Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging

19 Páginas.-- 7 FigurasATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.This work was funded by grants from the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, co-funded by Fondos FEDER (PI15/00134, PI18/01590, CPII19/00023 to A.M.M.) and the Ministerio de Ciencia e Innovación (PID2021-123965OB-100 to A.M.M.). A.M.M. is funded by the Junta de Andalucía P20_00480, the Spanish Society of Diabetes, and CSIC 202220I059. M.S.K. is funded by the Nordea Foundation (#02-2017-1749), the Novo Nordisk Foundation (#NNF17OC0027812), the Neye Foundation, the Lundbeck Foundation (#R324-2019-1492), the Ministry of Higher Education and Science of Denmark (#0238-00003B). V.C.G. is funded by the Instituto de Salud Carlos III (CP19/00046), co-funded by FEDER. F.M. is funded by the CIBERDEM of the Instituto de Salud Carlos III. A.M.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. We acknowledge the support of the group of basic research on diabetes of the Spanish Society of Diabetes.Peer reviewe

Development and validation of a score to predict postoperative respiratory failure in a multicentre European cohort : A prospective, observational study

BACKGROUND Postoperative respiratory failure (PRF) is the most frequent respiratory complication following surgery. OBJECTIVE The objective of this study was to build a clinically useful predictive model for the development of PRF. DESIGN A prospective observational study of a multicentre cohort. SETTING Sixty-three hospitals across Europe. PATIENTS Patients undergoing any surgical procedure under general or regional anaesthesia during 7-day recruitment periods. MAIN OUTCOME MEASURES Development of PRF within 5 days of surgery. PRF was defined by a partial pressure of oxygen in arterial blood (PaO2) less than 8 kPa or new onset oxyhaemoglobin saturation measured by pulse oximetry (SpO(2)) less than 90% whilst breathing room air that required conventional oxygen therapy, noninvasive or invasive mechanical ventilation. RESULTS PRF developed in 224 patients (4.2% of the 5384 patients studied). In-hospital mortality [95% confidence interval (95% CI)] was higher in patients who developed PRF [10.3% (6.3 to 14.3) vs. 0.4% (0.2 to 0.6)]. Regression modelling identified a predictive PRF score that includes seven independent risk factors: low preoperative SpO(2); at least one preoperative respiratory symptom; preoperative chronic liver disease; history of congestive heart failure; open intrathoracic or upper abdominal surgery; surgical procedure lasting at least 2 h; and emergency surgery. The area under the receiver operating characteristic curve (c-statistic) was 0.82 (95% CI 0.79 to 0.85) and the Hosmer-Lemeshow goodness-of-fit statistic was 7.08 (P = 0.253). CONCLUSION A risk score based on seven objective, easily assessed factors was able to predict which patients would develop PRF. The score could potentially facilitate preoperative risk assessment and management and provide a basis for testing interventions to improve outcomes. The study was registered at ClinicalTrials.gov (identifier NCT01346709)