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Category: Publications (Page 2 of 16)

p63 controls metabolic activation of hepatic stellate cells and fibrosis via an HER2-ACC1 pathway

Marcos F. Fondevila, Eva Novoa, Maria J. Gonzalez-Rellan, Uxia Fernandez, Violeta Heras, Begoña Porteiro, Tamara Parracho, Valentina Dorta, Cristina Riobello, Natalia da Silva Lima, Samuel Seoane, Maria Garcia-Vence, Maria P. Chantada-Vazquez, Susana B. Bravo, Ana Senra, Magdalena Leiva, Miguel Marcos, Guadalupe Sabio, Roman Perez-Fernandez, Carlos Dieguez, Vincent Prevot, Markus Schwaninger, Ashwin Woodhoo, Maria L. Martinez-Chantar, Robert Schwabe, Francisco J. Cubero, Marta Varela-Rey, Javier Crespo, Paula Iruzubieta, Ruben Nogueiras.

The p63 protein has pleiotropic functions and, in the liver, participates in the progression of nonalcoholic fatty liver disease (NAFLD). However, its functions in hepatic stellate cells (HSCs) have not yet been explored.

TAp63 is induced in HSCs from animal models and patients with liver fibrosis and its levels positively correlate with NAFLD activity score and fibrosis stage. In mice, genetic depletion of TAp63 in HSCs reduces the diet-induced liver fibrosis. In vitro silencing of p63 blunts TGF-β1-induced HSCs activation by reducing mitochondrial respiration and glycolysis, as well as decreasing acetyl CoA carboxylase 1 (ACC1).

Ectopic expression of TAp63 induces the activation of HSCs and increases the expression and activity of ACC1 by promoting the transcriptional activity of HER2. Genetic inhibition of both HER2 and ACC1 blunt TAp63-induced activation of HSCs. Thus, TAp63 induces HSC activation by stimulating the HER2-ACC1 axis and participates in the development of liver fibrosis.

A combination of a dopamine receptor 2 agonist and a kappa opioid receptor antagonist synergistically reduces weight in diet-induced obese rodents

Beatriz Cicuéndez, Javier Pérez-García & Cintia Folgueira.

As the global obesity rate increases, so does the urgency to find effective anti-obesity drugs. In the search for therapeutic targets, central nervous system (CNS) mechanisms engaged in the regulation of energy expenditure and food intake, such as the opioid and dopamine systems, are crucial.

Increased temperature in a mouse treated with BC and PF-04455242 (Image: Cintia Folgueira).

In this study, we examined the effect on body weight of two drugs: bromocriptine (BC), a D2R receptor agonist, and PF-04455242, a selective κ opioid receptor (KOR) antagonist. Using diet-induced obese (DIO) rats, we aimed to ascertain whether the administration of BC and PF-04455242, independently or in combination, could enhance body weight loss. Furthermore, the present work demonstrates that the peripheral coadministration of BC and PF-04455242 enhances the reduction of weight in DIO rats and leads to a decrease in adiposity in a food-intake-independent manner. These effects were based on heightened energy expenditure, particularly through the activation of brown adipose tissue (BAT) thermogenesis.

Overall, our findings indicate that the combination of BC and PF-04455242 effectively induces body weight loss through increased energy expenditure by increasing thermogenic activity and highlight the importance of the combined use of drugs to combat obesity.

MCJ: A mitochondrial target for cardiac intervention in pulmonary hypertension

Ayelén M. Santamans, Beatriz Cicuéndez, Alfonso Mora , María Villalba-Orero, Sanela Rajlic, María Crespo, Paula Vo, Madison Jerome, Álvaro Macías, Juan Antonio López, Magdalena Leiva, Susana F. Rocha, Marta León, Elena Rodríguez, Luis Leiva, Aránzazu Pintor Chocano, Inés García Lunar, Ana García-Álvarez, Pablo Hernansanz-Agustín, Víctor I. Peinado, Joan Albert Barberá, Borja Ibañez, Jesús Vázquez, Jessica B. Spinelli, Andreas Daiber, Eduardo Oliver & Guadalupe Sabio.

Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies.

MCJ stainimg in lungs of patients with chronic obstructive pulmonary disease.

Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure.

These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition

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