Attenuation of oxidative stress-induced lesions in skeletal muscle in a mouse model of obesity-independent hyperlipidaemia and atherosclerosis through the inhibition of Nox2 activity

Obesity leading to hyperlipidaemia and atherosclerosis is recognised to induce morphological and metabolic changes in many tissues. However, both hyperlipidaemia and atherosclerosis can occur in the absence of obesity. The impact of the latter scenario on skeletal muscle and liver is not understood sufficiently. In this regard, we used the Apolipoprotein E-deficient (ApoE-/-) mouse model, an established model of hyperlipidaemia and atherosclerosis, that does not become obese when subjected to a high-fat diet, to determine the impact of Western-type diet (WD) and ApoE deficiency on skeletal muscle morphological, metabolic and biochemical properties. To establish the potential of therapeutic targets, we further examined the impact of Nox2 pharmacological inhibition on skeletal muscle redox biology. We found ectopic lipid accumulation in skeletal muscle and the liver, and altered skeletal muscle morphology and intramuscular triacylglycerol fatty acid composition. WD and ApoE deficiency had a detrimental impact in muscle metabolome, followed by perturbed gene expression for fatty acid uptake and oxidation. Importantly, there was enhanced oxidative stress in the skeletal muscle and development of liver steatosis, inflammation and oxidative protein modifications. Pharmacological inhibition of Nox2 decreased reactive oxygen species production and protein oxidative modifications in the muscle of ApoE-/- mice subjected to a Western-type diet. This study provides key evidence to better understand the pathophysiology of skeletal muscle in the context of hyperlipidaemia and atherosclerosis and identifies Nox2 as a potential target for attenuating oxidative stress in skeletal muscle in a mouse model of obesity-independent hyperlipidaemia

Effects of lifelong exercise and aging on the blood metabolic fingerprint of rats

Regular exercise is an important part of a healthy lifestyle, as it helps maintain a healthy weight and reduces the risk of chronic diseases. We explored the effects of lifelong exercise and aging on rat metabolism through a metabolomics approach. Thirty-six rats were divided into four equal groups: exercise during the 1st half of life (3–12 months), lifelong exercise (3–21 months), no exercise, and exercise during the 2nd half of life (12–21 months). Exercise consisted in swimming for 20 min, five times a week. Blood samples collected at 3, 12, and 21 months of life were analysed by 1H NMR spectroscopy. The groups that exercised during the 2nd half of life weighed less than the groups that did not. Exercise had an orexigenic effect during the 1st half and an anorexigenic effect during the 2nd half. Multivariate analysis showed a clear discrimination between ages when groups were treated as one and between the exercising and non-exercising groups at 12 months. Univariate analysis showed many effects of aging and some effects of exercise on metabolites involved in carbohydrate, lipid and protein metabolism. Especially during the 1st half, exercise had anabolic effects, whereas aging had catabolic effects on amino acid metabolism. In two cases (glycine and succinate), exercise (especially during the 1st half) mitigated potentially harmful effects of aging. The higher values of succinate and the lower values of lactate during the 1st half in the exercising groups suggest increased oxidative metabolism. In conclusion, moderate-intensity exercise for life or half-life had strong and potentially healthful effects on body weight and (partly) appetite, as well as on some blood metabolites. The effects of aging on the rat blood metabolome seemed to be stronger than those of exercise. © 2020, Springer Nature B.V

Association of NFKB1, NKX2-5, GATA4 and RANKL gene polymorphisms with sporadic congenital heart disease in Greek patients

Congenital heart disease (CHD) is a group of structural defects of the heart and the great vessels, and one of the leading causes of death among infants and young adults. Several gene variants are involved in diverse mechanisms of cardiac and vessel development and could thus be considered candidate mutated genes for a congenital heart defect or a specific variant could predispose a person to CHD. In the present study, variants in four such genes are investigated for the first time in a group of young Greek CHD patients: the NFKB1 gene polymorphism (–94ins/ delATTG), rs28362491, NKX2-5 gene polymorphism rs2277923, GATA4 gene polymorphism rs11785481 and RANKL gene polymorphism rs4531631. A total of 43 CHD patients and 100 healthy adults were included in the study. The polymerase chain reaction-restriction fragment length polymorphism (PRC-RFLP) method was used to genotype the aforementioned polymorphisms of NFKB1, NKX2-5, GATA4 and RANKL. The association analysis identified that there was a protective association between CHD and the A allele of rs2277923 polymorphism (p = 0.004). The D allele of the rs28362491 polymorphism is also a likely risk factor for causing CHD (p = 0.006). The differences of the rs4531631 and rs11785481 variant contribution had no statistical significance between the groups (p >0.05). In conclusion, our results revealed that the rs28362491 and rs2277923 gene polymorphisms, but not the rs4531631 and rs11785481 polymorphisms, may contribute to CHD risk in a cohort of Greek CHD patients

Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): a multicentre cohort study

Background: To date, 750 000 patients with COVID-19 worldwide have required mechanical ventilation and thus are at high risk of acute brain dysfunction (coma and delirium). We aimed to investigate the prevalence of delirium and coma, and risk factors for delirium in critically ill patients with COVID-19, to aid the development of strategies to mitigate delirium and associated sequelae. Methods: This multicentre cohort study included 69 adult intensive care units (ICUs), across 14 countries. We included all patients (aged 6518 years) admitted to participating ICUs with severe acute respiratory syndrome coronavirus 2 infection before April 28, 2020. Patients who were moribund or had life-support measures withdrawn within 24 h of ICU admission, prisoners, patients with pre-existing mental illness, neurodegenerative disorders, congenital or acquired brain damage, hepatic coma, drug overdose, suicide attempt, or those who were blind or deaf were excluded. We collected de-identified data from electronic health records on patient demographics, delirium and coma assessments, and management strategies for a 21-day period. Additional data on ventilator support, ICU length of stay, and vital status was collected for a 28-day period. The primary outcome was to determine the prevalence of delirium and coma and to investigate any associated risk factors associated with development of delirium the next day. We also investigated predictors of number of days alive without delirium or coma. These outcomes were investigated using multivariable regression. Findings: Between Jan 20 and April 28, 2020, 4530 patients with COVID-19 were admitted to 69 ICUs, of whom 2088 patients were included in the study cohort. The median age of patients was 64 years (IQR 54 to 71) with a median Simplified Acute Physiology Score (SAPS) II of 40\ub70 (30\ub70 to 53\ub70). 1397 (66\ub79%) of 2088 patients were invasively mechanically ventilated on the day of ICU admission and 1827 (87\ub75%) were invasively mechanical ventilated at some point during hospitalisation. Infusion with sedatives while on mechanical ventilation was common: 1337 (64\ub70%) of 2088 patients were given benzodiazepines for a median of 7\ub70 days (4\ub70 to 12\ub70) and 1481 (70\ub79%) were given propofol for a median of 7\ub70 days (4\ub70 to 11\ub70). Median Richmond Agitation\u2013Sedation Scale score while on invasive mechanical ventilation was \u20134 (\u20135 to \u20133). 1704 (81\ub76%) of 2088 patients were comatose for a median of 10\ub70 days (6\ub70 to 15\ub70) and 1147 (54\ub79%) were delirious for a median of 3\ub70 days (2\ub70 to 6\ub70). Mechanical ventilation, use of restraints, and benzodiazepine, opioid, and vasopressor infusions, and antipsychotics were each associated with a higher risk of delirium the next day (all p 640\ub704), whereas family visitation (in person or virtual) was associated with a lower risk of delirium (p<0\ub70001). During the 21-day study period, patients were alive without delirium or coma for a median of 5\ub70 days (0\ub70 to 14\ub70). At baseline, older age, higher SAPS II scores, male sex, smoking or alcohol abuse, use of vasopressors on day 1, and invasive mechanical ventilation on day 1 were independently associated with fewer days alive and free of delirium and coma (all p<0\ub701). 601 (28\ub78%) of 2088 patients died within 28 days of admission, with most of those deaths occurring in the ICU. Interpretation: Acute brain dysfunction was highly prevalent and prolonged in critically ill patients with COVID-19. Benzodiazepine use and lack of family visitation were identified as modifiable risk factors for delirium, and thus these data present an opportunity to reduce acute brain dysfunction in patients with COVID-19. Funding: None. Translations: For the French and Spanish translations of the abstract see Supplementary Materials section