, strength, cerebrovascular, and cognitive measurements, and a blood collection. Transcranial Doppler ultrasonography determined cerebrovascular responsiveness (CVR) to hypercapnia and cognitive stimuli. The trained group had a higher CVR to hypercapnia (80.3 ± 7.2 vs 35.1 ± 6.7%, P < 0.001), CVR to cognitive stimuli (30.1 ± 2.9 vs 17.8 ± 1.4%, P = 0.001) and total composite cognitive score (117 ± 2 vs 98 ± 4, P < 0.001) than the controls. These parameters no longer remained statistically different between the groups following adjustments for covariates. There were positive correlations between the total composite cognitive score and CVR to hypercapnia (r = 0.474, P = 0.014) and CVR to cognitive stimuli (r = 0.685, P < 0.001). We observed a relationship between cerebrovascular and cognitive function in older adults and an interaction between regular lifelong aerobic exercise training and cardiometabolic factors that may directly influence these functions.

The Effects of Aerobic Exercise Training on Cerebrovascular and Cognitive Function in Sedentary, Obese, Older Adults.

Cerebrovascular function and cognition decline with age and are further exacerbated by obesity and physical inactivity. This decline may be offset by aerobic exercise training (AT). We investigated the effects of 16 weeks AT on cerebrovascular and cognitive function in sedentary, obese, older adults. Twenty-eight participants were randomly allocated to AT or a control group. Before and after the intervention, transcranial Doppler ultrasonography was used to measure the cerebrovascular responsiveness (CVR) to physiological (hypercapnia, 5% carbon dioxide) and cognitive stimuli. AT increased the CVR to hypercapnia (98.5 ± 38.4% vs. 58.0 ± 42.0%, P = 0.021), CVR to cognitive stimuli (25.9 ± 6.1% vs. 16.4 ± 5.4%, P < 0.001) and total composite cognitive score (111 ± 14 vs. 104 ± 14, P = 0.004) compared with the control group. A very strong relationship was observed between the number of exercise sessions completed and CVR to cognitive stimuli (r = 0.878, P < 0.001), but not for CVR to hypercapnia (r = 0.246, P = 0.397) or total composite cognitive score (r = 0.213, P = 0.465). Cerebrovascular function and cognition improved following 16 weeks of AT and a dose-response relationship exists between the amount of exercise sessions performed and CVR to cognitive stimuli.

Benefits of exercise training on cerebrovascular and cognitive function in ageing.

Derangements in cerebrovascular structure and function can impair cognitive performance throughout ageing and in cardiometabolic disease states, thus increasing dementia risk. Modifiable lifestyle factors that cause a decline in cardiometabolic health, such as physical inactivity, exacerbate these changes beyond those that are associated with normal ageing. The purpose of this review was to examine cerebrovascular, cognitive and neuroanatomical adaptations to ageing and the potential benefits of exercise training on these outcomes in adults 50 years or older. We systematically searched for cross-sectional or intervention studies that included exercise (aerobic, resistance or multimodal) and its effect on cerebrovascular function, cognition and neuroanatomical adaptations in this age demographic. The included studies were tabulated and described narratively. Aerobic exercise training was the predominant focus of the studies identified; there were limited studies exploring the effects of resistance exercise training and multimodal training on cerebrovascular function and cognition. Collectively, the evidence indicated that exercise can improve cerebrovascular function, cognition and neuroplasticity through areas of the brain associated with executive function and memory in adults 50 years or older, irrespective of their health status. However, more research is required to ascertain the mechanisms of action.

The Gut-Brain Axis, the Human Gut Microbiota and Their Integration in the Development of Obesity.

Obesity is a global epidemic, placing socioeconomic strain on public healthcare systems, especially within the so-called Western countries, such as Australia, United States, United Kingdom, and Canada. Obesity results from an imbalance between energy intake and energy expenditure, where energy intake exceeds expenditure. Current non-invasive treatments lack efficacy in combating obesity, suggesting that obesity is a multi-faceted and more complex disease than previously thought. This has led to an increase in research exploring energy homeostasis and the discovery of a complex bidirectional communication axis referred to as the gut-brain axis. The gut-brain axis is comprised of various neurohumoral components that allow the gut and brain to communicate with each other. Communication occurs within the axis via local, paracrine and/or endocrine mechanisms involving a variety of gut-derived peptides produced from enteroendocrine cells (EECs), including glucagon-like peptide 1 (GLP1), cholecystokinin (CCK), peptide YY3-36 (PYY), pancreatic polypeptide (PP), and oxyntomodulin. Neural networks, such as the enteric nervous system (ENS) and vagus nerve also convey information within the gut-brain axis. Emerging evidence suggests the human gut microbiota, a complex ecosystem residing in the gastrointestinal tract (GIT), may influence weight-gain through several inter-dependent pathways including energy harvesting, short-chain fatty-acids (SCFA) signalling, behaviour modifications, controlling satiety and modulating inflammatory responses within the host. Hence, the gut-brain axis, the microbiota and the link between these elements and the role each plays in either promoting or regulating energy and thereby contributing to obesity will be explored in this review.

Capsaicin in Metabolic Syndrome.

Capsaicin, the major active constituent of chilli, is an agonist on transient receptor potential vanilloid channel 1 (TRPV1). TRPV1 is present on many metabolically active tissues, making it a potentially relevant target for metabolic interventions. Insulin resistance and obesity, being the major components of metabolic syndrome, increase the risk for the development of cardiovascular disease, type 2 diabetes, and non-alcoholic fatty liver disease. In vitro and pre-clinical studies have established the effectiveness of low-dose dietary capsaicin in attenuating metabolic disorders. These responses of capsaicin are mediated through activation of TRPV1, which can then modulate processes such as browning of adipocytes, and activation of metabolic modulators including AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor α (PPARα), uncoupling protein 1 (UCP1), and glucagon-like peptide 1 (GLP-1). Modulation of these pathways by capsaicin can increase fat oxidation, improve insulin sensitivity, decrease body fat, and improve heart and liver function. Identifying suitable ways of administering capsaicin at an effective dose would warrant its clinical use through the activation of TRPV1. This review highlights the mechanistic options to improve metabolic syndrome with capsaicin.

A model of the direct and indirect effects of aprotinin administration on the overall costs of coronary revascularization surgery in a university teaching hospital cardiothoracic unit.

BACKGROUND: Cardiac patients sometimes bleed postoperatively and consequently require rethoracotomy, necessitating a longer stay in the intensive care unit (ICU) of the cardiothoracic unit (CTU). When ICU capacity is limited, rethoracotomy necessitates postponing treatment of the next patient. Aprotinin, a bovine lung-derived proteinase inhibitor, has been shown to reduce the frequency of rethoracotomies in cardiac patients. OBJECTIVE: This study was undertaken to quantify the reduction of potentially avoidable cost to the CTU of postoperative bleeding, both directly and indirectly, by administering aprotinin before and during coronary artery bypass graft (CABG). METHODS: A novel, validated operational research model was developed, featuring the principal CABG-related health care resource parameters believed to influence waiting lists and times. Factors and costs were derived from both local data from a CTU and relevant recent literature. RESULTS: According to the model, aprotinin therapy reduced the waiting list by approximately 3% by reducing the number of rethoracotomies. Using data from the literature, for an annual throughput of 431 patients who would receive aprotinin costing 97,333 pounds per year, the annual net savings to the CTU would be 46,586 pounds, which comprised direct savings on blood products of 35,036 pounds and indirect marginal savings of 11,550 pounds derived from 3.2% fewer rethoracotomies (each at a marginal cost of 837 pounds). By reason, then, reinvesting savings in increasing CTU capacity would yield further waiting-list reductions and improve patient morbidity. These results had 2 major limitations. First, it was assumed that all operations would have the same duration and all surgeons would perform operations in the same manner. Second, nonurgent patients were assumed to have been treated in order of strict referral sequence, which may not be done in real-world practice. CONCLUSIONS: Aprotinin reduced costs in CABG directly by reducing the use of blood products and indirectly by reducing waiting lists, as well as by reducing morbidity and mortality associated with waiting time.