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Category: Publications (Page 3 of 15)

p38γ/δ activation alters cardiac electrical activity and predisposes to ventricular arrhythmia

Rafael Romero-Becerra, Francisco M. Cruz, Alfonso Mora, Juan Antonio Lopez, Daniela Ponce-Balbuena, Andrew Allan, Roberto Ramos-Mondragón, Bárbara González-Terán, Marta León, Maria Elena Rodríguez, Luis Leiva-Vega, Guadalupe Guerrero-Serna, Eric N. Jimenez-Vazquez, David Filgueiras-Rama, Jesús Vázquez, José Jalife & Guadalupe Sabio.

Ventricular fibrillation (VF) is a leading immediate cause of sudden cardiac death. There is a strong association between aging and VF, although the mechanisms are unclear, limiting the availability of targeted therapeutic interventions.

Heart depolarizations recorded by optical membrane potential (Imagen: Rafael Romero-Becerra).

Here we found that the stress kinases p38γ and p38δ are activated in the ventricles of old mice and mice with genetic or drug-induced arrhythmogenic conditions. We discovered that, upon activation, p38γ and p38δ cooperatively increase the susceptibility to stress-induced VF. Mechanistically, our data indicate that activated p38γ and p38δ phosphorylate ryanodine receptor 2 (RyR2) disrupt Kv4.3 channel localization, promoting sarcoplasmic reticulum calcium leak, Ito current reduction and action potential duration prolongation. In turn, this led to aberrant intracellular calcium handling, premature ventricular complexes and enhanced susceptibility to VF. Blocking this pathway protected genetically modified animals from VF development and reduced the VF duration in aged animals.

These results indicate that p38γ and p38δ are a potential therapeutic target for sustained VF prevention.

Predominantly pro-inflammatory phenotype with mixed M1/M2 polarization of peripheral blood classical monocytes and monocyte-derived macrophages among patients with excessive ethanol intake

María Fernández-Regueras, Cristina Carbonell, Daniel Salete-Granado, Juan-Luis García, Marcos Gragera, María-Ángeles Pérez-Nieto, Francisco-Javier Morán-Plata, Andrea Mayado, Jorge-Luis Torres, Luis-Antonio Corchete, Ricardo Usategui-Martín, Elena Bueno-Martínez, Maura Rojas-Pirela, Guadalupe Sabio, Rogelio González-Sarmiento, Alberto Orfao, Francisco-Javier Laso, Julia Almeida & Miguel Marcos.

Excessive alcohol consumption impairs the immune system, induces oxidative stress, and triggers the activation of peripheral blood (PB) monocytes, thereby contributing to alcoholic liver disease (ALD).

miRNA of isolated CD14+ blood monocytes from excessive alcohol drinkers.

We analyzed the M1/M2 phenotypes of circulating classical monocytes and macrophage-derived monocytes (MDMs) in excessive alcohol drinkers (EADs). PB samples from 20 EADs and 22 healthy controls were collected for isolation of CD14+ monocytes and short-term culture with LPS/IFNγ, IL4/IL13, or without stimulation. These conditions were also used to polarize MDMs into M1, M2, or M0 phenotypes. Cytokine production was assessed in the blood and culture supernatants. M1/M2-related markers were analyzed using mRNA expression and surface marker detection. Additionally, the miRNA profile of CD14+ monocytes was analyzed. PB samples from EADs exhibited increased levels of pro-inflammatory cytokines. Following short-term culture, unstimulated blood samples from EADs showed higher levels of soluble TNF-α and IL-8, whereas monocytes expressed increased levels of surface TNF-α and elevated mRNA expression of pro-inflammatory cytokines and inducible nitric oxide synthase. MDMs from EADs showed higher levels of TNF-α and CD206 surface markers and increased IL-10 production. LPS/IFNγ induced higher mRNA expression of Nrf2 only in the controls. miRNA analysis revealed a distinctive miRNA profile that is potentially associated with liver carcinogenesis and ALD through inflammation and oxidative stress.

This study confirms the predominantly pro-inflammatory profile of PB monocytes among EADs and suggests immune exhaustion features in MDMs.

Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition

Vitor Ferreira, Cintia Folgueira, María García-Altares, Maria Guillén, Mónica Ruíz-Rosario, Giada DiNunzio, Irma Garcia-Martinez, Rosa Alen, Christoph Bookmeyer, John G. Jones, Juan C. Cigudosa, Pilar López-Larrubia, Xavier Correig-Blanchar, Roger J. Davis, Guadalupe Sabio, Patricia Rada & Ángela M. Valverde.

Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p.

Olanzapine iniection increases hypothalamic JNK phosphorylation
Olanzapine iniection increases hypothalamic JNK phosphorylation (Imagen: Cintia Folgueira).

Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis.

The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.

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