Tankyrase1/2 inhibitor XAV-939 reverts EMT and suggests that PARylation partially regulates aerobic activities in human hepatocytes and HepG2 cells.

The maintenance of a highly functional metabolic epithelium in vitro is challenging. Metabolic impairments in primary human hepatocytes (PHHs) over time is primarily due to epithelial-to-mesenchymal transitioning (EMT). The immature hepatoma cell line HepG2 was used as an in vitro model to explore strategies for enhancing the hepatic phenotype. The phenotypic characterization includes measuring the urea cycle, lipid storage, tricarboxylic acid-related metabolites, reactive oxygen species, endoplasmic reticulum calcium efflux, mitochondrial membrane potentials, oxygen consumptions rate, and CYP450 biotransformation capacity. Expression studies were performed with transcriptomics, co-immunoprecipitation and proteomics. CRISPR/Cas9 was also employed to genetically engineer HepG2 cells. After confirming that PHHs develop an EMT phenotype, expression of tankyrase1/2 was found to increase over time. EMT was reverted when blocking tankyrases1/2-dependent poly-ADP-ribosylation (PARylation) activity, by biochemical and genetic perturbation. Wnt/ß-catenin inhibitor XAV-939 blocks tankyrase1/2 and treatment elevated several oxygen-consuming reactions (electron-transport chain, OXHPOS, CYP450 mono-oxidase activity, phase I/II xenobiotic biotransformation, and prandial turnover), suggesting that cell metabolism was enhanced. Glutathione-dependent redox homeostasis was also significantly improved in the XAV-939 condition. Oxygen consumption rate and proteomics experiments in tankyrase1/2 double knockout HepG2 cells then uncovered PARylation as master regulator of aerobic-dependent cell respiration. Furthermore, novel tankyrase1/2-dependent PARylation targets, including mitochondrial DLST, and OGDH, were revealed. This work exposed a new mechanistic framework by linking PARylation to respiration and metabolism, thereby broadening the current understanding that underlies these vital processes. XAV-939 poses an immediate and straightforward strategy to improve aerobic activities, and metabolism, in (immature) cell cultures.

Pulmonary vascular pressure respiratory swings in COPD and ILD candidates for lung transplantation: Large but different.

We analyzed the effect of respiratory swings on interpreting intravascular pulmonary vascular pressures (PVPs) in chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) candidates for lung transplantation (LTx) and the role of the alterations in pulmonary function tests on the dynamic respiratory variations. Twenty-eight consecutive patients were included. All patients underwent a complete hemodynamic study (right atrial, mean pulmonary arterial, and pulmonary arterial occlusion pressures [RAP, mPAP, and PAOP]-) and pulmonary function testing (force vital capacity [FVC], forced expiratory volume in the first second [FEV1], and residual volume [RV]). A subgroup of 10 patients underwent simultaneous esophageal pressure (PES). All hemodynamic parameters and PES were collected during apnea after an unforced expiration (ee) and during spontaneous breathing averaging five respiratory cycles (mrc). The respiratory swing (osc) was estimated as the difference between maximum-minimum values of pressures during the respiratory cycle. Intravascular RAPee, mPAPee, and PAOPee were higher than mrc values (p < 0.05), leading to 11% of pulmonary hypertension (PH) misdiagnosis and 37% of postcapillary PH misclassification. PAOPosc of COPD was higher than ILD patients and RAPosc (p < 0.05). Only PAOPosc correlated with FVC, FEV1, and RV (p < 0.05). ILD PESmrc was lower than COPD (p < 0.05), and it was associated with a significantly higher transmural than intravascular RAPmrc, mPAPmrc, and PAOPmrc. PESmrc was significantly correlated with FVC. Transmural mPAPmrc and PAOPmrc readings determined around 20% of reclassification of the patients compared to ee measurements. Candidates for LTx showed large respiratory swings in PVP, which were correlated with pulmonary function alterations. mrc PVP would be more closely approximated to the true transmural PVP leading to PH reclassification. Adjusting PVP for PES should be considered in COPD and ILD candidates of LTx with severe alterations in pulmonary functional tests and suspicion of a PESmrc far from 0. PES respiratory swings could be different in ILD to COPD patients.

Grasa epicárdica en la población general de mediana edad y su asociación con el síndrome metabólico / Epicardial adipose tissue in the general middle-aged population and its association with metabolic syndrome

Introducción y objetivos: Actualmente hay cada vez más interés en el tejido adiposo epicárdico (TAE) como marcador de enfermedad cardiovascular. Nuestro objetivo es describir el TAE medido por ecocardiograma, y determinar su asociación con el síndrome metabólico (SM), dentro del estudio poblacional RIVANA. Métodos: Se incluyó a 880 sujetos de 45 a 74 años (492 con SM según la definición armonizada). Se realizó una exploración física y se tomó una muestra sanguínea para obtener el perfil bioquímico. Se midió el espesor del TAE con ecocardiografía transtorácica al final de la sístole. Resultados: Entre los sujetos sin SM, la prevalencia de TAE ≥ 5 mm aumentaba significativamente con la edad (> 65 frente a 45-54 años, OR = 8,22; IC95%, 3,90-17,35; p lineal < 0,001). El TAE se asoció significativamente con el SM (5.o frente a 1.er quintil, OR = 3,26; IC95%, 1,59-6,71; p lineal = 0,001). Respecto a los criterios individuales, el TAE se asoció independientemente con los criterios colesterol unido a lipoproteínas de alta densidad bajo (5.o frente a 1.er quintil, OR = 2,65; IC95%, 1,16-6,05; p lineal = 0,028), triglicéridos altos (5.o frente a 1.er quintil, OR = 2,22; IC95%, 1,26-3,90; p lineal = 0,003) y elevado perímetro abdominal (5.o frente a 1.er quintil, OR = 6,85; IC95%, 2,91-16,11; p lineal < 0,001). Conclusiones En una submuestra de la población general, la grasa epicárdica aumentó significativa e independientemente con la edad, y su incremento se asoció independientemente con el SM, el colesterol unido a lipoproteínas de alta densidad bajo, los triglicéridos altos y un elevado perímetro abdominal (AU)

Introduction and objectives: There is currently increasing interest in epicardial adipose tissue (EAT) as a marker of cardiovascular disease. Our purpose was to describe EAT, measured by transthoracic echocardiography, and to assess its association with metabolic syndrome (MS) in the RIVANA population-based study. Methods: Physical examination was performed in 880 participants aged 45 to 74 years (492 of them with MS according to the harmonized definition). Fasting glucose, high-density lipoprotein cholesterol, triglyceride, and C-reactive protein concentrations were determined in a blood sample. In all participants, EAT thickness was measured with transthoracic echocardiography at end-systole. Results: Among participants without MS, the prevalence of EAT ≥ 5 mm significantly increased with age (OR > 65 years vs 45-54 years = 8.22; 95%CI, 3.90-17.35; P for trend < .001). Increasing EAT quintiles were significantly associated with MS (OR fifth quintile vs first quintile = 3.26; 95%CI, 1.59-6.71; P for trend = .001). Considering the different MS criteria, increasing quintiles of EAT were independently associated with low high-density lipoprotein cholesterol (OR fifth quintile vs first quintile = 2.65; 95%CI, 1.16-6.05; P for trend = .028), high triglycerides (OR fifth quintile vs first quintile = 2.22; 95%CI, 1.26-3.90; P for trend = .003), and elevated waist circumference (OR fifth quintile vs first quintile = 6.85; 95%CI, 2.91-16.11; P for trend < .001). Conclusions: In a subsample of the general population, EAT measured by echocardiography increased significantly and independently with age. Increased EAT thickness was independently associated with MS and with low high-density lipoprotein cholesterol, high triglycerides, and elevated waist circumference as individual criteria (AU)